Respiratory viruses are common culprits for severe infection in post transplant patients.Particularly, in lung transplantation, its associated with detrimental consequences on the short and long term outcomes. It was reported to be associated with higer incidence of acute and chronic rejections. Several DNA and RNA viruses are observed including;
1]Influenza virus.
2]Para-influenza vs.
3]Respiratory syncytial vs.
4]Corona vs.
5]Rhinovirus.
6]Adenovirus
7]KI and WU polyomavirus. With exception of influenza virus,, unfortunatelly, there is no definite prophylactic or therapeutic strategy to follow.
The incidence of viral infection post transplantation hover above 0.7-0.9 per patient per year. The incidence is more common on autumn and winter. Respiratory viral infection presentation is common for all of the viruses, with no particular differentiating features.
Progression to lower respiratory tract infection is variab between 6-40%.
Nucleic acid testing is the gold standerd for diagnosis with sensitivity of 72-100%. Influenza viral infection:
Its RNA virus with common presentations include cough, fever, gastrointestinal tract symptoms and headache.It might differ from the classic influenza like illness. Its associated commonly with variable complications include:
1] pneumonia. bacterial and fungal superinfection
2] Encephalitis.
3] pericarditis and myocarditis.
4] myositis. Prophylaxis:
Inactivated virus vaccin is the gold slandered, prophylactic anti viral is another strategy to protect against potential infection. Treatment
Neuraminidase inhibitors is the most commonly used medicine for influenza include oseltamivir. Drug resistance is emerging in the treatment, The current options are to change to another medications.
1. Please summarise this article.In recipient post-transplantation the incidence of respiratory viral infection ranges between 0.76-0.91 episodes per patient per year. It was higher in Lung transplant. There is higher incidence in the autumn and winter.Epidemiology;Influenza virus is a single stranded RNA virus. There are multiple strains but A,B are involved in human infections.Clinical presentations;The most common symptoms was cough followed by fever, myalgia, rhinorrhea, sore throat, and GI symptoms.Prevention;Vaccination, there is some risk of dissemination of risk of contaminated vaccine.Treatment;There are different groups of drugs approved like, M2 inhibitors (risk of resistance).Neuraminidase inhibitors the most commonly used.Newer agent the Baloxavir its single dose oral medication. Its more effective then the NAIs.2. What is the level of evidence provided by this article?Level V
Respiratory viruses are a significant cause of morbidity and mortality among transplant recipients. Detection is better with the use of molecular diagnostic methods. Effective therapies are available only for influenza, and also to some extent for RSV infection. Preventive measures are also lacking, as vaccination is only available against influenza at this time.
Level of evidence is 5
Introduction:
Respiratory viruses have a significant impact on the health of immunocompromised organ transplant recipients, with the incidence of respiratory viral infections ranging from 0.76-0.91 episodes per patient-year. This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV,adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients. Diagnosis:
Nucleic acid testing (NAT) is now the gold standard for diagnosing respiratory viral infections and has a sensitivity of 72-100%. Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity. Influenza Virus:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. It is seasonal, circulating mainly in the winter and causing a significant proportion of RTIs. Immunocompromised individuals are at increased risk for complications, such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc. Risk factors associated with severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic. Prevention : Influenza vaccination is the most important means of prevention for transplant recipients and close contacts, and has been shown to decrease infection rates, complications and mortality. Antiviral prophylaxis is recommended to prevent influenza infection in transplant recipients, but there is concern that some may develop antiviral resistance. Treatment: Three groups of drugs are approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, which has a novel mechanism of action and is a single dose oral medication.
Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and patients with symptoms > 48 h should be treated.
Treatment for influenza should be started empirically as soon as possible, usually before test results are available. Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, and M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain. Respiratory Syncytial Virus:
RSV is a seasonal virus with peak incidence in the winter and spring and is a significant source of transmission in LTRs. Risk factors for lower RTI and mortality include young children, recent transplant, lung or multivisceral transplant and recent rejection. Clinical presentation is similar to other respiratory viruses, but RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
Palivizumab prophylaxis is not given to adult SOT recipients, and monoclonal antibody development is focused on developing antibodies with extended half-lives. Ribavirin treatment is associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
Presatovir is a new antiviral with specific anti-RSV activity, but two phase 2b RCTs failed to show significant improvements, and 20% of patients developed resistance. Human Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Studies have identified HMPV in 3.6-6.8% of positive respiratory samples, and 8/18 (44%) had a lower RTI. Ribavirin has in vitro activity against HMPV, but data derived from HSCT recipients do not demonstrate a mortality benefit. Prevention is mainly based on infection control practices, including contact precautions in hospitalized patients. Parainfluenza Virus:
PIV is a single-stranded RNA virus of the Paramyxoviridae family, and is associated with a high rate of symptomatic disease and lower RTI. Treatment is based on supportive care and prevention in the hospital setting. Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions. Coronaviruses:
Coronaviruses are single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs). Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, while other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2) are associated with outbreaks of severe respiratory disease. Human CoVs are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. Studies on 85 immunocompromised and 1152 immunocompetent children .demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively). In-vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen. Adenovirus:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes, and can cause viremia without obvious symptoms. Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route, and prevention is based on maintaining droplet and contact precautions. Treatment options include reduction of immunosuppression, brincidofovir, IVIG and adenovirusspecific cytotoxic T lymphocytes.
Bocavirus:
Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making its contribution to RTIs unknown. KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family, with higher frequency in HSCT recipients. Respiratory Viruses and Rejection in Lung Transplantation:
LTRs are at increased risk for RTIs due to continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression. Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections. Summary:
Development of new antivirals and vaccines is needed to reduce respiratory viral infections in the immunocompromised population. What is the level of evidence provided by this article?
level V
Introduction New respiratory viruses and serotypes often affect immunocompromised organ transplant recipients. Organ transplant recipients get 0.76–0.91 respiratory virus infections each year. Lung transplant recipients (LTRs) have greater rates of respiratory infections. In this review, influenza, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, adenovirus, bocavirus, and KI and WU polyomaviruses affecting immunocompromised organ transplant recipients are discussed.
Influenza virus Influenza is a single-stranded RNA Orthomyxoviridae virus that can cause difficulties in immunocompromised people. Risk factors for severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and nature of the epidemic. Influenza vaccination is the best way to prevent the disease. Drugs approved to treat influenza: Neuraminidase inhibitors (NAIs); M2 inhibitors (Amantadine and Rimantadine); and Baloxavir; single-dose oral memantine with a novel mechanism of action.
Respiratory Syncytial Virus (RSV): RSV is winter and spring season virus – a major cause of transmission in LTRs. Young children, recent transplant, lung or multi-visceral transplant, and rejection are risk factors for lower RTI and mortality. Clinical presentation is comparable to other respiratory viruses, but RSV more often causes lower RTI, including bronchitis, bronchiolitis, and pneumonia. Ribavirin reduces lower RTI mortality and higher RTI progression. Human Metapneumovirus (HMPV): a single-stranded RNA virus belonging to Pneumoviridae family that resembles RSV in many ways. Although ribavirin has in vitro efficacy against HMPV, data from HSCT recipients do not show reduction in mortality. Mainstay of prevention are infection control procedures, such as contact precautions.
Parainfluenza Virus: single-stranded RNA virus belonging to the Paramyxoviridae family that is known to cause higher symptomatic illness, and lower rate of RTI. In a hospital context, treatment is based on preventative measures and supportive care.
Coronaviruses (CoV): Single-stranded RNA Coronaviridae viruses that cause upper respiratory infections (RTIs). 12.4-17.8% of LTR positive samples are human CoVs, second only to rhinoviruses. Among 85 immunocompromised and 1152 immunocompetent children, RTI was 22% and 26%, respectively. Ribavirin and interferon were active against the virus in-vitro, but there was no therapeutic benefit. Adenovirus Adenoviridae double-stranded DNA virus with seven subgroups and 90 serotypes that can induce viremia without symptoms. Droplet and contact precautions prevent adenovirus infections, which are spread through respiratory droplets, direct conjunctival inoculation, person-to-person contact, contaminated fomites, and the fecal–oral pathway. Reduce immunosuppression, Cidofovir, Brincidofovir, IVIG are the mainstay therpy. Treatment Summary:
1. M2 inhibitors – amantadine, rimantadine – for influenza 2. Neuraminidase inhibitors (NAIs) – oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea) – for influenza 3. Ribavirin – for RSV, Human Metapneumovirus, PIV 4. IVIG – for RSV, Adenovirus Prevention Summary: 1. Droplet precaution (Influenza, Rhinovirus, Coronavirus, Adenovirus) 2. Contact precaution (RSV, Human Metapnumovirus, PIV, Coronavirus, Adenovirus) 3. Vaccination (Influenza, Coronavirus) 5. Antiviral prophylaxis – PEP with oseltamivir (influenza), palivizumab, nirsevimab (RSV), Brincidofovir; Adenovirus (Not yet approved by FDA)
Conclusions In SOTRs, respiratory viral illness are substantial cause of mobility and mortality. Only a few respiratory viruses, including the flu virus, have effective treatments. As only influenza virus vaccine is available for clinical use; other preventive measures, supportive treatments and contact precautions are mandatory. Research for novel antivirals and vaccines are necessary, particularly in light of the serious effects that individuals with impaired immune systems experience from respiratory virus infections.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year, although part of the studies also included asymptomatic infections. The incidence appears to be higher among lung transplant recipients (LTRs), but is not affected by time from transplant. Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses.
Influenza Virus Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There are multiple strains, although only influenza A and B are generally associated with disease in humans. Influenza viruses are seasonal, circulate mainly in the winter (months Novem- ber to May in the Northern Hemisphere and May to October in the Southern Hemisphere), and cause a significant proportion of RTIs during that time.
Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness. In a prospective multicenter study including 477 SOT recipients and 139 patients after hematopoietic stem cell transplant (HSCT) with confirmed influenza infection, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) . Immunocompromised individuals are also at increased risk for complications.
Prevention
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions as outbreaks in the hospital setting have been described. However, the most important means for prevention is vaccination of the transplant recipi- ent and close contacts.
Only inactivated influenza vaccines should be given to transplant recipients. There is a theoretical risk of dissemination of virus contained in the live attenuated intranasal influenza vaccine, which is therefore contraindicated for SOT recipients [20]. The inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains. Previous trivalent formulations are being phased out.
Treatment
There are three groups of drugs approved for the treatment of influenza . M2 inhibitors (amantadine and rimantadine) are not used today since they are inherently inactive against influenza B and circulating influenza A strains carry a high rate of re- sistance. The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea). Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single dose oral medication. It has been shown to be effective in uncomplicated influenza in the non-immunocompromised population . Baloxavir may also be more effective against influenza B strains than NAIs
Respiratory Syncytial Virus Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyx- oviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children, who are a significant source of transmission .In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens and is a cause of significant morbidity and mortality due to the development of lower RTI
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection
Clinical Manifestations
The clinical presentation of RSV is similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea . Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia . This is especially true for LTRs, where lower RTI rates can be as high as 72%.
Prevention
Hospitalized patients should be placed under contact precautions as RSV droplets form large particles and are transmitted by contact. The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based . A survey conducted among 67 pediatric SOT centers in the US revealed that approximately half of these centers use palivizumab prophylaxis.
Treatment
A survey conducted in 11 transplant centers in the United States revealed differences in treatment regimens in lung transplant compared to other organs. Among 10 lung transplant centers all treat lower RTI with ribavirin and three centers add intravenous immunoglobulin (IVIG), whereas only 6/10 centers treat upper RTI with ribavirin and none give IVIG. Among 11 non-lung transplant centers 7/11 treat lower RTI with ribavirin and only one center adds IVIG, whereas in upper RTI no center gives treatment [61]. Data on treatment for RSV infection in SOT recipients are limited to case series in lung transplants .Data in the HSCT population are slightly more robust and include larger case series, prospective cohorts and one small RCT.
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Its seasonality also follows that of RSV, with most cases identified in the winter and spring . Studies conducted on LTRs identified HMPV in 3.6–6.8% of positive respiratory samples . Most of these patients had symptoms of RTI, and in one study cohort, 8/18 (44%) had a lower RTI.
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. There are four serotypes of PIV ,serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter
As with other respiratory viruses, PIV infection was mainly studied in LTRs, where it accounts for 3.6–20.9% of the respiratory viruses isolated
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI [2]. In a study on 24 LTRs with PIV infection, mostly PIV3, 21% experienced respiratory failure.
Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus. Serotypes A–C circulate year-round and are the predominant cause for the common cold
As such, these viruses are isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients. In studies among LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6% of the positive samples
One study compared infection rates in 36 LTRs with a cohort of 235 immunocompromised and immunocompetent patients, and showed a higher infection rate among LTRs (41.7% vs. 14.5%, p < 0.001)
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. This review will not cover infections caused by SARS-CoV-2.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples
Symptoms are generally similar to other respiratory viruses. A study on 85 immunocompromised and 1152 immunocom- petent children demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively); however, the immunocompromised group had a significantly higher rate of severe lower RTI [84]. Studies done on LTRs and HSCT recipients [85] showed comparable rates of lower RTI.
Adenovirus
Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes [97]. Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition
Adenoviruses show no seasonal variability and have been associated with institutional outbreaks
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
In a study of 263 SOT recipients, adenovirus in blood was checked at regular intervals during the first year post- transplant. As much as 7.2% developed viremia; however, only 4/19 (21%) were symptomatic
Clinical Manifestations
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemor- rhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephri- tis
Mortality can be as high as 50% for adenoviral pneumonia and 80% for dis- seminated adenoviral infection [102]. Although in most cases there are no long term sequelae [103,106], development of bronchiolitis obliterans has been described in lung transplant recipients
Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precau- tions
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. It was tested in a phase two RCT for pre- emptive treatment of adenovirus viremia in HSCT recipients and showed benefits however, it is not FDA approved and the appropriate dose for treatment of adenovirus is not established.
Treatment
Data on treatment modalities for adenovirus disease are derived from case reports and small case series. Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus- specific cytotoxic T lymphocytes (investigational). Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression . Contemporary data, the largest series being 13 liver transplant recipients, show promising results with the use of brincidofovir as well as with its use in combination with the reduction of immunosuppression
Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses
Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples. Additionally, similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence
This, combined with the high co-infection rate, makes their true contribution to RTIs unknown.
KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri- dae family that were discovered in 2007. Studies in HSCT recipients suggested a higher frequency of infection with these viruses
A study done in kidney transplant recipi- ents identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively [118]. However, it is still unclear whether this has any clinical significance Respiratory Viruses and Rejection in Lung Transplantation
As previously mentioned, LTRs are at increased risk for RTIs in general and specif- ically lower RTIs [4]. This may be related to continuous contact of the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and a relatively greater immunosuppression compared to other organ transplants. Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data
A systematic review and meta-analysis published in 2011 demonstrated no association between respiratory viral infection and acute rejection, although only four studies were included in the analysis. It also showed a non-significant trend towards association with BOS, but that was limited by small numbers
1) Introduction: Respiratory viral infections (RNA and DNA viruses) are one of the most common infections in solid organ transplant recipients having similar symptoms and clinical presentation, with incidence ranging from 0.76-0.91 episodes per patient-year, being higher among lung transplant recipients.it presents throughout the year with high incidence in autumn and winter. Lack of data on mortality associated with viral pneumonia in solid organ transplantation. 2) Diagnosis: viral culture, direct fluorescent antibody (DFA) staining and serology were previously used. Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72–100%. 3) influenza virus: It is a single-stranded RNA virus of the Orthomyxoviridae family with multiple strain but A and B associated with the disease which is seasonal mainly in winter. Risk factors include: age (with higher rates in children), likelihood of exposure, level of immunity (due to prior vaccination or disease), degree of immunosuppression and the nature of the epidemic. Clinical presentations are cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache. immunosuppressed patients have increased risk of complications like pneumonia, fungal or bacterial coinfection, pericarditis, encephalitis Prevention: droplet precautions, vaccination (requiring high-dose) and antiviral prophylaxis Treatment: neuraminidase inhibitors (oseltamivir, zanamivir, pramivir), baloxavir, and M2 inhibitors (amantadine and rimantadine, not used nowadays). Early antiviral treatment is associated with lower complications and ICU admissions. Symptomatic SOT recipients should be treated irrespective of duration of the symptoms. 4) Respiratory Syncytial Virus: It is a single-stranded RNA virus of the Pneumoviridae family with two strains: RSV-A and RSV-B and it a seasonal virus with peak incidence in the winter and spring. presented with fever, cough, dyspnea and rhinorrhea. Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection Prevention:contact precautions, monthly palvizumab prophylaxis in children <2 year age during the RSV season, and nirsevimab once every season. Multiple vaccines are also available, especially for elderly, pregnant, and pediatric population. Treatment: URTI: Ribavirin LRTI: Ribavirin with or without IV immunoglobulin Presatovir has been shown to reduce progression to LRTI in lymphopenic hematopoietic stem cell transplant (HSCT) recipients. 5) Human metapneumovirus (HMPV): It is a single-stranded RNA virus of the Pneumoviridae family like RCV Prevented by contact precautions Treated by supportive care 6) Parainfluenza virus (PIV ) : it is single strand RNA virus of the Paramyxoviridae family. It has 4 serotypes type 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter. symptoms like other respiratory viruses PIV3, 21% experienced respiratory failure. treated by supportive care and prevented by contact precautions. 7)Rhinovirus: It is a single stranded RNA virus of Picornaviridae family, It has 3 serotypes (A,B,C), causing common cold and most common in lung transplant patients. treated by supportive care and prevented by contact precautions. 8)Coronaviruses (CoV) : CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. SARS COV1 has high mortality up to 20% treated with interferon and high dose of steroid.MERS-CoV infection has high mortality rates of up to 50% treated with ribavirin, interferon, and steroids. 9) Adenovirus: It is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes. It causes viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate Rates of infection differ with age and the transplanted organ and higher among children, and in intestinal transplantation. Clinical presentation: conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft Mortality is 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection. Prevention: maintaining droplet and contact precautions and Brincidofovir shows benefit. Treatment: supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational). 10) Bocavirus: It is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses. 11) KI and WU Polyomaviruses: It is double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007. 12. Summary: Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Level of evidence is V.
Introduction
New respiratory viruses and serotypes are found often, affecting immunocompromised organ transplant recipients. Organ transplant recipients get 0.76–0.91 respiratory virus infections each year. Lung transplant recipients have greater rates (LTRs). In this review, influenza, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV, adenovirus, bocavirus, and KI and WU polyomaviruses affect immunocompromised organ transplant recipients. Influenza virus
Influenza is a single-stranded RNA Orthomyxoviridae virus that can cause difficulties in immunocompromised people.
Risk factors for severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic.
Influenza vaccination is the best way to prevent the disease. Three groups of drugs are approved to treat influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, a single-dose oral memantine with a novel mechanism of action. Respiratory Syncytial Virus
Respiratory Syncytial Virus (RSV): RSV is a winter and spring virus that is a major cause of transmission in LTRs.
Young children, recent transplant, lung or multi-visceral transplant, and rejection are risk factors for lower RTI and mortality. Clinical presentation is comparable to other respiratory viruses, but RSV more often causes lower RTI, including bronchitis, bronchiolitis, and pneumonia. Ribavirin reduces lower RTI mortality and higher RTI progression. Human Metapneumovirus
Human Metapneumovirus (HMPV) is a single-stranded RNA virus belonging to the Pneumoviridae family that resembles RSV in many ways. Although ribavirin has in vitro efficacy against HMPV, data from HSCT recipients do not show that it reduces mortality. Infection control procedures, such as contact precautions, are the mainstay of prevention. Parainfluenza Virus
The parainfluenza virus is a single-stranded RNA virus belonging to the Paramyxoviridae family that is known to cause symptomatic illness at a high rate and RTI at a lower rate. In a hospital context, treatment is based on preventative measures and supportive care. Coronaviruses
Single-stranded RNA Coronaviridae viruses that cause upper respiratory infections (RTIs). 12.4-17.8% of LTR positive samples are human CoVs, second only to rhinoviruses. Among 85 immunocompromised and 1152 immunocompetent children, RTI was 22% and 26%, respectively. Ribavirin and interferon were active against the virus in-vitro, but there was no therapeutic benefit. Adenovirus
Adenoviridae double-stranded DNA virus with seven subgroups and 90 serotypes that can induce viremia without symptoms. Droplet and contact precautions prevent adenovirus infections, which are spread through respiratory droplets, direct conjunctival inoculation, person-to-person contact, contaminated fomites, and the fecal–oral pathway. Reduce immunosuppression, Cidofovir, Brincidofovir, IVIG are the mainstay therpy. Conclusions
For recipients of solid organ transplants, respiratory viruses are a substantial source of mobility and mortality. Only a few respiratory viruses, including the flu virus, have effective treatments. Due to the fact that there is now just an influenza vaccine available, preventative measures are also missing. Research of novel antivirals for vaccines is necessary, particularly in light of the serious effects that individuals with impaired immune systems experience from respiratory virus infections. Level of evidence
Review article, V
SOT recipients have higher incidence of respiratory viral infections between 0.76–0.91 episodes per patient-year although some are asymptomatic being the highest among lung transplant recipients (LTRs).
All respiratory viruses globally share similar symptoms and clinical presentations. Diagnoses are now based on serology as they are more useful for epidemiological studies and diagnosing acute infection since both acute- and convalescent-phase sera are needed. Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis of higher sensitivity of 72–100%.
Multiplex NAT has the advantage of permitting testing for several viruses simultaneously with a turnaround time of only 12–24 h.
Influenza Virus
It is a single-stranded RNA virus belongs to the Orthomyxoviridae family. Influenza A and B are the main pathogens for human. Immunocompromised individuals express increased risk for complications as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy and encephalitis. Estimated a total of 947 SOT recipients with influenza (both 2009 pandemic H1N1 and seasonal), hospitalization, intensive care unit (ICU) admission, pneumonia and mortality rates were 57–71%, 11–16%, 22–35% and 4–7.8% respectively.
Risk factors are known to be older age, diabetes, use of mycophenolate mofetil, use of antilymphocyte globulin in the past six months, lymphopenia as well as hypogammaglobulinemia. Thereby prevention should be sought by vaccination of the transplant recipient and close contacts.
The American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant due to the fact that vaccine immunogenicity up to six months post-transplant can be poor. High-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used.
Pre-exposure prophylaxis using low-dose oseltamivir was evaluated among 477 transplant recipients, mostly SOT, and demonstrated 80% efficacy against PCR-confirmed influenza (1.7% vs. 8.4%). It can be tried in contraindications to the influenza vaccine or cases that are not expected to develop an immune response or cases of hospital outbreaks to patients in the affected wards.
Treatment currently is by neuraminidase inhibitors (NAIs) as oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir.
Baloxaviris a selective inhibitor of influenza cap-dependent endonuclease with advantage of a single dose oral medication.
Studies in SOT recipients documented that early antiviral treatment (within 24–48 h) is improved complications and lowered ICU admission rates. It is to be considered that transplant patients have prolonged shedding of influenza virus, thus recommendations aroused to treat all symptomatic patients irrespective of symptom duration for instance treatment duration (e.g., 10-day oseltamivir treatment compared to the recommended 5-day regimen) in SOT recipients who are still symptomatic.
Favipiravir is active against a wide spectrum of RNA viruses is still under phase III investigational trials. It is a new promising agent of low resistance rates as well as it is has a synergistic effect on combination to oseltamivir.
Respiratory Syncytial Virus
RSV is a single-stranded RNA virus belongs to the Pneumoviridae family (RSV-A and RSV-B). In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens led to significant morbidity and mortality after the development of lower RTI.
Proposed risk factors for lower RTI and mortality in the SOT population are young children, recent transplant, lung or multivisceral transplant besides recent rejection episodes.
The clinical presentation of RSV displays more frequently features of lower RTI as bronchitis, bronchiolitis and pneumonia about 72% of LTRs. The American Academy of Pediatrics suggests consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein. Its advantage is being of extended half-life so, it can be given once per season and has already shown favorable results.
Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Data in lung transplants are of low quality only supportive care and demonstrated that oral ribavirin treatment was associated with improvement in graft function and reduction in bronchiolitis obliterans syndrome.
Inhaled ribavirin is challenging as it needs to be given in negative-pressure rooms owing to its teratogenicity. It is also extremely expensive, so oral ribavirin is a more wise option. Systemic ribavirin has significant side effects as hemolytic anemia, leukopenia, neuropsychiatric symptoms and teratogenicity.
Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells. Newly investigated drugs are classified into fusion inhibitors (RV521, AK0529/ziresovir) and replication inhibitors (PC786, EDP-938).
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family. Current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices and implementation of contact precautions in hospitalized patients.
Parainfluenza Virus
PIV is a single-stranded RNA virus belongs to the Paramyxoviridae family. It has 4 serotypes; serotype 3 is the commonest. In LTRs PIV accounts for 3.6–20.9% of the respiratory viruses isolated.
DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, thus preventing attachment and entry of viruses such as PIV and influenza virus into respiratory cells, yet it is not currently FDA approved. So, management is via supportive care and prevention in the hospital setting based on adherence to contact precautions.
Rhinovirus
Single-stranded RNA viruses that are members of the Picornaviridae family. Among LTRs about 41.8–61.6% of the positive samples are rhinoviruses. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2 are associated with outbreaks of severe respiratory disease.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples.
Thanks to strict infection control practices the outbreak was controlled and there were no more cases of SARS-CoV1.
Adenovirus
It is a double-stranded DNA virus of the Adenoviridae family. It has latency in lymphoid tissue; so infection can represent reactivation or de novo community acquired. It manifests more in cases of intestinal transplantation, as they have the higher amount of lymphoid tissue in the allograft and greater immunosuppression.
Adenovirus infection can be presented by conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis with special predilection for the transplanted allograft. Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection. Cases of bronchiolitis obliterans has been described in lung transplant recipients.
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir but it is still under investigations.
Besides supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational).
Bocavirus
It is a single-stranded DNA virus of the Parvoviridae family. Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
KI and WU Polyomaviruses
They are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007. KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens respectively in kidney transplant recipients.
Respiratory Viruses and Rejection in Lung Transplantation
It is more correlated to continuous contact of the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and a relatively greater immunosuppression compared to other organ transplants.
A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections.
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD (OR 0.24, 95% CI 0.1–0.59).
Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
Preventive measures are also lacking so development of new antivirals and vaccines is urgently needed.
CLAD or BOS is associated with acute viral infection post lung transplant suggesting different pathophysiology of viral infection
it is very interesting to know this different behaviour of virus
Respiratory viral infections is common after SOT
Effective therapies are available only for influenza, and also to some extent for RSV infection
All respiratory viral infections share similar clinical manifestations and are all currently diagnosed using nucleic acid testing
Nucleic acid testing (NAT) for respiratory viruses is gold standard
symptoms are common cough , fever rhinorrhoea GI symptoms
Risk factors associated with severe disease in multivariate analysis include older age, diabetes and use of mycophenolate mofetil
INFLUENZA VIRUS =
DROPLET PRECAUTION
PRE AND POST EXPOSURE PROPHYALAXIS
VACCINATION IS AVAILABE FOR INFLUENZA
The inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains
Another measure to prevent influenza infection would be using antiviral prophylaxis.
oseltamivir 75 mg od
Respiratory viral infections are one of the most prevalent infections, and are a cause of significant morbidity and mortality, especially among lung transplant recipients.
Respiratory viral infections can appear at any time post-transplant and are usually acquired in the community.
n organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year [1–3], although part of the studies also included asymptomatic infections. The incidence appears to be higher among lung transplant recipients (LTRs) [4], but is not affected by time from transplant [1]. Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses [2]. All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses [1,5]. Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs [2,6]. Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1% .
Diagnosis
Historically, viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infections.
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%
Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus
Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There are multiple strains, although only influenza A and B are generally associated with disease in humans.
The influenza attack rate depends on several factors, including age (with higher rates in children), likelihood of exposure, level of immunity (due to prior vaccination or disease), degree of immunosuppression and the nature of the epidemic
most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) [13]. Immunocompromised individuals are also at increased risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis
Risk factors associated with severe disease in multivariate analysis include older age, diabetes and use of mycophenolate mofetil. Univariate analysis also identified multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission
Prevention
However, the most important means for prevention is vaccination of the transplant recipient and close contacts. Only inactivated influenza vaccines should be given to transplant recipients.
The American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant, acknowledging the fact that vaccine immunogenicity up to six months post-transplant can be poor
Therefore, 2019 guidelines by the American Society of Transplantation recommend that high-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used [20]. Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs [26,28], however there is no recommendation to withhold treatment around vaccination
Pre-exposure prophylaxis using low-dose oseltamivir demonstrated 80% efficacy against PCR-confirmed influenza.
Post-exposure prophylaxis has been evaluated in the non-immunocompromised population [30,31] and can be given in cases of exposure to influenza among transplant recipients who have contraindications to receiving the influenza vaccine or who are not expected to mount an immune response
Consideration should be given to treating these patients with therapeutic-dose oseltamivir [9]. Guidelines published by The Infectious Diseases Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak to patients in the affected wards
The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea). Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single dose oral medication.
Observational studies in SOT recipients show that early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates [13,16,17]. There is also some evidence in transplant recipients [16] and the general population [39] that suggests patients who have symptoms > 48 h also benefit from treatment.
However, an attempt should be made to start treatment empirically as soon as possible, usually before test results are available. Trials in immunocompetent patients failed to show superiority of high-dose (oseltamivir 150 mg twice daily) antiviral treatment
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes subtherapeutic (as in post-exposure prophylaxis)
case reports of emergent resistance during NAI use have been published, mainly among patients with hematological malignancies or after stem cell transplants .
Respiratory Syncytial Virus
Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyxoviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring.
cause of significant morbidity and mortality due to the development of lower RTI
The clinical presentation of RSV is similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea [1,5,55]. Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia
Hospitalized patients should be placed under contact precautions [18] as RSV droplets form large particles and are transmitted by contact. The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter
Thus, the mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions .
Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples
Treatment options used in published case reports include ribavirin, interferon and steroids [93,94]. MERS-CoV still causes sporadic infections, mainly in the Middle East [95].
Adenovirus
Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes
Rates of adenovirus infection differ with age and the transplanted organ. Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression [99,102,104].
Clinical Manifestations
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft [99,102]. In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis [105]. Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection
Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precautions [18]. Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. It was tested in a phase two RCT for preemptive treatment of adenovirus viremia in HSCT recipients and showed benefits [108]; however, it is not FDA approved and the appropriate dose for treatment of adenovirus is not established.
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes (investigational).
Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
Additionally, similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence [9]. This, combined with the high co-infection rate, makes their true contribution to RTIs unknown.
KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
Respiratory Viruses and Rejection in Lung Transplantation
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD (OR 0.24, 95% CI 0.1–0.59)
Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Given the severe implications respiratory viral infections have on the immunocompromised population, development of new antivirals and vaccines is needed.
1) Introduction:
Respiratory viral infections (RNA and DNA viruses) are one of the most common infections in solid organ transplant recipients having similar symptoms and clinical presentation, with incidence ranging from 0.76-0.91 episodes per patient-year, being higher among lung transplant recipients.it presents throughout the year with high incidence in autumn and winter.
Lack of data on mortality associated with viral pneumonia in solid organ transplantation. 2) Diagnosis:
viral culture, direct fluorescent antibody (DFA) staining and serology were previously used.
Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72–100%. 3) influenza virus:
It is a single-stranded RNA virus of the Orthomyxoviridae family with multiple strain but A and B associated with the disease which is seasonal mainly in winter.
Risk factors include: age (with higher rates in children), likelihood of exposure, level of immunity (due to prior vaccination or disease), degree of immunosuppression and the nature of the epidemic.
Clinical presentations are cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache. immunosuppressed patients have increased risk of complications like pneumonia, fungal or bacterial coinfection, pericarditis, encephalitis
Prevention: droplet precautions, vaccination (requiring high-dose) and antiviral prophylaxis
Treatment:neuraminidase inhibitors (oseltamivir, zanamivir, pramivir), baloxavir, and M2 inhibitors (amantadine and rimantadine, not used nowadays). Early antiviral treatment is associated with lower complications and ICU admissions. Symptomatic SOT recipients should be treated irrespective of duration of the symptoms. 4) Respiratory Syncytial Virus:
It is a single-stranded RNA virus of the Pneumoviridae family with two strains: RSV-A and RSV-B and it a seasonal virus with peak incidence in the winter and spring. presented with fever, cough, dyspnea and rhinorrhea.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection
Prevention:contact precautions, monthly palvizumab prophylaxis in children <2 year age during the RSV season, and nirsevimab once every season. Multiple vaccines are also available, especially for elderly, pregnant, and pediatric population.
Treatment: URTI: Ribavirin
LRTI: Ribavirin with or without IV immunoglobulin
Presatovir has been shown to reduce progression to LRTI in lymphopenic hematopoietic stem cell transplant (HSCT) recipients. 5)Human metapneumovirus (HMPV):
It is a single-stranded RNA virus of the Pneumoviridae family like RCV
Prevented by contact precautions
Treated by supportive care 6) Parainfluenza virus (PIV ) :
it is single strand RNA virus of the Paramyxoviridae family. It has 4 serotypes type 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter. symptoms like other respiratory viruses PIV3, 21% experienced respiratory failure. treated by supportive care and prevented by contact precautions. 7)Rhinovirus:
It is a single stranded RNA virus of Picornaviridae family,
It has 3 serotypes (A,B,C), causing common cold and most common in lung transplant patients. treated by supportive care and prevented by contact precautions. 8)Coronaviruses (CoV) :
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. SARS COV1 has high mortality up to 20% treated with interferon and high dose of steroid.MERS-CoV infection has high mortality rates of up to 50% treated with ribavirin, interferon, and steroids. 9) Adenovirus:
It is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
It causes viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
Rates of infection differ with age and the transplanted organ and higher among children, and in intestinal transplantation.
Clinical presentation:
conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
Mortality is 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention:
maintaining droplet and contact precautions and Brincidofovir shows benefit.
Treatment:
supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational). 10) Bocavirus:
It is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses. 11) KI and WU Polyomaviruses:
It is double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007. 12. Summary:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection. Preventive measures are also lacking, as vaccination is only available against influenza at this time.
Level of evidence is V.
Respiratory Viruses in Solid Organ Transplant Recipients.
1. Introduction
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year.
The incidence appears to be higher among lung transplant recipients (LTRs) , but is not affected by time from transplant
there is a higher incidence in the autumn and winter, and patterns differ between viruses.
All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses .
Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs .
2. Diagnosis :
a- viral culture,
b- direct fluorescent antibody (DFA) staining
c- serology
are used to diagnose respiratory viral infections.
3. Influenza Virus
3.1. Epidemiology and Risk Factors :
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There
are multiple strains, although only influenza A and B are generally associated with disease in humans. Influenza viruses are seasonal, circulate mainly in the winter .
The influenza attack rate depends on several factors, including
a- age (with higher rates in children).
b- likelihood of exposure.
c- level of immunity (due to prior vaccination or disease).
d- degree of immunosuppression.
e- the nature of the epidemic.
The incidence is about 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively 3.2. Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness.
most common symptom are cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) .
Immunocompromised individuals are also at increased risk for complications.
The complication include
a- viral pneumonia.
b- bacterial superinfection.
c- fungal coinfections.
d- pericarditis and myocarditis.
e- myositis.
f- encephalopathy and encephalitis, etc.
3.3. Prevention
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions.
However, the most important means for prevention is vaccination of the transplant recipient and close contacts.
Only inactivated influenza vaccines should be given to transplant recipients.
Immunogenicity of influenza vaccine in SOT is variable, but generally lower compared to a non-immunocompromised population . Still, influenza vaccine has been shown to decrease influenza infection rates, complications and mortality in the SOT population .
Another small study conducted during an influenza outbreak in a kidney transplant unit revealed that the unvaccinated population had significantly high rates of influenza infection and mortality.
Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs , however there isno recommendation to withhold treatment around vaccination.
Another preventive measure influenza infection would be using antiviral prophylaxis.
prophylaxis using low-dose oseltamivir was demonstrated to be 80% effective against influenza.
3.4. Treatment
There are three groups of drugs approved for the treatment of influenza :
1- M2 inhibitors (amantadine and rimantadine) are not used today since they are inherently
inactive against influenza B and circulating influenza A strains carry a high rate of re sistance.
2- neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
3- Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenz cap-dependent endonuclease and is a single dose oral medication
There have been no trials comparing drugs, doses or treatment durations in the SOT population. According to trials comparing different NAIs in the immunocompetent population, no drug seems to be superior.
Observational studies in SOT recipients show that early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates .
There are several investigational antivirals for influenza. Favipiravir is active against
a wide spectrum of RNA viruses and as such can inhibit both influenza A and B viruses.
Several monoclonal antibodies targeting various hemagglutinins of influenza virus
have been developed , showing mixed results .
Immunocompromised patients are at increased risk for antiviral resistance due to
prolonged viral replication combined with antiviral exposure, which is sometimes subthera
peutic (as in post-exposure prophylaxis) . As stated, M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain .
4. Respiratory Syncytial Virus
4.1. Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyx oviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children, who are a significant source of transmission.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant
and recent rejection. 4.2. Clinical Manifestations:
similar to other respiratory viruses,
a- fever,
b- cough,
c- dyspnea
d- rhinorrhea.
Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia . This is especially true for LTRs, where lower RTI rates can be as high as 72%.
4.3. Prevention :
Hospitalized patients should be placed under contact precautions as RSV droplets
form large particles and are transmitted by contact.
The American Academy of Pediatricsrecommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based .
Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein. Due to its extended half-life, it can be given once per season and has shown favorable results in a recently published randomized trial conducted on preterm infants.
There are currently multiple vaccines under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based .
In a combined analysis of trials done in HSCT, ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a non –significant reduction in progression to lower RTI .
Several new drugs targeting RSV are currently under development, however none
have reached phase three trials
5. Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling
RSV. Its seasonality also follows that of RSV, with most cases identified in the winter and
Spring.
Ribavirin has in vitro activity against HMPV.
Data in SOT are based solely on lung transplants and are limited to small case series
Prevention is mainly based on infection control practices, including implementation of
contact precautions in hospitalized patients.
6. Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no
seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear
in the fall and winter.
Utility of antivirals for PIV infection in SOT is unknown. A systematic review on antiviral treatment for PIV infection in HSCT recipients showed no benefit in this population.
Thus, the mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions.
7. Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae
family, which is part of the Enterovirus genus. Serotypes A–C circulate year-round and
are the predominant cause for the common cold.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
8. Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human
CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute
respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV,
SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs,
accounting for 12.4–17.8% of the positive samples.
Symptoms are generally similar to other respiratory viruses.
The immunocompromised group had a significantly higher rate of severe lower RTI.
SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%.
MERS-CoV infection was first identified in Saudi Arabia [92] and is associated with severe respiratory illness and mortality rates as high as 50%.
Treatment options used in published case reports include ribavirin, interferon and steroids [93,94]. MERS-CoV still causes sporadic infections, mainly in the Middle East [95
9. Adenovirus
9.1. Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
Adenoviruses show no seasonal variability [9,99] and have been associated with institutional outbreaks.
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate.
Rates of adenovirus infection differ with age and the transplanted organ. Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression.
9.2. Clinical Manifestations:
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis.
Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
9.3. Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. prevention in the hospital setting is based on maintaining droplet and contact precau tions. Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks
the nephrotoxicity associated with cidofovir shows benefit.
9.4. Treatment
treatment modalities for adenovirus disease are derived from case reports and small case series.
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational)
10. Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated
from respiratory specimens, and in positive specimens, there is often co-infection with other
respiratory viruses
11. KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively. But, it is still unclear whether this has any clinical significanc
New respiratory viruses and serotypes are found affecting immunocompromised organ transplant patients.
This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, as they relate to organ transplant recipients. Lung transplant research will dominate the discussion.
This evaluation does not concentrate on hematopoietic stem cell transplantation, however, findings from this group will guide organ transplant therapy. This series will cover the SARS-CoV-2 epidemic.
Influenza Virus:
Immunocompromised people may not have influenza.
Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms.
Complications are viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis.
Treatment:
The most regularly used NAIs are oseltamivir, zanamivir, peramivir, and laninamivir (available only in Japan and South Korea).
Recently licensed baloxavir provides a unique method of action. The single-dose oral medicine selectively inhibits influenza cap-dependent endonuclease. It works for uncomplicated influenza in non-immunocompromised people.
Baloxavir may work better than NAIs against influenza B strains.
RSV:
RSV, like other respiratory viruses, causes fever, cough, dyspnea, and rhinorrhea.
RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses. LTRs have decreased RTI rates as much as possible.
Treatment
Lung transplant care differed from other organs in a US assessment of 11 transplant hospitals. All 10 lung transplant facilities treat lower RTI with ribavirin, and three add IVIG, whereas only 6/10 treat upper RTI and none offer IVIG.
Human Metapneumonia:
is similar to RSV. Like RSV, most occurrences occur in winter and spring. LTRs found HMPV in 3.6–6.8% of positive respiratory samples. 8/18 (44%) of these individuals had a lower RTI.
Ribavirin fights HMPV in vitro. Antivirals and immunomodulators do not reduce mortality in HSCT patients.
Parainfluenza:
a single-stranded RNA paramyxoviridae virus.
has four serotypes (1–4): serotype 3 is the most frequent, has no seasonality, and has caused outbreaks, whereas serotypes 1 and 2 occur in the autumn and winter.
In LTRs- accounts for 3.6–20.9% of respiratory viruses isolated.
After post hoc analysis, the highly immunocompromised category had better results. DAS 181 is FDA-unapproved.
supportive care is the core therapy, and hospital prevention relies on adherence to protocols.
Rhinovirus:
single-stranded RNA viruses of the Picornaviridae family of enteroviruses.
Serotypes A–C produce most colds year-round.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
single-stranded RNA. Established human CoVs (229E, NL63, OC43, and HKU1) induce upper respiratory tract infection, whereas others (SARS-CoV1, MERS-CoV, and SARS-CoV-2) produce outbreaks.
Ribavirin, interferon, and steroids were administered in case reports. MERS-CoV still produces some Middle Eastern illnesses.
Adenovirus:
double-stranded DNA virus contains seven subgroups (A-G) and over 90 serotypes.
Latency in lymphoid tissue allows adenoviruses to reactivate or create a new colony.
IVIG is sometimes used with antivirals. HSCT patients with cytomegalovirus and EBV infections may benefit from virus-specific cytotoxic T cells.
Lung Transplant Rejection and Respiratory Viruses:
LTRs are at higher risk for RTIs, especially lower RTIs. Continuous contact with the environment, decreased mucociliary clearance, cough reflex, and more immunosuppression than other organ transplants may cause this. Many studies have examined the relationship between respiratory viral infection and acute rejection, or CLAD/bronchiolitis obliterans syndrome (BOS), with inconsistent results.
Numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year.
The incidence appears to be higher among lung transplant recipients (LTRs).
Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter.
Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs.
Data on mortality associated with viral pneumonia in SOT recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1%. 2. Diagnosis:
NAT for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
Turnaround time of only 12–24 h.
Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and low sensitivity. Influenza Virus: Epidemiology and Risk Factors:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
There are multiple strains, although only influenza A and B are generally associated with disease in humans.
Influenza viruses are seasonal, circulate mainly in the winter (months November to May in the Northern Hemisphere and May to October in the Southern Hemisphere), and cause a significant proportion of RTIs during that time. Presentation: Common symptom:
Cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) Increased risk for complications:
Viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis. Risk factors associated with severe disease:
Older age, diabetes and use of mycophenolate mofetil.
Risk factors for pneumonia or ICU admission:
Multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition. Prevention:
Droplet precautions
Vaccination.
Pre-exposure prophylaxis using low-dose oseltamivir.
Post-exposure prophylaxis.
Guidelines published by The Infectious Diseases Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak to patients in the affected wards.
An outbreak is defined as two healthcare-associated cases diagnosed within 72 h in the same ward, and prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case. Treatment:
Reduction of immunosuppression is recommended for all severe respiratory illnesses
Neuraminidase inhibitors:
Oseltamivir (oral):
Treatment Dose 75 mg q12h (5 days)
Prophylactic Dose 75 mg q24h.
Zanamivir (inhaled) 10 mg q12h (5 days) Prophylactic Dose 10 mg q24h.
Peramivir (IV) 600 mg once.
Baloxavir (oral) 40 mg (80 kg) Prophylactic Dose 40 mg (80 kg).
Ribavirin (IV/oral) LD 600 mg then 200 mg q8h for 1 day then 400 mg q8h. Can increase to maximum 10 mg/kg q8h.
Cidofovir (IV) 1 mg/kg 3 times a week, or 5 mg/kg once a week for 2 weeks and then every 2 weeks add probenecid and hydration.
NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals.
Treatment options include changing to a different NAI, changing to a different antiviral class, or combination antiviral. Respiratory Syncytial Virus: Epidemiology and Risk Factors:
RSV is a single-stranded RNA virus of the Pneumoviridae family.
Two strains: RSV-A and RSV-B.
It is a seasonal virus with peak incidence in the winter and spring.
Circulates mainly among young children, who are a significant source of transmission.
In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses. Significant morbidity and mortality due to the development of lower RT.
Risk factors for lower RTI and mortality in the SOT:
Young children (less than two years old), recent transplant, lung or multivisceral transplant.
Clinical Manifestations:
Fever, cough, dyspnea and rhinorrhea.
More frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
In LTRs, where lower RTI rates can be as high as 72%. Prevention:
Contact precautions. Treatment:
Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RT, plus minus IVIG. Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family.
Most cases identified in the winter and spring.
Studies conducted on LTRs identified HMPV in 3.6–6.8%.
Current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients. Parainfluenza Virus:
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
Four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
In LTRs, it accounts for 3.6–20.9% of the respiratory viruses isolated. PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI and RF.
The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact.
DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, thus preventing attachment and entry of viruses such as PIV and influenza virus into respiratory cell, ITS STILL IVESTIGATIONAL DRUG. Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus. Serotypes A–C circulate year-round and are the predominant cause for the common cold.
These viruses are isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients. TRAEMENT IS SUPPORTIVE. Coronaviruses:
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
Second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples.
Symptoms are generally similar to other respiratory viruses.
The immunocompromised group had a significantly higher rate of severe lower RTI.
MERS-CoV is associated with severe respiratory illness and mortality rates as high as 50%, Human to human transmission is associated with healthcare settings, and in one of the cohorts studied, and 25% of the people infected were healthcare workers. There is also ongoing zoonotic transmission from camels Two Treatment options used in published case reports include ribavirin, interferon and steroids MERS-CoV still causes sporadic infections, mainly in the Middle East . Adenovirus.
Epidemiology:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
Adenoviruses show no seasonal variability and have been associated with institutional outbreaks Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate. Clinical Manifestations:
Conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
. In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis.
Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention:
Droplet and contact precaution.
Treatment:
. Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes (investigational). Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression. Bocavirus:
Is a single-stranded DNA virus of the Parvoviridae family?
It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses. KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family.
Respiratory Viruses and Rejection in Lung Transplantation:
As previously mentioned, LTRs are at increased risk for RTIs in general and specifically lower RTIs.
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data. Summary:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipient, effective vaccine and medication is needed.
Introduction: Respiratory viral infections (both RNA and DNA viruses) are one of the most common infections in solid organ transplant (SOT) recipients having similar symptoms and clinical presentation, with incidence ranging from 0.76-0.91 episodes per patient-year, being higher among lung transplant recipients. Higher incidence is seen in autumn and winter seasons, with no relation to time post-transplant. Progression to lower respiratory tract infection (LRTI) is seen in 6.2% to 40% with mortality of 5.1%.
Diagnosis: Although viral culture, direct fluorescent antibody staining, and serology were used previously, Nucleic acid testing (NAT) is the gold standard with sensitivity of 72% to 100% for diagnosis. Multiplex NAT can be used to detect several viruses simultaneously. Rapid antigen tests are available for respiratory syncytial virus (RSV) and influenza, although with low sensitivity.
Influenza virus: It is a single stranded RNA (ssRNA) virus of Orthomyxoviridae family, with multiple strains (A and B associated with human infections) and affects seasonally (in winter months) with highest incidence in lung transplant recipients. Symptoms include cough, fever, rhinorrhea, myalgia etc. Immunosuppressed patients have increased risk of complications like pneumonia, fungal or bacterial coinfection, pericarditis, encephalitis, etc. Older age, diabetes, and MMF use, antilymphocyte globulin use in last 6 months, lymphopenia, influenza A, and hypogammaglobulinemia is associated with severe disease. Prevention involves droplet precautions, vaccination (requiring high-dose) and antiviral prophylaxis (pre- and post-exposure) using oseltamivir (to be given in case of hospital outbreak). Treatment involves using neuraminidase inhibitors (oseltamivir, zanamivir, pramivir), baloxavir, and M2 inhibitors (amantadine and rimantadine, not used nowadays). Early antiviral treatment is associated with lower complications and ICU admissions. Symptomatic SOT recipients should be treated irrespective of duration of the symptoms.
RSV: It is a ssRNA virus of Pneumoviridae family, with 2 strains (RSV-A and RSV-B), affecting mainly young children seasonally (in winter and spring). Symptoms are like other respiratory viruses. Risk factors for LRTI (upto 72% in lung transplant recipients) include recent rejection, or lung or multivisceral transplant. Prevention include contact precautions, monthly palvizumab prophylaxis in children <2 year age during the RSV season, and nirsevimab once every season. Multiple vaccines are also available, especially for elderly, pregnant, and pediatric population. Treatment for upper RTI includes ribavirin (shown to reduce progression to LRTI), while for LRTI involves use of ribavirin with or without intravenous immunoglobulin (IVIG), which has shown to reduce mortality. Presatovir has been shown to reduce progression to LRTI in lymphopenic hematopoietic stem cell transplant (HSCT) recipients.
Human metapneumovirus (HMPV): It is a ssRNA virus of Pneumoviridae family affecting seasonally (in winter and spring). Symptoms are similar to other respiratory viruses. Treatment involves supportive care, although ribavirin use has been shown to be associated with mortality benefit and lower chronic lung allograft disease. Prevention involves contact precautions.
Parainfluenza virus (PIV): It is a ssRNA virus of Paramyxoviridae family, with 4 serotypes (PIV 1-4), with type 3 being most common (showing no seasonality) and type 1 and 2 affecting seasonally (in winter and fall). Symptoms are like other respiratory viruses. High rate of symptomatic disease and LRTI with up to 21% respiratory failure is seen in PIV infection. Treatment involves supportive care and contact precautions for prevention. Antiviral treatment has shown no benefit in PIV. DAS 181 (inhaled sialidase) has shown trend towards better outcome.
Rhinovirus: It is a ssRNA virus of Picornaviridae family, with 3 serotypes (A,B,C), circulating year-round, predominantly causing common cold. They are most common respiratory viruses in lung transplant recipients, frequently associated with other infections and treatment is mainly supportive measures with droplet precautions for prevention.
Coronaviruses (CoV): These are ssRNA viruses of Coronaviridae family, associated with URTI (by 229E, NL63, OC43, HKU1) or severe respiratory disease (by severe acute respiratory syndrome- CoV1, SARS-CoV1, SARS-CoV2, and middle eastern respiratory syncrome-CoV, MERS-CoV). They are associated with significantly higher rates of severe LRTI in immunocompromised patients. SARS-CoV1 infection has high mortality of up to 20%, having better outcomes with use of interferon and high-dose steroids. MERS-CoV infection has high mortality rates of up to 50% with treatment options being ribavirin, interferon, and steroids.
Adenovirus: It is a double stranded DNA virus of Adenoviridae family, with 7 subgroups (A-G), and 90 serotypes. They are latent in lymphoid tissue, hence can be either de novo, or due to reactivation of the infection. They are associated with institutional outbreaks, lacking any seasonal variability, and present with viremia without any symptoms (21% of viremic patients had symptoms). It can manifest as conjunctivitis, URTI, LRTI, hemorrhagic cystitis, pyelonephritis, hepatitis, and enterocolitis, with predilection for the allograft. High mortality (50% for pneumonia, and 80% for disseminated infection) is seen. Prevention involves maintaining droplet and contact precautions and antiviral brincidofovir has shown some benefit. Treatment includes supportive care, reduction in immunosuppression, cidofovir, brincidofovir, IVIG, and adenovirus-specific cytotoxic T lymphocytes.
Bocavirus: It is a ssDNA virus of Parvoviridae family, rarely isolated from respiratory specimens, mostly seen as co-infection with other respiratory viruses, and is known for viral persistence.
KI and WU Polyomaviruses: They are dsDNA viruses of Polyomaviridae family, but their clinical significance is unknown.
Respiratory viruses and rejection in lung transplantation: No association of respiratory viral infections and acute rejection has been seen, although there is a non-significant trend towards bronchiolitis obliterans syndrome (BOS). There is no definitive association between rhinoviruses and CoVs and rejection or BOS.
Summary: Respiratory viruses cause significant morbidity and mortality in transplant recipients. Prevention using contact and droplet precautions (and vaccination for influenza) is the key for better outcomes, although effective therapies are available for influenza and RSV infection.
2. What is the level of evidence provided by this article?
● In organ transplant recipients, the incidence of respiratory viral infections ranges between 0.76–0.91 episodes per patient-year
● The incidence appears to be higher among lung transplant recipients (LTRs) and in the autumn and winter
● Rate of progression to lower (RTI) ranges between 6.2–40% in LTRs
● Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients
Diagnosis
● Viral culture has a long time of 10 days for standard viral culture and two days for shell vial culture.
● DFA staining is available for limited number of respiratory viruses and requires expertise in interpreting the results.
● Serology have been useful only for epidemiological studies and not for diagnosing acute infection
● Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis with a sensitivity of 72–100%
● Multiplex NAT allows testing with a turnaround time of only 12–24 h
● Rapid antigen tests, allowing results within minutes available for influenza and RSV only with low sensitivity
Influenza Virus
● Epidemiology and Risk Factors
☆ RNA virus
☆ Only influenza A and B are generally associated with disease in humans.
☆ They are seasonal in the winter
☆ The influenza attack rate depends on:
* Age (higher in children)
* Likelihood of exposure
* Level of immunity
* Degree of immunosuppression
* Nature of the epidemic
☆ The incidence is 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively
● Clinical Presentation
☆ Immunocompromised patients may not fit the classic influenza-like illness.
☆ The most common symptom is cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), headache (30%)
☆ Increased risk of complications as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis,
☆ Risk factors for severe disease :
* Older age
* Diabetes
* Use of mycophenolate mofetil.
* Use of antilymphocyte globulin in the past six months
* Lymphopenia
* Hypogammaglobulinemia
* Influenza A and nosocomial acquisition
● Prevention
☆ patients should be placed under droplet precautions
☆ Vaccination of the transplant recipient and close contacts.
☆ Vaccinating with an inactivated influenza vaccine as soon a one month post transplant
☆ Immunogenicity of influenza vaccine in SOT is variable, but lower compared to a non-immunocompromised population
☆ Influenza vaccine decreases influenza infection rates, complications and mortality in the SOT population
☆ 2019 guidelines by AST recommend:
* High-dose vaccination is preferred
* Two doses of standard vaccine also used
☆ Using antiviral prophylaxis antiviral resistance may develope so it should be given in the case of a hospital outbreak to patients in the affected wards for 14 days
● Treatment
☆ M2 inhibitors (amantadine and rimantadine) it is inactive against influenza B with high rate of resistance to influenza A strains
☆ Neuraminidase inhibitors (NAIs) :
* most commonly used
* include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
☆ Baloxavir:
* recently approved
* Has a novel mechanism of action.
* A selective inhibitor of influenza endonuclease
* A single dose oral medication.
* It is effective in uncomplicated influenza in the immunocompetent population
* It is more effective against influenza B strains than NAIs
☆ Early antiviral treatment(within 24–48 h) in SOT patients is associated with a decrease in influenza complications and lower ICU admission rates
☆ Due to prolonged shedding in SOT patients some extend treatment duration or use high doses
☆ Favipiravir has low resistance rates and is synergistic when combined with oseltamivir. It is currently licensed only in Japan for use in influenza unresponsive or insufficiently responsive to current antivirals
☆ Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with subtherapeutic antiviral exposure
☆ M2 inhibitors have high resistance in the currently circulating influenza A strains.
☆ Resistance to NAIs is uncommon except in the A/H1N1 strain
☆ The most common mutation is H275Y, in A/H1N1but it still susceptle to zanamivir
☆ NAI resistance suspected in
• A prolonged illness
• Persistent viral replication
• Developed influenza shortly after receiving low dose antivirals.
☆ Treatment options include:
▪︎Changing to a different NAI
▪︎Changing to a different antiviral class
▪︎Combination antivirals.
☆ Resistance documented in 9.7% of patients treated with baloxavir
Respiratory Syncytial Virus
● Epidemiology and Risk Factors
☆ RNA virus
☆ Has 2 strains RSV-A and RSV-B.
☆ It is a seasonal virus with peak incidence in the winter and spring
☆ Mainly among young children
☆ In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens
☆ Risk factors for lower RTI and mortality:
* Young children (less than two years old)
* Recent transplant
* Lung or multivisceral transplant
* Recent rejection
● Clinical Manifestations
☆ Fever, cough, dyspnea and rhinorrhea
☆ RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia
☆ In LTRs lower RTI is high ( 72% )
● Prevention
☆ Contact precautions
☆ Palivizumab prophylaxis is recommeneded during the RSV season in children under 24 months of age who are severely immunocompromised,
☆ Nirsevimab
* A monoclonal targets an epitope of the RSV fusion protein.
* It has extended half-life
* It is given once per season
☆ Vaccines are recommended for :
* lderly persons
* Pregnant women
* Pediatric population
● Treatment
☆ There are differences in treatment regimens in lung transplant compared to other organs.
☆ In HSCT, ribavirin treatment was associated with reduced progression to lower RTI and decreased mortality among patients with lower RTI.
☆ A combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a nonsignificant reduction in progression to lower RTI
☆ Systemic ribavirin is associate with SEs as hemolytic anemia, leukopenia, neuropsychiatric symptoms, teratogenic
☆ Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells , it decreases progression to lower RTI with developing resistance in (20%) of patients
Human Metapneumovirus
● RNA virus
● closely resembling RSV.
● Its seasonality is in winter and spring
● Most of patients had symptoms of RTI, and in (44%) had a lower RTI
● Ribavirin has in vitro activity against HMPV.
● Studies do not demonstrate a mortality benefit with antivirals or immunomodulator
● In LTRs ribavirin was associated with significantly less chronic lung allograft disease in RTi
● Prevention is mainly based on infection control practices, including implementation of contact precautions
Parainfluenza Virus
☆ RNA virus
☆ There are four serotypes of PIV (1–4)
☆ Serotype 3 is the most common with no
seasonality and outbreaks, whereas serotypes 1 and 2 appear in the fall
☆ It accounts for 3.6–20.9% of the respiratory viruses isolated in LTRs
☆ PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI
☆ DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, thus preventing attachment and entry of viruses such as PIV and influenza virus into respiratory cells
it is not currently FDA approved.
☆ The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions
Rhinovirus
☆ RNA viruses
☆ Serotypes A–C circulate year-round
☆ The predominant cause for the common cold
☆ They are isolated in respiratory samples taken from immunocompetent patients as well as SOT recipients.
☆ In LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6%
☆ Rhinoviruses are frequently found as a coinfection with other viruses or bacteria
☆ Symptoms are usually those of the common cold
☆ Treatment is based on supportive measures and droplet precautions
Coronaviruses
☆ RNA viruses
☆ Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI
☆ But CoVs SARS-CoV1, MERS-CoV2
are associated with severe respiratory disease.
☆ Human coronaviruses are second only to rhinoviruses for prevalence among LTRs,
accounting for 12.4–17.8% of the positive samples
☆ The immunocompromised group had a significantly higher rate of severe lower RTI
☆ SARS-CoV1 was associated with high rates of lower RTI and mortality 20%
☆ The better outcomes were with interferon and high-dose steroids in conjunction with supportive care
☆ MERS-CoV2 is associated with severe respiratory illness and mortality rates 50%
☆ Treatment include ribavirin, interferon and steroids
Adenovirus
● Epidemiology
☆ A double-stranded DNA
☆ Establish latency in lymphoid tissue
☆ Infection can represent reactivation or de novo community acquisition
☆ they show no seasonal variability
☆ 7.2% of SOT patients with adenovirus developed viremia and 21% were symptomatic
☆ Rates of adenovirus infection are higher:
• A mong children
• In intestinal transplantation
● Clinical Manifestations :
☆ Conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
☆ Fever of unknown origin and rise in creatinine In a kidney transplant recipient with adenovirus should be considered as a cause of pyelonephritis
☆ Mortality is 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection
☆ Bronchiolitis obliterans as a sequelae
has been described in lung transplant recipients
● Prevention :
☆ Maintaining droplet and contact precautions
☆ Brincidofovir is an orally bioavailable of cidofovir that lacks the nephrotoxicity associated with cidofovir.
● Treatment
☆ Supportive care
☆ Reduction of immunosuppression
☆ Cidofovir
☆ Brincidofovir (investigational)
☆ IVIG
☆ Adenovirus specific cytotoxic T lymphocytes (investigational)
☆ Favorable outcomes were with combining cidofovir with RI
Bocavirus
● A single-stranded DNA
● It is isolated from respiratory specimens in 0.5–1% among LTRs and often coinfection with other respiratory viruses
● It has viral persistence
KI and WU Polyomaviruses
● Double-stranded DNA viruses
● HSCT recipients have higher frequency of infection with these viruses
● kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens
Respiratory Viruses and Rejection in Lung Transplantation
● LTRs are at increased risk for RTIs in general and specifically lower RTIs due to
* Continuous contact of the allograft with
the environment
* Impaired mucociliary clearance
* Impaired cough reflex
* Geater immunosuppression compared to other organ transplants.
●There is no association between respiratory viral infection and acute rejection
● A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and
biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infec-
tions
● Associations have also been reported for influenza, HMPV, RSV, PIV, adenovirus
● There is no definitive association between rhinoviruses and CoVs and rejection or CLAD
● Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections
III. Respiratory Viruses in Solid Organ Transplant Recipients
Summarise this article
Introduction
– numerous viruses have an impact on the health of SOT recipients
– incidence of respiratory viral infections in SOT recipients ranges
between 0.76-0.91 episodes per patient-year
– all respiratory viruses cause similar symptoms, hence the clinical
presentation does not differentiate between the viruses
– data on mortality associated with viral pneumonia among SOT recipients is lacking
Diagnosis
– previously, viral culture, direct fluorescent antibody (FA) staining and serology were used in the diagnosis of respiratory viral infections
– each of these methods had its own disadvantage
– viral culture had a long turnaround time
– DFA staining is only available for certain respiratory viruses and it requires expertise in interpreting the results
– serology has only been useful in epidemiological studies, it is not useful in the diagnosis of acute infection since acute- and convalescent- phase sera are needed
– molecular strategies for diagnosis are now available, making these other traditional methods obsolete
– nucleic acid testing (NAT) is now the gold standard for diagnosis of respiratory viruses, sensitivity is 72-100%
– multiplex NAT has a TAT of 12-24 hours and it allows for testing of various respiratory viruses simultaneously
– rapid antigen tests are clinically available to test for influenza and RSV only, the results are ready in a few minutes but they have a low sensitivity
Influenza virus
Epidemiology and risk factors
– has multiple strains but only Influenza A and B are associated with disease in humans
– influenza viruses are seasonal
– risk factors for influenza infection include: degree of immunosuppression, age (higher rates in children), level of immunity (due to prior disease or vaccination), likelihood of exposure, nature of the epidemic
Clinical presentation
– immunosuppressed patients may not present with the classical symptoms of an influenza-like illness
– immunocompromised patients are at increased risk of complications like bacterial superinfection, viral pneumonia, fungal co-infections, pericarditis, myocarditis, encephalopathy, encephalitis, myositis
– risk factors associated with severe disease include: diabetes, older age, use of MMF
– risk factors for pneumonia or ICU admission include: use of ATG in the past 6 months, multiple comorbidities, lymphopenia, influenza A, nosocomial acquisition
Prevention
– to avoid outbreaks/ disease spread within the hospital, droplet precautions should be taken
– vaccination of transplant recipients and their close contacts remains the optimal preventive strategy
– transplant recipients should only receive inactivated influenza vaccines due to the risk of dissemination of the virus contained in the live attenuated intranasal influenza vaccine
– currently, there is a quadrivalent inactivated influenza vaccine which has two A strains (H1N1 and H3N2) and two B strains
– the inactivated influenza vaccine can be given as soon as 1 month post-transplant bearing in mind that vaccine immunogenicity can be poor in the first 6 months post-transplant
– influenza vaccine decreased infection rates, complications and mortality among SOT recipients
– high-dose vaccination, where available, is preferred although two doses of standard vaccine can be used -high-dose is associated with higher seroconversion rates
– patients on mycophenolate have been shown to have worse antibody response compared to other immunosuppressive agents but there is no recommendation to withhold treatment during vaccination
– antiviral pre-prophylaxis with low-dose oseltamivir can be used to prevent influenza infection
– post-exposure prophylaxis can result in antiviral resistance hence for such patients therapeutic-dose oseltamivir should be considered
– antiviral prophylaxis should be offered during a hospital outbreak, this is usually given for 14days and at least 7 days after symptom onset in the last identified case
Treatment
– 3 groups of drugs have been approved:
M2 inhibitors (amantadine and rimantadine) – no longer used since they are inactive against influenza B and circulating influenza A strains carry a high rate of resistance
Neuraminidase inhibitors (NAIs) – most commonly used e.g., oseltamivir (oral), zanamivir (inhaled and IV), peramivir (IV), laninamivir (available only in Japan and South Korea)
Baloxavir (recently approved, single-dose oral medication, more effective against influenza B strains than NAIs)
– early antiviral treatment (within 24-48h) is associated with a decrease in influenza complications and lower ICU admission rates among SOT recipients
– SOT patients have prolonged shedding of the influenza virus therefore they should be treated irrespective of symptom duration
– empiric treatment should be started as soon as possible
– treatment duration can be extended from 5days to 10days in immunocompromised patients due to the prolonged shedding of the virus
– immunosuppressed patients are at increased risk for antiviral resistance due to the prolonged viral replication and subtherapeutic antiviral exposure as can occur during post-exposure prophylaxis
– suspect NAI resistance in transplant patients with prolonged illness, persistent viral replication or in those who develop influenza while on or shortly after receiving low dose antivirals
– management options for NAI resistance include: switch to a different NAI, change to a different antiviral class, combination antivirals
Respiratory syncytial virus
Epidemiology and risk factors
– RSV has two strains: RSV-A and RSV-B
– it is seasonal, young children are a significant source of transmission
– risk factors for lower RTI and mortality in SOT recipients include: recent transplant, recent rejection, lung or multivisceral transplant
– contact precautions should be observed since the RSV droplets form large particles which are transmitted by contact
– palivizumab prophylaxis is not routinely used in adult SOT recipients
– nirsevimab, a monoclonal antibody, given once a season since it has an extended half-life
– vaccines are still under development, they are recommended for the paediatric population, pregnant women and the elderly
Treatment
– ribavirin treatment was associated with reduced progression of upper RTI to lower RTI
– combination of ribavirin and an immunomodulator like IVIG, RSV-IVIG or palivizumab, significantly lowered the mortality
– inhaled ribavirin is expensive and requires negative -pressure rooms due to its teratogenicity
– systemic ribavirin is associated with significant side effects like hemolytic anaemia, leukopenia, teratogenicity, neuropsychiatric symptoms Adenovirus Epidemiology
– has 7 subgroups, 90 serotypes
– establish latency in lymphoid tissue, hence an infection arises after reactivation or can be de novo (community acquired)
– no seasonal variability, is associated with institutional outbreaks
– causes viremia without obvious symptoms hence it is prudent to differentiate infection and disease
– risk factors for adenovirus infection: age (higher among children), intestinal transplantation (due to the higher amount of lymphoid tissue in the allograft and greater immunosuppression)
Clinical manifestations
– conjunctivitis, URTI, LRTI, hepatitis, enterocolitis, pyelonephritis, hemorrhagic cystitis, has a predilection for the transplanted allograft
– fever, rising serum creatinine would suggest pyelonephritis due to adenovirus
– high mortality rate: 80% for disseminated adenoviral infection, 50% for adenoviral pneumonia
– prevention: maintain droplet and contact precautions
Treatment
– supportive care, reduction in immunosuppression, cidofovir (nephrotoxic), brincidofovir (investigational), IVIG, adenovirus specific CTLs (investigational)
Summary
– respiratory viruses cause significant morbidity and mortality among SOT recipients
– molecular diagnostic methods have made diagnosis easier
– at the moment, effective therapies are only available for influenza and RSv
– there are new drugs in the pipeline
– preventive measures are limited: vaccination is only available for influenza only
– there is need to develop new antiviral agents and vaccines
Respiratory viral infection after solid organ transplantation Summary
Respiratory viral infection can occur at any time after SOT and can be associated with morbidity and mortality risk, especially among lung transplantation, and in some reports even can trigger rejection and chronic allograft dysfunction. respiratory viral infection among SOT can be acquired from the community and share the same respiratory symptoms and reported incidence in the range of 0.6-0.9 per patient /year, mainly diagnosed with nucleic acid test NAT, influenza virus good treatment options and prevention with vaccination, however, this can be restricted by resistance to neuraminidase inhibitors, and low vaccine immunogenicity with the use of immunosuppression after SOT also many of respiratory virus have limited treatment and prevention methods. The rate of progression to lower respiratory tract infection (RTI) has been reported between 6.2–40% in LTRs with reported mortality in LRT infection up to 5.1%. This review article summarizes the epidemiology of respiratory viral infection, its diagnosis, treatment options, and preventive challenges for RNA and DNA respiratory viruses hoping for improvement in the future preventive and treatment options.
Diagnosis
Diagnosis of respiratory viral infections depends on viral cultures, serology, and Direct fluorescence antibodies viral staining (DFA), more recent diagnoses are based on molecular studies like NAT which is the gold standard for diagnosis and has a sensitivity of 72–100%. Using multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h
Rapid antigen tests also can give the results within minutes but with low sensitivity. Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family, we have influenza A and B, usually seasonal with a peak in winter and autumn time, such infections can present with cough, fever, sneezing, and congestion and can increase the risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy, and encephalitis, risk factors for such complications include old age comorbid like DM, use of IS like MMF, intense immunosuppression like induction with ATG, Prolong lymphopenia, and low albumin, influenza A associated with a higher rate of ICU admission and mortality Prevention
Vaccination with seasonal inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains which is for all transplant patients at risk with household people, preferred to be given after 1 month from transplantation and its effective in decrease influenza infection rates, complications and mortality in the SOT population.
Also, the use of prophylaxis antivirals like Pre-exposure prophylaxis using low-dose oseltamivir was found to be effective in up to 80% with a low risk of Oseltamivir resistance Treatments
The table1,2 summarizes the treatment options
Neuraminidase inhibitors (NAIs)the most widely used include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous), and zanamivir (available only in Japan and South Korea).
Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single-dose oral most observational studies in SOT recipients demonstrate that early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates. However, transplant patients have prolonged viral shedding of the influenza virus, and preferred all symptomatic patients should be treated irrespective of symptoms duration and some extended the course up to 10 days instead of 5 days.
M2 inhibitors are not recommended due to the high resistance rate to influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1strain. Respiratory Syncytial Virus
RSV is a single strained RNA virus of the Pneumoviridae family and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence
in the winter and spring, it circulates among children and they are the main source of transmission carry a high risk of both upper and lower respiratory tract infections and have been associated with significant morbidity and mortality due to LRTI, especially in post-lung transplantation, presentation similar to other respiratory common symptoms like fever cough, sob, runny nose, bronchitis, bronchiolitis, pneumonia, especially with LTRS
Prevention
Contact precaution in hospitalized patients in addition to droplet precaution
palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence-based
many vaccinations under development treatment
ribavirin or ribavirin with IVIG mainly for LRTI, however ribavirin used for URTI will lower the risk of progression to LRTI and reduced mortality rate, trials of a combination of IVIG, RSV-IVIG or Palivizumab significantly lower mortality when used for LRTI.
Ribavirin was studied in limited case series mainly in the lung transplantation group with diverse results it also has a wide range of side effects including hemolytic anemia, neurotoxicity, leukopenia, and teratogenicity Rhinovirus
Double-stranded DNA virus,
Parainfluenza virus (PIV)
Single-stranded RNA virus, there are four serotypes of PIV(1-4). The most common one is type 3 PIV which can happen as outbreaks, while serotype 1, 2 seasonal predilections to winter and fall, accounts for 3.6-20.9% of respiratory viral isolation and is usually associated with symptomatic LRTI and risk of respiratory failure reported up to 21%.
Treatment is mainly symptomatic, and prevention by contact precaution some data is limited to case series use of ribavirin with or without immunomodulators also trials of DAS181 in LRTI but not yet approved. Adenovirus
double-stranded DNA viruses can cause both URTI, LRTI and many serotypes
can cause asymptomatic viremia , hemorrhagic cystitis , conjuctivitis , enterocoltitis , hepatitis and ,pyelonephritis prevention by droplet and contact precaution and treatment cidofovir, IVIG
in summary
respiratory viral infections among SOT are common and associated with morbidity and mortality, no effective treatment or vaccination is available and we need more studies
Introduction This review will cover both RNA and DNA respiratory viruses, including influenza, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients. · Respiratory viral infections in organ transplant recipients range from 0.76-0.91 episodes per patient per year, with a higher incidence in the autumn and winter. · The rate of progression to lower respiratory tract infection (RTI) varies between 6.2-40%. Mortality associated with viral pneumonia in LTRs is 5.1%. Diagnosis Viral culture, direct fluorescent antibody (DFA) staining, and serology have been used to diagnose respiratory viral infections, but each has its own shortcomings. · Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72-100%. · Multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12-24 h. Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity. Influenza Viruses · Epidemiology and risk factors ·Influenza viruses are seasonal, circulate mainly in the winter, and cause a significant the proportion of RTIs. · The attack rate depends on age, the likelihood of immunity, the degree of immunosuppression, and the nature of the epidemic. Clinical Presentation · Immunocompromised patients are at increased risk for complications such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, encephalitis, etc. · Risk factors include older age, diabetes, use of antilymphocyte globulin, lymphopenia, hypogammaglobulinemia, influenza A, and nosocomial acquisition. Prevention · Vaccination is the most important means for the prevention of influenza in the hospital setting, with a large prospective multicenter study showing that vaccination in the same influenza season was associated with a reduction in odds for pneumonia. · Antiviral prophylaxis using low-dose oseltamivir was evaluated among 477 transplant recipients and demonstrated 80% efficacy. Treatment · Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and there are several investigational antivirals for influenza. . Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure. · Treatment options include changing NAIs, changing to a different antiviral class, or combining antivirals. · Respiratory syncytial virus Epidemiology and risk factors · RSV is a seasonal virus with a peak incidence in the winter and spring and is a major source of transmission in LTRs. . Risk factors include young children, a recent transplant, lung or multi-visceral transplant, and recent rejection. Clinical manifestations · RSV causes lower RTI than other respiratory viruses, especially for LTRs. Prevention · Palivizumab prophylaxis is not evidence-based, Nirsevimab is a monoclonal antibody with extended half-lives, and ResVax is a nanoparticle-based vaccine.
Treatment · Ribavirin treatment has been associated with reduced progression of upper RTI to lower RTI and decreased mortality, but data on lung transplants is low quality. · Presatovir has failed to improve clinical and virologic outcomes. Human Metapneumovirus · HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Studies have identified HMPV in 3.6-6.8% of positive respiratory samples, and 8/18 (44%) had a lower RTI. . Ribavirin has in vitro activity against HMPV, but data derived from HSCT re-recipients do not demonstrate a mortality benefit. · Treatment is primarily based on supportive care, and prevention is mainly based on infection control practices. Parainfluenza Virus · Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. · It is mainly studied in LTRs, where it is associated with a high rate of symptomatic disease and lower RTI. · Utility of antivirals for PIV infection in SOT is unknown. DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium but is not currently FDA-approved. · Supportive care and prevention in the hospital setting are based on adherence to contact precautions. Rhinovirus . Rhinoviruses are single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples. ·Treatment is based on supportive measures and prevention in the hospital setting. Coronaviruses · CoVs are single-stranded RNA viruses of the Coronaviridae family, which are associated with outbreaks of severe respiratory disease. · Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. · SARS-CoV1 infection emerged in southern China in 2002 and was associated with high rates of lower RTI and mortality. · MERS-CoV infection was first identified in Saudi Arabia and is associated with severe respiratory illness and mortality rates as high as 50%. · Human to human transmission is associated with healthcare settings and 25% of the people infected were healthcare workers. Adenovirus Epidemiology · Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes. · It is known to cause viremia without obvious symptoms, and in a study of 263 SOT recipients, 7.2% developed viremia, but only 4/19 were symptomatic. · Rates of infection differ with age and the transplanted organ. Clinical manifestation . Adenovirus infection can cause conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis, and enterocolitis. Mortality can be high. Prevention . Adenovirus infections are transmitted through respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites, and fecal-oral routes. ·Brincidofovir is an orally bioavailable lipid conjugate that lacks nephrotoxicity. Treatment · Treatment modalities for adenovirus disease include reduction of immunosuppression, cidofovir, and IVIG, as well as virus-specific cytotoxic T lymphocytes for treatment of cytomegalovirus and Epstein–Barr virus infections. Bocavirus · Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making it true contribution to RTIs unknown. KI and WU Polyomavirus · KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri- dae family, with higher frequency in HSCT recipients. Respiratory Viruses and Rejection in lung transplantation · LTRs are at increased risk for RTIs due to impaired mucociliary clearance, cough reflex, and immunosuppression, but treatment with ribavirin is associated with lower rates. Summary · Respiratory viruses are a major cause of morbidity and mortality among SOT recipients, and effective therapies are only available for influenza and RSV infection. · New antivirals and vaccines are needed ============== Level of Evidence 5
Introduction
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients.
The most common culprit viruses are
Influenza virus
Respiratory syncytial virus (RSV),
Human metapneumovirus (HMPV)
Parainfluenza virus (PIV),
Rhinovirus coronavirus (CoV)
Adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1%.
DIAGNOSIS
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
CONCLUSION
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Given the severe implications respiratory viral infections have on the immuno- compromised population, development of new antivirals and vaccines is needed.
Respiratory Viruses in Solid Organ Transplant Recipients: Introduction;
-In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year.
-Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses.
-All respiratory viruses cause similar symptoms and the clinical presentation does not differentiate between the viruses.
-Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs. Diagnosis; –Viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infections. –Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
-Using multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h. Influenza Virus;
-Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
-There are multiple strains, although only influenza A and B are generally associated with disease in humans.
-Influenza viruses are seasonal, circulate mainly in the winter, and cause a significant proportion of RTIs during that time. Risk factors;
-Associated with older age, diabetes and use of mycophenolate mofetil. Univariate analysis also identified multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission. Clinical Presentation;
-The most common symptom; cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
-Immunocompromised individuals are also at increased risk for complications. Prevention;
-In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions.
-The most important means for prevention is vaccination of the transplant recipient and close contact.
-Only inactivated influenza vaccines should be given to transplant recipients.
-The American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant.
-The American Society of Transplantation guidelines (2019); recommend that high-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used.
-Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs , however there is no recommendation to withhold treatment around vaccination.
-Guidelines published by The Infectious Diseases Society of America recommend that antiviral prophylaxis (oseltamivir) should be given in the case of a hospital outbreak to patients in the affected wards.
-prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case. Treatment;
–M2 inhibitors (amantadine and rimantadine); are not used today since they are inherently inactive against influenza B and circulating influenza A strains carry a high rate of resistance.
–The neuraminidase inhibitors (NAIs); are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
–Baloxavir; was recently approved and is a single dose oral medication , It has been shown to be effective in uncomplicated influenza in the non-immunocompromised population, it also be more effective against influenza B strains than NAIs.
-There have been no trials comparing drugs, doses or treatment durations in the SOT population. Respiratory Syncytial Virus; –RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyxoviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring , and circulates mainly among young children, who are a significant source of transmission.
-In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens, and is a cause of significant morbidity and mortality due to the development of lower RTI. Clinical Manifestations;
-Similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea
-Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia, especially for LTRs, where lower RTI rates can be as high as 72%. Prevention;
-Hospitalized patients should be placed under contact precautions as RSV droplets form large particles and are transmitted by contact.
-The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
-Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein, given once per season because of its extended half-life, and has favorable results.
-ResVax vaccine is recommended for elderly persons, pregnant women or the pediatric population, however, a recent phase three trial of this vaccine in pregnant women did not reduce RSV infections in infants after birth. Treatment;
-In a combined analysis of trials done in HSCT, ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
-Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a nonsignificant reduction in progression to lower RTI.
-Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells. Human Metapneumovirus; –HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
-Its seasonality also follows that of RSV, with most cases identified in the winter and spring.
-Studies conducted on LTRs identified HMPV in 3.6–6.8% of positive respiratory samples.
-Ribavirin has in vitro activity against HMPV, with favorable outcomes on graft function with or without steroids.
-However, current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients. Parainfluenza Virus; –Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
-There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
-In LTRs, PIV infection accounts for 3.6–20.9% of the respiratory viruses isolated and associated with a high rate of symptomatic disease and lower RTI.
-Studies in SOT recipients are limited to small case series describing the use of ribavirin with and without immunomodulators in LTRs with mixed viral infections (PIV and RSV with/without HMPV).
-The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions. Rhinovirus; –Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
-Serotypes A–C circulate year-round and are the predominant cause for the common cold.
-Rhinoviruses accounted for 41.8–61.6% in immunocompetent patients as well as SOT recipients.
-Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown.
-Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs.
-Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions. Coronaviruses; –CoVs are single-stranded RNA viruses of the Coronaviridae family.
-Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
-SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%.
-Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care. Adenovirus; Epidemiology; –Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
-Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition.
-Adenoviruses show no seasonal variability and have been associated with institutional outbreaks. Clinical Manifestations;
-Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
-Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection. Prevention; –Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precautions.
-Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. Treatment;
-Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir , IVIG and adenovirusspecific cytotoxic T lymphocytes. Bocavirus; –Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
-It is rarely isolated from respiratory specimens (0.5-1 %) , and in positive specimens, there is often co-infection with other respiratory viruses.
-Similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence KI and WU Polyomaviruses; –KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
-Studies in HSCT recipients suggested a higher frequency of infection with these viruses. Summary; –Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
-With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity.
-Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise.
-Preventive measures are also lacking, as vaccination is only available against influenza at this time.
Respiratory Viruses in Solid Organ Transplant Recipients
Published: 25 October 2021 MDPI, Basel, Switzerland.
The incidence 0.76–0.91 episodes per patient-year with progression to LRTI in 6.2-40% of cases and mortality around 5.1%.
Clinical picture is almost the same for all respiratory viruses which includes cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), GIT symptoms (40%), sore throat (35%).
Diagnosis:
o PCR is the gold standard (sensitivity 70-100%) but results appear within 12-24 hours.
o Rapid antigen test: rapid test with lower sensitivity and applicable only for influenza and RSV. Influenza virus
Structure: Single-stranded RNA virus
Prevention can be done by application of droplet precautions
Presentation similar to other respiratory viruses
Vaccination: available but has lower efficacy in SOT compared to general population.it should be given at least 1 month after transplantation (3months after depleting medications like ATG and rituximab)
Prophylaxis medications: available in the form of oseltamiver (only in patients not vaccinated either on exposure or in case of outbreaks).
Treatment: available includes oseltamivir (oral 75-150 mg twice daily for 5-10 days), zanamivir (inhaled and intravenous), peramivir (intravenous).
Respiratory Syncytial Virus
Structure: RSV is a single-stranded RNA virus, 2 strains exists A and B
Presentation similar to other respiratory viruses
Prevention can be done by applying contact precautions,
Prophylactic medications: palivizumab prophylaxis during the RSV season in immunocompromised children lower than 2 years old (not indicated in adults), Nirsevimab can be given once per season
Vaccination: not available but under development and is recommended for elderly, pregnant and children.
Treatment includes ribavirin and IVIG.
Human Metapneumovirus
Structure: a single-stranded RNA virus.
Presentation similar to other respiratory viruses
Prevention can be done by applying contact precautions.
Prophylactic medications: not available.
Vaccination: not available
Treatment: ribavirin
Parainfluenza Virus:
Structure: single-stranded RNA virus
Presents similar to other respiratory viruses
Prevention can be done by applying contact precautions
Prophylactic medications: not available.
Vaccination: not available
Treatment: ribavirin
Rhinovirus
Structure: single-stranded RNA virus.
Presents: similar to other respiratory.
Prevention can be done by applying droplet precautions
Prophylactic medications: not available.
Vaccination: not available
Treatment is generally supportive
Coronaviruses
Structure: single-stranded RNA viruses
Presents similar to other respiratory viruses.
Adenovirus
Structure: double-stranded DNA virus that’s why it can be latent in the lymphoid tissue, once immunity falls it can be reactivated
Presentation: Viremia can occur while the patient is asymptomatic but it can cause conjunctivitis, hemorrhagic cystitis, hepatitis and enterocolitis.Adenoviral pneumonia associated mortality may reach 50%.
Prevention: droplet and contact precautions,
prophylactic medications: Brincidofovir is now tested for preemptive treatment of viremia.
Vaccination: still not available
Treatment: cidofovir, brincidofovir, IVIG and adenovirus specific cytotoxic T lymphocytes.
Summary: Introduction:
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered. In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year. The incidence appears to be higher among lung transplant recipients (LTRs). This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV,adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients. Influenza Virus: · Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family · Immunocompromised individuals are at increased risk for complications · Risk factors associated with severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic. · Influenza vaccination is the most important means of prevention · Three groups of drugs are approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, which has a novel mechanism of action and is a single dose oral medication. · Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and patients with symptoms > 48 h should be treated. Respiratory Syncytial Virus: · RSV is a seasonal virus with peak incidence in the winter and spring and is a significant source of transmission in LTRs. · Risk factors for lower RTI and mortality include young children, recent transplant, lung or multi-visceral transplant and recent rejection. · Clinical presentation is similar to other respiratory viruses, but RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia. · Ribavirin treatment is associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Human Metapneumovirus: · HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. · Ribavirin has in vitro activity against HMPV, but data derived from HSCT recipients do not demonstrate a mortality benefit. · Prevention is mainly based on infection control practices, including contact precautions. Parainfluenza Virus: · Single-stranded RNA virus of the Paramyxoviridae family, and is associated with a high rate of symptomatic disease and lower RTI. Treatment is based on supportive care and prevention in the hospital setting. Rhinovirus: · Single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples. · Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions. Coronaviruses: · Single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs). · Human CoVs are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. Studies on 85 immunocompromised and 1152 immunocompetent children .demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively). · In-vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen. Adenovirus: · Double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes, and can cause viremia without obvious symptoms. · Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route, and prevention is based on maintaining droplet and contact precautions. · Treatment options include reduction of immunosuppression, Cidofovir, Brincidofovir, IVIG. Bocavirus: · Single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making its contribution to RTIs unknown. · No specific treatment options only standard precaution. Conclusion:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Given the severe implications respiratory viral infections have on the immunocompromised population, development of new antivirals and vaccines is needed. Level of evidence: level V
Please summarise this article RESP VIRUSES IN SOT.
Introduction.
Incidence of resp viruses in SOT;0.76-0.91 Episode/pt yr and is higher among lung transplant recipients .In LTR, mortality of upto 5.1% has been recorded.
Diagnosis;
Viral culture, DFA staining and serology used previously.
NAT is now the gold standard with a sensitivity of 72-100%.
Influenza virus;
Single stranded RNA virus with A and B types being associated with disease in humans.
Has non specific multi systemic manifestations and complications.
Risk factors ; old age, DM, use of MMF, multiple comorbidities, ATG use, lymphopenia and decreased gamma globulin levels.
Single stranded RNA of pneumoviridae family with RSV A and B strains.
Risk factors ; young children less than 2 yrs, recent transplant, lung or multivisceral transplant and recent rejection.
No specific URTI presentation with more RTI compared to other resp viruses.
Prevention ;Contact prevention, palivizumab prophylaxis in those < 2yrs of age.
TX ;Ribavirin +/- IVIG.
Human Metapnemovirus.
Same family and features as RSV.
Found in upto 3.6-6.8% of LTRs sampled in various studies.
Ribavirin associated with less chronic lung dx in LTRs.
Prevention ;Infection control practices.
Parainfluenza virus.
Single stranded RNA of paramyxoviridae famliy with 4 serotypes with serotype 3 being the most common.
Accounts for 3.6-20.9% in LTR from isolated samples in studies.
Tx ; Supportive care and prevention. No antivirals approved.
Rhinovirus.
Single stranded RNA of picornaviridae family.
Accounts for 41.8-61..6% of +VE samples in resp specimens from immunocompromised pts.
TX ; Supportive and preventive in hospital settings.
Coronavirus.
Single stranded RNA virus of coronaviridae family.
Accounts for 12.4-17.8% of +VE samples.
Types ;SARS COV 1 and 2,MERS COV.
Prevention ; Airborne ,contact and droplet precaution.
TX; Ribavirin, Interferons and steroids.
Adenovirus.
Double stranded DNA virus of adenoviridae family with 7 subgroups (A-G).
Can cause asymptomatic viraemia.
Has multisystemic manifestations with a mortality of 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention ;Droplet and contact precaution.
Tx ;RIS, Cidofovir, Brincidofovir, IVIG and Adenovirus specific cytotoxic T lymphocyte.
Bocavirus.
Single stranded DNA of parvoviridae family.
The prevalence in SOTS RTI not clear.
KI and WU Polyomavirus.
Double stranded DNA virus of polyomaviridae family with a prevalence of 14.3% and 9.1% respectively of resp specimens sampled. The impact in SOT is unclear.
Resp Virus and rejection in LTR.
No association btn resp viral infections and acute rejection in a small analysis of 4 studies.
Ribavirin tx associated with lower rates of CLAD/BOS in LTRs with RSV,HMPV and PIV infections.
What is the level of evidence provided by this article?
Level 5 – Narration.
III. Respiratory Viruses in Solid Organ Transplant Recipients
Please summarise this article.
There are many viruses that affect repiratory system have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered, specifically as they relate to organ transplant recipients
Including: Influenza virus
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There are multiple strains, although only influenza A and B are generally associated with disease in humans,affection circulate mainly in the winter.
The influenza attack rate depend on :
age(withhigherratesinchildren)
Level of immunity (due to priorvaccination or disease)
Degree of immunosuppression and the nature of the epidemic. Prevention by vaccination of the transplant recipient and close contacts. inactivated influenza vaccines should be given to transplant recipients.
Another measure to prevent influenza infection would be using antiviral prophylaxis. Treatment There are three groups of drugs approved for the treatment of influenza:
1.M2 inhibitors (amantadine and rimantadine).
2.The neuraminidase inhibitors (NAIs).
3.Baloxavir. Respiratory syncytial virus (RSV)
Is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyxoviridae) and has two strains: RSV-A and RSV-B.it seasonal and peak in the winter and spring. Clinical Manifestations
Fever
Cough
Dyspnea
Rhinorrhea Prevention
palivizumab prophylaxis
Nirsevimab
Vaccine like ResVax, Treatment
Ribavirin was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RT.
immunoglobulin(IVIG)
Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a non significant reduction in progression to lower RTI. Human metapneumovirus (HMPV)
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
most cases identified in the winter and spring. Ribavirin has in vitro activity against HMPV.
Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients. Parainfluenza virus (PIV)
Parainfluenzavirus(PIV)is asingle-stranded RNAvirus of the Paramyxoviridae family.
There are four serotypes of PIV , serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
Utility of antivirals for PIV infection in SOT is unknown.
The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions . Rhinovirus, coronavirus (CoV)
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown.
Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions. Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples.
Treatment options used in published case reports include ribavirin,interferon and steroids.
MERS-CoV still causes sporadic infections ,mainly in the Middle East . Adenovirus
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotype.
Adenoviruses show no seasonal variability.
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate. Clinical Manifestations
Conjunctivitis
Upper RTI
Lower RTI
Hemorrhagic cystitis
Pyelonephritis
Hepatitis
Enterocolitis. Prevention BY :
Maintaining droplet and contact precautions.
Brincidofovir not FDA approved . Treatment
Reduction of immunosuppression.
Cidofovir.
Brincidofovir (investigational).
IVIG and adenovirus specific cytotoxic T lymphocytes. Bocavirus and KI
Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples. WU polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
A study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively .
However, it is still unclear whether this has any clinical significance.
All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses.
What is the level of evidence provided by this article: LEVEL V.
Respiratory Viruses in Solid Organ Transplant Recipients
Summary:
· Respiratory viral infections are common cause of morbidity and mortality posttransplant especially in lung transplantation.
· These viruses include RSV, human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV).
· It can occur at any time after transplantation, mainly in autumn and winter.
· Most of infections has common clinical manifestation as fever, rhinorrhea, cough, chest pain, myalgia and bone aches, some GI manifestations as diarrhea.
· The clinical presentation is worse among SOT with progression to LRTI and pneumonia especially lung transplantation (develop bronchiolitis obliterans).
· Risk factors associated with increased disease severity as older age, and use of MMF/ ATG induction or in ttt of AR, multiple comorbidities as DM, HTN, CVD, lymphopenia, hypogammaglobulinemia
· Diagnosis by viral culture, direct fluorescent antibody (DFA) staining and serology.
o Viral culture needs long time (10 days), special staining is not available for all viruses, so molecular isolation of viral DNA and RNA (Nucleic acid testing (NAT)) remains the golden standard for diagnosis, sensitivity 75-100 % (done from respiratory secretion =nasal and nasopharyngeal swabs).
o Rapid antigen tests, give results within minutes, but not sensitive and available only for influenza, COVID 19 and RSV.
· Influenza A, B types cause pandemic, commonly affect children, annual influenza vaccine decrease infection rate and ttt by oseltamivir is effective to fasten recovery and decrease mortality. In BMT and SOT can be complicated by bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc.
o Killed influenza vaccine (injection) (rather than intranasal live attenuated vaccine) is recommended in all SOT cases, contacts and also in health care workers to minimize risk of infection. Vaccine decrease risk of progression to pneumonia and also decrease mortality.
o Antiviral ttt= neuraminidase inhibitors (NAIs) as (oral) oseltamivir, zanamivir (inhaled and IV), peramivir (intravenous) and laninamivir
o Best response with early initialtion in 1st 48 hours from symptoms.
· RSV:
o Palivizumab prophylaxis used in children under 24 months of age who are severely immunocompromised, but no data to support its use in adult SOT recipients.
o Ttt by ribavirin + intravenous immunoglobulin (IVIG).
· Human Metapneumovirus: ribavirin may be beneficial in ttt.
· Adenovirus (feco-oral transmission and vomitus, and through organ donation)
· Ribavirin is used in (RSV, parainfluenza, human mtapneumovirus, and adenovirus).
· COVID 19=remdisvir.
· Treatment of all viral infection is mainly supportive (IV fluids, antipyretics, oxygen support as needed or even non-invasive or invasive ventilation.
· Reduction of IS therapy (especially ant proliferative MMF /AZA is warranted in severe hospitalized cases.
· Addition of antiviral therapy as mentioned above in each virus may fasten the recovery and shorten hospital stay in such compromised patients.
· IVIG may be beneficial in severe cases combined with above-mentioned therapy.
Introduction:
respiratory viruses and serotypes are affecting immunocompromised organ transplant recipients. This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses. Lung transplant data is dominating.
In organ transplant recipients, respiratory viral infections occur 0.76–0.9 times per patient-year, including silent infections. Lung transplant recipients (LTRs) have higher incidence. Respiratory viruses are present year-round, but winter and autumn are peak seasons. Clinical signs are generally similar for all respiratory viruses. Diagnosis:
The gold standard for diagnosing respiratory viruses is now nucleic acid testing (NAT), which has a sensitivity of 72–100%.
Rapid antigen tests can give results in minutes are only available for influenza and RSV, with low sensitivity.
– Influenza Virus Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. multiple strains, but only influenza A and B are generally associated with disease
in humans. seasonal, mainly in the winter. Clinical Presentation
Immunocompromised people may not have classical influenza. Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms in a prospective multicenter analysis of 477 SOT recipients and 139 HSCT recipients with confirmed influenza infection .
Complications include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis. Hospitalization, ICU admission, pneumonia, and high mortality rates.
Age, diabetes, and mycophenolate mofetil use are multivariate risk factors for severe illness. Univariate analysis indicated several comorbidities, antilymphocyte globulin use in the past six months, lymphopenia, hypogammaglobulinemia, influenza A, and nosocomial acquisition were risk factors for pneumonia or ICU admission. Prevention
droplet precautions should be considered for influenza patient.
Vaccination of transplant recipients and close contacts is the best prevention. Transplant recipients should receive only inactivated vaccinations.
Live attenuated intranasal influenza vaccines are contraindicated for SOT recipients because they may spread the virus.
the American Society of Transplantation recommends inactivated influenza vaccination one-month post-transplant.
vaccine reduces infection, complications, and mortality.
Vaccination in the same influenza season reduced the odds of pneumonia and ICU hospitalization.
no difference between high-dose intradermal and standard-dose intramuscular vaccination.
the 2019 American Society of Transplantation guidelines advocate high-dose vaccination when available, although two doses of regular vaccine can also be administered. Mycophenolate patients had a lower antibody response but no need to stop it around the vaccine.
Antiviral prophylaxis can also prevent influenza.
In 477 transplant recipients, predominantly SOT, low-dose oseltamivir pre-exposure prophylaxis prevented PCR-confirmed influenza by 80% without increasing resistance. Since these patients may already be infected post-exposure, preventive oseltamivir doses may cause antiviral resistance. Therapeutic-dose oseltamivir may be appropriate. Two healthcare-associated cases in the same ward within 72 hours indicate an outbreak, and prophylaxis should be provided for 14 days and at least 7 days following symptom onset. Treatment
Oseltamivir (oral) therapeutic dose 75 mg q12h , preventive dose (5 days) 75 mg q24h
Single dose of Baloxavir (oral) 40 mg (<80 kg), 80 mg (>80 kg)
Due to extended viral replication and subtherapeutic antiviral exposure, immunocompromised patients are at risk for antiviral resistance (as in post-exposure prophylaxis)
Treatment options include switching NAIs classes, or combination antivirals. 9.7% of baloxavir-treated patients showed resistance, which prolonged viral shedding and delayed symptom relief. Respiratory Syncytial Virus Epidemiology and Risk Factors
RSV-A and RSV-B are Pneumoviridae (previously Paramyxoviridae) single-stranded RNA viruses. peak occurrence in winter and spring.
accounted for 2.4–6.2% of respiratory viruses in upper and lower respiratory tract specimens and causes significant morbidity and mortality due to lower RTI. Young children, recent transplant, lung or multivisceral transplant, and recent rejection are risk factors for lower RTI and mortality in SOT patients. Clinical Manifestations
causes fever, cough, dyspnea, and rhinorrhea. RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses. Prevention
Contact precaution for hospitalized patients.Palivizumab prophylaxis during RSV season is not evidence-based, however, the American Academy of Pediatrics recommends it for severely immunocompromised children under 24 months old. vaccines are under development. Treatment
Ribavirin reduced upper RTI progression to lower RTI and lower RTI mortality. patients treated for lower RTI with ribavirin and an immunomodulator (IVIG, RSV-IVIG, or palivizumab) had considerably decreased mortality and nonsignificantly lower progression to lower RTI. Human Metapneumovirus
HMPV, a Pneumoviridae virus, resembles RSV. Like RSV, most occurrences occur in winter and spring.
Ribavirin (mainly oral) reduced chronic lung allograft disease. In two small studies of 15 and 19 lung transplant recipients with HMPV infection, ribavirin with or without steroids improved graft function.
Ribavirin may benefit lung transplants, however, controlled research are limited and current treatment is mostly supportive.
Infection control, including contact precautions in hospitalized patients, is the principal prevention method. Parainfluenza Virus
Single-stranded RNA Paramyxoviridae virus.
Serotype 3 is the most common, has no seasonality.
21% of 24 PIV-infected LTRs, primarily PIV3, had respiratory failure.
PIV antiviral therapy in HSCT recipients had no effect.
PIV antiviral therapy in HSCT recipients had no effect. supportive care is the main treatment. Rhinovirus
single-stranded RNA viruses of the Picornaviridae family of Enteroviruses. causes cold symptoms, but LTRs have had lower RTI. Droplet precautions and supportive treatment are hospital-based. Coronaviruses
single-stranded RNA. cause upper RTI, while SARS-CoV1, MERS-CoV, and SARS-CoV-2 induce severe respiratory illness outbreaks. This evaluation excludes SARS-CoV-2 illnesses.
Symptoms resemble other respiratory infections. immunocompromised population had a greater rate of severe lower RTI.
SARS-CoV1 appeared in southern China in late 2002 [86] and caused a significant incidence of lower RTI and 20% mortality. Ribavirin and interferon were active against the virus in vitro, but no clinical effect was reported. Interferon, high-dose steroids, and supportive care improved outcomes in case series and a short RCT. The first SARS-CoV1-infected transplant recipient was a liver transplant patient who infected multiple healthcare staff. He died after ribavirin treatment. SARS-CoV1 was eliminated through strict infection control.
MERS-CoV, first discovered in Saudi Arabia, causes severe respiratory disease and 50% death. Camel zoonosis continues transmission. One kidney transplant recipient recovered. Ribavirin, interferon, and steroids are reported treatments. MERS-CoV still produces sporadic Middle Eastern attacks. Adenovirus
can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis, and enterocolitis, and has a predilection for the
transplanted allograft. Adenovirus may cause pyelonephritis in kidney transplant recipients with unexplained fever and rising creatinine. Adenoviral pneumonia can kill 50% and disseminated infection 80%. Lung transplant recipients can develop bronchiolitis obliterans. prevention in the hospital setting is based on droplet and contact precautions
Supportive care, immunosuppression reduction, cidofovir, brincidofovir (investigational), IVIG, and adenovirus-specific cytotoxic T cells are therapy options. Using cidofovir with immunosuppression improved outcomes.
IVIG with antivirals, use of virus-specific cytotoxic T cell also is an option. Summary
For SOT recipients, respiratory viruses are a significant cause of morbidity and mortality. They are now more frequent and in more different ways detected due to the development of molecular diagnostic techniques. Only influenza and, to a lesser extent, RSV infection have effective treatments; however, emerging medication classes offer some promise.
currently only an influenza vaccine is available, and preventive measures are still inadequate. demand for novel antivirals and vaccinations.
Respiratory Viruses in Solid Organ Transplant Recipients
1. Respiratory viral infections can appear at any time post-transplant and are usually acquired in the community.
2. The incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year. With higher incidence among lung transplant recipients (LTRs).
3. Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs.
4. Viral pneumonia in solid organ transplant (SOT) recipients is associated with an attributable mortality of 5.1%.
5. Diagnosis of respiratory viral infection can be as follows:
a) Historically:
· Viral culture:has a long turnaround time of 10 days for standard viral culture and two days for shell vial culture.
· Direct fluorescent antibody (DFA) staining:available for only a limited number of respiratory viruses.
· Serology:useful only for epidemiological studies.
b) Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
c) multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h.
d) Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity.
Influenza Virus
1. Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family, seasonal virus with peak incidence in the winter.
2. Influenza A and B are generally associated with disease in humans.
3. In SOT recipients, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
4. Immunocompromised individuals are at increased risk for complications: viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
5. Risk factors associated with severe disease include older age, diabetes and use of mycophenolate mofetil.
6. Prevention:
· Droplet precautions.
· Vaccination of the transplant recipient and close contacts is the most important mean of prevention. Only inactivated influenza vaccines should be given to transplant recipients.
· Using antiviral prophylaxis; low-dose oseltamivir(75 mg OD).
7. Treatment of influenza:
a) M2 inhibitors (amantadine and rimantadine) are not used today since they are inherently inactive against influenza B and circulating influenza A strains carry a high rate of resistance.
b) The neuraminidase inhibitors (NAIs) include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir.
c) Selective inhibitor of influenza cap-dependent endonuclease: Baloxavir is a single dose oral medication. Baloxavir may also be more effective against influenza B strains than NAIs.
d) Favipiravir may be promising as it seems to have low resistance rates and is synergistic when combined with oseltamivir.
e) Treatment challenges: the high mutation rates (H275Y in A/H1N1&R292K in A/H3N2)
Respiratory Syncytial Virus
1. RSV is a single-stranded RNA virus of the Pneumoviridae family, seasonal virus with peak incidence in the winter and spring.
2. Commonly presents with fever, cough, dyspnea and rhinorrhea. RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
3. Prevention:
· Contact precautions.
· Palivizumab for age < 2 years.
4. Treatment:
· Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
· Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI.
Human Metapneumovirus
5. HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. It is aseasonal virus with peak incidence in the winter and spring.
6. HMPV was identified in 3.6–6.8% of positive respiratory samples in LTRs.
7. Clinically present with RTI and lower RTI are encountered.
8. Treatment of HMPV:
· data derived from HSCT recipients do not demonstrate a mortality benefit with antivirals or immunomodulators.
· Two small series of 15 and 19 lung transplant recipients with HMPV infection demonstrated favorable outcomes on graft function among patients treated with ribavirin with or without steroids.
9. Prevention of HMPV:
· Implementation of contact precautions in hospitalized patients. Parainfluenza Virus
1. Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
2. There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
3. PIV accounts for 3.6–20.9% of the respiratory viruses isolated in LTRs.
4. Clinically presents with a high rate of symptomatic disease, lower RTI and 21% experienced respiratory failure.
5. Treatment: the mainstay of treatment for PIV infection is supportive care and prevention.
6. Prevention is based on adherence to contact precautions. Rhinovirus
1. Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family(part of the Enterovirus genus).
2. Serotypes A–C circulate year-round and are the predominant cause for the common cold.
3. Rhinoviruses accounted for 41.8–61.6% of the positive samples in LTRs.
4. Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown.
5. Clinically presents with symptoms of the common cold, although there have been case reports of lower RTI in LTRs.
6. Treatment is based on supportive measures and prevention.
7. Prevention in the hospital setting mandates droplet precaution. Coronaviruses
1. CoVs are single-stranded RNA viruses of the Coronaviridae family.
2. CoVs cause upper RTI, whereas:
· SARS CoV1: severe acute respiratory syndrome (SARS), infection emerged in southern China in late 2002.
· MERS-CoV: Middle Eastern respiratory syndrome (MERS), was first identified in Saudi Arabia.
· SARS-CoV-2: are associated with outbreaks of severe respiratory disease.
3. Human coronaviruses are accounting for 12.4–17.8% of the positive samples among LTRs.
4. Symptoms are generally similar to other respiratory viruses. The immunocompromised patients had a significantly higher rate of severe lower RTI.
5. Treatment :
· In-vitro; ribavirin and interferon are active against the virus, although no clear clinical benefit of ribavirin was seen.
· Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care.
6. Prevention: due to strict infection control practices, the outbreak was controlled and there were no more cases of SARS-CoV1. Adenovirus
1. Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G).
2. Transmission: Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
3. Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition.
4. Adenoviruses show no seasonal variability and have been associated with institutional outbreaks.
5. Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
6. Clinical Manifestations:
· Viremia without obvious symptoms.
· Can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis.
· It has a predilection for the transplanted allograft. In a KTRs with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis. Development of bronchiolitis obliterans has been described in LTRs.
7. Prevention:
· prevention in the hospital setting is based on maintaining droplet and contact precautions.
· Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. However, it is not FDA approved.
8. Treatment:
· Supportive care and reduction of immunosuppression.
· Other options: cidofovir, brincidofovir (investigational), IVIG and adenovirus- specific cytotoxic T lymphocytes (investigational).
· There are promising results in liver transplant recipients with the use of brincidofovir in combination with the reduction of immunosuppression.
· IVIG, usually in addition to an antiviral drug.
· Data regarding virus-specific cytotoxic T lymphocytes for adenovirus infections are scarce. Bocavirus
1. Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
2. It is rarely isolated from respiratory specimens. Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
3. Similar to parvovirus B19, bocaviruses are known for their viral persistence.
4. The viral persistence combined with the high co-infection rate, makes their true contribution to RTIs unknown. KI and WU Polyomaviruses
1. KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri- dae family that were discovered in 2007.
2. KI and WU polyomaviruses were identified in 14.3% and 9.1% of respiratory specimens, respectively.
3. It is still unclear whether this has any clinical significance.
Respiratory Viruses and Rejection in Lung Transplantation
1. Respiratory viral infection is associated with significant higher rates of acute rejection (16%) and biopsy-proven bronchiolitis obliterans (10% ) among LTRs with respiratory infections.
· Associations have been reported for specific respiratory viruses; influenza, HMPV and RSV, PIVand adenovirus.
· Treatment with ribavirin was associated with lower rates of CLAD/BOS(bronchiolitis obliterans syndrome).
· in LTRs with RSV, HMPV and PIV infections.
2. It seems, however, that there is no definitive association between rhinoviruses and CoVs and rejection or chronic lung allograft disease(CLAD).
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
Respiratory viruses have a significant impact on the health of immunocompromised organ transplant recipients, with the incidence of respiratory viral infections ranging from 0.76-0.91 episodes per patient-year. This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV,adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
Diagnosis:
Nucleic acid testing (NAT) is now the gold standard for diagnosing respiratory viral infections and has a sensitivity of 72-100%. Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity.
Influenza Virus:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. It is seasonal, circulating mainly in the winter and causing a significant proportion of RTIs. Immunocompromised individuals are at increased risk for complications, such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc. Risk factors associated with severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic. Prevention : Influenza vaccination is the most important means of prevention for transplant recipients and close contacts, and has been shown to decrease infection rates, complications and mortality. Antiviral prophylaxis is recommended to prevent influenza infection in transplant recipients, but there is concern that some may develop antiviral resistance. Treatment: Three groups of drugs are approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, which has a novel mechanism of action and is a single dose oral medication. Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and patients with symptoms > 48 h should be treated. Treatment for influenza should be started empirically as soon as possible, usually before test results are available. Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, and M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain.
Respiratory Syncytial Virus:
RSV is a seasonal virus with peak incidence in the winter and spring and is a significant source of transmission in LTRs. Risk factors for lower RTI and mortality include young children, recent transplant, lung or multivisceral transplant and recent rejection. Clinical presentation is similar to other respiratory viruses, but RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia. Palivizumab prophylaxis is not given to adult SOT recipients, and monoclonal antibody development is focused on developing antibodies with extended half-lives. Ribavirin treatment is associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Presatovir is a new antiviral with specific anti-RSV activity, but two phase 2b RCTs failed to show significant improvements, and 20% of patients developed resistance.
Human Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Studies have identified HMPV in 3.6-6.8% of positive respiratory samples, and 8/18 (44%) had a lower RTI. Ribavirin has in vitro activity against HMPV, but data derived from HSCT recipients do not demonstrate a mortality benefit. Prevention is mainly based on infection control practices, including contact precautions in hospitalized patients.
Parainfluenza Virus:
PIV is a single-stranded RNA virus of the Paramyxoviridae family, and is associated with a high rate of symptomatic disease and lower RTI. Treatment is based on supportive care and prevention in the hospital setting.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviruses are single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs). Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, while other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2) are associated with outbreaks of severe respiratory disease. Human CoVs are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. Studies on 85 immunocompromised and 1152 immunocompetent children .demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively). In-vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen.
Adenovirus:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes, and can cause viremia without obvious symptoms. Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route, and prevention is based on maintaining droplet and contact precautions. Treatment options include reduction of immunosuppression, brincidofovir, IVIG and adenovirusspecific cytotoxic T lymphocytes. Bocavirus:
Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making its contribution to RTIs unknown.
KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family, with higher frequency in HSCT recipients.
Respiratory Viruses and Rejection in Lung Transplantation:
LTRs are at increased risk for RTIs due to continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression. Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections.
Summary: Development of new antivirals and vaccines is needed to reduce respiratory viral infections in the immunocompromised population.
What is the level of evidence provided by this article? level V
Respiratory Viruses in Solid Organ Transplant Recipients
Solid organ transplantation is often lifesaving, but does carry an increased risk of infection. Respiratory viral infections are one of the most prevalent infections, and are a cause of significant morbidity and mortality, especially among lung transplant recipients.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year
All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses
Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40%
Diagnosis
Viral culture has a long turnaround time of 10 days for standard viral culture and two days for shell vial culture
DFA staining is available for only a limited number of respiratory viruses and requires expertise in interpreting the result
Serology have been useful only for epidemiological studies and not for diagnosing acute infection
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%
Rapid antigen tests- allows results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family
Immunocompromised individuals are also at increased risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis
Risk factors associated with severe disease in multivariate analysis include older age, diabetes and use of mycophenolate mofetil
Patients diagnosed with influenza should be placed under droplet precautions
There is a theoretical risk of dissemination of virus contained in the live attenuated intranasal influenza vaccine, which is therefore contraindicated for SOT recipients
Pre-exposure prophylaxis using low-dose oseltamivir was evaluated has demonstrated 80% efficacy against PCR-confirmed cases
The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir
Respiratory Syncytial Virus
It is a seasonal virus with peak incidence in the winter and spring
It presents with fever, cough, dyspnea and rhinorrhea
Hospitalized patients should be placed under contact precautions
Treatment- Ribavarine. IVIG
Human Metapneumovirus
Its seasonality also follows that of RSV, with most cases identified in the winter and spring
Ribavirin has in vitro activity against HMPV
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI
The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions
Rhinovirus
Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions
Coronaviruses
Symptoms are generally similar to other respiratory viruses
Treatment options used in published case reports include ribavirin, interferon and steroids
Adenovirus
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes
Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses
KI and WU Polyomaviruses
Double-stranded DNA viruses of the Polyomaviridae family
unclear whether this has any clinical significance
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity.
Effective therapies are available only for influenza, and also to some extent for RSV infection
Introduction:
Immune compromised organ transplant recipients are at a significant risk of contracting numerous respiratory viruses that can affect their health. Most respiratory viruses generally cause similar symptoms, and their clinical presentation does not help to differentiate between them. This review assesses several respiratory viruses in relation to organ transplant recipients.
Diagnosis:
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has high sensitivity. Rapid antigen tests are available for influenza and RSV, but have low sensitivity.
Influenza Virus
Influenza virus is a RNA virus, single stranded from the Orthomyxoviridae family. They are seasonal and see more commonly during winter. The incidence rate depends on age, likelihood of exposure, level of immunity, degree of immune suppression and nature of the epidemic.
The most common symptom seen are cough, fever, rhinorrhea, myalgia, gastrointestinal symptoms, sore throat, and headache in transplant recipients. Transplant recipients are at an increased risk of complications, such as viral pneumonia, bacterial superinfection, fungal infections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Risk factors associated with severe disease include older age, diabetes and use of mycophenolate mofetil. The most important form of prevention in transplant patients is vaccination. There are three groups of drugs that can be used for the treatment of influenza. These include M2 inhibitors, neuromunidase inhibitors and baloxavir. It is recommended that all symptomatic transplant recipient should be treated irrespective of symptom duration.
Respiratory Syncytial Virus (RSV)
RSV is a single stranded RNA virus. It belongs to the pneumoviridae family. It’s OK it’s mainly among young children and during winter. Children are a significant source of transmission. The virus has been identified in upper and lower respiratory tract specimen. It is a cause of significant morbidity and mortality. Risk factors include young children, recent transplant and recent rejection of transplant. Common symptoms include fever, cough, dyspnea and rhinorrhea. Lower respiratory tract infection symptoms include bronchitis, bronchiolitis and pneumonia. Hospitalized patients should be placed under contacts precautions. Palivizumab can be used as prophylaxis during the RSV season in children who are immune compromised. Ribavirin can be used for treatment. Unfortunately, data for transplant recipients is scarce.
Human Metapneumovirus (HMPV)
It is a single stranded RNA virus. It belongs to the pneumoviridae family. It resembles RSV. Most cases are identified in winter and spring. Ribavirin also has activity against HMPV. Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients.
Parainfluenza Virus (PIV)
It belongs to the paramyxoviridae family. It is a single stranded RNA virus. No season has been associated with its outbreaks. It may also cause lower respiratory tract disease and respiratory failure. The mainstay of treatment for PIV infections is supportive care and prevention in hospital settings based on adherence to contact precautions.
Rhinovirus
Rhinoviruses are single stranded RNA viruses. They belong to the picornaviridae family. They are the predominant cause of the common cold. They are usually found as part of coinfection with other viruses and bacteria symptoms are usually those of a common cold, although some cases of lower respiratory tract infections have been noted in transplant recipients. I study suggested a correlation between higher viral load and more symptoms. Treatment is based on supportive care and prevention in the hospital setting (droplet precautions).
Coronaviruses (CoVs)
They are single stranded RNA viruses of the Coronaviridae family. They may because upper respiratory tract infection, however some forms are associated with outbreaks of severe respiratory disease. The SARS-CoV1 infection emerged in late 2002 and was associated with high rate of lower respiratory tract infection and high mortality. MERS-CoV infection was first identified in Saudi Arabia, and was associated with severe respiratory illness and high mortality rates. Two cases in kidney transplant recipient have been described and only one of the two patients survived. Treatment options include ribavirin, interferon and steroids.
Adenovirus
It is a double stranded DNA virus of the Adenoviridae family. It’s establishes latency in lymphoid tissue. Therefore, infection can represent reactivation or de novo acquisition. They are known to cause viremia without obvious symptoms. Rates of infection differ with age and the transplanted organ. Higher rates are seen among children. They are also seen in intestinal transplantation, possibly due to the high amount of lymphoid tissue in the allograft and greater immune suppression. Adenovirus can manifest with conjunctivitis, upper and lower respiratory tract infections, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis. It has a predilection for the transplanted organ. Adenovirus should be considered as a cause of pyelonephritis when a kidney transplant recipient presents with fever of unknown origin and arising creatinine.
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal-oral route. Prevention is based on maintaining droplet and contact precautions in hospitals. Treatment involves supportive care, reduction in immune suppression medications, cidofovir, brincidofovir, IVIG and adenovirus-specific cytotoxic T lymphocytes.
Bocavirus
It is a single stranded DNA virus. It belongs to the parvoviridae family. They are known for their viral persistence. They usually occur in coinfection with other respiratory viruses. Since they have a high co-infection rate, it makes their true contribution to respiratory tract infections unknown.
KI and WU polyomaviruses
They are double stranded DNA viruses of the Polyomaviridae family. They have been detected in transplant recipients, unfortunately it is unclear whether they present any clinical significance.
Respiratory viruses and rejection in lung transplantation
Lung transplant recipients are at an increased risk for respiratory tract infections, especially lower respiratory tract infections. This may be related to continuous contact of the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and higher levels of immune suppression compared to other organ transplants. Studies have been inconclusive regarding respiratory viruses and incidence of rejection of lung transplants.
Summary
Respiratory viruses are a significant cause of mobility and mortality among solid organ transplant recipients. Effective therapies are only available for some of the respiratory viruses such as influenza. Preventative measures are also lacking as vaccination is only available against influenza currently. Development of new antivirals in vaccines is needed, especially given the severe implications that respiratory viral infections have on immune compromised patients.
Level Of Evidence:
It is a narrative review. The LOE is level V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
Introduction
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered.
All organ types will be discussed, the vast majority of data comes from studies of lung transplant recipients.
The incidence of respiratory viral infection in transplant ranges between 0.76–0.91 episodes per patient-year part of the studies included asymptomatic infections.
The incidence appears to be higher among lung transplant recipients (LTRs), but is not affected by time from transplant.
Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses,
Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on.
98 LTRs found an attributable mortality of 5.1% [2] Diagnosis
Viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infection
DFA staining is available for only a limited number of respiratory viruses and requires expertise in interpreting the results. Nucleic acid testing (NAT) for respiratory viruses is the gold standard for diagnosis and has a sensitivity of 72–100%.
In a study of 93 LTRs, 5/93 had respiratory viruses identified in bronchoalveolar lavage using viral culture and DFA staining, whereas 48/93 had respiratory viruses identified by NAT on the same samples.
Using multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h.
Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity. Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
There are multiple strains, only influenza A and B are generally associated with disease in humans.
Circulate mainly in the winter, and cause a significant proportion of RTIs during that time.
The influenza attack rate depends on several factors, including age, likelihood of exposure, level of immunity, degree of immunosuppression and the nature of the epidemic .
A study evaluating incidence of influenza infections in.
3569 SOT recipients between the years 1990 and 2000 calculated an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively. Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness.
In a prospective multicenter study including 477 SOT recipients and 139 patients after hematopoetic stem cell transplantation with confirmed influenza infection, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
Immunocompromised individuals are at increased risk for complications
These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc.
Compiling data from four studies with a total of 947 SOT recipients with influenza, hospitalization, intensive care unit admission, pneumonia and mortality rates were 57–71%, 11–16%, 22–35% and 4–7.8%, respectively.
Univariate analysis identified multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission. Prevention
Patients diagnosed with influenza should be placed under droplet precautions [18 ], as outbreaks in the hospital setting have been described.
Another small study conducted during an influenza outbreak in a kidney transplant unit revealed that the unvaccinated population had significantly high rates of influenza infection.
Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs, there is no recommendation to withhold treatment around vaccination
Another measure to prevent influenza infection would be using antiviral prophylaxis.
Post-exposure prophylaxis has been evaluated in the non-immunocompromised population and can be given in cases of exposure to influenza among transplant recipients who have contraindications to receiving the influenza vaccine or who are not expected to mount an immune response.
Similar management can be pursued for an outbreak on a transplant ward Treatment
There are three groups of drugs approved for the treatment of influenza.
Favipiravir may be promising as it seems to have low resistance rates and is synergistic when combined with oseltamivir
It is currently licensed only in Japan for use in influenza unresponsive or insufficiently responsive to current antivirals.
Several monoclonal antibodies targeting various hemagglutinins of influenza virus have been developed.
These were tested in phase two studies as monotherapy or in combination with antiviral drugs, showing mixed results.
NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals.
Resistance has been documented in 9.7% of patients treated with baloxavir; this was associated with prolonged shedding of the virus and longer time to alleviation of symptoms. Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family and has two strains: RSV-A and RSV-B.
It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children, who are a significant source of transmission.
In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens and is a cause of significant morbidity and mortality due to the development of lower RTIs.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children, recent transplant, lung or multivisceral transplant and recent rejection. Clinical Manifestations
The clinical presentation of RSV is similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea.
Compared to other respiratory viruses, RSV more frequently causes lower RTI.including bronchitis, bronchiolitis and pneumonia.
This is especially true for LTRs, where lower RTI rates can be as high as Prevention
Hospitalized patients should be placed under contact precautions as RSV droplets form large particles and are transmitted by contact.
The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based.
Since prophylaxis is given on a monthly basis during the RSV season and dosing is weight-based, costs of treatment in adults are extremely high.
Due to its extended half-life, it can be given once per season and has shown favorable results in a recently published randomized trial conducted on preterm infants.
There are currently multiple vaccines under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based.
These vaccines are recommended for elderly persons, pregnant women or the pediatric population.
The most advanced is ResVax, which is a nanoparticlebased vaccine; a recent phase three trial of this vaccine in pregnant women did not reduce RSV infections in infants after birth. Treatment
A survey conducted in 11 transplant centers in the United States revealed differences in treatment regimens in lung transplant compared to other organs.
Among 11 non-lung transplant centers 7/11 treat lower RTI with ribavirin and only one center adds IVIG , whereas in upper RTI no center gives treatment.
Data on treatment for RSV infection in SOT recipients are limited to case series in lung transplants.
In a combined analysis of trials done in HSCT, ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
A study on 10 lung transplant recipients with lower RTI due to RSV showed good outcomes with mainly supportive care.
All trials failed to show significant improvements in clinical and virologic outcomes in the presatovir group, except for a possible decrease in progression to lower RTI in lymphopenic HSCT recipients.
These drugs can be divided into fusion inhibitors (RV521, AK0529/ziresovir) and replication inhibitors (PC786, EDP-938) Human Metapneumovirus
Studies conducted on LTRs identified HMPV in 3.6–6.8% of positive respiratory samples.
In a study that included 139 LTRs with infections due to either RSV. HMPV or PIV, ribavirin was associated with significantly less chronic lung allograft disease (CLAD, OR 0.24, 95% CI 0.1–0.59).
Two other small series of 15 and 19 lung transplant recipients with HMPV infection demonstrated favorable outcomes on graft function among patients treated with ribavirin with or without steroids.
These data may suggest some benefit from ribavirin in lung transplants, controlled studies are lacking, and current treatment is primarily based on supportive care.
Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients. Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower.
A systematic review on antiviral treatment for PIV infection in HSCT recipients showed no benefit in this population.
Studies in SOT recipients are limited to small case series describing the use of ribavirin with and without immunomodulators in LTRs with mixed viral infection ( PIV and RSV with/without HMPV) These studies showed mixed responses to the treatments used.
DAS 181 was evaluated in an RCT among immunocompromised patients with lower RTI secondary to PIV infection.
The mainstay of treatment for PIVinfection is supportive care and prevention in the hospital setting is based on adherence to contact precautions. Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
Serotypes A–C circulate year-round and are the predominant cause for the common cold.
As such, these viruses are isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients.
In studies among LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6% of the positive samples.
One study compared infection rates in 36 LTRs with a cohort of 235 immunocompromised and immunocompetent patients, and showed a higher infection rate among LTRs (41.7% vs. 14.5%, p < 0.001).
Symptoms of rhinovirus infection are usually those of the common cold, there have been case reports of lower RTI in LTRs. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions. Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human.
SARS-CoV1 infection emerged in southern China in late 2002, and was associated with high rates of lower RTI and mortality as high as 20% .
SARS-CoV1 infection was described in two transplant recipients; the first was a liver transplant patient that was exposed in the healthcare setting and infected several healthcare workers.
He was treated with ribavirin, but eventually succumbed.
MERS-CoV infection was first identified in Saudi Arabia, and is associated with severe respiratory illness and mortality rates as high as 50%.
Human to human transmission is associated with healthcare settings, and in one of the cohorts studied, 25% of the people infected were healthcare workers.
MERS-CoV still causes sporadic infections, mainly in the Middle East. Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
Adenoviruses establish latency in lymphoid tissue; infection can represent reactivation or de novo community.
Adenoviruses are known to cause viremia without obvious symptoms; differentiating infection and disease may be more appropriate.
In a study of 263 SOT recipients, adenovirus in blood was checked at regular intervals during the first year posttransplant.
As much as 7.2% (19/263) developed viremia; only 4/19 (21%) were symptomatic.
Rates of adenovirus infection differ with age and the transplanted organ.
Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression. Clinical Manifestations
Adenovirus infection can manifest with conjunctivitis, upper RTI lower RTI. hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis [105 ].
Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
In most cases there are no long term sequelae, development of bronchiolitis obliterans has been described in lung transplant recipients. Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
Prevention in the hospital setting is based on maintaining droplet and contact precautions.
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir.
It was tested in a phase two RST for preemptive treatment of adenovirus viremia in HSCT recipients and showed benefits. it is not FDA approved and the appropriate dose for treatment of adenovirus is not established Treatment
Data on treatment modalities for adenovirus disease are derived from case reports and small case series.
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir, IVIG and adenovirusspecific cytotoxic T lymphocytes.
Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression.
Contemporary data, the largest series being 13 liver transplant recipients, show promising results with the use of brincidofovir as well as with its use in combination with the reduction of immunosuppression.
Some may use IVIG , usually in addition to an antiviral drug.
Using virus-specific cytotoxic T lymphocytes for the treatment of cytomegalovirusand Epstein–Barr virus infections in HSCT recipients shows great promise.
Data regarding adenovirus infections are scarce in HSCT, and still lacking in SOT 10. Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses.
Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
B19, bocaviruses are known for their viral persistence.
This, combined with the high co-infection rate, makes their true contribution to RTIs unknown 11. KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
Studies in HSCT recipients suggested a higher frequency of infection with these viruses.
A study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively.
It is still unclear whether this has any clinical significance 12. Respiratory Viruses and Rejection in Lung Transplantation
LTRs are at increased risk for RTIs in general and lower RTIs.
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data.
A systematic review and meta-analysis published in 2011 demonstrated no association between respiratory viral infection and acute rejection, only four studies were included in the analysis
It showed a non-significant trend towards association with.
It seems, that there is no definitive association between rhinoviruses and CoVs and rejection or CLAD.
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV , HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD . Findings
A large prospective multicenter study on 616 transplant recipients, mostly SOT, showed that vaccination in the same influenza season was associated with a reduction in odds for pneumonia (odds ratio (OR) 0.51, 95% CI 0.21–0.55).
Another small study conducted during an influenza outbreak in a kidney transplant unit revealed that the unvaccinated population had significantly high rates of influenza infection.
In a study that included 139 LTRs with infections due to either RSV , HMPV or PIV,ribavirin was associated with significantly less chronic lung allograft disease (CLAD, OR 0.24, 95% CI 0.1–0.59).
In LTRs with RSV, HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD . 13. Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity.
Effective therapies are available only for influenza, and to some extent for RSV infection; new drug classes show some promise.
Preventive measures are lacking, as vaccination is only available against influenza at this time.
Given the severe implications respiratory viral infection have on the immunocompromised population, development of new antivirals and vaccines is needed Level of evidence is 5
Respiratory Viruses in Solid Organ Transplant Recipients. Introduction.
Organ transplant recipient are higher risk for respiratory viral infection due to their immunocompromised status specially post lung transplant with the incidence ranges between 0.76–0.91 episodes per patient-year, one study on 98 LTRs found an attributable mortality of 5.1% and usually sharing same clinical manifestation.
Diagnosis is mainly depends on Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%, for short turnaround time diagnosis rapid antigen tests, allowing results within minutes, and suffer from low sensitivity. 1-Influenza Virus. Epidemiology and Risk Factors:
A study evaluating incidence of influenza infections in 3569 SOT recipients between the years 1990 and 2000 calculated an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively and 39% of all respiratory infections were caused by influenza and 32% of all viral infections were observed among LTRs. Clinical presentation:
Usually different in immunocompromised patient, one study shown that the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
Risk factors for severe disease include: recent use of high-dose steroids, recent rejection, lymphocyte depletion, and lung transplantation. Treatment:
Annual influenza vaccination is the most effective strategy to prevent infection and is currently recommended for all patients, their families, and healthcare personnel, three drugs currently approved by the FDA for use in the USA and approved by the CDC for the treatment of influenza infections include: oseltamivir, zanamivir, and peramivir, which have activity against influenza A and B virus, as opposed to the M2 protein inhibitors which are only effective against influenza A and this antivirals must be initiated within 48 h of symptom onset for maximum benefit, but should be initiated in this population regardless of the duration of symptoms also early treatment with oseltamivir may prevent progression to pneumonia in about 70% of the patients and reduce mortality to <10%. 2-Respiratory Syncytial Virus Epidemiology, clinical picture and Risk Factors:
Has two strains: RSV-A and RSV-B, it is a seasonal virus with peak incidence in the winter and spring, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens in LTR. Has many risk factors such as young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection and presented as all respiratory viruses but Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia. Prevention:
Isolation of infected patient is a great step in preventing the transmission, palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised which is given monthly and still need more studies also Nirsevimab is a novel monoclonal that shown strong preventive effect in RCTs. Treatment.
Early diagnosis of infection and timely institution of antiviral therapy is critical to prevent progression toLRTI and to achieve a favourable outcome, aerosolized ribavirin is logistically difficult to administer and has teratogenic potential, some studies shown that systemic oral and intravenous ribavirin has been effective, but with no available evidence to strongly recommend a specific route of administration and several reports describe combining ribavirin with intravenous immunoglobulin (IVIG) or RSV-specificimmune globulin. 3-Human Metapneumovirus.
Most cases identified in the winter and spring, LTRs identified HMPV in 3.6–6.8%, prevention is better than cure as still no specific therapy identified for this viral infection and mainly depends on supportive treatment and Ribavirin that also not based on robust evident. 4-Parainfluenza Virus.
PIV is a single-stranded RNA virus of the Paramyxoviridae family, there are four serotypes of PIV (1–4), LTRs, where it accounts for 3.6–20.9% of the respiratory viruses isolated, the mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions. 5-Rhinovirus.
Most infections are limited to the upper respiratory tract, but involvement of the lower respiratory tract is observed among patients with profound immunosuppression, in a prospective study performed among LTRs, 14.7% of patients had rhinovirus identified in respiratory specimens. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions. 6-Adenovirus.
The American Society of Transplantation defines ADV infections based on symptoms, detection of virus by PCR or culture, and the presence of tissue invasive disease, the incidence of ADV infections ranges from 2.5-14% among autologous HSCT recipients and from 5-47% among allogeneic HSCT recipients. The incidence is highest during the first 100 days following transplantation.
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft, mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
General precautions to prevent Adenovirus infection are required and regarding the treatment supportive care and treatment options include reduction of immunosuppression, Cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational) might has a role. Respiratory Viruses and Rejection in Lung Transplantation.
Lung transplant recipients are considered higher risk for these viruses because the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and a relatively greater immunosuppression compared to other organ transplants, some studies demonstrated that there are significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections, and other shown that treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections. Conclusion:
Respiratory viruses are significant factors for morbidity and mortality in overall population and particularly for SOT recipients whose are immunocompromised specially LTR and HSCT, need more studies to find vaccines for them and mainly their treatment depends on supportive therapy. Level of evidence: V (Narrative article).
Summary Introduction
Incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-years.
Incidence is higher among lung transplant recipients.
They cause similar symptoms and the clinical presentation does not differentiate between the viruses.
Rate of progression to lower respiratory tract infection ranges between 6.2–40% in LTRs.
Diagnosis
Viral culture has a long turnaround time of 10 days for standard viral culture and two days for shell vial culture.
Direct fluorescent antibody (DFA) staining is available for only a limited number of respiratory viruses and requires expertise in interpreting the results.
Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72–100%.
Influenza virus
Single-stranded RNA virus of the Orthomyxoviridae family.
There are multiple strains, although only influenza A and B are generally associated with disease in humans.
They are seasonal, circulate mainly in the winter.
Immunocompromised individuals are also at increased risk for complications- viral pneumonia, bacterial superinfection, fungal co-infections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Risk factors associated with severe disease include older age, diabetes and use of MMF, multiple co-morbidities, use of anti-lymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia.
Most important means for prevention is vaccination of the transplant recipient and close contacts.
Only inactivated influenza vaccines should be given, live attenuated intranasal vaccine is contraindicated in SOT.
American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant, acknowledging the fact that vaccine immunogenicity up to six months post-transplant can be poor.
Immunogenicity in SOT is variable, but generally lower compared to a non-immunocompromised population.
Still, influenza vaccine has been shown to decrease influenza infection rates, complications and mortality in the SOT population.
American Society of Transplantation 2019 guidelines recommend that high-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used.
Infectious Diseases Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak to patients in the affected wards.
An outbreak is defined as two healthcare-associated cases diagnosed within 72 h in the same ward, and prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case.
The neuraminidase inhibitors (NAIs) are the group most commonly used for treatment- oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
All symptomatic patients should be treated, irrespective of symptom duration.
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes sub-therapeutic (as in post-exposure prophylaxis).
Respiratory Syncytial Virus
Single-stranded RNA virus of the Pneumoviridae family.
Two strains: RSV-A and RSV-B.
Seasonal virus with peak incidence in the winter and spring.
Young children are a significant source of transmission.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multi-visceral transplant and recent rejection.
Clinical presentation is similar to other respiratory viruses.
Frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
Multiple vaccines under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based.
Data on treatment for RSV infection in SOT recipients are limited to case series in lung transplants.
Human Metapneumovirus
Single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
Most cases identified in the winter and spring.
Current treatment is primarily based on supportive care.
Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients .
Parainfluenza Virus
Single-stranded RNA virus of the Paramyxoviridae family.
Four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
Utility of antivirals in SOT is unknown.
Rhinovirus
Single-stranded RNA viruses that are members of the Picornaviridae family.
Serotypes A–C circulate year-round and are the predominant cause for the common cold.
Coronaviruses
Second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8%.
Symptoms are generally similar to other respiratory viruses.
Adenovirus
Double-stranded DNA virus of the Adenoviridae family.
Latency is in lymphoid tissue thus, infection can represent reactivation or de novo community acquisition.
No seasonal variability and have been associated with institutional outbreaks.
May cause viremia without obvious symptoms; therefore, differentiating infection and disease is important.
Manifestation include conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
Kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis.
Mortality is high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Transmission by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
Prevention is by maintaining droplet and contact precautions.
Treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus- specific cytotoxic T lymphocytes (investigational).
Respiratory Viruses and Rejection in Lung Transplantation.
Associations have also been reported for specific respiratory viruses, including influenza, HMPV and RSV, PIV and adenovirus. However there is no definitive association between rhinoviruses and CoVs and rejection.
Respiratory Viruses in Solid Organ Transplant Recipients
Please summarise this article.
Introduction Incidence of respiratory viral infection among organ transplant recipients range from 0.76-0.91episode/patient-year. Incidence higher in LTR, but it is not affected by time from transplantation. Can occur all over the year, but higher incidence in autumn & winter. The symptoms are similar in all respiratory viruses. Progression to lower RTI range 6.2%-40% I LTR & mortality in 5.1%.
New respiratory viruses and serotypes are found often, affecting immunocompromised organ transplant patients. This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, as they relate to organ transplant recipients. Lung transplant research will dominate the discussion. This evaluation does not concentrate on hematopoietic stem cell transplantation, however, findings from this group will guide organ transplant therapy. This series will cover the SARS-CoV-2 epidemic. Diagnosis:
viral culture: need long time (10days for standard viral culture & 2 days for shell viral culture).
DFA staining available only in limited number of respiratory centers & need expertise in interpretation of data. Serology: useful only for epidemiological studies & not for diagnosis of acute infection. NAT: gold standard for diagnosis with sensitivity 72%-100%. Multiplex NAT can test several viruses simultaneously in only 12-24hours. Rapid antigen test: results within minutes, low sensitivity, available for influenza virus & RSV.
Influenza Virus:
cinical manifestation Immunocompromised people may not have influenza. Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms. Complications are also more common in immunocompromised people. They include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis.
Treatment:
M2 inhibitors (amantadine and rimantadine) are not utilized since they are inactive against influenza B while circulating influenza A strains are resistant. The most regularly used NAIs are oseltamivir, zanamivir, peramivir, and laninamivir (available only in Japan and South Korea). Recently licensed baloxavir provides a unique method of action. The single-dose oral medicine selectively inhibits influenza cap-dependent endonuclease. It works for uncomplicated influenza in non-immunocompromised people. Baloxavir may work better than NAIs against influenza B strains.
Respiratory Syncytial Virus:
Symptoms
RSV, like other respiratory viruses, causes fever, cough, dyspnea, and rhinorrhea. RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses. LTRs have decreased RTI rates as much as possible. Therapy Lung transplant care differed from other organs in a US assessment of 11 transplant hospitals. All 10 lung transplant facilities treat lower RTI with ribavirin, and three add IVIG, whereas only 6/10 treat upper RTI and none offer IVIG.
Human Metapneumonia:
HMPV, a Pneumoviridae virus, is similar to RSV. Like RSV, most occurrences occur in winter and spring. LTRs found HMPV in 3.6–6.8% of positive respiratory samples. 8/18 (44%) of these individuals had a lower RTI. Ribavirin fights HMPV in vitro. Antivirals and immunomodulators do not reduce mortality in HSCT patients.
Parainfluenza:
PIV is a single-stranded RNA paramyxoviridae virus. PIV has four serotypes (1–4): serotype 3 is the most frequent, has no seasonality, and has caused outbreaks, whereas serotypes 1 and 2 occur in the autumn and winter. In LTRs, PIV infection accounts for 3.6–20.9% of respiratory viruses isolated. After post hoc analysis, the highly immunocompromised category had better results. DAS 181 is FDA-unapproved. Therefore, supportive care is the core of PIV infection therapy, and hospital prevention relies on adherence to protocols.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses of the Picornaviridae family of enteroviruses. Serotypes A–C produce most colds year-round. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviride viruses are single-stranded RNA. Established human CoVs (229E, NL63, OC43, and HKU1) induce upper respiratory tract infections (RTI), whereas others (SARS-CoV1, MERS-CoV, and SARS-CoV-2) produce outbreaks. One kidney transplant recipient recovered. Ribavirin, interferon, and steroids were administered in case reports. MERS-CoV still produces some Middle Eastern illnesses.
Adenovirus:
Adenoviridae’s double-stranded DNA virus Adenovirus contains seven subgroups (A-G) and over 90 serotypes. Latency in lymphoid tissue allows adenoviruses to reactivate or create a new colony. IVIG is sometimes used with antivirals. HSCT patients with cytomegalovirus and Epstein–Barr virus infections may benefit from virus-specific cytotoxic T cells. HSCT adenovirus data is sparse.
Lung Transplant Rejection and Respiratory Viruses:
LTRs are at higher risk for RTIs, especially lower RTIs. Continuous contact with the environment, decreased mucociliary clearance, cough reflex, and more immunosuppression than other organ transplants may cause this. Many studies have examined the relationship between respiratory viral infection and acute rejection, or CLAD/bronchiolitis obliterans syndrome (BOS), with inconsistent results.
What is the level of evidence provided by this article? Level of evidence is V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.Please use sub-headings ins addition to headings to make easier to read your write-up. Please use bold or underline to highlight sub-headings as well.
Respiratory Viruses in Solid Organ Transplant Recipients :incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year – a higher incidence in the autumn and winter. All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses – Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs -Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1% DIAGNOSIS Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100% -multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h .-Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity Influenza Virus is a single-stranded RNA virus of the Orthomyxoviridae family. influenza A and B associated with disease in humans. are seasonal, mainly in the winter . In a prospective multicenter study including 477 SOT recipients and 139 patients after hematopoietic stem cell transplant (HSCT) with confirmed influenza infection, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) increased risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis,
Risk factors older age, diabetes and use of mycophenolate mofetil. use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, patients diagnosed with influenza should be placed under droplet precautions the most important means for prevention is vaccination of the transplant recipient and close contacts. Only inactivated influenza vaccines should be given to transplant recipients. The inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains..
Pre-exposure prophylaxis using low-dose oseltamivir can be given in cases of exposure to influenza among transplant recipients who have contraindications to receiving the influenza vaccine or who are not expected to mount an immune response
drugs approved for the treatment of influenza The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) -Baloxavir may also be more effective against influenza B strains than NAIs
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes subtherapeutic (as in post-exposure prophylaxis). NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals. Treatment options include changing to a different NAI, changing to a different antiviral class, or combination antivirals. Respiratory Syncytial Virus a single-stranded RNA virus of the Pneumoviridae family has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring ] and circulates mainly among young children, who are a significant source of transmission . In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens and is a cause of significant morbidity and mortality due to the development of lower RTI . Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia
ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a nonsignificant reduction in progression to lower RTI
.Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with possible decrease in progression to lower RTI in lymphopenic HSCT recipients. Human Metapneumovirus HMPV is a single-stranded RNA virus of the Pneumoviridae family, . Its seasonality also follows that of RSV, with most cases identified in the winter and spring . had symptoms of RTI,Data in SOT are based solely on lung transplants and are limited to small case series. In a study that included 139 LTRs with infections due to either RSV, HMPV or PIV
ribavirin (mostly given using oral preparation) was associated with significantly less chronic lung allograft disease -some benefit from ribavirin in lung transplants, Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. There are four serotypes of PIV serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter in LTRs is associated with a high rate of symptomatic disease and lower RTI A systematic review on antiviral treatment for PIV infection in HSCT recipients showed no benefit in this population Studies in SOT recipients are limited to small case series describing the use of ribavirin with and without immunomodulators in LTRs with mixed viral infections (PIV and RSV with/without HMPV) Rhinovirus Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients. In studies among LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6% of the positive samples -are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown -Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs Treatment is based on supportive measures and droplet precautions prevention in the hospital. Coronaviruses CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples . Symptoms are generally similar to other respiratory viruses. ribavirin and interferon as active against the virus although no clear clinical benefit of ribavirin was seen. MERS-CoV infection was first identified in Saudi Arabia and is associated with severe respiratory illness and mortality rates as high as 50% . Human to human transmission is associated with healthcare settings, and in one of the cohorts studied, 25% of the people infected were healthcare workers -Treatment options used in published case reports include ribavirin, interferon and steroids . MERS-CoV still causes sporadic infections, mainly in the Middle East Adenovirus. is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition -no seasonal variability – associated with institutional outbreaks Rates of adenovirus infection differ with age and the transplanted organ. Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression-Clinical Manifestations Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection . Prevention Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precautions -treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes (investigational). Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression
.Bocavirus a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses . similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence . This, combined with the high co-infection rate, makes their true contribution to RTIs unknown KI and WU Polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family Studies in HSCT recipients suggested a higher frequency of infection with these viruses A study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively However, it is still unclear whether this has any clinical significance Respiratory Viruses and Rejection in Lung Transplantation . A systematic review and meta-analysis published in 2011 demonstrated no association between respiratory viral infection and acute rejection, although only four studies were included in the analysis. It also showed a non-significant trend towards association with BOS, but that was limited by small numbers A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections – Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections,
level of evidence provided by this article Level V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.Please use sub-headings ins addition to headings to make easier to read your write-up. Please use bold or underline to highlight sub-headings as well.
Introduction: This review covers both RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), humanmetapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV),adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients. In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76-0.91 episodes per patient-year, with higher incidence in the autumn and winter. Rates of progression to lower respiratory tract infection (RTI) vary between 6.2-40% in LTRs, and data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking. Diagnosis: By viral culture, direct fluorescent antibody (DFA) staining, and serology, although each technique has drawbacks of its own. NAT, which has a sensitivity range of 72–100%, is currently the gold standard for diagnosis. A turnaround time of only 12 to 24 hours is possible with multiplex NAT when testing for many viruses at once. The sensitivity of rapid antigen tests is poor and they are only available for RSV and influenza. Influenza virus: Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. Only influenza A and B are typically linked to illness in people. Influenza viruses are seasonal and circulate mainly in the winter, with an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants.
Clinical features: Cough was the most frequent symptom (85%), followed by fever (63%), rhinorrhea (48%), Myalgia, gastrointestinal issues, a sore throat, and a headache all made up 40% of the list. Immunocompromised patients may not fit the classic definition of influenza-like illness, but are at increased risk for complications such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Prevention:
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions and vaccination of the transplant recipient and close contacts is the most important means for prevention. Inactivated influenza vaccines should be given to transplant recipients, as there is a theoretical risk of dissemination of virus contained in the live attenu-Viruses 2021, 13, 2146 3 of 16ated intranasal influenza vaccine, which is therefore contraindicated for SOT recipients. Immunogenicity of influenza vaccine in SOT is variable, but generally lower compared to a non-immunocompromised population. Vaccination has been shown to decrease influenza infection rates, complications and mortality in the SOT population, with a large prospective multicenter study on 616 transplant recipients showing that vaccination in the same influenza season wasassociated with a reduction in odds for pneumonia (odds ratio (OR) 0.51, 95% CI 0.21–0.55) and admission to the ICU (OR 0.49). However, several studies have evaluated different vaccination strategies and had variable outcomes.
Treatment: Amantadine and rimantadine, M2 inhibitors, are no longer utilized because they are naturally inert against influenza B and circulating influenza. High levels of resistance are present in strain A. The most widely used class of drugs are neuraminidase inhibitors (NAIs), and include zanamivir (inhaled and intravenous), peramivir, and oseltamivir (oral) (intravenous). Influenza A strains are so highly resistant, M2 inhibitors are not advised. Early treatment within 48 hours of illness controls the disease complication rate, and ICU admissions.
Respiratory Syncytial Virus: RSV is a single-stranded RNA virus of the Pneumoviridae family, has two strains: RSV-A and RSV-B. Peak incidence on winter, RSV accounts for 2.4–6.2% of respiratory viruses. Risk factors: include young children, recent transplant, lung or multivisceral transplant, and recent rejection. Clinical manifestation: fever, cough, dyspnea and rhinorrhea, but more frequently causes lower RTI.
Prevention: Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein. Vaccination: under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based, ResVax being the most advanced.
Treatment: Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Presatovir is a new antiviral with specific anti-RSV activity, but two phase 2b RCTs failed to show significant improvements in clinical and virologic outcomes, and 20% of patients developed resistance.
Human Metapneumovirus: HMPV is a single-stranded RNA virus of the Pneumoviridae family, more at winter and spring. Isolated in 3.6–6.8% of positive respiratory samples, 44 % presents with LRTI. Ribavirin has in vitro activity against HMPV, but data from HSCT recipients do not demonstrate a mortality benefit, and current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices.
Parainfluenza Virus: (PIV) is a single-stranded RNA virus of the Paramyxoviridae family, with 4 genotypes, type 3 is the most common , types 1+2 occurs in fall and winter. PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI, with 21% experiencing respiratory failure. Antivirals for PIV infection in SOT are unknown, and DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, but does not reach statistical significance. Treatment is based on adherence to contact precautions.
Rhinovirus: Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, Serotypes A–C, the predominant cause for the common cold. Rhinoviruses accounted for 41.8-61.6% of the positive respiratory PCR samples. Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses: CoVs are single-stranded RNA viruses of the Coronaviridae family, the second prevalent respiratoy virus post rhinoviruses. Symptoms are generally similarto other respiratory viruses. SARS-CoV1 infection emerged in southern China in 2002 and was associated with lower RTI and mortality. In-vitro studies identified ribavirin and interferon as active against the virus, but of no clear benefit. MERS-CoV is associated with severe respiratory illness and mortality rates, and is spread through healthcare settings, camels, and kidney transplant recipients. Treatment options include ibavirin, interferon, and steroids.
Adenovirus: Adenovirus is a double-stranded DNA virus of the Adenoviridae family, of 7 subgroups, Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition. Adenoviruses can cause viremia without obvious symptoms, and rates vary with age and organ transplantation. Clinical features: Adenovirus infection can cause conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and can be fatal in kidney transplant recipients. Adenovirus is transmitted through respiratory droplets, direct conjunctivalinoculation, person-to-person contact, infected fomites, and fecal-oral routes. Treatment options include reduction of immunosuppression, brincidofovir, IVIG, and adenovirusspecific cytotoxic T lymphocytes. Data is scarce in HSCT and still lacking in SOT.
Bocavirus: Bocavirus is a single-stranded DNA virus of the Parvoviridae family, there is often co-infection with other respiratory viruses, isolated from only 0.5–1% of the positive respiratory samples.
KI and WU Polyomaviruses: KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family, discovered in 2007. KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens. Respiratory Viruses and Rejection in Lung Transplantation: Risk factors of LRTI are: continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression. There is a higher rate of rejection in viral LRTI. reatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections. Summary: Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. Detected more frequently by molecular diagnostic methods, effective therapies are available only for influenza, and some of RSV infection
What is the level of evidence provided by this article?Level of evidence V- erratic review
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.Please use sub-headings ins addition to headings to make easier to read your write-up. Please use bold or underline to highlight sub-headings as well.
Please summarise this article. Introduction
o Respiratory viruses are a cause of significant morbidity and mortality among SOT recipients
o The incidence of respiratory viral infections in SOT recipients is 0.76–0.91 episodes per patient-year (higher among lung transplant recipients)
o All respiratory viruses generally cause similar symptoms and similar clinical presentations
o Rate of progression to lower respiratory tract infection (LTRs) ranges between 6.2–40% in LTRs
o Mortality associated with viral pneumonia in SOT recipients is 5.1%
Aim of the study: review the epidemiology, clinical manifestations, therapies and preventive measures for clinically significant respiratory viruses (both RNA and DNA) with the exception of SARS-CoV-2. The vast majority of data comes from studies of lung transplant recipients
Diagnosis
1. viral culture: 10 days for standard viral culture and two days for shell vial culture
2. direct fluorescent antibody (DFA) staining: available for only a limited number of respiratory viruses and requires expertise
3. serology: useful only for epidemiological studies and not for diagnosing acute infection
4. Nucleic acid testing (NAT) for respiratory viruses: the gold standard for diagnosis and has a sensitivity of 72-100%. Use multiplex NAT with time only of 12–24h
5. Rapid antigen tests: allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus
Epidemiology and Risk Factors
o It is a single-stranded RNA virus (Orthomyxoviridae family)
o Only influenza A and B are generally associated with disease in humans
o Is seasonal, mainly in the winter (months November to May in the Northern Hemisphere and May to October in the Southern Hemisphere), and cause a significant proportion of RTIs
Clinical Presentation
o The most common symptom are cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%)
o Immunocompromised individuals are at increased risk for complications (viral pneumonia, bacterial super infection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis)
Risk factors for severe disease:
1. older age
2. diabetes
3. use of mycophenolate mofetil
4. multiple comorbidities
5. use of antilymphocyte globulin in the past six months
6. lymphopenia
7. hypogammaglobulinemia
8. influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission
Prevention
1. Droplet precautions
2. Vaccination of the transplant recipient (the inactivated influenza vaccine includes two A strains (H1N1 and H3N2) and two B strains) and close contacts
3. Pre-exposure and post-exposure antiviral prophylaxis: should be given in the case of a hospital outbreak to patients in the affected wards. An outbreak is defined as two healthcare-associated cases diagnosed within 72 h in the same ward, and prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case
Treatment
o Early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates
o Patients who have symptoms > 48 h also benefit from treatment (SOT recipients and general population)
o All symptomatic patients should be treated, irrespective of symptom duration
Antiviral resistance:
o Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure
o NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals
o Treatment options include changing to a different NAI, changing to a different antiviral class, or combination antivirals
Neuraminidase inhibitors (NAIs):
1. oseltamivir (oral): 75 mg q12h (5 days), prophylactic Dose is 75 mg q24h
2. zanamivir (inhaled and intravenous): 10 mg q12h (5 days), prophylactic Dose is 10 mg q24h
3. peramivir (intravenous): 600 mg once
4. laninamivir (available only in Japan and South Korea):
5. Baloxavir: recently approved. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single dose oral medication. It is effective in uncomplicated influenza in the non-immunocompromised population. It may also be more effective against influenza B strains than NAIs. Dose is 40 mg (<80 kg), 80 mg (>80 kg) and prophylactic dose is 40 mg (<80 kg), 80 mg (>80 kg)
Respiratory Syncytial Virus
Epidemiology and Risk Factors
o Single-stranded RNA virus (pneumoviridae family)
o Have two strains (RSV-A and RSV-B)
o Seasonal virus with peak incidence in the winter and spring
o Mainly affects young children (a significant source of transmission)
o In LTRs, accounts for 2.4–6.2% of respiratory viruses and is a cause of significant morbidity and mortality
o Risk factors for lower RTI include young children (<2 years old), recent transplant, lung or multivisceral transplant and recent rejection
Clinical Presentation
o Commonly presents with fever, cough, dyspnea and rhinorrhea
o More frequently causes lower RTI (bronchitis, bronchiolitis and pneumonia): 72%
Prevention
1. Contact precautions
2. Palivizumab for age < 2 years Treatment
Ribavirin ± IVIG/steroids
Human Metapneumovirus (HMPV)
o Single-stranded RNA virus (Pneumoviridae family) closely resembling RSV
o Accounts for 3.6–6.8% of LTRs causes
o Treatment: Ribavirin ± IVIG/steroids?
o Prevention: contact precautions
Parainfluenza Virus
o A single-stranded RNA virus (Paramyxoviridae family)
o Four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter
o Accounts for 3.6–20.9% of LTRs
o Treatment: Ribavirin ± IVIG/steroids?
o Prevention: contact precautions
Rhinovirus
o Single-stranded RNA viruses (Picornaviridae family)
o Serotypes A–C circulates year-round and are the predominant cause for the common cold
o Accounts for 41.8–61.6% of LTRs
o Symptoms: common cold
o Treatment: supportive
o Prevention: droplet precautions
Coronaviruses (CoVs)
o Single-stranded RNA viruses (coronaviridae family)
o Are second only to rhinoviruses for prevalence among LTRs (12.4–17.8% of the positive samples)
o Symptoms are generally similar to other respiratory viruses
o SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%
o MERS-CoV infection was first identified in Saudi Arabia [92] and is associated with severe respiratory illness and mortality rates as high as 50%
o Treatment: Ribavirin, interferon, steroids
o Prevention: airborne & contact & droplet precautions
Adenovirus Epidemiology
o Double-stranded DNA virus (Adenoviridae) family
o Have seven subgroups (A-G) and currently 90 serotypes
o Infection can be reactivation or de novo
o No seasonal variability
o Can cause viremia without obvious symptoms (differentiating infection and disease may be more appropriate)
o Rates are higher among children
Clinical Manifestations
o Conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis
o In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis
o Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection
o Cause bronchiolitis obliterans in lung transplant recipients
Prevention
o Transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route
o Prevention: droplet & contact precautions
Treatment
o Cidofovir, brincidofovir (investigational), IVIG
Bocavirus
o Single-stranded DNA virus (parvoviridae family)
o In LTRs, isolated from only 0.5–1%
o There is often co-infection with other respiratory viruses
o Prevention: Standard precautions
KI and WU Polyomaviruses
o Are double-stranded DNA viruses (Polyomaviridae family)
o In kidney transplant recipient’s identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively
Respiratory Viruses and Rejection in Lung Transplantation
o A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections
Conclusions
o Respiratory viruses cause a significant morbidity among SOT recipients
o With the introduction of molecular diagnostic methods, now can be detected easily
o Effective therapies are available only for influenza (and to some extent for RSV infection)
o Vaccination is only available for influenza virus
o New antivirals and vaccines is needed due to severe implications of respiratory viral infections on the immunocompromised population
What is the level of evidence provided by this article?Level V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
solid organ transplantation associated with better survival ,but at the same time associated with hazards of infection, cardiovascular and malignancy issues.
respiratory viral infections among the most common infections, especially lung transplantation
there are different viruses (such as influenza, para influenza, respiratory syncytial virus, adenovirus, rhino virus, COVID-19 and human metapneumovirus ) that seriously affect the health of immunocompromised patients such as transplantation
Viruses could be DNA or RNA
clinically and radiologically ….nearly all same
symptoms varying from asymptomatic ,symptomatic URTI or LRTI or non-specific symptoms and may be GIT
viral infections occur all the time ,mostly in autumn and winter and mostly community acquired
progression into LRTI around 6-40% ,and of them about 5% will die because of infection
DX.:
previously , viral culture, direct fluorescent antibody staining and serology
nowadays gold standard NAT/PCR
Preventions:
general measures for all such as mask , hand hygiene, distance and vaccination
treatment:
supportive treatment
there is no specific treatment for majority except influenza virus
some time may get benefit from intravenous IVIG
I like your well-structured summary, and conclusions.Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Introduction:
-Respiratory viruses have a significant impact on the health of immunocompromised individuals.
-It incidence in SOTR between 0.76–0.91 episodes per patient-year, and it is highest among lung transplant recipients LTR.
-It does not affected by the transplantation time, It occurs throughout the year with some seasonal variation.
– It can progress to lower respiratory tract infection in 6.2–40% in LTRs with reported mortality 5.1 % in LTR.
Diagnosis
-Viral culture, direct fluorescent antibody (DFA) staining and serology were used for diagnosis.
– NAT for respiratory viruses is now the gold standard with sensitivity of 72–100%
-Multiplex NAT; testing for several viruses simultaneously with a turnaround time of only 12–24 h.
– Rapid antigen tests, allowing results within minutes, available for influenza and RSV only and has low sensitivity.
Influenza Virus Epidemiology and Risk Factors
-Single-stranded RNA virus with different stain, A&B cause disease in human.
-Seasonal virus, mainly in the winter.
– Attack rate affected by; age, immunity ( previous vaccination), degree of immunosuppresion.
-Incidence in higher among LTR.
Clinical Presentation
-The most common symptom: cough, fever, rhinorrhea, myalgia, GIT symptoms, sore throat and headache.
– SOTR at high risk of complications: viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and
myocarditis, myositis, encephalopathy and encephalitis.
– Risk factors increase disease severity: old age, comorbidities DM, use of MMF, ATG, lymphopenia, low Ig, Influenza A and nosocomial infection.
Prevention
– Droplet precautions for hospitalized persons.
– Vaccination of SOTR and close contacts, only inactivated vaccine , the live attenuated one is contraindicated.
– Variable immunogenicity and lower compared to immunocompetent, however, it is still decrease infection & complication.
– AST recommend that high-dose vaccination is the preferred strategy
– Antiviral prophylaxis; pre-exposure or post-exposure, concern about risistance.
– ID Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak.
Treatment
Three groups of drugs:
–M2 inhibitors (amantadine and rimantadine) are not used today
–Neuraminidase inhibitors (NAIs) most commonly used, oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
– Selective inhibitor of cap-dependent endonuclease; Baloxavir ; recently approved, more effective against influenza B strains than NAIs
-Early initiation (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates, should be started before the availability of results.
-It is recommended that all symptomatic patients should be treated, irrespective of symptom duration.
-SOTR have prolong viral shedding, therefore, extend treatment duration in symptomatic individuals.
– Several monoclonal antibodies targeting various hemagglutinins of influenza virus have been developed
– NAI resistance has been reported.
– Treatment options include changing to different NAI, changing to a different antiviral class, or combination antivirals. Respiratory Syncytial Virus Epidemiology and Risk Factors
-Single-stranded RNA virus and has two strains: RSV-A and RSV-B.
– It is a seasonal virus with peak incidence in the winter and spring
– Mainly among young children (significant source of transmission)
– Accounts for 2.4–6.2% of respiratory viruses
– Cause a significant morbidity and mortality due to the development of lower RTI. Clinical Manifestations
– Commonly presents with fever, cough, dyspnea and rhinorrhea.
– RSV more frequently causes lower RTI (up to 72%); bronchitis, bronchiolitis and pneumonia.
Prevention
– Hospitalized person should be under contact precautions.
– AAP recommended Palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
– Nirsevimab ; monoclonal antibody with extended half-lives against RSV can be give once per season and showed favorable results on preterm infants
– Multiple type of vaccine underdevelopment.
Treatment
– Lower RTI treated with ribavirin +/- (IVIG).
– Data on treatment in SOT are limited to case series in LTR.
– Oral ribavirin treatment in LTR is associated with improvement in graft function and reduction in bronchiolitis obliterans syndrome
– Inhaled and systemic IV ribavirin are not preferred for the side effects systemic hemolytic anemia, leukopenia, neuropsychiatric, and teratogenic.
– Several new drugs are under development.
Human Metapneumovirus
– Closely similar to RSV. Its seasonality also follows that of RSV.
– Account for 3.6–6.8% of positive respiratory samples and cause Lower RTI in 44%.
– Ribavarin in LTR showed favorable outcomes on graft function, less chronic lung allograft disease.
– Prevention is mainly based on infection control practices.
Parainfluenza Virus
– Single-stranded RNA virus with four serotypes of PIV (1–4).
– PIV3 3 is the most common and shows no seasonality, whereas PIV-1& 2 appear in the fall and winter.
– Accounts for 3.6–20.9% of the respiratory viruses isolated.
– In LTRs is associated with a high rate of symptomatic disease and lower RTI, 21% respiratory failure.
– Utility of antivirals for PIV infection in SOT is unknown, mixed result with ribavirin.
– DAS 181 is a novel, inhaled sialidase, not yet FDA approved.
– Treatment is supportive care and preventive measures, contact precautions.
Rhinovirus
– Single-stranded RNA, serotypes A–C are the predominant cause for the common cold.
– Accounted for 41.8–61.6% of the positive samples.
– Seen frequently as part of coinfection with other viruses or bacteria.
– Symptoms of common cold, and in LRT cause lower RTI .
– Treatment is supportive care and preventive measures, droplet precautions.
Coronaviruses
-Single-stranded RNA viruses cause URTI, can cause outbreak of severe respiratory disease SARS-CoV1 (China in 2002, mortality 20 % ), MERS-CoV (Saudi Arabia 2012, mortality 50%), and SARS-CoV-2.
– CoVs second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8%.
– Immunocompromised group had a significantly higher rate of severe lower RTI.
– Treatment options include ribavirin, interferon and steroids
Adenovirus Epidemiology
-Double-stranded DNA virus 7 subgroups (A-G) and 90 serotypes.
– Establish latency in lymphoid tissue; can be reactivated or de novo infection.
– No seasonal variability.
– Can cause viremia without obvious symptoms.
– Rates of infection differ with age (higher in children) and the transplanted organ ( higher in intestinal Tx).
Clinical Manifestation:
-Can present with conjunctivitis, upper or lower RTI, hemorrhagiccystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for thetransplanted allograft.
-KTR: fever of unknown origin and rise in creatinine.
-Mortality 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
-LTR can be complicated with bronchiolitis obliterans. Prevention
-Droplet and contact precautions.
– Brincidofovir not yet approved by FDA.
Treatment
-Supportive care.
– Treatment options include reduction of IS, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific
cytotoxic T lymphocytes (investigational).
Bocavirus
– Single-stranded DNA, rarely isolated.
– Often co-infection with other respiratory viruses.
– Closely related parvovirus B19, known for their viral persistence.
KI and WU Polyomaviruses
– Double-stranded DNA viruses.
– Their clinical significance is still unclear.
Respiratory Viruses and Rejection in Lung Transplantation
-The are conflicting for association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS).
– Associations have also been reported for influenza, HMPV and RSV, PIV and adenovirus
– No definitive association with rhinoviruses and CoVs
-Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV
Summary:
-Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
-Effective therapies are available only for influenza, and also to some extent for RSV infection
-Development of new antivirals and vaccines is needed.
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
III. Respiratory Viruses in Solid Organ Transplant Recipients Please summarise this article. Introduction
SOT can save lives, but it is also associated with a higher risk of infection.
Respiratory viral infections are common & cause major morbidity & mortality, particularly in lung transplant patients. They are also associated with acute rejection & chronic lung allograft dysfunction.
After a TX, respiratory virus infections can develop at any moment & are typically contracted in the community.
Nowadays, NAT is used to diagnose respiratory viral infections.
There are effective anti-influenza treatments & preventative measures; however, these are constrained by neuraminidase inhibitor resistance & decreased vaccination immunogenicity in the TX recipients.
Unfortunately, there are few effective therapies & prevention measures for other respiratory viruses.
Influenza virus:
SS RNA virus
Family- Orthomyxoviridae
Only A & B strains cause human disease.
Infection is seasonal (winter months)
Attack rate depends on age (higher in children), contact history, immunity levels (prior vaccination or disease), degree of IS & the epidemic nature.
Incidence among SOT recipients (1990 to 2000): 41.8, 2.8, & 4.3/1000 patient years in lung, liver & KTX, respectively.
Clinical manifestations
Immunocompromised patients may not exhibit classic findings.
The most common symptoms: cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), GIT (40%), sore throat (35%) & headache (30%).
Increased risk for complications in immunosuppressed patients.
SS RNA virus of the Pneumoviridae family & has 2 strains: RSV-A and RSV-B.
A seasonal virus (peak in winter & spring)
Mainly affect young children, who are a source of transmission.
Clinical features
Similar to other respiratory viruses (fever, cough, dyspnea & rhinorrhea).
More frequently causes lower RTI (bronchitis, bronchiolitis & pneumonia).
Prevention
Contact precautions (RSV droplets form large particles) The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
======================= HMPV
SS RNA virus of the Pneumoviridae family (resembleRSV).
Seasonality follows that of RSV (winter & spring).
======================= Parainfluenza virus (PIV)
SS-RNA virus of the Paramyxoviridae family.
4 serotypes of PIV (1–4); serotype 3 is the most common, has no seasonality & has been associated with outbreaks.
PIV infection is associated with a high rate of symptomatic disease & lower RTI.
======================= Rhinoviruses
SS-RNA viruses that are members of the Picornaviridae family.
Serotypes A–C circulate year-round & are the predominant cause for the common cold.
Isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients.
Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria.
Symptoms of rhinovirus infection are usually those of the common cold.
======================= Coronaviruses (CoVs)
SS-RNA viruses of the Coronaviridae family.
Human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (SARS-CoV1, MERS-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
======================= Adenovirus
Double-stranded DNA virus of the Adenoviridae family.
7 subgroups (A-G) & 90 serotypes.
Latency in lymphoid tissue (infection can represent reactivation or de novo community acquisition).
No seasonal variability & associated with institutional outbreaks.
Known to cause viremia without obvious symptoms (differentiating infection & disease may be more appropriate).
Higher rates among children & in intestinal TX (higher amount of lymphoid tissue in the graft & greater IS medications).
Ribavirin (IV/oral): LD 600 mg then 200 mg q8h for 1 day then 400 mg q8h. Can increase to maximum 10 mg/kg q8h.
Cidofovir (IV): 1 mg/kg 3 times a week, or 5 mg/kg once a week for 2 weeks and then every 2 weeks. Add probenecid & hydration.
Investigational antivirals for influenza:
Favipiravir may be promising & has low resistance rates & synergistic when combined with oseltamivir.
Pimodivir discontinued due to lack of benefit.
Several monoclonal antibodies showed mixed results.
Antiviral resistance
Due to extended viral replication & antiviral exposure (occasionally subtherapeutic), immunocompromised people are more likely to develop antiviral resistance.
Due to the significant level of resistance in the influenza A strains, M2 inhibitors are not advised.
Seasonal influenza resistance to NAIs is rare & mostly affects the A/H1N1 strain.
Summary
For SOT recipients, respiratory viruses are a substantial source of illness & mortality. They are now more frequently detected because of the development of molecular diagnostic techniques.
Only influenza &, to a lesser extent, RSV infection have effective treatments; however, emerging medication classes hold some promise.
Since there is currently only an influenza vaccine available, preventive measures are also inadequate.
The necessity for the development of novel antivirals and vaccines is driven by the serious effects that respiratory viral infections have on the immunocompromised population.
========================= What is the level of evidence provided by this article?
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
Respiratory Viruses in SOT recipients Introduction Respiratory viruses
Influenza virus.
Respiratory Syncytial virus, RSV.
Human metapneumovirus, HMPV.
Parainfluenza virus, PIV.
Rhinovirus.
Coronavirus, C0V.
Adenovirus.
Bocavirus.
KI and WU polyomavirus.
Influenza virus Epidemiology and risk factors
A single-stranded RNA virus of the Orthomyxoviridae family.
There are influenza A and B strains.
Season; winter.
Risk factors include;
I) Age. II) Exposure. III) Level of immunity. IV) Degree of immunosuppressants. V) Nature of the epidemic. Clinical presentation
Immunocompromised patients may not present with the classic picture of infection.
Cough (85%).
Fever (63%).
Rhinorrhea (48%).
Myalgia (40%).
GIT symptoms (40%).
Sore throat (35%).
Headache (30%).
Risk after exposure in immunocompromised patients
I) Viral pneumonia. II) Bacterial superinfection. III) Fungal co-infection. IV) Pericarditis, myocarditis, and myositis. V) Encephalopathy and encephalitis.
Risk to severe disease
I) Older age. II) DM. III) MMF Prevention
Vaccination (inactivated forms) of the transplant recipients and close contacts, as soon as 1 month after Tx.
Immunogenicity is generally lower in SOT compared to non-immunocompromised patients, but the vaccine is shown to reduce infection rate, complication, and mortality rate.
It could be a high-dose or two-dose standard vaccine.
Antiviral prophylaxis
I) Low-dose oseltamivir in outbreak condition. Treatment
M2 inhibitors (amantadine, and rimantadine) are now obsolete.
The neuraminidase inhibitors (NAIs) include (oseltaminvir, zanaminvir, peramivir, and laninamivir.
Baloxavir is approved to have a novel mechanism of action, a single-dose oral medication, effective in non-complicated influenza in non-immunocompromised patients.
Favipiravir is active against both strains.
Pomidivir against influenza A.
Respiratory Syncytial Virus Epidemiology and risk factors
A single-stranded RNA virus, of pneumoviridae family.
There are 2 strains A and B.
Seasonal virus with peak incidence during winter and spring.
Affects mainly, young children.
It causes mainly LRTI.
Clinical manifestation
Fever, cough, dyspnea, and rhinorrhea.
Bronchitis, bronchiolitis, and pneumonia.
Prevention
Palivizumab prophylaxis during the RSV season in children under 24 months who are severely immunocompromised, (Not evident).
Not given to adults SOT recipients.
Nirsevimab, a novel monoclonal, with an extended half-life, can be given once per season, (recently shown favorable results).
Many vaccines are still under trial.
Treatment
Ribavirin +/- IVIG, is associated with the lower complication of LRTI and mortality.
Ribavirin AE (hemolytic anemia, leukopenia, neuropsychiatric, and teratogenicity).
Presatovir has specific anti-RSV activity, is less effective than ribavirin, and reduces the incidence of LRTI.
Many other antiviral treatments are under development and reached phase three trials.
Human metapneumovirus
HMPV is a single-stranded RNA virus of the pneumoviridae family.
Seasonal during winter and sprint.
Prevention is based on prevention precautions.
Treatment with ribavirin.
Parainfluenza virus
PIV is a single-stranded RNA virus of paramyxoviridae family.
there are 4 subtypes (PIV 1-4).
Serotype 3 is the most common and shows no seasonality and is associated with an outbreak.
Subtype 1-2 has seasonal activity during winter and fall.
Mainly cause LRTI, usually asymptomatic, with some incidence of respiratory failure.
Limited studies for antiviral, ribavirin show positive results.
SAD 181 is a novel, inhaled sialidase that prevents attachment and entry of the virus.
The main treatment is supportive care and prevention with precaution.
Rhinovirus
A single-stranded RNA virus of picornaviridae.
The predominant cause of the common cold.
Frequently isolated from immunocompromised patients, as well as SOT recipients.
Frequently found as coinfection with viruses and bacteria.
Treatment is based on supportive measures and precautions.
Coronaviruses
A single-stranded RNA virus of the coronaviridae family.
May cause URTI, SARS-CoV1, MERS-CoV, and SARS-CoV2, and is mostly associated with severe respiratory diseases.
Similar symptoms to respiratory viral infections.
Severe disease in immunocompromised patients.
Adenovirus Epidemiology
A double-strand DNA virus of the adenoviridae family.
Seven subgroups (A-G).
May become latent in lymphoid issues, so has a reactivation feature or it can be a de novo disease.
No seasonal variability, and associated with outbreaks.
Infection rates are higher among children and immunocompromised patients.
Clinical manifestation
Conjunctivitis.
URTI.
LRTI.
Hemorrhagic cystitis.
Pyelonephritis, (considered in SOT if present with fever, rising Cr, and pyelonephritis.
Hepatitis.
Enterocolitis.
Mortality can be as high as 50% for pneumonia, 80% for disseminated infection.
Bronchiolitis obliterans in LTRs.
Prevention
Prevention based on precautions.
Brincidofovir, a bioavailable lipid conjugate.
Treatment
Supporting care.
Reduction of immunosuppressants.
Cidofovir, brincidofovir.
IVIG and adenovirus-specific cytotoxic T lymphocytes.
Bocavirus
A single-stranded DNA virus of parvoviridae family.
Rarely isolated from respiratory specimens.
Often present as co-infection with other viruses.
KI and WU polyomaviruses
A double-stranded DNA virus of the polymaviridae family.
A study done on kidney transplant recipients identified KI and WU in 14.4% and 9.1% of respiratory specimens respectively.
Respiratory virus and rejection in lung transplantation
LTRs are at increased risk of RTIs and specifically LRTIs.
Risk factors; impaired mucociliary clearance, impaired cough reflex, and relatively greater immunosuppressants compared to other transplants.
Many studies show conflicting data on the association between respiratory viral infection and acute rejection.
Some reported between influenza, HMPV, RSV, PIV, and adenovirus with acute rejection.
No definitive association between rhinovirus and CoVs and rejection or CLAD.
Summary Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. Detection is at the great frequency with the introduction of molecular diagnostic methods. Effective therapy is available only for influenza and to some extent RSV. Development of new antivirals and vaccines is warranted as the respiratory viral infection have a n implications in immunocompromised patients Level of evidence Level ((V)) review article
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
It has been proven beyond doubt that solid organ transplantation offers a better long quality of life for those with organ failure. However, there is a challenge of increased tendency to develop infection especially respiratory tract infection which sometimes can be fatal. The incidence of respiratory tract infection is 0.76-0.91 per patient per year, and the majority of these viruses have similar clinical signs and symptoms. Diagnosis is usually through virus culture, DFA, serology, rapid antigen test, and NAT which is the gold standard
Influenza Virus
Is a single-stranded RNA virus of the Orthomyxoviridae family
the attack rate depends on age, level of immunity, exposure, and nature of the epidemic
other risk factors are old age, DM, immunosuppression, and use of MMF
the incidence of 41.8, 2.8, and 4.3 per 1000 patient-years in lung, liver, and kidney transplants, respectively
the clinical presentations are cough, fever, rhinorrhea, myalgia, gastrointestinal symptoms, sore throat, and headache in decreasing order of frequency
the best form of prevention is vaccination followed by the use of antiviral prophylaxis, low-dose oseltamivir
treatment involves the use of oseltamivir, zanamivir, peramivir, laninamivir, and baloxavir which use is recent
Respiratory syncytial virus
RSV is a single-stranded RNA virus of the Pneumoviridae family and has two strains RSV-A, and RSV-B
RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens.
risk factors are young children (less than two years old), a recent transplant, lung or multi-visceral transplant, and recent rejection
Clinical signs are fever, cough, rhinorrhea, and dyspnea
The hospitalized patients should be placed under contact precaution and the use of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised
Ribavirin and immunoglobulin are used for treatment
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples
SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%
MERS-CoV infection was first identified in Saudi Arabia and is associated with severe respiratory illness and mortality rates as high as 50%.
MERS-CoV still causes sporadic infections, mainly in the Middle East.
Adenovirus
is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes
Adenoviruses show no seasonal variability and have been associated with institutional outbreaks
Clinical manifestation could vary from conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis, and enterocolitis, and a predilection for the transplanted allograft
Treatment includes supportive care and reduction of immunosuppressives drugs, though IR plus cidofovir has been reported in some studies
Respiratory Viruses and Rejection in Lung Transplantation
Factors like continuous contact of lung allograft to the environment, impaired mucociliary clearance, and weak cough reflex can predispose to lower respiratory tract infection.
Severa studies have evaluated the association between respiratory viral infection and acute rejection
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV, and PIV infections as shown in a study.
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
-SUMMARY Introduction
In organ transplant recipients, the incidence of respiratory viral infections
among lung transplant recipients (LTRs) supposed to be higher.
Clinical picture is not different from one virus to another.
The progression to lower respiratory tract infection (RTI) is variable and ranges 6.2–40% in LTRs Diagnosis
Historically viral culture was used but it takes a long time ,Direct fluorescent antibody (DFA) staining which is available for limited viruses and serology was used in epidemiological studies.
Nucleic acid testing (NAT) for respiratory viruses is the gold standard for diagnosis and has a sensitivity of 72–100% Influenza virus Epidemiology
It is a single-stranded RNA virus of the Orthomyxoviridae family. There are many strains but A ,B can cause disease in humans. The infection rate varies according to age and immunity. Clinical picture
A study on SOT and HSCT recipients demonstrated that cough ,fever ,rhinorrhea, gastrointestinal symptoms ,sore throat and headache
Immunosuppressed specially those who are old age , diabetics and on MMF therapy ,cases are liable to more severe complications as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis Prevention
Involves isolation and vaccination , only inactivated influenza vaccines need to be given to transplant recipients.
The vaccine include quadrivalent formulation of 2 A strains (H1N1 and H3N2) and 2 B strains.
It is administered as soon as 1month post-transplant, as immunogenicity till 6 months post-transplant can be decreased.
The influenza vaccine can lower influenza infection rates, complications and mortality in the SOT.
One study revealed that high-dose intramuscular vaccine provide high rate of seroconversion of once strain compared to a standard-dose vaccine.
American Society of Transplantation 2019 guidelines recommend that high dose vaccination is better meanwhile 2 doses of standard vaccine can be used.
Antiviral prophylaxis using low-dose oseltamivir pre or post exposure. Treatment
Neuraminidase inhibitors (NAIs) including oseltamivir , zanamivir, peramivir and laninamivir. Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease ,taken as a single dose oraly, specialy in uncomplicated non-immunocompromised cases against influenza B virus .
Favipiravir has low resistance rate and can potentiate oseltamivir effect.
Monoclonal antibodies showed variable results.
Immunocompromised patients are liable for antiviral resistance .
NAIs resistance occurs in the A/H1N1 strain, the common mutation is H275Y, found in A/ /H1N1, maintaining susceptibility to zanamivir.
And in A/H3N2 the common mutation is R292K, with decreased response to oseltamivir and zanamivir Respiratory Syncytial Virus Epidemiology and Risk Factors
It is a single-stranded RNA virus of the Pneumoviridae family and has 2 strains: RSV-A and RSV-B.
Risk factor include young age, recent transplant, lung or multivisceral transplant and recent rejection. Clinical manifestations
Similar to other respiratory viruses ,RSV is more liable to cause Lower RTIs reaching 72% Prevention
Contact precautions are needed. Palivizumab prophylaxis during the RSV season for children younger than 24 months whom are severely immunocompromised although that is not evidence based. Palivizumab is not given to adult SOT recipients.
Nirsevimab is a novel monoclonal that targets RSV fusion protein epitope
Vaccines are underdevelopment and is recommended for elderly , pregnant women or the pediatrics Treatment
Lung transplant centers use ribavirin with or without intravenous immunoglobulin (IVIG) for LRTI treatment.
For HSCT cases , ribavirin reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
A combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) decreased mortality when used for LRTI, and did not significantly reduce progression to LRTI.
Presatovir a new antiviral but did not show promising results.
New drugs targeting RSV are under development including fusion inhibitors
and replication inhibitors. Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, similar to RSV.
Ribavirin has antiviral activity towards HMPV. HSCT recipients did not show a mortality benefit with antivirals or immunomodulators
Current treatment is based on supportive care.
Prevention is based on infection control. Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family including 4 serotypes of PIV ,serotype 3 is the most common
A study showed that PIV infection, mostly PIV3, lead to respiratory failure in 21 % of the cases .
Antivirals effectiveness for PIV infection in SOT is unknown
DAS 181 prevents attachment and entry of the virus ,it was assessed in immunocompromised patients with lower RTI secondary to PIV infection with a trend towards better outcome ,it did not reach statistical significance
Treatment for PIV infection is supportive care and prevention involves contact
precautions. Rhinoviruses
They are single-stranded RNA viruses that are members of the Picornaviridae
family.
Rhinoviruses accounted for 41.8–61.6% of Lung transplant recipient cases in a study.
Rhinoviruses are usually associated with coinfection with other viruses or bacteria, the symptoms are similar to common cold symptoms .
Treatment is supportive measures and prevention includes droplet precautions. Coronaviruses
They are single-stranded RNA viruses of the Coronaviridae family.Human CoVs (229E, NL63, OC43, HKU1) can lead to upper RTI, other CoVs (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, (SARS-CoV-2) can lead to outbreaks of severe respiratory disease.
It can cause severe LRTI in immunocompromised cases.
Studies showed that interferon , high-dose steroids and supportive care treatment for SARS- COVID 1 have favourable outcomes
MERS-CoV infection can lead to severe respiratory illness and mortality rates as high as 50%.Treatment include ribavirin, interferon and steroids Adenovirus Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family with 7 subgroups (A-G) and 90 serotypes.
Infection can be due to reactivation or de novo infection ,commonly cause viremia which is asymptomatic .
Risk factors include younger age and intestinal transplantation. Clinical picture
Includes conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis and allografts affection.
In renal transplant recipients it presents with rising creatinine and fever of unknown origin.
Mortality can reach 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection. Prevention
Through droplet and contact precautions . Brincidofovir without nephrotoxicity showed benefits in treatment of adenovirus viremia in HSCT. Treatment
include supportive therapy ,reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational). Bocavirus
It is a single-stranded DNA virus of the Parvoviridae family. The co infection rate is high rendering it’s actual role unknown. KI and WU Polyomaviruses
Both are double-stranded DNA viruses of the Polyomaviridae family . HSCT recipients had higher infection rate with these viruses Respiratory Viruses and Rejection in Lung Transplantation
LTRs are at high risk for RTIs especially lower RTIs due to impaired mucociliary clearance, impaired cough reflex and greater immunosuppression compared to other organ transplants.
A systematic review demonstrated lack of association between respiratory viral infection and acute rejection.
Another study showed significantly high acute rejection rate and biopsy-proven bronchiolitis obliterans among cases having respiratory infections
Ribavirin decreased rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections .
The incidence of respiratory viral infection in SOT ranges between 0.76–0.91 episodes per patient-year higher incidence observed in lung transplants
Higher frequency observed in the autumn and winter
Clinical picture is almost the same for all respiratory viruses
Progression to LRTI occurs in 6.2-40% of cases
Attributable mortality of infections is 5.1% in one study
Diagnosis
PCR is the gold standard, with result appear within 12-24 hrs, with sensitivity of 72-100%
Antigen detection although has lower sensitivity but it is a rapid method for diagnosis (result within minutes) but applicable only for influenza and RSV
Culture and serology are old methods and now obsolete
Influenza virus
Single-stranded RNA virus, several strains available but only A and B are associated with disease
Infection occur mainly in winter between November and May in the Northern Hemisphere and May to October in the Southern Hemisphere
The incidence rate in SOT differ according to t transplant type with higher incidicne reported in lung compared to liver and kidney transplantation
The most common presenting symptom in immunocompromised patients was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), GIT symptoms (40%), sore throat (35%) then headache (30%).
Immunocompromised patients are at higher risk of hospitalization, ICU admission, death and influenza related complications including pneumonia, bacterial and fungal suprer-infection, pericarditis, myocarditis, myositis, encephalopathy and encephalitis.
Risk factors for severe disease includes older age, DM, multiple comorbidities, lymphopenia, the use of MMF and ATG (in the previos 6 months) and influenza A infetion
Prevention can be done by application of droplet precautions, and vaccination of transplant recipients together with their close contacts using inactivated vaccine
Vaccine although has lower efficacy in SOT compared to general population but decrease the incidence of pneumonia, complications and death among patient with SOT, it should be used before or at least 1 month after transplantation (should not be given within 1 month of transplantation)
Higher seroconversion rate can be obtained either by giving higher vaccine dose of giving a booster dose 5 weeks after the first dose
MMF decrease the seroconversion rate but it is not recommended to stop MMF to attain higher conversion rate
Prophylaxis using oseltamiver can be considered in patients not vaccinated either on exposure or in case of outbreaks, it should be given for 14 days and at least 7 days from the onset of symptoms of the last case
Treatment includes oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous), laninamivir (available only in Japan and South Korea), and Baloxavir . All are equivalent but should be initiated within 1-2 days of symptom onset, but may have benefit also if started after 2 days.
The recommended dose of oseltamiver is 75 mg twice daily for 5 days , in severe cases higher doses can be given (150 mg twice daily) for 10 days
Respiratory Syncytial Virus
RSV is a single-stranded RNA virus, 2 strains exists A and B
The incidence of infection increase in the winter and spring
Presents similar to other respiratory viruses but infect children more commonly and associated with higher incidence of progression to LRTI in SOT (72% )
Prevention can be done by applying contact precautions, and the use of palivizumab prophylaxis during the RSV season in immunocompromised children lower than 2 years old (not indicated in adults), but it is expensive. Nirsevimab is a novel monoclonal that can be given once per season with good outcome in preterm infants. Vaccines are under development and is recommended for elderly, pregnant and children.
Treatment includes ribavirin and IVIG (in severe cases) based on case reports. Presatovir is a new antiviral that failed to show improvement in outcome.
Human Metapneumovirus
Human Metapneumovirus is a single-stranded RNA virus.
The incidence of infection increase in the winter and spring
Presents similar to other respiratory viruses
Prevention can be done by applying contact precautions.
Treatment includes ribavirin which fail to demonstrate mortality benefit, on the other hand it may be associated with better outcome in the settings of lung transplantation
Parainfluenza Virus
Parainfluenza virus is a single-stranded RNA virus, 4 serotyes exists, with serotype 3 is the most common and it has no seasonal preference, on the other hand serotype 1 and 2 increase in winter and fall
Presents similar to other respiratory viruses but is associated with higher incidence of progression to LRTI in SOT.
Prevention can be done by applying contact precautions
Treatment includes ribavirin with mixed results
Rhinovirus
Rhinovirus is a single-stranded RNA virus, serotype A has no seasonal preference.
Presents similar to other respiratory viruses but is associated with higher incidence of progression to LRTI in SOT (41%).
Prevention can be done by applying droplet precautions
Treatment is generally supportive
Coronaviruses
CoVs are single-stranded RNA viruses
Presents similar to other respiratory viruses but is associated with higher rate of severe LRTI and mortality in SOT.
No clear benefit observed with the use of ribavirin
Adenovirus
Adenovirus is a double-stranded DNA virus, 90 serotypes was identified
It has no seasonal preference
Adenoviruses become latent in the lymphoid tissue, once immunity falls it can be reactivated
Viremia can occur while the patient is asymptomatic
Adenovirus infection usually is asymptomatic but can presents with conjunctivitis, upper, lower RTI, , hemorrhagic cystitis, pyelonephritis (may affect the graft and should be considered in cases of pyelonephritis), hepatitis and enterocolitis
Mortality in patient with adenoviral pneumonia is 50% and reach to 80% in dissiminated infection
Prevention can be done by applying both droplet and contact precautions, Brincidofovir is an orally bioavailable lipid conjugate of cidofovir without nephrotoxicity) is now tested for preemptive treatment of viremia in in HSCT recipients
Treatment includes reduction of immunosupresion, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational).
Introduction
· Soild organ transplantation is the standard of care for those individuals who suffer from end-stage organ failure. One of the problems associated with this procedure is infections especially respiratory viral infections. This issue is more common among lung transplant recipients and it is important cause of morbidity and mortality.
· The incidence ranges from 0.76 to 0.97 /patient/year throughout the year but mainly in the autumn and winter.
· It may progress to lower respiratory tract infection in up to 40% of cases with mortality around 5%
· All the viruses present with the same clinical picture
· The gold stranded for the diagnosis is Nucleic Acid Testing (NAT)
· The following are examples of respiratory viruses in solid organ transplantation
1.Infuenza virus
· Single stranded RNA virus of Orthomyxoviridae family
· Influenza A & B are responsible for human disease
· Seasonal viruses
· Risk factors are age (Extreme of age), immune suppression, and response to vaccination
· May present with fever, rhinorrhea, myalgia, GIT symptoms, sore throat and headache.
· Complications include viral pneumonia, superimpose bacterial infections, fungal infections, myopericarditis, myositis and encephalitis
· Prevention is mainly by inactivated vaccine in transplant population within one post-transplantation. The alternative is pre-exposure anti-viral prophylaxis by low dose oseltamivir.
· Treatment: The neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, and laninamivir) and the cap-dependent endonuclease inhibitor (baloxavir). The treatment should be started as early as possible even before the lab results and continued for 10 days.
2.Respiratory Synthcytial Virus (RSV)
· Single stranded RNA virus of pneumoviridae/paramyxoviridae family
· Two strains; A & B
· Seasonal mainly in winter & spring
· Largely affects children and they are the main source of transmission
· May progress to LRTI specially in children < 2 years, lung recipients, multi-visceral transplant and rejection. This is important cause of morbidity and mortality.
· Clinical picture is similar to other viruses but it has tendency to cause more LRTi
· Prevention: Avoid contacts, palivizumab in immunecompromised chidren < 2 years, Nirsevimab in preterm infants, and vaccine e.g., ResVax
· Treatment: Limited data in lung transplant, oral ribavirin has been used with some degree of success. New treatment on pipelines e.g., presatovir 3.Human Metapeumovirus (HMPV)
· This virus is similar to RSV
· LRTI occur in 3.6 to 6.8%
· Treatment: Ribavirin showed some benefit but in lung transplant , but these were small studies with limited data 4.Parainfuenza Virus (PIV)
· Single-stranded RNA virus of paramyoviridae family
· 4 Serotypes (serotype 3 is more prevalent)
· No seasonality
· Mainly LRTI resulting in respiratory failure in up to 20% of cases
· Treatment: no clear data, supportive and preventive measures are the best do 5.Rhinovirus
· Single-stranded RNA virus of the picornaviridae family (Enterovirus)
· Serotype A-C are the causes of common cold
· Occur in association with other viruses or bacteria
· Treatment is mainly supportive 6.Coronaviruses
· Single-stranded RNA of the corovaviridae family
· Associated with outbreaks of severe respiratory disease e.g., SARS-CoV1 (Southern China), MERS-CoV (Saudia Arabia, zoonotic transmission from Camels), SARS-CoV2 (Recent pandemic)
· LRTI in up to 17%
· High mortality rates 20 to 50% 7.Adenovirus
· Double-stranded DNA virus of the adenoviridae family
· May be dormant in lymphoid tissue
· No seasonality
· Common in children, intestinal transplant, and heavy immune-suppression
· May lead to pyelonephritis in renal recipient
· High mortality up to 80% in disseminated adenoviral disease
· Prevention is mainly by avoiding contacts
· Treatment: supportive, reduction of immune-suppression, and combination of cidofovir and IVIG. 8.Boca-virus
· Single-stranded DNA virus of parvoviridae family
· Rare
· Closely related to parvovirus B-19 9.KI and WU polyomaviruses
· Double-stranded DNA viruses of polyomaviridae family
· Discovered in 2007
· Found in 14% and 9% of kidney recipients respiratory specimen respectively Respiratory viruses and Rejection in Lung transplant
*LTR are at LRTI but the relationship between acute respiratory infection and rejection may not be linear. Conflicting data here and there.
*Risk factors for respiratory infections in LTRs are:
1. The allograft is open to the environment
2. Impaired mucociliary clearance
3. Impaired cough reflex
4. Higher amount of immune-suppression compared to other SOT
Conclusion
· Respiratory infections are important causes of morbidity and mortality in SOT particularly LTRs. Treatment is only limited to influenza and no prevention such as vaccination in most cases except for influenza. Therefore, the development of new antiviral treatment and vaccination are badly needed.
-Narrative review, level 5
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this very good article on respiratory viruses in transplant patients.
This article is about respiratory viral infections in SOT recipients. It is important to address this because of the significant morbidity and mortality that can caused by these infections. Added to this is the effect on the graft leading to acute rejection and chronic lung allograft dysfunction in lung transplant recipients. These infections can appear at any time post transplant, no just during hospital stay, but mainly from the community.
In this article, we are going to discuss a few of the major respiratory viruses and the impact caused by them on the graft and the patient.
Discussion
Traditional methods of diagnosis included viral culture, direct fluorescent antibody staining (DFA) and serology. The time frame for these tests were long, from a week to 10 days. In addition, it was difficult to accurately diagnose acute infection with these methods.
However, molecular techniques have changed these shortcomings, rendering traditional testing methods mostly obsolete. NAT for respiratory viruses are now the gold standard for diagnosis. Nucleic acid testing (NAT) has a sensitivity of 72-100%. Rapid antigen tests allow results within minutes, but are only clinically available fro influenza and RSV and have low sensitivity.
Influenza virus
Influenza virus is a single stranded RNA virus with multiple strains. These viruses are seasonal, mainly in winter. Infection rates are higher among children and degree of immunosuppression as wells likelihood of exposure all play a role in disease incidence.
Most common symptoms include cough, fever, sore throat, headache, rhinorrhoea, myalgia, GI symptoms. Immunocompromised patients are at increased risk of complications such as viral pneumonia, fungal confections, pericarditis, myocarditis, myositis, and encephalitis.
Risk factors included older age, diabetes, and use of MMF. Prevention includes vaccination of transplant recipients and close contacts. Live attenuated intranasal influenza vaccine is contraindicated for solid organ transplant recipients because of the risk of dissemination of virus. American society of Transplantation recommends vaccinating with inactivated influenza vaccine one month post transplant.
Treatment includes neuraminidase inhibitors(NAIs) such as oseltamivir, zanamivir, peramivir, and laninamivir.
Respiratory syncytial virus
RSV is a single stranded RNA virus with two strains – RSV A and RSV B. It is a seasonal virus, infecting mainly in winter and spring. Young children are affected the most and they also serve to disseminate the virus.
Clinical features include cough, fever, dyspnoea, and rhinnorhea. RSV is more effective in causing lower RTI such as bronchitis, bronchiolitis, and pneumonia, in comparison with other respiratory viruses.
Prevention include palivizumab prophylaxis around the RSV season in children under 24 months of age.
Treatment includes ribavirin and IVIG. Newer antivirals includes presatovir and ziresovir.
Human Metapneumovirus
HMPV is a single stranded RNA virus, affecting mostly in the winter and spring. Antivirals and immunomodulators are not enough to treat.
However, favorable outcomes can be seen with ribavirin with or without steroids. Current treatment is based primarily on supportive care.
Prevention is mainly based on infection control such as implementation of contact precautions among hospitalized patients.
Parainfluenza virus
Parainfluenza virus is a single stranded virus and does not show any seasonality. PIV infection is associated with a high rate of symptomatic disease and lower RTI.
There is mixed response when it comes to the use of antivirals for this infection. Currently, the mainline treatment for PIV involves supportive care and prevention in the hospital setting based on adherence to contact precautions.
Rhinovirus
Rhinoviruses are single stranded RNA viruses and are the cause for the common cold. Symptoms are similar to common cold, but case reports suggest lower RTI in LTRs. More symptoms may indicate higher viral load. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronavirus
Coronaviruses are single stranded RNA viruses. The virus is associated with lower RTI and high mortality. In vitro studies identify that ribavirin and interferon can give better outcome along with supportive care.
Adenovirus
Adenovirus can cause viremia without obvious clinical symptoms, with rates of infection higher among children, perhaps because they are likely to be non-immune. Intestinal transplant recipients also have a higher risk of infection due to the higher amount of lymphoid tissue in the allograft and more intensive immunosuppressive regimen.
Clinical symptoms include conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis. Infection transmission routes include respiratory droplets, direct conjunctival inoculation, person to person contact, infected somites, and faeco-oral route. Prevention includes maintenance of droplet and contact precautions.
Treatment includes supportive care, and reduction of immunosuppression, along with cidofovir, brincidofovir, IVIG and adenovirus specific cytotoxic T lymphocytes.
Bocavirus
Bocavirus is a single stranded DNA virus that usually appears in conjunction with other respiratory viruses. These viruses are very persistent and their contribution to RTIs is unknown.
KI and WU polyomaviruses
These viruses are double stranded DNA viruses that have a higher rate of infection among HSCT recipients. Clinical significance is unclear.
Respiratory virus and lung transplant
Lung transplant recipients are at increased risk for RTIs in general and lower RTIs in specific. This could be attributed to continuous contact of allograft with the environment, impaired mucociliary clearance, impaired cough reflex, and a relatively greater level of immunosuppression compared to other organ transplants.
Treatment with ribavirin is associated with lower rates of CLAD/Bronchilitis obliterates syndrome (BOS).
Conclusion
Respiratory viruses can cause significant morbidity and mortality among solid organ transplant recipients. Although traditional testing methods have worked in the past, molecular testing provides more quicker and accurate results which allow the transplant team to identify problems in a timely fashion and treat the patient appropriately so that both th patient and the graft are adequately protected. Preventive measures need to be developed further so that the incidence of respiratory infection is lower in immunosuppressed patients. Vaccination seems to be the only major preventive measure for most of these viruses, along with contact precautions in the hospital setting. Further studies are needed to standardize preventive measures and develop newer and more effective prevention. Development of new antivirals and vaccines is needed.
Level of evidence
This is a narrative review, and thus level of evidence is 5.
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this very good article on respiratory viruses in transplant patients.
This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV),adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
The incidence of respiratory viral infections in transplant recipients ranges between 0.76-0.91 episodes per patient-year, with higher incidence in the autumn and winter.
Rates of progression to lower respiratory tract infection (RTI) vary between the different studies and ranges between 6.2-40% in LTRs.
Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1%.
——————————————————————————————————————-
Diagnosis
Historically, viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infections, but these methods have become obsolete due to the advent of molecular strategies.
Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72-100%.
Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity.
—————————————————————————————————————
Influenza virus
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
It is seasonal, circulate mainly in the winter and cause a significant proportion of RTIs.
The incidence of influenza infections in 3569 SOT recipients between 1990 and 2000 calculated an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants.
Immunocompromised individuals are at increased risk for complications, such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc.
Risk factors associated with severe disease include older age, diabetes and use of mycophenolate mofetil.
Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness, and are at increased risk for pneumonia or ICU admission due to multiple comorbidities.
Cough was the most common symptom, followed by fever, rhinorrhea, myalgia, gastrointestinal symptoms, sore throat, and headache.
Prevention
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions and vaccination of the transplant recipient and close contacts is the most important means for prevention.
Only inactivated influenza vaccines should be given to transplant recipients, as there is a theoretical risk of dissemination of virus contained in the live attenuated intranasal influenza vaccine.
Immunogenicity of influenza vaccine in SOT is variable, but generally lower compared to a non immunocompromised population.
Vaccination has been shown to decrease influenza infection rates, complications and mortality in the SOT population, with a large prospective multicenter study on 616 transplant recipients showing that vaccination in the same influenza season was associated with a reduction in odds for pneumonia and admission to the ICU.
However, several studies have evaluated different vaccination strategies and had variable outcomes.
The 2019 guidelines by the American Society of Transplantation recommend that high dose vaccination is the preferred strategy, although two doses of standard vaccine could also be used.
Antiviral prophylaxis using low-dose oseltamivir was evaluated among 477 transplant recipients, mostly SOT, and demonstrated 80% efficacy against PCR-confirmed influenza.
Guidelines published by The Infectious Diseases Society of America recommend that antiviral pro-phylaxis should be given in the case of a hospital outbreak to patients in the affected wards.
Treatment
There are three groups of drugs approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine) and Baloxavir (available only in Japan and South Korea).
NAIs are a selective inhibitor of influenza cap-dependent endonuclease and have been shown to be effective in uncomplicated influenza in the non-immunocompromised population.
There have been no trials comparing drugs, doses or treatment durations in the SOT population.
Observational studies in SOT recipients show that early antiviral treatment (within 24-48 h) is associated with a decrease in influenza complications and lower ICU admission rates.
Treatment should be started empirically as soon as possible, usually before test results are available. Some experts may choose to use high doses in cases of severe disease.
Several monoclonal antibodies targeting various hemagglutinins of influenza virus have been developed, but phase three studies showed they were unlikely to be of benefit.
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes subthera-peutic.
M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains.
Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain.
Several case reports of emergent resistance during NAI use have been published, mainly among patients with hematological malignancies or after stem cell trans-plants.
Treatment options include changing NAIs, changing to a different antiviral class, or combination antivirals.
==================================================================== Respiratory Syncytial Virus Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children.
Risk factors include young children, recent transplant, lung or multivisceral transplant, and recent rejection.
Clinical Manifestations
RSV presents with fever, cough, dyspnea and rhinorrhea, leading to lower RTI rates than other respiratory viruses.
Prevention
The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, but this recommendation is not evidence-based.
Monoclonal antibody development is focused on developing antibodies with extended half-lives, such as Nirsevimab, which can be given once per season and has shown favorable results in a randomized trial.
Vaccines are under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based.
ResVax is the most advanced, but a recent phase three trial of this vaccine in pregnant women did not reduce RSV infections in infants after birth.
Treatment
Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
However, data in lung transplants are of low quality.
One case series published in 2011 compared 38 patients treated with oral ribavirin with 29 patients that received systemic ribavirin.
Oral ribavirin treatment was associated with improved graft function and reduction in bronchiolitis obliterans syndrome in lung transplant recipients with lower RTI due to RSV.
Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells.
However, phase 2b RCTs failed to show significant improvements in clinical and virologic outcomes in the presatovir group, except for a possible decrease in progression to lower RTI in lymphopenic HSCT recipients.
Several new drugs targeting RSV are currently under development, but none have reached phase three trials.
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. It is mainly studied in LTRs, where it accounts for 3.6-20.9% of the respiratory viruses isolated.
It is associated with a high rate of symptomatic disease and lower RTI. Utility of antivirals for PIV infection in SOT is unknown.
DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, but is not currently FDA approved.
Supportive care and prevention in the hospital setting is based on adherence to contact precautions.
Coronaviruses are single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs).
Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, while other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
Studies have shown that immunocompromised and immunocom-petent children have a similar rate of lower RTI in the two groups (22% and 26%, respectively).
In vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen.
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and 90 serotypes.
It is known to cause viremia without obvious symptoms, and in a study of 263 SOT recipients, 7.2% (19/263) developed viremia, but only 4/19 (21%) were symptomatic.
Rates of infection differ with age and the transplanted organ.
Clinical Manifestations
Adenovirus infectioncan cause conjunctivitis, upper RTI, lower RTI, hemor-rhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and can be fatal.
Prevention
Brincidofovir is an orally bioavailable lipid conjugate that is not FDA approved and the appropriate dose for treatment of adenovirus is not established.
Treatment
Adenovirus disease treatment options include reduction of immunosuppression, cidofovir, brincidovir, IVIG, and adenovirus-specific cytotoxic T lymphocytes, with promising results in 13 liver transplant recipients.
Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other viruses, making its true contribution to RTIs unknown.
=================================================================== KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri-dae family, with higher frequency in HSCT recipients.
=================================================================== Respiratory Viruses and Rejection in Lung Transplantation
LTRs are at increased risk for RTIs due to continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression.
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS).
A systematic review and meta-analysis found no association, but a study on 100 LTRs showed significantly higher rates of acute rejection.
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections.
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this very good article on respiratory viruses in transplant patients.
Typing whole sentence in bold amounts to shouting.
Summary Introduction:
New respiratory viruses and serotypes are found often, affecting immunocompromised organ transplant patients. This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, as they relate to organ transplant recipients. Lung transplant research will dominate the discussion. This evaluation does not concentrate on hematopoietic stem cell transplantation, however, findings from this group will guide organ transplant therapy. This series will cover the SARS-CoV-2 epidemic.
Influenza Virus: cinical manifestation
Immunocompromised people may not have influenza. Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms.
Complications are also more common in immunocompromised people. They include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis. Treatment:
M2 inhibitors (amantadine and rimantadine) are not utilized since they are inactive against influenza B while circulating influenza A strains are resistant. The most regularly used NAIs are oseltamivir, zanamivir, peramivir, and laninamivir (available only in Japan and South Korea). Recently licensed baloxavir provides a unique method of action. The single-dose oral medicine selectively inhibits influenza cap-dependent endonuclease. It works for uncomplicated influenza in non-immunocompromised people.
Baloxavir may work better than NAIs against influenza B strains.
Respiratory Syncytial Virus: Symptoms
RSV, like other respiratory viruses, causes fever, cough, dyspnea, and rhinorrhea. RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses. LTRs have decreased RTI rates as much as possible. Therapy
Lung transplant care differed from other organs in a US assessment of 11 transplant hospitals. All 10 lung transplant facilities treat lower RTI with ribavirin, and three add IVIG, whereas only 6/10 treat upper RTI and none offer IVIG.
Human Metapneumonia:
HMPV, a Pneumoviridae virus, is similar to RSV. Like RSV, most occurrences occur in winter and spring. LTRs found HMPV in 3.6–6.8% of positive respiratory samples. 8/18 (44%) of these individuals had a lower RTI.
Ribavirin fights HMPV in vitro. Antivirals and immunomodulators do not reduce mortality in HSCT patients.
Parainfluenza:
PIV is a single-stranded RNA paramyxoviridae virus.
PIV has four serotypes (1–4): serotype 3 is the most frequent, has no seasonality, and has caused outbreaks, whereas serotypes 1 and 2 occur in the autumn and winter. In LTRs, PIV infection accounts for 3.6–20.9% of respiratory viruses isolated.
After post hoc analysis, the highly immunocompromised category had better results. DAS 181 is FDA-unapproved. Therefore, supportive care is the core of PIV infection therapy, and hospital prevention relies on adherence to protocols.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses of the Picornaviridae family of enteroviruses. Serotypes A–C produce most colds year-round.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviride viruses are single-stranded RNA. Established human CoVs (229E, NL63, OC43, and HKU1) induce upper respiratory tract infections (RTI), whereas others (SARS-CoV1, MERS-CoV, and SARS-CoV-2) produce outbreaks.
One kidney transplant recipient recovered. Ribavirin, interferon, and steroids were administered in case reports. MERS-CoV still produces some Middle Eastern illnesses.
Adenovirus:
Adenoviridae’s double-stranded DNA virus Adenovirus contains seven subgroups (A-G) and over 90 serotypes. Latency in lymphoid tissue allows adenoviruses to reactivate or create a new colony.
IVIG is sometimes used with antivirals. HSCT patients with cytomegalovirus and Epstein–Barr virus infections may benefit from virus-specific cytotoxic T cells.
HSCT adenovirus data is sparse.
Lung Transplant Rejection and Respiratory Viruses:
LTRs are at higher risk for RTIs, especially lower RTIs. Continuous contact with the environment, decreased mucociliary clearance, cough reflex, and more immunosuppression than other organ transplants may cause this. Many studies have examined the relationship between respiratory viral infection and acute rejection, or CLAD/bronchiolitis obliterans syndrome (BOS), with inconsistent results.
The review highlights the severity of respiratory viral infections in SOT recipients and their significant impact on morbidity and mortality.In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year
Dignosis with Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%
The article has very good table attached in pic with the treatment options and drug dosing for common viruses
Incidence of respiratory viral infection among organ transplant recipients range from 0.76-0.91episode/patient-year.
Incidence higher in LTR, but it is not affected by time from transplantation.
Can occur all over the year, but higher incidence in autumn & winter.
The symptoms are similar in all respiratory viruses.
Progression to lower RTI range 6.2%-40% I LTR & mortality in 5.1%.
Diagnosis:
viral culture: need long time (10days for standard viral culture & 2 days for shell viral culture).
DFA staining: available only in limited number of respiratory centers & need expertise in interpretation of data.
Serology: useful only for epidemiological studies & not for diagnosis of acute infection.
NAT: gold standard for diagnosis with sensitivity 72%-100%. Multiplex NAT can test several viruses simultaneously in only 12-24hours.
Rapid antigen test: results within minutes, low sensitivity, available for influenza virus & RSV.
Influenza virus:
ssRNA, only A & B strain affect human.
It is seasonal virus mainly in winter.
Influenza attack depend on age(high in children), likelihood of exposure, level of immunity, degree of immunosuppression & nature of epidemic.
Immunocompromised patient may not present classic influenza like illness & associated with increased risk of complication e.g. viral pneumonia, pericarditis, bacterial superinfection, fungal confection, myocarditis, myositis, encephalitis).
Risk factors associated with severe disease include: age, DM, use of MMF, ATG use in past 6 months, lymphopnea, hypogammaglobulinemia.
Most important preventive measure is vaccination & in hospital is droplet precaution.
Only inactivated virus vaccine should be given to transplant recipient. AST recommend vaccine within 1 month post transplantation.
AST recommend use of high dose vaccine as preferred strategy, but 2 doses of standard vaccine could be used.
Oseltamivir recommended as prophylaxis in hospital outbreak to patient in affected ward.
Drugs used in treatment are M2 inhibitors(not used today), NAIs(commonly used) & Baloxavir. No drug superior over others but early treatment (24-48 hours) associated with reduce complication & lower ICU admission.
Favipiravir is the only drug licensed in Japan with low resistant rate.
Monoclonal Abs tested in phase II trials as monotherapy or in combination with antivirals.
Drug resistant risk increased in ICU patients which can be overcome by changing to different NAI, changing to different antiviral class or combination antiviral.
RSV:
ssRNA virus, 2 strain RSV-A & RSV-B.
Seasonal virus with peak in winter & spring, mainly affect children.
Risk factors for lower RTI include young children, recent transplant, lung or multi visceral transplant & recent rejection.
Similar clinical presentation to other respiratory viruses but it cause more frequent lower RTI as bronchitis, bronchiolitis & pneumonia.
Prevention: in hospital by contact precaution & monoclonal Abs & vaccine in elderly, pregnant & paediartic.
Treatment: ribavirin with IVIG for lower RTI. New antiviral presatovir ,fusion inhibitor & replication inhibitors.
Human Metapneumonia:
ssRNA, mainly in winter & spring.
ribavirin demonstrate favorable graft outcome in LTR.
Parainfluenza virus (PIV):
ssRNA, 4 serotypes (1-4)
Most common serotype is 3 with no seasonality, associated with out breaks, serotype 1 & 2 occur in fall & winter.
In LTR associated with high rate of symptomatic disease & lower RTI.
Treatment is supportive.
Rhinovirus:
ssRNA virus, serotypes A-C, circulate year round, & it is the main cause of common cold.
Frequently found as co-infection with other bacterial or viruses.
Treatment is supportive.
Coronavirus:
ssRNA virus.
Human CoV cause upper RTI, other CoV associated with outbreaks of severe respiratory diseases.
SARS-CoV-1 associated with high rate of Lowe RTI & mortality as high as 20%.
Treatment is IN, high dose steroid & supportive care.
MERS-CoV infection associated with severe respiratory disease & mortality reach 50%. Treatment with INF, ribavirin & supportive.
Adenovirus:
dsDNA virus, 7 subgroups A-G, 90 serotypes.
Infection can be reactivation or de novo.No seasonal variability.
High infection rate in children( non immune) & intestinal transplant (high lymphoid tissue in graft & high immunosuppression dose).
50% mortality in adenovirus pneumonia & 80% for disseminated adenovirus infection.
Prevention in hospital based on maintaining droplet & contact precaution.
Treatment: Supportive care, reduction of immunosuppression , cidofovir, brincidofovir(investigational), IVIG & adenovirus specific cytotoxic T cells(investigational).
Bocavirus:
ssDNA.
Usually presented co-infection with other viruses.
It is known for virus persistence & high co-infection rate make true contribution of RTI unknown.
KI & WU polyomavirus:
dsDNA.
HSCT recipients have higher frequency of infection.
In KTR KI virus found in 14.3% & WU virus found in 9.1% of respiratory specimens
Unclear clinical significance.
Respiratory viruses & rejection in lung transplant recipients:
LTR are at increased risk of RTI in general & specifically lower RTI & this increased risk due to:
continuous contact of graft with environment.
impaired mucociliary clearance.
impaired cough reflex.
high immunosuppression dose compared to other organ transplant.
Ribavirin associated with lower rate of CLAD/BOS in LTR with RSV, HMPV & PIV infection.
Respiratory viruses are common culprits for severe infection in post transplant patients.Particularly, in lung transplantation, its associated with detrimental consequences on the short and long term outcomes. It was reported to be associated with higer incidence of acute and chronic rejections. Several DNA and RNA viruses are observed including;
1]Influenza virus.
2]Para-influenza vs.
3]Respiratory syncytial vs.
4]Corona vs.
5]Rhinovirus.
6]Adenovirus
7]KI and WU polyomavirus.
With exception of influenza virus,, unfortunatelly, there is no definite prophylactic or therapeutic strategy to follow.
The incidence of viral infection post transplantation hover above 0.7-0.9 per patient per year. The incidence is more common on autumn and winter. Respiratory viral infection presentation is common for all of the viruses, with no particular differentiating features.
Progression to lower respiratory tract infection is variab between 6-40%.
Nucleic acid testing is the gold standerd for diagnosis with sensitivity of 72-100%.
Influenza viral infection:
Its RNA virus with common presentations include cough, fever, gastrointestinal tract symptoms and headache.It might differ from the classic influenza like illness. Its associated commonly with variable complications include:
1] pneumonia. bacterial and fungal superinfection
2] Encephalitis.
3] pericarditis and myocarditis.
4] myositis.
Prophylaxis:
Inactivated virus vaccin is the gold slandered, prophylactic anti viral is another strategy to protect against potential infection.
Treatment
Neuraminidase inhibitors is the most commonly used medicine for influenza include oseltamivir. Drug resistance is emerging in the treatment, The current options are to change to another medications.
Level of evidence 5
1. Please summarise this article.In recipient post-transplantation the incidence of respiratory viral infection ranges between 0.76-0.91 episodes per patient per year. It was higher in Lung transplant. There is higher incidence in the autumn and winter.Epidemiology;Influenza virus is a single stranded RNA virus. There are multiple strains but A,B are involved in human infections.Clinical presentations;The most common symptoms was cough followed by fever, myalgia, rhinorrhea, sore throat, and GI symptoms.Prevention;Vaccination, there is some risk of dissemination of risk of contaminated vaccine.Treatment;There are different groups of drugs approved like, M2 inhibitors (risk of resistance).Neuraminidase inhibitors the most commonly used.Newer agent the Baloxavir its single dose oral medication. Its more effective then the NAIs.2. What is the level of evidence provided by this article?Level V
Respiratory viruses are a significant cause of morbidity and mortality among transplant recipients. Detection is better with the use of molecular diagnostic methods. Effective therapies are available only for influenza, and also to some extent for RSV infection. Preventive measures are also lacking, as vaccination is only available against influenza at this time.
Level of evidence is 5
Please summarise this article.
Introduction:
Respiratory viruses have a significant impact on the health of immunocompromised organ transplant recipients, with the incidence of respiratory viral infections ranging from 0.76-0.91 episodes per patient-year. This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV,adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
Diagnosis:
Nucleic acid testing (NAT) is now the gold standard for diagnosing respiratory viral infections and has a sensitivity of 72-100%. Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity.
Influenza Virus:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. It is seasonal, circulating mainly in the winter and causing a significant proportion of RTIs. Immunocompromised individuals are at increased risk for complications, such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc. Risk factors associated with severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic.
Prevention : Influenza vaccination is the most important means of prevention for transplant recipients and close contacts, and has been shown to decrease infection rates, complications and mortality. Antiviral prophylaxis is recommended to prevent influenza infection in transplant recipients, but there is concern that some may develop antiviral resistance.
Treatment: Three groups of drugs are approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, which has a novel mechanism of action and is a single dose oral medication.
Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and patients with symptoms > 48 h should be treated.
Treatment for influenza should be started empirically as soon as possible, usually before test results are available. Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, and M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain.
Respiratory Syncytial Virus:
RSV is a seasonal virus with peak incidence in the winter and spring and is a significant source of transmission in LTRs. Risk factors for lower RTI and mortality include young children, recent transplant, lung or multivisceral transplant and recent rejection. Clinical presentation is similar to other respiratory viruses, but RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
Palivizumab prophylaxis is not given to adult SOT recipients, and monoclonal antibody development is focused on developing antibodies with extended half-lives. Ribavirin treatment is associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
Presatovir is a new antiviral with specific anti-RSV activity, but two phase 2b RCTs failed to show significant improvements, and 20% of patients developed resistance.
Human Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Studies have identified HMPV in 3.6-6.8% of positive respiratory samples, and 8/18 (44%) had a lower RTI. Ribavirin has in vitro activity against HMPV, but data derived from HSCT recipients do not demonstrate a mortality benefit. Prevention is mainly based on infection control practices, including contact precautions in hospitalized patients.
Parainfluenza Virus:
PIV is a single-stranded RNA virus of the Paramyxoviridae family, and is associated with a high rate of symptomatic disease and lower RTI. Treatment is based on supportive care and prevention in the hospital setting.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviruses are single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs). Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, while other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2) are associated with outbreaks of severe respiratory disease. Human CoVs are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. Studies on 85 immunocompromised and 1152 immunocompetent children .demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively). In-vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen.
Adenovirus:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes, and can cause viremia without obvious symptoms. Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route, and prevention is based on maintaining droplet and contact precautions. Treatment options include reduction of immunosuppression, brincidofovir, IVIG and adenovirusspecific cytotoxic T lymphocytes.
Bocavirus:
Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making its contribution to RTIs unknown.
KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family, with higher frequency in HSCT recipients.
Respiratory Viruses and Rejection in Lung Transplantation:
LTRs are at increased risk for RTIs due to continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression. Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections.
Summary:
Development of new antivirals and vaccines is needed to reduce respiratory viral infections in the immunocompromised population.
What is the level of evidence provided by this article?
level V
Introduction
New respiratory viruses and serotypes often affect immunocompromised organ transplant recipients. Organ transplant recipients get 0.76–0.91 respiratory virus infections each year. Lung transplant recipients (LTRs) have greater rates of respiratory infections. In this review, influenza, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, adenovirus, bocavirus, and KI and WU polyomaviruses affecting immunocompromised organ transplant recipients are discussed.
Influenza virus
Influenza is a single-stranded RNA Orthomyxoviridae virus that can cause difficulties in immunocompromised people.
Risk factors for severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and nature of the epidemic.
Influenza vaccination is the best way to prevent the disease. Drugs approved to treat influenza: Neuraminidase inhibitors (NAIs); M2 inhibitors (Amantadine and Rimantadine); and Baloxavir; single-dose oral memantine with a novel mechanism of action.
Respiratory Syncytial Virus (RSV):
RSV is winter and spring season virus – a major cause of transmission in LTRs.
Young children, recent transplant, lung or multi-visceral transplant, and rejection are risk factors for lower RTI and mortality. Clinical presentation is comparable to other respiratory viruses, but RSV more often causes lower RTI, including bronchitis, bronchiolitis, and pneumonia. Ribavirin reduces lower RTI mortality and higher RTI progression.
Human Metapneumovirus (HMPV): a single-stranded RNA virus belonging to Pneumoviridae family that resembles RSV in many ways. Although ribavirin has in vitro efficacy against HMPV, data from HSCT recipients do not show reduction in mortality. Mainstay of prevention are infection control procedures, such as contact precautions.
Parainfluenza Virus: single-stranded RNA virus belonging to the Paramyxoviridae family that is known to cause higher symptomatic illness, and lower rate of RTI. In a hospital context, treatment is based on preventative measures and supportive care.
Coronaviruses (CoV):
Single-stranded RNA Coronaviridae viruses that cause upper respiratory infections (RTIs). 12.4-17.8% of LTR positive samples are human CoVs, second only to rhinoviruses. Among 85 immunocompromised and 1152 immunocompetent children, RTI was 22% and 26%, respectively. Ribavirin and interferon were active against the virus in-vitro, but there was no therapeutic benefit.
Adenovirus
Adenoviridae double-stranded DNA virus with seven subgroups and 90 serotypes that can induce viremia without symptoms. Droplet and contact precautions prevent adenovirus infections, which are spread through respiratory droplets, direct conjunctival inoculation, person-to-person contact, contaminated fomites, and the fecal–oral pathway. Reduce immunosuppression, Cidofovir, Brincidofovir, IVIG are the mainstay therpy.
Treatment Summary:
1. M2 inhibitors – amantadine, rimantadine – for influenza
2. Neuraminidase inhibitors (NAIs) – oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea) – for influenza
3. Ribavirin – for RSV, Human Metapneumovirus, PIV
4. IVIG – for RSV, Adenovirus
Prevention Summary:
1. Droplet precaution (Influenza, Rhinovirus, Coronavirus, Adenovirus)
2. Contact precaution (RSV, Human Metapnumovirus, PIV, Coronavirus, Adenovirus)
3. Vaccination (Influenza, Coronavirus)
5. Antiviral prophylaxis – PEP with oseltamivir (influenza), palivizumab, nirsevimab (RSV), Brincidofovir; Adenovirus (Not yet approved by FDA)
Conclusions
In SOTRs, respiratory viral illness are substantial cause of mobility and mortality.
Only a few respiratory viruses, including the flu virus, have effective treatments.
As only influenza virus vaccine is available for clinical use; other preventive measures, supportive treatments and contact precautions are mandatory.
Research for novel antivirals and vaccines are necessary, particularly in light of the serious effects that individuals with impaired immune systems experience from respiratory virus infections.
Level of evidence: Systematic Review, level V
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year, although part of the studies also included asymptomatic infections. The incidence appears to be higher among lung transplant recipients (LTRs), but is not affected by time from transplant. Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses.
Influenza Virus
Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There are multiple strains, although only influenza A and B are generally associated with disease in humans. Influenza viruses are seasonal, circulate mainly in the winter (months Novem- ber to May in the Northern Hemisphere and May to October in the Southern Hemisphere), and cause a significant proportion of RTIs during that time.
Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness. In a prospective multicenter study including 477 SOT recipients and 139 patients after hematopoietic stem cell transplant (HSCT) with confirmed influenza infection, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) . Immunocompromised individuals are also at increased risk for complications.
Prevention
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions as outbreaks in the hospital setting have been described. However, the most important means for prevention is vaccination of the transplant recipi- ent and close contacts.
Only inactivated influenza vaccines should be given to transplant recipients. There is a theoretical risk of dissemination of virus contained in the live attenuated intranasal influenza vaccine, which is therefore contraindicated for SOT recipients [20]. The inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains. Previous trivalent formulations are being phased out.
Treatment
There are three groups of drugs approved for the treatment of influenza . M2 inhibitors (amantadine and rimantadine) are not used today since they are inherently inactive against influenza B and circulating influenza A strains carry a high rate of re- sistance. The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea). Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single dose oral medication. It has been shown to be effective in uncomplicated influenza in the non-immunocompromised population . Baloxavir may also be more effective against influenza B strains than NAIs
Respiratory Syncytial Virus
Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyx- oviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children, who are a significant source of transmission .In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens and is a cause of significant morbidity and mortality due to the development of lower RTI
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection
Clinical Manifestations
The clinical presentation of RSV is similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea . Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia . This is especially true for LTRs, where lower RTI rates can be as high as 72%.
Prevention
Hospitalized patients should be placed under contact precautions as RSV droplets form large particles and are transmitted by contact. The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based . A survey conducted among 67 pediatric SOT centers in the US revealed that approximately half of these centers use palivizumab prophylaxis.
Treatment
A survey conducted in 11 transplant centers in the United States revealed differences in treatment regimens in lung transplant compared to other organs. Among 10 lung transplant centers all treat lower RTI with ribavirin and three centers add intravenous immunoglobulin (IVIG), whereas only 6/10 centers treat upper RTI with ribavirin and none give IVIG. Among 11 non-lung transplant centers 7/11 treat lower RTI with ribavirin and only one center adds IVIG, whereas in upper RTI no center gives treatment [61]. Data on treatment for RSV infection in SOT recipients are limited to case series in lung transplants .Data in the HSCT population are slightly more robust and include larger case series, prospective cohorts and one small RCT.
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Its seasonality also follows that of RSV, with most cases identified in the winter and spring . Studies conducted on LTRs identified HMPV in 3.6–6.8% of positive respiratory samples . Most of these patients had symptoms of RTI, and in one study cohort, 8/18 (44%) had a lower RTI.
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. There are four serotypes of PIV ,serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter
As with other respiratory viruses, PIV infection was mainly studied in LTRs, where it accounts for 3.6–20.9% of the respiratory viruses isolated
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI [2]. In a study on 24 LTRs with PIV infection, mostly PIV3, 21% experienced respiratory failure.
Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus. Serotypes A–C circulate year-round and are the predominant cause for the common cold
As such, these viruses are isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients. In studies among LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6% of the positive samples
One study compared infection rates in 36 LTRs with a cohort of 235 immunocompromised and immunocompetent patients, and showed a higher infection rate among LTRs (41.7% vs. 14.5%, p < 0.001)
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. This review will not cover infections caused by SARS-CoV-2.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples
Symptoms are generally similar to other respiratory viruses. A study on 85 immunocompromised and 1152 immunocom- petent children demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively); however, the immunocompromised group had a significantly higher rate of severe lower RTI [84]. Studies done on LTRs and HSCT recipients [85] showed comparable rates of lower RTI.
Adenovirus
Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes [97]. Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition
Adenoviruses show no seasonal variability and have been associated with institutional outbreaks
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
In a study of 263 SOT recipients, adenovirus in blood was checked at regular intervals during the first year post- transplant. As much as 7.2% developed viremia; however, only 4/19 (21%) were symptomatic
Clinical Manifestations
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemor- rhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephri- tis
Mortality can be as high as 50% for adenoviral pneumonia and 80% for dis- seminated adenoviral infection [102]. Although in most cases there are no long term sequelae [103,106], development of bronchiolitis obliterans has been described in lung transplant recipients
Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precau- tions
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. It was tested in a phase two RCT for pre- emptive treatment of adenovirus viremia in HSCT recipients and showed benefits however, it is not FDA approved and the appropriate dose for treatment of adenovirus is not established.
Treatment
Data on treatment modalities for adenovirus disease are derived from case reports and small case series. Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus- specific cytotoxic T lymphocytes (investigational). Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression . Contemporary data, the largest series being 13 liver transplant recipients, show promising results with the use of brincidofovir as well as with its use in combination with the reduction of immunosuppression
Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses
Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples. Additionally, similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence
This, combined with the high co-infection rate, makes their true contribution to RTIs unknown.
KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri- dae family that were discovered in 2007. Studies in HSCT recipients suggested a higher frequency of infection with these viruses
A study done in kidney transplant recipi- ents identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively [118]. However, it is still unclear whether this has any clinical significance
Respiratory Viruses and Rejection in Lung Transplantation
As previously mentioned, LTRs are at increased risk for RTIs in general and specif- ically lower RTIs [4]. This may be related to continuous contact of the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and a relatively greater immunosuppression compared to other organ transplants. Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data
A systematic review and meta-analysis published in 2011 demonstrated no association between respiratory viral infection and acute rejection, although only four studies were included in the analysis. It also showed a non-significant trend towards association with BOS, but that was limited by small numbers
Level V
1) Introduction:
Respiratory viral infections (RNA and DNA viruses) are one of the most common infections in solid organ transplant recipients having similar symptoms and clinical presentation, with incidence ranging from 0.76-0.91 episodes per patient-year, being higher among lung transplant recipients.it presents throughout the year with high incidence in autumn and winter.
Lack of data on mortality associated with viral pneumonia in solid organ transplantation.
2) Diagnosis:
viral culture, direct fluorescent antibody (DFA) staining and serology were previously used.
Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72–100%.
3) influenza virus:
It is a single-stranded RNA virus of the Orthomyxoviridae family with multiple strain but A and B associated with the disease which is seasonal mainly in winter.
Risk factors include: age (with higher rates in children), likelihood of exposure, level of immunity (due to prior vaccination or disease), degree of immunosuppression and the nature of the epidemic.
Clinical presentations are cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache. immunosuppressed patients have increased risk of complications like pneumonia, fungal or bacterial coinfection, pericarditis, encephalitis
Prevention: droplet precautions, vaccination (requiring high-dose) and antiviral prophylaxis
Treatment: neuraminidase inhibitors (oseltamivir, zanamivir, pramivir), baloxavir, and M2 inhibitors (amantadine and rimantadine, not used nowadays). Early antiviral treatment is associated with lower complications and ICU admissions. Symptomatic SOT recipients should be treated irrespective of duration of the symptoms.
4) Respiratory Syncytial Virus:
It is a single-stranded RNA virus of the Pneumoviridae family with two strains: RSV-A and RSV-B and it a seasonal virus with peak incidence in the winter and spring. presented with fever, cough, dyspnea and rhinorrhea.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection
Prevention: contact precautions, monthly palvizumab prophylaxis in children <2 year age during the RSV season, and nirsevimab once every season. Multiple vaccines are also available, especially for elderly, pregnant, and pediatric population.
Treatment: URTI: Ribavirin
LRTI: Ribavirin with or without IV immunoglobulin
Presatovir has been shown to reduce progression to LRTI in lymphopenic hematopoietic stem cell transplant (HSCT) recipients.
5) Human metapneumovirus (HMPV):
It is a single-stranded RNA virus of the Pneumoviridae family like RCV
Prevented by contact precautions
Treated by supportive care
6) Parainfluenza virus (PIV ) :
it is single strand RNA virus of the Paramyxoviridae family. It has 4 serotypes type 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter. symptoms like other respiratory viruses PIV3, 21% experienced respiratory failure. treated by supportive care and prevented by contact precautions.
7) Rhinovirus:
It is a single stranded RNA virus of Picornaviridae family,
It has 3 serotypes (A,B,C), causing common cold and most common in lung transplant patients. treated by supportive care and prevented by contact precautions.
8) Coronaviruses (CoV) :
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. SARS COV1 has high mortality up to 20% treated with interferon and high dose of steroid. MERS-CoV infection has high mortality rates of up to 50% treated with ribavirin, interferon, and steroids.
9) Adenovirus:
It is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
It causes viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
Rates of infection differ with age and the transplanted organ and higher among children, and in intestinal transplantation.
Clinical presentation:
conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
Mortality is 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention:
maintaining droplet and contact precautions and Brincidofovir shows benefit.
Treatment:
supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational).
10) Bocavirus:
It is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses.
11) KI and WU Polyomaviruses:
It is double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
12. Summary:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection. Preventive measures are also lacking, as vaccination is only available against influenza at this time.
Level of evidence is V.
Introduction
New respiratory viruses and serotypes are found often, affecting immunocompromised organ transplant recipients. Organ transplant recipients get 0.76–0.91 respiratory virus infections each year. Lung transplant recipients have greater rates (LTRs). In this review, influenza, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV, adenovirus, bocavirus, and KI and WU polyomaviruses affect immunocompromised organ transplant recipients.
Influenza virus
Influenza is a single-stranded RNA Orthomyxoviridae virus that can cause difficulties in immunocompromised people.
Risk factors for severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic.
Influenza vaccination is the best way to prevent the disease. Three groups of drugs are approved to treat influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, a single-dose oral memantine with a novel mechanism of action.
Respiratory Syncytial Virus
Respiratory Syncytial Virus (RSV): RSV is a winter and spring virus that is a major cause of transmission in LTRs.
Young children, recent transplant, lung or multi-visceral transplant, and rejection are risk factors for lower RTI and mortality. Clinical presentation is comparable to other respiratory viruses, but RSV more often causes lower RTI, including bronchitis, bronchiolitis, and pneumonia. Ribavirin reduces lower RTI mortality and higher RTI progression.
Human Metapneumovirus
Human Metapneumovirus (HMPV) is a single-stranded RNA virus belonging to the Pneumoviridae family that resembles RSV in many ways. Although ribavirin has in vitro efficacy against HMPV, data from HSCT recipients do not show that it reduces mortality. Infection control procedures, such as contact precautions, are the mainstay of prevention.
Parainfluenza Virus
The parainfluenza virus is a single-stranded RNA virus belonging to the Paramyxoviridae family that is known to cause symptomatic illness at a high rate and RTI at a lower rate. In a hospital context, treatment is based on preventative measures and supportive care.
Coronaviruses
Single-stranded RNA Coronaviridae viruses that cause upper respiratory infections (RTIs). 12.4-17.8% of LTR positive samples are human CoVs, second only to rhinoviruses. Among 85 immunocompromised and 1152 immunocompetent children, RTI was 22% and 26%, respectively. Ribavirin and interferon were active against the virus in-vitro, but there was no therapeutic benefit.
Adenovirus
Adenoviridae double-stranded DNA virus with seven subgroups and 90 serotypes that can induce viremia without symptoms. Droplet and contact precautions prevent adenovirus infections, which are spread through respiratory droplets, direct conjunctival inoculation, person-to-person contact, contaminated fomites, and the fecal–oral pathway. Reduce immunosuppression, Cidofovir, Brincidofovir, IVIG are the mainstay therpy.
Conclusions
For recipients of solid organ transplants, respiratory viruses are a substantial source of mobility and mortality. Only a few respiratory viruses, including the flu virus, have effective treatments. Due to the fact that there is now just an influenza vaccine available, preventative measures are also missing. Research of novel antivirals for vaccines is necessary, particularly in light of the serious effects that individuals with impaired immune systems experience from respiratory virus infections.
Level of evidence
Review article, V
Respiratory Viruses in Solid Organ Transplant Recipient
Respiratory viruses and diagnostic test
1. Influenza virus – Nucleic acid testing, others; viral culture, DFA, Serology
2. RSV
3. Parainfluenza
4. Human Metapneumovirus
5. Rhinovirus
6. Human Coronaviruses
7. Rhinovirus -PCR
8. Adenovirus (viremia and disease)
9. Bocavirus
10. Coronavirus – PCR
Treatment
1. M2 inhibitors – amantadine, rimantadine; influenza
2. Neuraminidase inhibitors (NAIs) – oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea); influenza
3. Ribavirin; RSV, Human Metapneumovirus, PIV
4. IVIG; RSV, Adenovirus
Prevention
1. Droplet precaution (Influenza, Rhinovirus, Coronavirus, Adenovirus)
2. Contact precaution (RSV, Human Metapnumovirus, PIV, Coronavirus, Adenovirus)
3. Vaccination (Influenza, Coronavirus)
5. Antiviral prophylaxis- PEP with oseltamivir (influenza), palivizumab, nirsevimab (RSV), Brincidofovir; Adenovirus (Not yet received FDA apptroval)
Level of evidence is 5
Introduction
SOT recipients have higher incidence of respiratory viral infections between 0.76–0.91 episodes per patient-year although some are asymptomatic being the highest among lung transplant recipients (LTRs).
All respiratory viruses globally share similar symptoms and clinical presentations. Diagnoses are now based on serology as they are more useful for epidemiological studies and diagnosing acute infection since both acute- and convalescent-phase sera are needed. Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis of higher sensitivity of 72–100%.
Multiplex NAT has the advantage of permitting testing for several viruses simultaneously with a turnaround time of only 12–24 h.
Influenza Virus
It is a single-stranded RNA virus belongs to the Orthomyxoviridae family. Influenza A and B are the main pathogens for human. Immunocompromised individuals express increased risk for complications as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy and encephalitis. Estimated a total of 947 SOT recipients with influenza (both 2009 pandemic H1N1 and seasonal), hospitalization, intensive care unit (ICU) admission, pneumonia and mortality rates were 57–71%, 11–16%, 22–35% and 4–7.8% respectively.
Risk factors are known to be older age, diabetes, use of mycophenolate mofetil, use of antilymphocyte globulin in the past six months, lymphopenia as well as hypogammaglobulinemia. Thereby prevention should be sought by vaccination of the transplant recipient and close contacts.
The American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant due to the fact that vaccine immunogenicity up to six months post-transplant can be poor. High-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used.
Pre-exposure prophylaxis using low-dose oseltamivir was evaluated among 477 transplant recipients, mostly SOT, and demonstrated 80% efficacy against PCR-confirmed influenza (1.7% vs. 8.4%). It can be tried in contraindications to the influenza vaccine or cases that are not expected to develop an immune response or cases of hospital outbreaks to patients in the affected wards.
Treatment currently is by neuraminidase inhibitors (NAIs) as oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir.
Baloxaviris a selective inhibitor of influenza cap-dependent endonuclease with advantage of a single dose oral medication.
Studies in SOT recipients documented that early antiviral treatment (within 24–48 h) is improved complications and lowered ICU admission rates. It is to be considered that transplant patients have prolonged shedding of influenza virus, thus recommendations aroused to treat all symptomatic patients irrespective of symptom duration for instance treatment duration (e.g., 10-day oseltamivir treatment compared to the recommended 5-day regimen) in SOT recipients who are still symptomatic.
Favipiravir is active against a wide spectrum of RNA viruses is still under phase III investigational trials. It is a new promising agent of low resistance rates as well as it is has a synergistic effect on combination to oseltamivir.
Respiratory Syncytial Virus
RSV is a single-stranded RNA virus belongs to the Pneumoviridae family (RSV-A and RSV-B). In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens led to significant morbidity and mortality after the development of lower RTI.
Proposed risk factors for lower RTI and mortality in the SOT population are young children, recent transplant, lung or multivisceral transplant besides recent rejection episodes.
The clinical presentation of RSV displays more frequently features of lower RTI as bronchitis, bronchiolitis and pneumonia about 72% of LTRs. The American Academy of Pediatrics suggests consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein. Its advantage is being of extended half-life so, it can be given once per season and has already shown favorable results.
Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Data in lung transplants are of low quality only supportive care and demonstrated that oral ribavirin treatment was associated with improvement in graft function and reduction in bronchiolitis obliterans syndrome.
Inhaled ribavirin is challenging as it needs to be given in negative-pressure rooms owing to its teratogenicity. It is also extremely expensive, so oral ribavirin is a more wise option. Systemic ribavirin has significant side effects as hemolytic anemia, leukopenia, neuropsychiatric symptoms and teratogenicity.
Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells. Newly investigated drugs are classified into fusion inhibitors (RV521, AK0529/ziresovir) and replication inhibitors (PC786, EDP-938).
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family. Current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices and implementation of contact precautions in hospitalized patients.
Parainfluenza Virus
PIV is a single-stranded RNA virus belongs to the Paramyxoviridae family. It has 4 serotypes; serotype 3 is the commonest. In LTRs PIV accounts for 3.6–20.9% of the respiratory viruses isolated.
DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, thus preventing attachment and entry of viruses such as PIV and influenza virus into respiratory cells, yet it is not currently FDA approved. So, management is via supportive care and prevention in the hospital setting based on adherence to contact precautions.
Rhinovirus
Single-stranded RNA viruses that are members of the Picornaviridae family. Among LTRs about 41.8–61.6% of the positive samples are rhinoviruses. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2 are associated with outbreaks of severe respiratory disease.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples.
Thanks to strict infection control practices the outbreak was controlled and there were no more cases of SARS-CoV1.
Adenovirus
It is a double-stranded DNA virus of the Adenoviridae family. It has latency in lymphoid tissue; so infection can represent reactivation or de novo community acquired. It manifests more in cases of intestinal transplantation, as they have the higher amount of lymphoid tissue in the allograft and greater immunosuppression.
Adenovirus infection can be presented by conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis with special predilection for the transplanted allograft. Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection. Cases of bronchiolitis obliterans has been described in lung transplant recipients.
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir but it is still under investigations.
Besides supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational).
Bocavirus
It is a single-stranded DNA virus of the Parvoviridae family. Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
KI and WU Polyomaviruses
They are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007. KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens respectively in kidney transplant recipients.
Respiratory Viruses and Rejection in Lung Transplantation
It is more correlated to continuous contact of the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and a relatively greater immunosuppression compared to other organ transplants.
A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections.
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD (OR 0.24, 95% CI 0.1–0.59).
Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
Preventive measures are also lacking so development of new antivirals and vaccines is urgently needed.
Level of evidence is V.
CLAD or BOS is associated with acute viral infection post lung transplant suggesting different pathophysiology of viral infection
it is very interesting to know this different behaviour of virus
Respiratory viral infections is common after SOT
Effective therapies are available only for influenza, and also to some extent for RSV infection
All respiratory viral infections share similar clinical manifestations and are all currently diagnosed using nucleic acid testing
Nucleic acid testing (NAT) for respiratory viruses is gold standard
symptoms are common cough , fever rhinorrhoea GI symptoms
Risk factors associated with severe disease in multivariate analysis include older age, diabetes and use of mycophenolate mofetil
INFLUENZA VIRUS =
DROPLET PRECAUTION
PRE AND POST EXPOSURE PROPHYALAXIS
VACCINATION IS AVAILABE FOR INFLUENZA
The inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains
Another measure to prevent influenza infection would be using antiviral prophylaxis.
oseltamivir 75 mg od
Respiratory Syncytial Virus- RIBAVERIN – CONTACT PREVENTION
Parainfluenza Virus – RIBAVERIN –CONTACT PREVENTION
Human Metapneumovirus-RIBAVERIN -CONTACT PREVENTION
ADENOVIRIS –cidofovir, brincidofovir (investigational)
Respiratory virus are not associated with acute graft rejection
level of evidence- 5
Respiratory viral infections are one of the most prevalent infections, and are a cause of significant morbidity and mortality, especially among lung transplant recipients.
Respiratory viral infections can appear at any time post-transplant and are usually acquired in the community.
n organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year [1–3], although part of the studies also included asymptomatic infections. The incidence appears to be higher among lung transplant recipients (LTRs) [4], but is not affected by time from transplant [1]. Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses [2]. All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses [1,5]. Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs [2,6]. Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1% .
Diagnosis
Historically, viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infections.
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%
Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus
Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There are multiple strains, although only influenza A and B are generally associated with disease in humans.
The influenza attack rate depends on several factors, including age (with higher rates in children), likelihood of exposure, level of immunity (due to prior vaccination or disease), degree of immunosuppression and the nature of the epidemic
most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) [13]. Immunocompromised individuals are also at increased risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis
Risk factors associated with severe disease in multivariate analysis include older age, diabetes and use of mycophenolate mofetil. Univariate analysis also identified multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission
Prevention
However, the most important means for prevention is vaccination of the transplant recipient and close contacts. Only inactivated influenza vaccines should be given to transplant recipients.
The American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant, acknowledging the fact that vaccine immunogenicity up to six months post-transplant can be poor
Therefore, 2019 guidelines by the American Society of Transplantation recommend that high-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used [20]. Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs [26,28], however there is no recommendation to withhold treatment around vaccination
Pre-exposure prophylaxis using low-dose oseltamivir demonstrated 80% efficacy against PCR-confirmed influenza.
Post-exposure prophylaxis has been evaluated in the non-immunocompromised population [30,31] and can be given in cases of exposure to influenza among transplant recipients who have contraindications to receiving the influenza vaccine or who are not expected to mount an immune response
Consideration should be given to treating these patients with therapeutic-dose oseltamivir [9]. Guidelines published by The Infectious Diseases Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak to patients in the affected wards
The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea). Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single dose oral medication.
Observational studies in SOT recipients show that early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates [13,16,17]. There is also some evidence in transplant recipients [16] and the general population [39] that suggests patients who have symptoms > 48 h also benefit from treatment.
However, an attempt should be made to start treatment empirically as soon as possible, usually before test results are available. Trials in immunocompetent patients failed to show superiority of high-dose (oseltamivir 150 mg twice daily) antiviral treatment
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes subtherapeutic (as in post-exposure prophylaxis)
case reports of emergent resistance during NAI use have been published, mainly among patients with hematological malignancies or after stem cell transplants .
Respiratory Syncytial Virus
Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyxoviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring.
cause of significant morbidity and mortality due to the development of lower RTI
The clinical presentation of RSV is similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea [1,5,55]. Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia
Hospitalized patients should be placed under contact precautions [18] as RSV droplets form large particles and are transmitted by contact. The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter
Thus, the mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions .
Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples
Treatment options used in published case reports include ribavirin, interferon and steroids [93,94]. MERS-CoV still causes sporadic infections, mainly in the Middle East [95].
Adenovirus
Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes
Rates of adenovirus infection differ with age and the transplanted organ. Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression [99,102,104].
Clinical Manifestations
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft [99,102]. In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis [105]. Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection
Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precautions [18]. Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. It was tested in a phase two RCT for preemptive treatment of adenovirus viremia in HSCT recipients and showed benefits [108]; however, it is not FDA approved and the appropriate dose for treatment of adenovirus is not established.
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes (investigational).
Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
Additionally, similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence [9]. This, combined with the high co-infection rate, makes their true contribution to RTIs unknown.
KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
Respiratory Viruses and Rejection in Lung Transplantation
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD (OR 0.24, 95% CI 0.1–0.59)
Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Given the severe implications respiratory viral infections have on the immunocompromised population, development of new antivirals and vaccines is needed.
level of evidence 5
1) Introduction:
Respiratory viral infections (RNA and DNA viruses) are one of the most common infections in solid organ transplant recipients having similar symptoms and clinical presentation, with incidence ranging from 0.76-0.91 episodes per patient-year, being higher among lung transplant recipients.it presents throughout the year with high incidence in autumn and winter.
Lack of data on mortality associated with viral pneumonia in solid organ transplantation.
2) Diagnosis:
viral culture, direct fluorescent antibody (DFA) staining and serology were previously used.
Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72–100%.
3) influenza virus:
It is a single-stranded RNA virus of the Orthomyxoviridae family with multiple strain but A and B associated with the disease which is seasonal mainly in winter.
Risk factors include: age (with higher rates in children), likelihood of exposure, level of immunity (due to prior vaccination or disease), degree of immunosuppression and the nature of the epidemic.
Clinical presentations are cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache. immunosuppressed patients have increased risk of complications like pneumonia, fungal or bacterial coinfection, pericarditis, encephalitis
Prevention: droplet precautions, vaccination (requiring high-dose) and antiviral prophylaxis
Treatment: neuraminidase inhibitors (oseltamivir, zanamivir, pramivir), baloxavir, and M2 inhibitors (amantadine and rimantadine, not used nowadays). Early antiviral treatment is associated with lower complications and ICU admissions. Symptomatic SOT recipients should be treated irrespective of duration of the symptoms.
4) Respiratory Syncytial Virus:
It is a single-stranded RNA virus of the Pneumoviridae family with two strains: RSV-A and RSV-B and it a seasonal virus with peak incidence in the winter and spring. presented with fever, cough, dyspnea and rhinorrhea.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection
Prevention: contact precautions, monthly palvizumab prophylaxis in children <2 year age during the RSV season, and nirsevimab once every season. Multiple vaccines are also available, especially for elderly, pregnant, and pediatric population.
Treatment: URTI: Ribavirin
LRTI: Ribavirin with or without IV immunoglobulin
Presatovir has been shown to reduce progression to LRTI in lymphopenic hematopoietic stem cell transplant (HSCT) recipients.
5) Human metapneumovirus (HMPV):
It is a single-stranded RNA virus of the Pneumoviridae family like RCV
Prevented by contact precautions
Treated by supportive care
6) Parainfluenza virus (PIV ) :
it is single strand RNA virus of the Paramyxoviridae family. It has 4 serotypes type 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter. symptoms like other respiratory viruses PIV3, 21% experienced respiratory failure. treated by supportive care and prevented by contact precautions.
7) Rhinovirus:
It is a single stranded RNA virus of Picornaviridae family,
It has 3 serotypes (A,B,C), causing common cold and most common in lung transplant patients. treated by supportive care and prevented by contact precautions.
8) Coronaviruses (CoV) :
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. SARS COV1 has high mortality up to 20% treated with interferon and high dose of steroid. MERS-CoV infection has high mortality rates of up to 50% treated with ribavirin, interferon, and steroids.
9) Adenovirus:
It is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
It causes viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
Rates of infection differ with age and the transplanted organ and higher among children, and in intestinal transplantation.
Clinical presentation:
conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
Mortality is 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention:
maintaining droplet and contact precautions and Brincidofovir shows benefit.
Treatment:
supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational).
10) Bocavirus:
It is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses.
11) KI and WU Polyomaviruses:
It is double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
12. Summary:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection. Preventive measures are also lacking, as vaccination is only available against influenza at this time.
Level of evidence is V.
Respiratory Viruses in Solid Organ Transplant Recipients.
1. Introduction
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year.
The incidence appears to be higher among lung transplant recipients (LTRs) , but is not affected by time from transplant
there is a higher incidence in the autumn and winter, and patterns differ between viruses.
All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses .
Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs .
2. Diagnosis :
a- viral culture,
b- direct fluorescent antibody (DFA) staining
c- serology
are used to diagnose respiratory viral infections.
3. Influenza Virus
3.1. Epidemiology and Risk Factors :
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There
are multiple strains, although only influenza A and B are generally associated with disease in humans. Influenza viruses are seasonal, circulate mainly in the winter .
The influenza attack rate depends on several factors, including
a- age (with higher rates in children).
b- likelihood of exposure.
c- level of immunity (due to prior vaccination or disease).
d- degree of immunosuppression.
e- the nature of the epidemic.
The incidence is about 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively
3.2. Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness.
most common symptom are cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) .
Immunocompromised individuals are also at increased risk for complications.
The complication include
a- viral pneumonia.
b- bacterial superinfection.
c- fungal coinfections.
d- pericarditis and myocarditis.
e- myositis.
f- encephalopathy and encephalitis, etc.
3.3. Prevention
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions.
However, the most important means for prevention is vaccination of the transplant recipient and close contacts.
Only inactivated influenza vaccines should be given to transplant recipients.
Immunogenicity of influenza vaccine in SOT is variable, but generally lower compared to a non-immunocompromised population . Still, influenza vaccine has been shown to decrease influenza infection rates, complications and mortality in the SOT population .
Another small study conducted during an influenza outbreak in a kidney transplant unit revealed that the unvaccinated population had significantly high rates of influenza infection and mortality.
Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs , however there is no recommendation to withhold treatment around vaccination.
Another preventive measure influenza infection would be using antiviral prophylaxis.
prophylaxis using low-dose oseltamivir was demonstrated to be 80% effective against influenza.
3.4. Treatment
There are three groups of drugs approved for the treatment of influenza :
1- M2 inhibitors (amantadine and rimantadine) are not used today since they are inherently
inactive against influenza B and circulating influenza A strains carry a high rate of re sistance.
2- neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
3- Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenz cap-dependent endonuclease and is a single dose oral medication
There have been no trials comparing drugs, doses or treatment durations in the SOT population. According to trials comparing different NAIs in the immunocompetent population, no drug seems to be superior.
Observational studies in SOT recipients show that early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates .
There are several investigational antivirals for influenza. Favipiravir is active against
a wide spectrum of RNA viruses and as such can inhibit both influenza A and B viruses.
Several monoclonal antibodies targeting various hemagglutinins of influenza virus
have been developed , showing mixed results .
Immunocompromised patients are at increased risk for antiviral resistance due to
prolonged viral replication combined with antiviral exposure, which is sometimes subthera
peutic (as in post-exposure prophylaxis) . As stated, M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain .
4. Respiratory Syncytial Virus
4.1. Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyx oviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children, who are a significant source of transmission.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include
young children (less than two years old), recent transplant, lung or multivisceral transplant
and recent rejection.
4.2. Clinical Manifestations:
similar to other respiratory viruses,
a- fever,
b- cough,
c- dyspnea
d- rhinorrhea.
Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia . This is especially true for LTRs, where lower RTI rates can be as high as 72%.
4.3. Prevention :
Hospitalized patients should be placed under contact precautions as RSV droplets
form large particles and are transmitted by contact.
The American Academy of Pediatricsrecommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based .
Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein. Due to its extended half-life, it can be given once per season and has shown favorable results in a recently published randomized trial conducted on preterm infants.
There are currently multiple vaccines under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based .
In a combined analysis of trials done in HSCT, ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a non –significant reduction in progression to lower RTI .
Several new drugs targeting RSV are currently under development, however none
have reached phase three trials
5. Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling
RSV. Its seasonality also follows that of RSV, with most cases identified in the winter and
Spring.
Ribavirin has in vitro activity against HMPV.
Data in SOT are based solely on lung transplants and are limited to small case series
Prevention is mainly based on infection control practices, including implementation of
contact precautions in hospitalized patients.
6. Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no
seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear
in the fall and winter.
Utility of antivirals for PIV infection in SOT is unknown. A systematic review on antiviral treatment for PIV infection in HSCT recipients showed no benefit in this population.
Thus, the mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions.
7. Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae
family, which is part of the Enterovirus genus. Serotypes A–C circulate year-round and
are the predominant cause for the common cold.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
8. Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human
CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute
respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV,
SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs,
accounting for 12.4–17.8% of the positive samples.
Symptoms are generally similar to other respiratory viruses.
The immunocompromised group had a significantly higher rate of severe lower RTI.
SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%.
MERS-CoV infection was first identified in Saudi Arabia [92] and is associated with severe respiratory illness and mortality rates as high as 50%.
Treatment options used in published case reports include ribavirin, interferon and steroids [93,94]. MERS-CoV still causes sporadic infections, mainly in the Middle East [95
9. Adenovirus
9.1. Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
Adenoviruses show no seasonal variability [9,99] and have been associated with institutional outbreaks.
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate.
Rates of adenovirus infection differ with age and the transplanted organ. Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression.
9.2. Clinical Manifestations:
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis.
Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
9.3. Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
prevention in the hospital setting is based on maintaining droplet and contact precau
tions.
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks
the nephrotoxicity associated with cidofovir shows benefit.
9.4. Treatment
treatment modalities for adenovirus disease are derived from case reports and small case series.
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational)
10. Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated
from respiratory specimens, and in positive specimens, there is often co-infection with other
respiratory viruses
11. KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively. But, it is still unclear whether this has any clinical significanc
level of evidence is 5
New respiratory viruses and serotypes are found affecting immunocompromised organ transplant patients.
This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, as they relate to organ transplant recipients. Lung transplant research will dominate the discussion.
This evaluation does not concentrate on hematopoietic stem cell transplantation, however, findings from this group will guide organ transplant therapy. This series will cover the SARS-CoV-2 epidemic.
Influenza Virus:
Treatment:
RSV:
Treatment
Human Metapneumonia:
Parainfluenza:
Rhinovirus:
Coronaviruses:
Adenovirus:
Lung Transplant Rejection and Respiratory Viruses:
Numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year.
The incidence appears to be higher among lung transplant recipients (LTRs).
Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter.
Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs.
Data on mortality associated with viral pneumonia in SOT recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1%.
2. Diagnosis:
NAT for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
Turnaround time of only 12–24 h.
Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and low sensitivity.
Influenza Virus:
Epidemiology and Risk Factors:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
There are multiple strains, although only influenza A and B are generally associated with disease in humans.
Influenza viruses are seasonal, circulate mainly in the winter (months November to May in the Northern Hemisphere and May to October in the Southern Hemisphere), and cause a significant proportion of RTIs during that time.
Presentation:
Common symptom:
Cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%)
Increased risk for complications:
Viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Risk factors associated with severe disease:
Older age, diabetes and use of mycophenolate mofetil.
Risk factors for pneumonia or ICU admission:
Multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition.
Prevention:
Droplet precautions
Vaccination.
Pre-exposure prophylaxis using low-dose oseltamivir.
Post-exposure prophylaxis.
Guidelines published by The Infectious Diseases Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak to patients in the affected wards.
An outbreak is defined as two healthcare-associated cases diagnosed within 72 h in the same ward, and prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case.
Treatment:
Reduction of immunosuppression is recommended for all severe respiratory illnesses
Neuraminidase inhibitors:
Oseltamivir (oral):
Treatment Dose 75 mg q12h (5 days)
Prophylactic Dose 75 mg q24h.
Zanamivir (inhaled) 10 mg q12h (5 days) Prophylactic Dose 10 mg q24h.
Peramivir (IV) 600 mg once.
Baloxavir (oral) 40 mg (80 kg) Prophylactic Dose 40 mg (80 kg).
Ribavirin (IV/oral) LD 600 mg then 200 mg q8h for 1 day then 400 mg q8h. Can increase to maximum 10 mg/kg q8h.
Cidofovir (IV) 1 mg/kg 3 times a week, or 5 mg/kg once a week for 2 weeks and then every 2 weeks add probenecid and hydration.
NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals.
Treatment options include changing to a different NAI, changing to a different antiviral class, or combination antiviral.
Respiratory Syncytial Virus:
Epidemiology and Risk Factors:
RSV is a single-stranded RNA virus of the Pneumoviridae family.
Two strains: RSV-A and RSV-B.
It is a seasonal virus with peak incidence in the winter and spring.
Circulates mainly among young children, who are a significant source of transmission.
In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses. Significant morbidity and mortality due to the development of lower RT.
Risk factors for lower RTI and mortality in the SOT:
Young children (less than two years old), recent transplant, lung or multivisceral transplant.
Clinical Manifestations:
Fever, cough, dyspnea and rhinorrhea.
More frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
In LTRs, where lower RTI rates can be as high as 72%.
Prevention:
Contact precautions.
Treatment:
Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RT, plus minus IVIG.
Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family.
Most cases identified in the winter and spring.
Studies conducted on LTRs identified HMPV in 3.6–6.8%.
Current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients.
Parainfluenza Virus:
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
Four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
In LTRs, it accounts for 3.6–20.9% of the respiratory viruses isolated. PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI and RF.
The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact.
DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, thus preventing attachment and entry of viruses such as PIV and influenza virus into respiratory cell, ITS STILL IVESTIGATIONAL DRUG.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus. Serotypes A–C circulate year-round and are the predominant cause for the common cold.
These viruses are isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients. TRAEMENT IS SUPPORTIVE.
Coronaviruses:
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
Second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples.
Symptoms are generally similar to other respiratory viruses.
The immunocompromised group had a significantly higher rate of severe lower RTI.
MERS-CoV is associated with severe respiratory illness and mortality rates as high as 50%, Human to human transmission is associated with healthcare settings, and in one of the cohorts studied, and 25% of the people infected were healthcare workers. There is also ongoing zoonotic transmission from camels Two Treatment options used in published case reports include ribavirin, interferon and steroids MERS-CoV still causes sporadic infections, mainly in the Middle East .
Adenovirus.
Epidemiology:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
Adenoviruses show no seasonal variability and have been associated with institutional outbreaks Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate.
Clinical Manifestations:
Conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
. In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis.
Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention:
Droplet and contact precaution.
Treatment:
. Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes (investigational). Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression.
Bocavirus:
Is a single-stranded DNA virus of the Parvoviridae family?
It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses.
KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family.
Respiratory Viruses and Rejection in Lung Transplantation:
As previously mentioned, LTRs are at increased risk for RTIs in general and specifically lower RTIs.
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data.
Summary:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipient, effective vaccine and medication is needed.
level of evidence V.
1. Please summarise this article.
Introduction: Respiratory viral infections (both RNA and DNA viruses) are one of the most common infections in solid organ transplant (SOT) recipients having similar symptoms and clinical presentation, with incidence ranging from 0.76-0.91 episodes per patient-year, being higher among lung transplant recipients. Higher incidence is seen in autumn and winter seasons, with no relation to time post-transplant. Progression to lower respiratory tract infection (LRTI) is seen in 6.2% to 40% with mortality of 5.1%.
Diagnosis: Although viral culture, direct fluorescent antibody staining, and serology were used previously, Nucleic acid testing (NAT) is the gold standard with sensitivity of 72% to 100% for diagnosis. Multiplex NAT can be used to detect several viruses simultaneously. Rapid antigen tests are available for respiratory syncytial virus (RSV) and influenza, although with low sensitivity.
Influenza virus: It is a single stranded RNA (ssRNA) virus of Orthomyxoviridae family, with multiple strains (A and B associated with human infections) and affects seasonally (in winter months) with highest incidence in lung transplant recipients. Symptoms include cough, fever, rhinorrhea, myalgia etc. Immunosuppressed patients have increased risk of complications like pneumonia, fungal or bacterial coinfection, pericarditis, encephalitis, etc. Older age, diabetes, and MMF use, antilymphocyte globulin use in last 6 months, lymphopenia, influenza A, and hypogammaglobulinemia is associated with severe disease. Prevention involves droplet precautions, vaccination (requiring high-dose) and antiviral prophylaxis (pre- and post-exposure) using oseltamivir (to be given in case of hospital outbreak). Treatment involves using neuraminidase inhibitors (oseltamivir, zanamivir, pramivir), baloxavir, and M2 inhibitors (amantadine and rimantadine, not used nowadays). Early antiviral treatment is associated with lower complications and ICU admissions. Symptomatic SOT recipients should be treated irrespective of duration of the symptoms.
RSV: It is a ssRNA virus of Pneumoviridae family, with 2 strains (RSV-A and RSV-B), affecting mainly young children seasonally (in winter and spring). Symptoms are like other respiratory viruses. Risk factors for LRTI (upto 72% in lung transplant recipients) include recent rejection, or lung or multivisceral transplant. Prevention include contact precautions, monthly palvizumab prophylaxis in children <2 year age during the RSV season, and nirsevimab once every season. Multiple vaccines are also available, especially for elderly, pregnant, and pediatric population. Treatment for upper RTI includes ribavirin (shown to reduce progression to LRTI), while for LRTI involves use of ribavirin with or without intravenous immunoglobulin (IVIG), which has shown to reduce mortality. Presatovir has been shown to reduce progression to LRTI in lymphopenic hematopoietic stem cell transplant (HSCT) recipients.
Human metapneumovirus (HMPV): It is a ssRNA virus of Pneumoviridae family affecting seasonally (in winter and spring). Symptoms are similar to other respiratory viruses. Treatment involves supportive care, although ribavirin use has been shown to be associated with mortality benefit and lower chronic lung allograft disease. Prevention involves contact precautions.
Parainfluenza virus (PIV): It is a ssRNA virus of Paramyxoviridae family, with 4 serotypes (PIV 1-4), with type 3 being most common (showing no seasonality) and type 1 and 2 affecting seasonally (in winter and fall). Symptoms are like other respiratory viruses. High rate of symptomatic disease and LRTI with up to 21% respiratory failure is seen in PIV infection. Treatment involves supportive care and contact precautions for prevention. Antiviral treatment has shown no benefit in PIV. DAS 181 (inhaled sialidase) has shown trend towards better outcome.
Rhinovirus: It is a ssRNA virus of Picornaviridae family, with 3 serotypes (A,B,C), circulating year-round, predominantly causing common cold. They are most common respiratory viruses in lung transplant recipients, frequently associated with other infections and treatment is mainly supportive measures with droplet precautions for prevention.
Coronaviruses (CoV): These are ssRNA viruses of Coronaviridae family, associated with URTI (by 229E, NL63, OC43, HKU1) or severe respiratory disease (by severe acute respiratory syndrome- CoV1, SARS-CoV1, SARS-CoV2, and middle eastern respiratory syncrome-CoV, MERS-CoV). They are associated with significantly higher rates of severe LRTI in immunocompromised patients. SARS-CoV1 infection has high mortality of up to 20%, having better outcomes with use of interferon and high-dose steroids. MERS-CoV infection has high mortality rates of up to 50% with treatment options being ribavirin, interferon, and steroids.
Adenovirus: It is a double stranded DNA virus of Adenoviridae family, with 7 subgroups (A-G), and 90 serotypes. They are latent in lymphoid tissue, hence can be either de novo, or due to reactivation of the infection. They are associated with institutional outbreaks, lacking any seasonal variability, and present with viremia without any symptoms (21% of viremic patients had symptoms). It can manifest as conjunctivitis, URTI, LRTI, hemorrhagic cystitis, pyelonephritis, hepatitis, and enterocolitis, with predilection for the allograft. High mortality (50% for pneumonia, and 80% for disseminated infection) is seen. Prevention involves maintaining droplet and contact precautions and antiviral brincidofovir has shown some benefit. Treatment includes supportive care, reduction in immunosuppression, cidofovir, brincidofovir, IVIG, and adenovirus-specific cytotoxic T lymphocytes.
Bocavirus: It is a ssDNA virus of Parvoviridae family, rarely isolated from respiratory specimens, mostly seen as co-infection with other respiratory viruses, and is known for viral persistence.
KI and WU Polyomaviruses: They are dsDNA viruses of Polyomaviridae family, but their clinical significance is unknown.
Respiratory viruses and rejection in lung transplantation: No association of respiratory viral infections and acute rejection has been seen, although there is a non-significant trend towards bronchiolitis obliterans syndrome (BOS). There is no definitive association between rhinoviruses and CoVs and rejection or BOS.
Summary: Respiratory viruses cause significant morbidity and mortality in transplant recipients. Prevention using contact and droplet precautions (and vaccination for influenza) is the key for better outcomes, although effective therapies are available for influenza and RSV infection.
2. What is the level of evidence provided by this article?
Level of evidence: Level V – Narrative review
● In organ transplant recipients, the incidence of respiratory viral infections ranges between 0.76–0.91 episodes per patient-year
● The incidence appears to be higher among lung transplant recipients (LTRs) and in the autumn and winter
● Rate of progression to lower (RTI) ranges between 6.2–40% in LTRs
● Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients
Diagnosis
● Viral culture has a long time of 10 days for standard viral culture and two days for shell vial culture.
● DFA staining is available for limited number of respiratory viruses and requires expertise in interpreting the results.
● Serology have been useful only for epidemiological studies and not for diagnosing acute infection
● Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis with a sensitivity of 72–100%
● Multiplex NAT allows testing with a turnaround time of only 12–24 h
● Rapid antigen tests, allowing results within minutes available for influenza and RSV only with low sensitivity
Influenza Virus
● Epidemiology and Risk Factors
☆ RNA virus
☆ Only influenza A and B are generally associated with disease in humans.
☆ They are seasonal in the winter
☆ The influenza attack rate depends on:
* Age (higher in children)
* Likelihood of exposure
* Level of immunity
* Degree of immunosuppression
* Nature of the epidemic
☆ The incidence is 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively
● Clinical Presentation
☆ Immunocompromised patients may not fit the classic influenza-like illness.
☆ The most common symptom is cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), headache (30%)
☆ Increased risk of complications as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis,
☆ Risk factors for severe disease :
* Older age
* Diabetes
* Use of mycophenolate mofetil.
* Use of antilymphocyte globulin in the past six months
* Lymphopenia
* Hypogammaglobulinemia
* Influenza A and nosocomial acquisition
● Prevention
☆ patients should be placed under droplet precautions
☆ Vaccination of the transplant recipient and close contacts.
☆ Vaccinating with an inactivated influenza vaccine as soon a one month post transplant
☆ Immunogenicity of influenza vaccine in SOT is variable, but lower compared to a non-immunocompromised population
☆ Influenza vaccine decreases influenza infection rates, complications and mortality in the SOT population
☆ 2019 guidelines by AST recommend:
* High-dose vaccination is preferred
* Two doses of standard vaccine also used
☆ Using antiviral prophylaxis antiviral resistance may develope so it should be given in the case of a hospital outbreak to patients in the affected wards for 14 days
● Treatment
☆ M2 inhibitors (amantadine and rimantadine) it is inactive against influenza B with high rate of resistance to influenza A strains
☆ Neuraminidase inhibitors (NAIs) :
* most commonly used
* include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
☆ Baloxavir:
* recently approved
* Has a novel mechanism of action.
* A selective inhibitor of influenza endonuclease
* A single dose oral medication.
* It is effective in uncomplicated influenza in the immunocompetent population
* It is more effective against influenza B strains than NAIs
☆ Early antiviral treatment(within 24–48 h) in SOT patients is associated with a decrease in influenza complications and lower ICU admission rates
☆ Due to prolonged shedding in SOT patients some extend treatment duration or use high doses
☆ Favipiravir has low resistance rates and is synergistic when combined with oseltamivir. It is currently licensed only in Japan for use in influenza unresponsive or insufficiently responsive to current antivirals
☆ Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with subtherapeutic antiviral exposure
☆ M2 inhibitors have high resistance in the currently circulating influenza A strains.
☆ Resistance to NAIs is uncommon except in the A/H1N1 strain
☆ The most common mutation is H275Y, in A/H1N1but it still susceptle to zanamivir
☆ NAI resistance suspected in
• A prolonged illness
• Persistent viral replication
• Developed influenza shortly after receiving low dose antivirals.
☆ Treatment options include:
▪︎Changing to a different NAI
▪︎Changing to a different antiviral class
▪︎Combination antivirals.
☆ Resistance documented in 9.7% of patients treated with baloxavir
Respiratory Syncytial Virus
● Epidemiology and Risk Factors
☆ RNA virus
☆ Has 2 strains RSV-A and RSV-B.
☆ It is a seasonal virus with peak incidence in the winter and spring
☆ Mainly among young children
☆ In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens
☆ Risk factors for lower RTI and mortality:
* Young children (less than two years old)
* Recent transplant
* Lung or multivisceral transplant
* Recent rejection
● Clinical Manifestations
☆ Fever, cough, dyspnea and rhinorrhea
☆ RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia
☆ In LTRs lower RTI is high ( 72% )
● Prevention
☆ Contact precautions
☆ Palivizumab prophylaxis is recommeneded during the RSV season in children under 24 months of age who are severely immunocompromised,
☆ Nirsevimab
* A monoclonal targets an epitope of the RSV fusion protein.
* It has extended half-life
* It is given once per season
☆ Vaccines are recommended for :
* lderly persons
* Pregnant women
* Pediatric population
● Treatment
☆ There are differences in treatment regimens in lung transplant compared to other organs.
☆ In HSCT, ribavirin treatment was associated with reduced progression to lower RTI and decreased mortality among patients with lower RTI.
☆ A combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a nonsignificant reduction in progression to lower RTI
☆ Systemic ribavirin is associate with SEs as hemolytic anemia, leukopenia, neuropsychiatric symptoms, teratogenic
☆ Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells , it decreases progression to lower RTI with developing resistance in (20%) of patients
Human Metapneumovirus
● RNA virus
● closely resembling RSV.
● Its seasonality is in winter and spring
● Most of patients had symptoms of RTI, and in (44%) had a lower RTI
● Ribavirin has in vitro activity against HMPV.
● Studies do not demonstrate a mortality benefit with antivirals or immunomodulator
● In LTRs ribavirin was associated with significantly less chronic lung allograft disease in RTi
● Prevention is mainly based on infection control practices, including implementation of contact precautions
Parainfluenza Virus
☆ RNA virus
☆ There are four serotypes of PIV (1–4)
☆ Serotype 3 is the most common with no
seasonality and outbreaks, whereas serotypes 1 and 2 appear in the fall
☆ It accounts for 3.6–20.9% of the respiratory viruses isolated in LTRs
☆ PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI
☆ DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, thus preventing attachment and entry of viruses such as PIV and influenza virus into respiratory cells
it is not currently FDA approved.
☆ The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions
Rhinovirus
☆ RNA viruses
☆ Serotypes A–C circulate year-round
☆ The predominant cause for the common cold
☆ They are isolated in respiratory samples taken from immunocompetent patients as well as SOT recipients.
☆ In LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6%
☆ Rhinoviruses are frequently found as a coinfection with other viruses or bacteria
☆ Symptoms are usually those of the common cold
☆ Treatment is based on supportive measures and droplet precautions
Coronaviruses
☆ RNA viruses
☆ Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI
☆ But CoVs SARS-CoV1, MERS-CoV2
are associated with severe respiratory disease.
☆ Human coronaviruses are second only to rhinoviruses for prevalence among LTRs,
accounting for 12.4–17.8% of the positive samples
☆ The immunocompromised group had a significantly higher rate of severe lower RTI
☆ SARS-CoV1 was associated with high rates of lower RTI and mortality 20%
☆ The better outcomes were with interferon and high-dose steroids in conjunction with supportive care
☆ MERS-CoV2 is associated with severe respiratory illness and mortality rates 50%
☆ Treatment include ribavirin, interferon and steroids
Adenovirus
● Epidemiology
☆ A double-stranded DNA
☆ Establish latency in lymphoid tissue
☆ Infection can represent reactivation or de novo community acquisition
☆ they show no seasonal variability
☆ 7.2% of SOT patients with adenovirus developed viremia and 21% were symptomatic
☆ Rates of adenovirus infection are higher:
• A mong children
• In intestinal transplantation
● Clinical Manifestations :
☆ Conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
☆ Fever of unknown origin and rise in creatinine In a kidney transplant recipient with adenovirus should be considered as a cause of pyelonephritis
☆ Mortality is 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection
☆ Bronchiolitis obliterans as a sequelae
has been described in lung transplant recipients
● Prevention :
☆ Maintaining droplet and contact precautions
☆ Brincidofovir is an orally bioavailable of cidofovir that lacks the nephrotoxicity associated with cidofovir.
● Treatment
☆ Supportive care
☆ Reduction of immunosuppression
☆ Cidofovir
☆ Brincidofovir (investigational)
☆ IVIG
☆ Adenovirus specific cytotoxic T lymphocytes (investigational)
☆ Favorable outcomes were with combining cidofovir with RI
Bocavirus
● A single-stranded DNA
● It is isolated from respiratory specimens in 0.5–1% among LTRs and often coinfection with other respiratory viruses
● It has viral persistence
KI and WU Polyomaviruses
● Double-stranded DNA viruses
● HSCT recipients have higher frequency of infection with these viruses
● kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens
Respiratory Viruses and Rejection in Lung Transplantation
● LTRs are at increased risk for RTIs in general and specifically lower RTIs due to
* Continuous contact of the allograft with
the environment
* Impaired mucociliary clearance
* Impaired cough reflex
* Geater immunosuppression compared to other organ transplants.
●There is no association between respiratory viral infection and acute rejection
● A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and
biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infec-
tions
● Associations have also been reported for influenza, HMPV, RSV, PIV, adenovirus
● There is no definitive association between rhinoviruses and CoVs and rejection or CLAD
● Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections
● Level : 5
III. Respiratory Viruses in Solid Organ Transplant Recipients
Summarise this article
Introduction
– numerous viruses have an impact on the health of SOT recipients
– incidence of respiratory viral infections in SOT recipients ranges
between 0.76-0.91 episodes per patient-year
– all respiratory viruses cause similar symptoms, hence the clinical
presentation does not differentiate between the viruses
– data on mortality associated with viral pneumonia among SOT recipients is lacking
Diagnosis
– previously, viral culture, direct fluorescent antibody (FA) staining and serology were used in the diagnosis of respiratory viral infections
– each of these methods had its own disadvantage
– viral culture had a long turnaround time
– DFA staining is only available for certain respiratory viruses and it requires expertise in interpreting the results
– serology has only been useful in epidemiological studies, it is not useful in the diagnosis of acute infection since acute- and convalescent- phase sera are needed
– molecular strategies for diagnosis are now available, making these other traditional methods obsolete
– nucleic acid testing (NAT) is now the gold standard for diagnosis of respiratory viruses, sensitivity is 72-100%
– multiplex NAT has a TAT of 12-24 hours and it allows for testing of various respiratory viruses simultaneously
– rapid antigen tests are clinically available to test for influenza and RSV only, the results are ready in a few minutes but they have a low sensitivity
Influenza virus
Epidemiology and risk factors
– has multiple strains but only Influenza A and B are associated with disease in humans
– influenza viruses are seasonal
– risk factors for influenza infection include: degree of immunosuppression, age (higher rates in children), level of immunity (due to prior disease or vaccination), likelihood of exposure, nature of the epidemic
Clinical presentation
– immunosuppressed patients may not present with the classical symptoms of an influenza-like illness
– immunocompromised patients are at increased risk of complications like bacterial superinfection, viral pneumonia, fungal co-infections, pericarditis, myocarditis, encephalopathy, encephalitis, myositis
– risk factors associated with severe disease include: diabetes, older age, use of MMF
– risk factors for pneumonia or ICU admission include: use of ATG in the past 6 months, multiple comorbidities, lymphopenia, influenza A, nosocomial acquisition
Prevention
– to avoid outbreaks/ disease spread within the hospital, droplet precautions should be taken
– vaccination of transplant recipients and their close contacts remains the optimal preventive strategy
– transplant recipients should only receive inactivated influenza vaccines due to the risk of dissemination of the virus contained in the live attenuated intranasal influenza vaccine
– currently, there is a quadrivalent inactivated influenza vaccine which has two A strains (H1N1 and H3N2) and two B strains
– the inactivated influenza vaccine can be given as soon as 1 month post-transplant bearing in mind that vaccine immunogenicity can be poor in the first 6 months post-transplant
– influenza vaccine decreased infection rates, complications and mortality among SOT recipients
– high-dose vaccination, where available, is preferred although two doses of standard vaccine can be used -high-dose is associated with higher seroconversion rates
– patients on mycophenolate have been shown to have worse antibody response compared to other immunosuppressive agents but there is no recommendation to withhold treatment during vaccination
– antiviral pre-prophylaxis with low-dose oseltamivir can be used to prevent influenza infection
– post-exposure prophylaxis can result in antiviral resistance hence for such patients therapeutic-dose oseltamivir should be considered
– antiviral prophylaxis should be offered during a hospital outbreak, this is usually given for 14days and at least 7 days after symptom onset in the last identified case
Treatment
– 3 groups of drugs have been approved:
– early antiviral treatment (within 24-48h) is associated with a decrease in influenza complications and lower ICU admission rates among SOT recipients
– SOT patients have prolonged shedding of the influenza virus therefore they should be treated irrespective of symptom duration
– empiric treatment should be started as soon as possible
– treatment duration can be extended from 5days to 10days in immunocompromised patients due to the prolonged shedding of the virus
– immunosuppressed patients are at increased risk for antiviral resistance due to the prolonged viral replication and subtherapeutic antiviral exposure as can occur during post-exposure prophylaxis
– suspect NAI resistance in transplant patients with prolonged illness, persistent viral replication or in those who develop influenza while on or shortly after receiving low dose antivirals
– management options for NAI resistance include: switch to a different NAI, change to a different antiviral class, combination antivirals
Respiratory syncytial virus
Epidemiology and risk factors
– RSV has two strains: RSV-A and RSV-B
– it is seasonal, young children are a significant source of transmission
– risk factors for lower RTI and mortality in SOT recipients include: recent transplant, recent rejection, lung or multivisceral transplant
Clinical manifestations
– fever, dyspnoea, cough, rhinorrhoea
– RSV commonly causes lower respiratory tract infections including bronchitis, bronchiolitis, pneumonia
Prevention
– contact precautions should be observed since the RSV droplets form large particles which are transmitted by contact
– palivizumab prophylaxis is not routinely used in adult SOT recipients
– nirsevimab, a monoclonal antibody, given once a season since it has an extended half-life
– vaccines are still under development, they are recommended for the paediatric population, pregnant women and the elderly
Treatment
– ribavirin treatment was associated with reduced progression of upper RTI to lower RTI
– combination of ribavirin and an immunomodulator like IVIG, RSV-IVIG or palivizumab, significantly lowered the mortality
– inhaled ribavirin is expensive and requires negative -pressure rooms due to its teratogenicity
– systemic ribavirin is associated with significant side effects like hemolytic anaemia, leukopenia, teratogenicity, neuropsychiatric symptoms
Adenovirus
Epidemiology
– has 7 subgroups, 90 serotypes
– establish latency in lymphoid tissue, hence an infection arises after reactivation or can be de novo (community acquired)
– no seasonal variability, is associated with institutional outbreaks
– causes viremia without obvious symptoms hence it is prudent to differentiate infection and disease
– risk factors for adenovirus infection: age (higher among children), intestinal transplantation (due to the higher amount of lymphoid tissue in the allograft and greater immunosuppression)
Clinical manifestations
– conjunctivitis, URTI, LRTI, hepatitis, enterocolitis, pyelonephritis, hemorrhagic cystitis, has a predilection for the transplanted allograft
– fever, rising serum creatinine would suggest pyelonephritis due to adenovirus
– high mortality rate: 80% for disseminated adenoviral infection, 50% for adenoviral pneumonia
Prevention
– transmission: respiratory droplets, person-to-person contact, direct conjunctival inoculation, fecal-oral, infected fomites
– prevention: maintain droplet and contact precautions
Treatment
– supportive care, reduction in immunosuppression, cidofovir (nephrotoxic), brincidofovir (investigational), IVIG, adenovirus specific CTLs (investigational)
Summary
– respiratory viruses cause significant morbidity and mortality among SOT recipients
– molecular diagnostic methods have made diagnosis easier
– at the moment, effective therapies are only available for influenza and RSv
– there are new drugs in the pipeline
– preventive measures are limited: vaccination is only available for influenza only
– there is need to develop new antiviral agents and vaccines
Level of evidence provided by this article
– Level 5
Respiratory viral infection after solid organ transplantation
Summary
Respiratory viral infection can occur at any time after SOT and can be associated with morbidity and mortality risk, especially among lung transplantation, and in some reports even can trigger rejection and chronic allograft dysfunction. respiratory viral infection among SOT can be acquired from the community and share the same respiratory symptoms and reported incidence in the range of 0.6-0.9 per patient /year, mainly diagnosed with nucleic acid test NAT, influenza virus good treatment options and prevention with vaccination, however, this can be restricted by resistance to neuraminidase inhibitors, and low vaccine immunogenicity with the use of immunosuppression after SOT also many of respiratory virus have limited treatment and prevention methods. The rate of progression to lower respiratory tract infection (RTI) has been reported between 6.2–40% in LTRs with reported mortality in LRT infection up to 5.1%. This review article summarizes the epidemiology of respiratory viral infection, its diagnosis, treatment options, and preventive challenges for RNA and DNA respiratory viruses hoping for improvement in the future preventive and treatment options.
Diagnosis
Diagnosis of respiratory viral infections depends on viral cultures, serology, and Direct fluorescence antibodies viral staining (DFA), more recent diagnoses are based on molecular studies like NAT which is the gold standard for diagnosis and has a sensitivity of 72–100%. Using multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h
Rapid antigen tests also can give the results within minutes but with low sensitivity.
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family, we have influenza A and B, usually seasonal with a peak in winter and autumn time, such infections can present with cough, fever, sneezing, and congestion and can increase the risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy, and encephalitis, risk factors for such complications include old age comorbid like DM, use of IS like MMF, intense immunosuppression like induction with ATG, Prolong lymphopenia, and low albumin, influenza A associated with a higher rate of ICU admission and mortality
Prevention
Vaccination with seasonal inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains which is for all transplant patients at risk with household people, preferred to be given after 1 month from transplantation and its effective in decrease influenza infection rates, complications and mortality in the SOT population.
Also, the use of prophylaxis antivirals like Pre-exposure prophylaxis using low-dose oseltamivir was found to be effective in up to 80% with a low risk of Oseltamivir resistance
Treatments
The table1,2 summarizes the treatment options
Neuraminidase inhibitors (NAIs)the most widely used include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous), and zanamivir (available only in Japan and South Korea).
Baloxavir was only recently approved and has a novel mechanism of action. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single-dose oral most observational studies in SOT recipients demonstrate that early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates. However, transplant patients have prolonged viral shedding of the influenza virus, and preferred all symptomatic patients should be treated irrespective of symptoms duration and some extended the course up to 10 days instead of 5 days.
M2 inhibitors are not recommended due to the high resistance rate to influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1strain.
Respiratory Syncytial Virus
RSV is a single strained RNA virus of the Pneumoviridae family and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence
in the winter and spring, it circulates among children and they are the main source of transmission carry a high risk of both upper and lower respiratory tract infections and have been associated with significant morbidity and mortality due to LRTI, especially in post-lung transplantation, presentation similar to other respiratory common symptoms like fever cough, sob, runny nose, bronchitis, bronchiolitis, pneumonia, especially with LTRS
Prevention
Contact precaution in hospitalized patients in addition to droplet precaution
palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence-based
many vaccinations under development
treatment
ribavirin or ribavirin with IVIG mainly for LRTI, however ribavirin used for URTI will lower the risk of progression to LRTI and reduced mortality rate, trials of a combination of IVIG, RSV-IVIG or Palivizumab significantly lower mortality when used for LRTI.
Ribavirin was studied in limited case series mainly in the lung transplantation group with diverse results it also has a wide range of side effects including hemolytic anemia, neurotoxicity, leukopenia, and teratogenicity
Rhinovirus
Double-stranded DNA virus,
Parainfluenza virus (PIV)
Single-stranded RNA virus, there are four serotypes of PIV(1-4). The most common one is type 3 PIV which can happen as outbreaks, while serotype 1, 2 seasonal predilections to winter and fall, accounts for 3.6-20.9% of respiratory viral isolation and is usually associated with symptomatic LRTI and risk of respiratory failure reported up to 21%.
Treatment is mainly symptomatic, and prevention by contact precaution some data is limited to case series use of ribavirin with or without immunomodulators also trials of DAS181 in LRTI but not yet approved.
Adenovirus
double-stranded DNA viruses can cause both URTI, LRTI and many serotypes
can cause asymptomatic viremia , hemorrhagic cystitis , conjuctivitis , enterocoltitis , hepatitis and ,pyelonephritis prevention by droplet and contact precaution and treatment cidofovir, IVIG
in summary
respiratory viral infections among SOT are common and associated with morbidity and mortality, no effective treatment or vaccination is available and we need more studies
level 5 ofevidencee narrative review
Introduction
This review will cover both RNA and DNA respiratory viruses, including influenza,
respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza
virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and
WU polyomaviruses, specifically as they relate to organ transplant recipients.
· Respiratory viral infections in organ transplant recipients range from 0.76-0.91 episodes per patient per year, with a higher incidence in the autumn and winter.
· The rate of progression to lower respiratory tract infection (RTI) varies between 6.2-40%. Mortality associated with viral pneumonia in LTRs is 5.1%.
Diagnosis
Viral culture, direct fluorescent antibody (DFA) staining, and serology have been used
to diagnose respiratory viral infections, but each has its own shortcomings.
· Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72-100%.
· Multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12-24 h. Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity.
Influenza Viruses
· Epidemiology and risk factors
·Influenza viruses are seasonal, circulate mainly in the winter, and cause a significant
the proportion of RTIs.
· The attack rate depends on age, the likelihood of immunity, the degree of immunosuppression, and the nature of the epidemic.
Clinical Presentation
· Immunocompromised patients are at increased risk for complications such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis,
myositis, encephalopathy, encephalitis, etc.
· Risk factors include older age, diabetes, use of antilymphocyte globulin, lymphopenia, hypogammaglobulinemia, influenza A, and nosocomial acquisition.
Prevention
· Vaccination is the most important means for the prevention of influenza in the hospital
setting, with a large prospective multicenter study showing that vaccination in
the same influenza season was associated with a reduction in odds for
pneumonia.
· Antiviral prophylaxis using low-dose oseltamivir was evaluated among 477 transplant recipients and demonstrated 80% efficacy.
Treatment
· Early antiviral treatment is associated with a decrease in influenza complications
and lower ICU admission rates, and there are several investigational antivirals
for influenza.
. Immunocompromised patients are at increased risk for antiviral
resistance due to prolonged viral replication combined with antiviral exposure.
· Treatment options include changing NAIs, changing to a different antiviral class, or combining antivirals.
·
Respiratory syncytial virus
Epidemiology and risk factors
· RSV is a seasonal virus with a peak incidence in the winter and spring and is a major
source of transmission in LTRs.
. Risk factors include young children, a recent transplant, lung or multi-visceral transplant, and recent rejection.
Clinical manifestations
· RSV causes lower RTI than other respiratory viruses, especially for LTRs.
Prevention
· Palivizumab prophylaxis is not evidence-based, Nirsevimab is a monoclonal antibody with extended half-lives, and ResVax is a nanoparticle-based vaccine.
Treatment
· Ribavirin treatment has been associated with reduced progression of upper RTI to lower
RTI and decreased mortality, but data on lung transplants is low quality.
· Presatovir has failed to improve clinical and virologic outcomes.
Human Metapneumovirus
· HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling
RSV. Studies have identified HMPV in 3.6-6.8% of positive respiratory samples,
and 8/18 (44%) had a lower RTI.
. Ribavirin has in vitro activity against HMPV, but data derived from HSCT re-recipients do not demonstrate a mortality benefit.
· Treatment is primarily based on supportive care, and prevention is mainly based on infection control practices.
Parainfluenza Virus
· Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
· It is mainly studied in LTRs, where it is associated with a high rate of symptomatic disease and lower RTI.
· Utility of antivirals for PIV infection in SOT is unknown. DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium but is not currently FDA-approved.
· Supportive care and prevention in the hospital setting are based on adherence to contact precautions.
Rhinovirus
. Rhinoviruses are single-stranded RNA viruses that circulate year-round and are the
predominant cause of the common cold. In studies, rhinoviruses accounted for
41.8-61.6% of positive samples.
·Treatment is based on supportive measures and prevention in the hospital setting.
Coronaviruses
· CoVs are single-stranded RNA viruses of the Coronaviridae family, which are
associated with outbreaks of severe respiratory disease.
· Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples.
· SARS-CoV1 infection emerged in southern China in 2002 and was associated with high rates of lower RTI and mortality.
· MERS-CoV infection was first identified in Saudi Arabia and is associated with severe respiratory illness and mortality rates as high as 50%.
· Human to human transmission is associated with healthcare settings and 25% of the people infected were healthcare workers.
Adenovirus
Epidemiology
· Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven
subgroups and 90 serotypes.
· It is known to cause viremia without obvious symptoms, and in a study of 263 SOT recipients, 7.2% developed viremia, but only 4/19 were symptomatic.
· Rates of infection differ with age and the transplanted organ.
Clinical manifestation
. Adenovirus infection can cause conjunctivitis, upper RTI, lower RTI, hemorrhagic
cystitis, pyelonephritis, hepatitis, and enterocolitis. Mortality can be high.
Prevention
. Adenovirus infections are transmitted through respiratory droplets, direct conjunctival
inoculation, person-to-person contact, infected fomites, and fecal-oral routes.
·Brincidofovir is an orally bioavailable lipid conjugate that lacks nephrotoxicity.
Treatment
· Treatment modalities for adenovirus disease include reduction of immunosuppression,
cidofovir, and IVIG, as well as virus-specific cytotoxic T lymphocytes for
treatment of cytomegalovirus and Epstein–Barr virus infections.
Bocavirus
· Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory
specimens and co-infected with other respiratory viruses, making it true
contribution to RTIs unknown.
KI and WU Polyomavirus
· KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri- dae
family, with higher frequency in HSCT recipients.
Respiratory Viruses and Rejection in lung transplantation
· LTRs are at increased risk for RTIs due to impaired mucociliary clearance, cough
reflex, and immunosuppression, but treatment with ribavirin is associated with
lower rates.
Summary ·
Respiratory viruses are a major cause of morbidity and mortality among SOT recipients, and effective therapies are only available for influenza and RSV infection.
· New antivirals and vaccines are needed
==============
Level of Evidence 5
Introduction
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients.
The most common culprit viruses are
Influenza virus
Respiratory syncytial virus (RSV),
Human metapneumovirus (HMPV)
Parainfluenza virus (PIV),
Rhinovirus coronavirus (CoV)
Adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1%.
DIAGNOSIS
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
CONCLUSION
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Given the severe implications respiratory viral infections have on the immuno- compromised population, development of new antivirals and vaccines is needed.
Respiratory Viruses in Solid Organ Transplant Recipients:
Introduction;
-In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year.
-Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses.
-All respiratory viruses cause similar symptoms and the clinical presentation does not differentiate between the viruses.
-Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs.
Diagnosis;
–Viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infections.
–Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
-Using multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h.
Influenza Virus;
-Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
-There are multiple strains, although only influenza A and B are generally associated with disease in humans.
-Influenza viruses are seasonal, circulate mainly in the winter, and cause a significant proportion of RTIs during that time.
Risk factors;
-Associated with older age, diabetes and use of mycophenolate mofetil. Univariate analysis also identified multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission.
Clinical Presentation;
-The most common symptom; cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
-Immunocompromised individuals are also at increased risk for complications.
Prevention;
-In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions.
-The most important means for prevention is vaccination of the transplant recipient and close contact.
-Only inactivated influenza vaccines should be given to transplant recipients.
-The American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant.
-The American Society of Transplantation guidelines (2019); recommend that high-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used.
-Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs , however there is no recommendation to withhold treatment around vaccination.
-Guidelines published by The Infectious Diseases Society of America recommend that antiviral prophylaxis (oseltamivir) should be given in the case of a hospital outbreak to patients in the affected wards.
-prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case.
Treatment;
–M2 inhibitors (amantadine and rimantadine); are not used today since they are inherently inactive against influenza B and circulating influenza A strains carry a high rate of resistance.
–The neuraminidase inhibitors (NAIs); are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
–Baloxavir; was recently approved and is a single dose oral medication , It has been shown to be effective in uncomplicated influenza in the non-immunocompromised population, it also be more effective against influenza B strains than NAIs.
-There have been no trials comparing drugs, doses or treatment durations in the SOT population.
Respiratory Syncytial Virus;
–RSV is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyxoviridae) and has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring , and circulates mainly among young children, who are a significant source of transmission.
-In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens, and is a cause of significant morbidity and mortality due to the development of lower RTI.
Clinical Manifestations;
-Similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea
-Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia, especially for LTRs, where lower RTI rates can be as high as 72%.
Prevention;
-Hospitalized patients should be placed under contact precautions as RSV droplets form large particles and are transmitted by contact.
-The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
-Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein, given once per season because of its extended half-life, and has favorable results.
-ResVax vaccine is recommended for elderly persons, pregnant women or the pediatric population, however, a recent phase three trial of this vaccine in pregnant women did not reduce RSV infections in infants after birth.
Treatment;
-In a combined analysis of trials done in HSCT, ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
-Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a nonsignificant reduction in progression to lower RTI.
-Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with the host cells.
Human Metapneumovirus;
–HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
-Its seasonality also follows that of RSV, with most cases identified in the winter and spring.
-Studies conducted on LTRs identified HMPV in 3.6–6.8% of positive respiratory samples.
-Ribavirin has in vitro activity against HMPV, with favorable outcomes on graft function with or without steroids.
-However, current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients.
Parainfluenza Virus;
–Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
-There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
-In LTRs, PIV infection accounts for 3.6–20.9% of the respiratory viruses isolated and associated with a high rate of symptomatic disease and lower RTI.
-Studies in SOT recipients are limited to small case series describing the use of ribavirin with and without immunomodulators in LTRs with mixed viral infections (PIV and RSV with/without HMPV).
-The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions.
Rhinovirus;
–Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
-Serotypes A–C circulate year-round and are the predominant cause for the common cold.
-Rhinoviruses accounted for 41.8–61.6% in immunocompetent patients as well as SOT recipients.
-Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown.
-Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs.
-Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses;
–CoVs are single-stranded RNA viruses of the Coronaviridae family.
-Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease.
-SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%.
-Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care.
Adenovirus;
Epidemiology;
–Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
-Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition.
-Adenoviruses show no seasonal variability and have been associated with institutional outbreaks.
Clinical Manifestations;
-Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
-Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention;
–Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precautions.
-Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir.
Treatment;
-Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir , IVIG and adenovirusspecific cytotoxic T lymphocytes.
Bocavirus;
–Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
-It is rarely isolated from respiratory specimens (0.5-1 %) , and in positive specimens, there is often co-infection with other respiratory viruses.
-Similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence
KI and WU Polyomaviruses;
–KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
-Studies in HSCT recipients suggested a higher frequency of infection with these viruses.
Summary;
–Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
-With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity.
-Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise.
-Preventive measures are also lacking, as vaccination is only available against influenza at this time.
-This is review article with (LOE – V)
Respiratory Viruses in Solid Organ Transplant Recipients
Published: 25 October 2021 MDPI, Basel, Switzerland.
o PCR is the gold standard (sensitivity 70-100%) but results appear within 12-24 hours.
o Rapid antigen test: rapid test with lower sensitivity and applicable only for influenza and RSV.
Influenza virus
Respiratory Syncytial Virus
Human Metapneumovirus
Parainfluenza Virus:
Rhinovirus
Coronaviruses
Adenovirus
Level of evidence is V
Summary:
Introduction:
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered. In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year. The incidence appears to be higher among lung transplant recipients (LTRs). This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV,adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
Influenza Virus:
· Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family
· Immunocompromised individuals are at increased risk for complications
· Risk factors associated with severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic.
· Influenza vaccination is the most important means of prevention
· Three groups of drugs are approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, which has a novel mechanism of action and is a single dose oral medication.
· Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and patients with symptoms > 48 h should be treated.
Respiratory Syncytial Virus:
· RSV is a seasonal virus with peak incidence in the winter and spring and is a significant source of transmission in LTRs.
· Risk factors for lower RTI and mortality include young children, recent transplant, lung or multi-visceral transplant and recent rejection.
· Clinical presentation is similar to other respiratory viruses, but RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
· Ribavirin treatment is associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
Human Metapneumovirus:
· HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
· Ribavirin has in vitro activity against HMPV, but data derived from HSCT recipients do not demonstrate a mortality benefit.
· Prevention is mainly based on infection control practices, including contact precautions.
Parainfluenza Virus:
· Single-stranded RNA virus of the Paramyxoviridae family, and is associated with a high rate of symptomatic disease and lower RTI. Treatment is based on supportive care and prevention in the hospital setting.
Rhinovirus:
· Single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples.
· Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
· Single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs).
· Human CoVs are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. Studies on 85 immunocompromised and 1152 immunocompetent children .demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively).
· In-vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen.
Adenovirus:
· Double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes, and can cause viremia without obvious symptoms.
· Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route, and prevention is based on maintaining droplet and contact precautions.
· Treatment options include reduction of immunosuppression, Cidofovir, Brincidofovir, IVIG.
Bocavirus:
· Single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making its contribution to RTIs unknown.
· No specific treatment options only standard precaution.
Conclusion:
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients. With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity. Effective therapies are available only for influenza, and also to some extent for RSV infection; however, new drug classes show some promise. Preventive measures are also lacking, as vaccination is only available against influenza at this time. Given the severe implications respiratory viral infections have on the immunocompromised population, development of new antivirals and vaccines is needed.
Level of evidence: level V
Please summarise this article
RESP VIRUSES IN SOT.
Introduction.
Incidence of resp viruses in SOT;0.76-0.91 Episode/pt yr and is higher among lung transplant recipients .In LTR, mortality of upto 5.1% has been recorded.
Diagnosis;
Influenza virus;
RSV;
Human Metapnemovirus.
Parainfluenza virus.
Rhinovirus.
Coronavirus.
Adenovirus.
Bocavirus.
KI and WU Polyomavirus.
Resp Virus and rejection in LTR.
What is the level of evidence provided by this article?
Level 5 – Narration.
III. Respiratory Viruses in Solid Organ Transplant Recipients
Please summarise this article.
There are many viruses that affect repiratory system have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered, specifically as they relate to organ transplant recipients
Including:
Influenza virus
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. There are multiple strains, although only influenza A and B are generally associated with disease in humans,affection circulate mainly in the winter.
The influenza attack rate depend on :
age(withhigherratesinchildren)
Level of immunity (due to priorvaccination or disease)
Degree of immunosuppression and the nature of the epidemic.
Prevention by vaccination of the transplant recipient and close contacts. inactivated influenza vaccines should be given to transplant recipients.
Another measure to prevent influenza infection would be using antiviral prophylaxis.
Treatment There are three groups of drugs approved for the treatment of influenza:
1.M2 inhibitors (amantadine and rimantadine).
2.The neuraminidase inhibitors (NAIs).
3.Baloxavir.
Respiratory syncytial virus (RSV)
Is a single-stranded RNA virus of the Pneumoviridae family (formerly Paramyxoviridae) and has two strains: RSV-A and RSV-B.it seasonal and peak in the winter and spring.
Clinical Manifestations
Fever
Cough
Dyspnea
Rhinorrhea
Prevention
palivizumab prophylaxis
Nirsevimab
Vaccine like ResVax,
Treatment
Ribavirin was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RT.
immunoglobulin(IVIG)
Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a non significant reduction in progression to lower RTI.
Human metapneumovirus (HMPV)
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
most cases identified in the winter and spring. Ribavirin has in vitro activity against HMPV.
Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients.
Parainfluenza virus (PIV)
Parainfluenzavirus(PIV)is asingle-stranded RNAvirus of the Paramyxoviridae family.
There are four serotypes of PIV , serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
Utility of antivirals for PIV infection in SOT is unknown.
The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions .
Rhinovirus, coronavirus (CoV)
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown.
Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family.
Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples.
Treatment options used in published case reports include ribavirin,interferon and steroids.
MERS-CoV still causes sporadic infections ,mainly in the Middle East .
Adenovirus
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotype.
Adenoviruses show no seasonal variability.
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate.
Clinical Manifestations
Conjunctivitis
Upper RTI
Lower RTI
Hemorrhagic cystitis
Pyelonephritis
Hepatitis
Enterocolitis.
Prevention BY :
Maintaining droplet and contact precautions.
Brincidofovir not FDA approved .
Treatment
Reduction of immunosuppression.
Cidofovir.
Brincidofovir (investigational).
IVIG and adenovirus specific cytotoxic T lymphocytes.
Bocavirus and KI
Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
WU polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
A study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively .
However, it is still unclear whether this has any clinical significance.
All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses.
What is the level of evidence provided by this article: LEVEL V.
Respiratory Viruses in Solid Organ Transplant Recipients
Summary:
· Respiratory viral infections are common cause of morbidity and mortality posttransplant especially in lung transplantation.
· These viruses include RSV, human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV).
· It can occur at any time after transplantation, mainly in autumn and winter.
· Most of infections has common clinical manifestation as fever, rhinorrhea, cough, chest pain, myalgia and bone aches, some GI manifestations as diarrhea.
· The clinical presentation is worse among SOT with progression to LRTI and pneumonia especially lung transplantation (develop bronchiolitis obliterans).
· Risk factors associated with increased disease severity as older age, and use of MMF/ ATG induction or in ttt of AR, multiple comorbidities as DM, HTN, CVD, lymphopenia, hypogammaglobulinemia
· Diagnosis by viral culture, direct fluorescent antibody (DFA) staining and serology.
o Viral culture needs long time (10 days), special staining is not available for all viruses, so molecular isolation of viral DNA and RNA (Nucleic acid testing (NAT)) remains the golden standard for diagnosis, sensitivity 75-100 % (done from respiratory secretion =nasal and nasopharyngeal swabs).
o Rapid antigen tests, give results within minutes, but not sensitive and available only for influenza, COVID 19 and RSV.
· Influenza A, B types cause pandemic, commonly affect children, annual influenza vaccine decrease infection rate and ttt by oseltamivir is effective to fasten recovery and decrease mortality. In BMT and SOT can be complicated by bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc.
o Killed influenza vaccine (injection) (rather than intranasal live attenuated vaccine) is recommended in all SOT cases, contacts and also in health care workers to minimize risk of infection. Vaccine decrease risk of progression to pneumonia and also decrease mortality.
o Antiviral ttt = neuraminidase inhibitors (NAIs) as (oral) oseltamivir, zanamivir (inhaled and IV), peramivir (intravenous) and laninamivir
o Best response with early initialtion in 1st 48 hours from symptoms.
· RSV:
o Palivizumab prophylaxis used in children under 24 months of age who are severely immunocompromised, but no data to support its use in adult SOT recipients.
o Ttt by ribavirin + intravenous immunoglobulin (IVIG).
· Human Metapneumovirus: ribavirin may be beneficial in ttt.
· Adenovirus (feco-oral transmission and vomitus, and through organ donation)
· Ribavirin is used in (RSV, parainfluenza, human mtapneumovirus, and adenovirus).
· COVID 19=remdisvir.
· Treatment of all viral infection is mainly supportive (IV fluids, antipyretics, oxygen support as needed or even non-invasive or invasive ventilation.
· Reduction of IS therapy (especially ant proliferative MMF /AZA is warranted in severe hospitalized cases.
· Addition of antiviral therapy as mentioned above in each virus may fasten the recovery and shorten hospital stay in such compromised patients.
· IVIG may be beneficial in severe cases combined with above-mentioned therapy.
Level of evidence: narrative review (level 5).
Introduction:
respiratory viruses and serotypes are affecting immunocompromised organ transplant recipients. This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses. Lung transplant data is dominating.
In organ transplant recipients, respiratory viral infections occur 0.76–0.9 times per patient-year, including silent infections. Lung transplant recipients (LTRs) have higher incidence. Respiratory viruses are present year-round, but winter and autumn are peak seasons. Clinical signs are generally similar for all respiratory viruses.
Diagnosis:
The gold standard for diagnosing respiratory viruses is now nucleic acid testing (NAT), which has a sensitivity of 72–100%.
Rapid antigen tests can give results in minutes are only available for influenza and RSV, with low sensitivity.
– Influenza Virus
Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. multiple strains, but only influenza A and B are generally associated with disease
in humans. seasonal, mainly in the winter.
Clinical Presentation
Immunocompromised people may not have classical influenza. Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms in a prospective multicenter analysis of 477 SOT recipients and 139 HSCT recipients with confirmed influenza infection .
Complications include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis. Hospitalization, ICU admission, pneumonia, and high mortality rates.
Age, diabetes, and mycophenolate mofetil use are multivariate risk factors for severe illness. Univariate analysis indicated several comorbidities, antilymphocyte globulin use in the past six months, lymphopenia, hypogammaglobulinemia, influenza A, and nosocomial acquisition were risk factors for pneumonia or ICU admission.
Prevention
droplet precautions should be considered for influenza patient.
Vaccination of transplant recipients and close contacts is the best prevention. Transplant recipients should receive only inactivated vaccinations.
Live attenuated intranasal influenza vaccines are contraindicated for SOT recipients because they may spread the virus.
the American Society of Transplantation recommends inactivated influenza vaccination one-month post-transplant.
vaccine reduces infection, complications, and mortality.
Vaccination in the same influenza season reduced the odds of pneumonia and ICU hospitalization.
no difference between high-dose intradermal and standard-dose intramuscular vaccination.
the 2019 American Society of Transplantation guidelines advocate high-dose vaccination when available, although two doses of regular vaccine can also be administered. Mycophenolate patients had a lower antibody response but no need to stop it around the vaccine.
Antiviral prophylaxis can also prevent influenza.
In 477 transplant recipients, predominantly SOT, low-dose oseltamivir pre-exposure prophylaxis prevented PCR-confirmed influenza by 80% without increasing resistance. Since these patients may already be infected post-exposure, preventive oseltamivir doses may cause antiviral resistance. Therapeutic-dose oseltamivir may be appropriate. Two healthcare-associated cases in the same ward within 72 hours indicate an outbreak, and prophylaxis should be provided for 14 days and at least 7 days following symptom onset.
Treatment
Oseltamivir (oral) therapeutic dose 75 mg q12h , preventive dose (5 days) 75 mg q24h
Single dose of Baloxavir (oral) 40 mg (<80 kg), 80 mg (>80 kg)
Due to extended viral replication and subtherapeutic antiviral exposure, immunocompromised patients are at risk for antiviral resistance (as in post-exposure prophylaxis)
Treatment options include switching NAIs classes, or combination antivirals. 9.7% of baloxavir-treated patients showed resistance, which prolonged viral shedding and delayed symptom relief.
Respiratory Syncytial Virus
Epidemiology and Risk Factors
RSV-A and RSV-B are Pneumoviridae (previously Paramyxoviridae) single-stranded RNA viruses. peak occurrence in winter and spring.
accounted for 2.4–6.2% of respiratory viruses in upper and lower respiratory tract specimens and causes significant morbidity and mortality due to lower RTI. Young children, recent transplant, lung or multivisceral transplant, and recent rejection are risk factors for lower RTI and mortality in SOT patients.
Clinical Manifestations
causes fever, cough, dyspnea, and rhinorrhea. RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses.
Prevention
Contact precaution for hospitalized patients. Palivizumab prophylaxis during RSV season is not evidence-based, however, the American Academy of Pediatrics recommends it for severely immunocompromised children under 24 months old. vaccines are under development.
Treatment
Ribavirin reduced upper RTI progression to lower RTI and lower RTI mortality. patients treated for lower RTI with ribavirin and an immunomodulator (IVIG, RSV-IVIG, or palivizumab) had considerably decreased mortality and nonsignificantly lower progression to lower RTI.
Human Metapneumovirus
HMPV, a Pneumoviridae virus, resembles RSV. Like RSV, most occurrences occur in winter and spring.
Ribavirin (mainly oral) reduced chronic lung allograft disease. In two small studies of 15 and 19 lung transplant recipients with HMPV infection, ribavirin with or without steroids improved graft function.
Ribavirin may benefit lung transplants, however, controlled research are limited and current treatment is mostly supportive.
Infection control, including contact precautions in hospitalized patients, is the principal prevention method.
Parainfluenza Virus
Single-stranded RNA Paramyxoviridae virus.
Serotype 3 is the most common, has no seasonality.
21% of 24 PIV-infected LTRs, primarily PIV3, had respiratory failure.
PIV antiviral therapy in HSCT recipients had no effect.
PIV antiviral therapy in HSCT recipients had no effect. supportive care is the main treatment.
Rhinovirus
single-stranded RNA viruses of the Picornaviridae family of Enteroviruses. causes cold symptoms, but LTRs have had lower RTI. Droplet precautions and supportive treatment are hospital-based.
Coronaviruses
single-stranded RNA. cause upper RTI, while SARS-CoV1, MERS-CoV, and SARS-CoV-2 induce severe respiratory illness outbreaks. This evaluation excludes SARS-CoV-2 illnesses.
Symptoms resemble other respiratory infections. immunocompromised population had a greater rate of severe lower RTI.
SARS-CoV1 appeared in southern China in late 2002 [86] and caused a significant incidence of lower RTI and 20% mortality. Ribavirin and interferon were active against the virus in vitro, but no clinical effect was reported. Interferon, high-dose steroids, and supportive care improved outcomes in case series and a short RCT. The first SARS-CoV1-infected transplant recipient was a liver transplant patient who infected multiple healthcare staff. He died after ribavirin treatment. SARS-CoV1 was eliminated through strict infection control.
MERS-CoV, first discovered in Saudi Arabia, causes severe respiratory disease and 50% death. Camel zoonosis continues transmission. One kidney transplant recipient recovered. Ribavirin, interferon, and steroids are reported treatments. MERS-CoV still produces sporadic Middle Eastern attacks.
Adenovirus
can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis, and enterocolitis, and has a predilection for the
transplanted allograft. Adenovirus may cause pyelonephritis in kidney transplant recipients with unexplained fever and rising creatinine. Adenoviral pneumonia can kill 50% and disseminated infection 80%. Lung transplant recipients can develop bronchiolitis obliterans.
prevention in the hospital setting is based on droplet and contact precautions
Supportive care, immunosuppression reduction, cidofovir, brincidofovir (investigational), IVIG, and adenovirus-specific cytotoxic T cells are therapy options. Using cidofovir with immunosuppression improved outcomes.
IVIG with antivirals, use of virus-specific cytotoxic T cell also is an option.
Summary
For SOT recipients, respiratory viruses are a significant cause of morbidity and mortality. They are now more frequent and in more different ways detected due to the development of molecular diagnostic techniques. Only influenza and, to a lesser extent, RSV infection have effective treatments; however, emerging medication classes offer some promise.
currently only an influenza vaccine is available, and preventive measures are still inadequate. demand for novel antivirals and vaccinations.
level of evidence, a narrative review, level 5
Summary of the article
Respiratory Viruses in Solid Organ Transplant Recipients
1. Respiratory viral infections can appear at any time post-transplant and are usually acquired in the community.
2. The incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year. With higher incidence among lung transplant recipients (LTRs).
3. Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs.
4. Viral pneumonia in solid organ transplant (SOT) recipients is associated with an attributable mortality of 5.1%.
5. Diagnosis of respiratory viral infection can be as follows:
a) Historically:
· Viral culture: has a long turnaround time of 10 days for standard viral culture and two days for shell vial culture.
· Direct fluorescent antibody (DFA) staining: available for only a limited number of respiratory viruses.
· Serology: useful only for epidemiological studies.
b) Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%.
c) multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h.
d) Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity.
Influenza Virus
1. Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family, seasonal virus with peak incidence in the winter.
2. Influenza A and B are generally associated with disease in humans.
3. In SOT recipients, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
4. Immunocompromised individuals are at increased risk for complications: viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
5. Risk factors associated with severe disease include older age, diabetes and use of mycophenolate mofetil.
6. Prevention:
· Droplet precautions.
· Vaccination of the transplant recipient and close contacts is the most important mean of prevention. Only inactivated influenza vaccines should be given to transplant recipients.
· Using antiviral prophylaxis; low-dose oseltamivir(75 mg OD).
7. Treatment of influenza:
a) M2 inhibitors (amantadine and rimantadine) are not used today since they are inherently inactive against influenza B and circulating influenza A strains carry a high rate of resistance.
b) The neuraminidase inhibitors (NAIs) include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir.
c) Selective inhibitor of influenza cap-dependent endonuclease: Baloxavir is a single dose oral medication. Baloxavir may also be more effective against influenza B strains than NAIs.
d) Favipiravir may be promising as it seems to have low resistance rates and is synergistic when combined with oseltamivir.
e) Treatment challenges: the high mutation rates (H275Y in A/H1N1& R292K in A/H3N2)
Respiratory Syncytial Virus
1. RSV is a single-stranded RNA virus of the Pneumoviridae family, seasonal virus with peak incidence in the winter and spring.
2. Commonly presents with fever, cough, dyspnea and rhinorrhea. RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
3. Prevention:
· Contact precautions.
· Palivizumab for age < 2 years.
4. Treatment:
· Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
· Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI.
Human Metapneumovirus
5. HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. It is aseasonal virus with peak incidence in the winter and spring.
6. HMPV was identified in 3.6–6.8% of positive respiratory samples in LTRs.
7. Clinically present with RTI and lower RTI are encountered.
8. Treatment of HMPV:
· data derived from HSCT recipients do not demonstrate a mortality benefit with antivirals or immunomodulators.
· Two small series of 15 and 19 lung transplant recipients with HMPV infection demonstrated favorable outcomes on graft function among patients treated with ribavirin with or without steroids.
9. Prevention of HMPV:
· Implementation of contact precautions in hospitalized patients.
Parainfluenza Virus
1. Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
2. There are four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
3. PIV accounts for 3.6–20.9% of the respiratory viruses isolated in LTRs.
4. Clinically presents with a high rate of symptomatic disease, lower RTI and 21% experienced respiratory failure.
5. Treatment: the mainstay of treatment for PIV infection is supportive care and prevention.
6. Prevention is based on adherence to contact precautions.
Rhinovirus
1. Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family(part of the Enterovirus genus).
2. Serotypes A–C circulate year-round and are the predominant cause for the common cold.
3. Rhinoviruses accounted for 41.8–61.6% of the positive samples in LTRs.
4. Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown.
5. Clinically presents with symptoms of the common cold, although there have been case reports of lower RTI in LTRs.
6. Treatment is based on supportive measures and prevention.
7. Prevention in the hospital setting mandates droplet precaution.
Coronaviruses
1. CoVs are single-stranded RNA viruses of the Coronaviridae family.
2. CoVs cause upper RTI, whereas:
· SARS CoV1: severe acute respiratory syndrome (SARS), infection emerged in southern China in late 2002.
· MERS-CoV: Middle Eastern respiratory syndrome (MERS), was first identified in Saudi Arabia.
· SARS-CoV-2: are associated with outbreaks of severe respiratory disease.
3. Human coronaviruses are accounting for 12.4–17.8% of the positive samples among LTRs.
4. Symptoms are generally similar to other respiratory viruses. The immunocompromised patients had a significantly higher rate of severe lower RTI.
5. Treatment :
· In-vitro; ribavirin and interferon are active against the virus, although no clear clinical benefit of ribavirin was seen.
· Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care.
6. Prevention: due to strict infection control practices, the outbreak was controlled and there were no more cases of SARS-CoV1.
Adenovirus
1. Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G).
2. Transmission: Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
3. Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition.
4. Adenoviruses show no seasonal variability and have been associated with institutional outbreaks.
5. Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
6. Clinical Manifestations:
· Viremia without obvious symptoms.
· Can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis.
· It has a predilection for the transplanted allograft. In a KTRs with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis. Development of bronchiolitis obliterans has been described in LTRs.
7. Prevention:
· prevention in the hospital setting is based on maintaining droplet and contact precautions.
· Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir. However, it is not FDA approved.
8. Treatment:
· Supportive care and reduction of immunosuppression.
· Other options: cidofovir, brincidofovir (investigational), IVIG and adenovirus- specific cytotoxic T lymphocytes (investigational).
· There are promising results in liver transplant recipients with the use of brincidofovir in combination with the reduction of immunosuppression.
· IVIG, usually in addition to an antiviral drug.
· Data regarding virus-specific cytotoxic T lymphocytes for adenovirus infections are scarce.
Bocavirus
1. Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
2. It is rarely isolated from respiratory specimens. Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
3. Similar to parvovirus B19, bocaviruses are known for their viral persistence.
4. The viral persistence combined with the high co-infection rate, makes their true contribution to RTIs unknown.
KI and WU Polyomaviruses
1. KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviri- dae family that were discovered in 2007.
2. KI and WU polyomaviruses were identified in 14.3% and 9.1% of respiratory specimens, respectively.
3. It is still unclear whether this has any clinical significance.
Respiratory Viruses and Rejection in Lung Transplantation
1. Respiratory viral infection is associated with significant higher rates of acute rejection (16%) and biopsy-proven bronchiolitis obliterans (10% ) among LTRs with respiratory infections.
· Associations have been reported for specific respiratory viruses; influenza, HMPV and RSV, PIVand adenovirus.
· Treatment with ribavirin was associated with lower rates of CLAD/BOS(bronchiolitis obliterans syndrome).
· in LTRs with RSV, HMPV and PIV infections.
2. It seems, however, that there is no definitive association between rhinoviruses and CoVs and rejection or chronic lung allograft disease(CLAD).
The level of evidence provided by this article:
This is a narrative review article with level of evidence grade 5.
Please summarise this article?
Introduction:
Respiratory viruses have a significant impact on the health of immunocompromised organ transplant recipients, with the incidence of respiratory viral infections ranging from 0.76-0.91 episodes per patient-year. This review discusses respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus, CoV,adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients.
Diagnosis:
Nucleic acid testing (NAT) is now the gold standard for diagnosing respiratory viral infections and has a sensitivity of 72-100%. Rapid antigen tests are available for influenza and RSV only and suffer from low sensitivity.
Influenza Virus:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family. It is seasonal, circulating mainly in the winter and causing a significant proportion of RTIs. Immunocompromised individuals are at increased risk for complications, such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc. Risk factors associated with severe disease include age, likelihood of exposure, level of immunity, degree of immunosuppression, and the nature of the epidemic.
Prevention : Influenza vaccination is the most important means of prevention for transplant recipients and close contacts, and has been shown to decrease infection rates, complications and mortality. Antiviral prophylaxis is recommended to prevent influenza infection in transplant recipients, but there is concern that some may develop antiviral resistance.
Treatment: Three groups of drugs are approved for the treatment of influenza: neuraminidase inhibitors (NAIs), M2 inhibitors (amantadine and rimantadine), and Baloxavir, which has a novel mechanism of action and is a single dose oral medication.
Early antiviral treatment is associated with a decrease in influenza complications and lower ICU admission rates, and patients with symptoms > 48 h should be treated.
Treatment for influenza should be started empirically as soon as possible, usually before test results are available. Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, and M2 inhibitors are not recommended due to the high resistance rate in the currently circulating influenza A strains. Resistance to NAIs for seasonal influenza is uncommon and occurs predominantly in the A/H1N1 strain.
Respiratory Syncytial Virus:
RSV is a seasonal virus with peak incidence in the winter and spring and is a significant source of transmission in LTRs. Risk factors for lower RTI and mortality include young children, recent transplant, lung or multivisceral transplant and recent rejection. Clinical presentation is similar to other respiratory viruses, but RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
Palivizumab prophylaxis is not given to adult SOT recipients, and monoclonal antibody development is focused on developing antibodies with extended half-lives. Ribavirin treatment is associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
Presatovir is a new antiviral with specific anti-RSV activity, but two phase 2b RCTs failed to show significant improvements, and 20% of patients developed resistance.
Human Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV. Studies have identified HMPV in 3.6-6.8% of positive respiratory samples, and 8/18 (44%) had a lower RTI. Ribavirin has in vitro activity against HMPV, but data derived from HSCT recipients do not demonstrate a mortality benefit. Prevention is mainly based on infection control practices, including contact precautions in hospitalized patients.
Parainfluenza Virus:
PIV is a single-stranded RNA virus of the Paramyxoviridae family, and is associated with a high rate of symptomatic disease and lower RTI. Treatment is based on supportive care and prevention in the hospital setting.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that circulate year-round and are the predominant cause of the common cold. In studies, rhinoviruses accounted for 41.8-61.6% of positive samples. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviruses are single-stranded RNA viruses of the Coronaviridae family that cause upper respiratory infections (RTIs). Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, while other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, and SARS-CoV-2) are associated with outbreaks of severe respiratory disease. Human CoVs are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4-17.8% of positive samples. Studies on 85 immunocompromised and 1152 immunocompetent children .demonstrated a similar rate of lower RTI in the two groups (22% and 26%, respectively). In-vitro studies identified ribavirin and interferon as active against the virus, but no clear clinical benefit of ribavirin was seen.
Adenovirus:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups and 90 serotypes, and can cause viremia without obvious symptoms. Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route, and prevention is based on maintaining droplet and contact precautions. Treatment options include reduction of immunosuppression, brincidofovir, IVIG and adenovirusspecific cytotoxic T lymphocytes.
Bocavirus:
Bocavirus is a single-stranded DNA virus that is rarely isolated from respiratory specimens and co-infected with other respiratory viruses, making its contribution to RTIs unknown.
KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family, with higher frequency in HSCT recipients.
Respiratory Viruses and Rejection in Lung Transplantation:
LTRs are at increased risk for RTIs due to continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression. Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections.
Summary:
Development of new antivirals and vaccines is needed to reduce respiratory viral infections in the immunocompromised population.
What is the level of evidence provided by this article?
level V
Respiratory Viruses in Solid Organ Transplant Recipients
Solid organ transplantation is often lifesaving, but does carry an increased risk of infection. Respiratory viral infections are one of the most prevalent infections, and are a cause of significant morbidity and mortality, especially among lung transplant recipients.
In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year
All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses
Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40%
Diagnosis
Viral culture has a long turnaround time of 10 days for standard viral culture and two days for shell vial culture
DFA staining is available for only a limited number of respiratory viruses and requires expertise in interpreting the result
Serology have been useful only for epidemiological studies and not for diagnosing acute infection
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%
Rapid antigen tests- allows results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family
Immunocompromised individuals are also at increased risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis
Risk factors associated with severe disease in multivariate analysis include older age, diabetes and use of mycophenolate mofetil
Patients diagnosed with influenza should be placed under droplet precautions
There is a theoretical risk of dissemination of virus contained in the live attenuated intranasal influenza vaccine, which is therefore contraindicated for SOT recipients
Pre-exposure prophylaxis using low-dose oseltamivir was evaluated has demonstrated 80% efficacy against PCR-confirmed cases
The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir
Respiratory Syncytial Virus
It is a seasonal virus with peak incidence in the winter and spring
It presents with fever, cough, dyspnea and rhinorrhea
Hospitalized patients should be placed under contact precautions
Treatment- Ribavarine. IVIG
Human Metapneumovirus
Its seasonality also follows that of RSV, with most cases identified in the winter and spring
Ribavirin has in vitro activity against HMPV
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI
The mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions
Rhinovirus
Rhinoviruses are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions
Coronaviruses
Symptoms are generally similar to other respiratory viruses
Treatment options used in published case reports include ribavirin, interferon and steroids
Adenovirus
Adenoviruses are known to cause viremia without obvious symptoms; therefore, differentiating infection and disease may be more appropriate
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes
Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses
KI and WU Polyomaviruses
Double-stranded DNA viruses of the Polyomaviridae family
unclear whether this has any clinical significance
Introduction:
Immune compromised organ transplant recipients are at a significant risk of contracting numerous respiratory viruses that can affect their health. Most respiratory viruses generally cause similar symptoms, and their clinical presentation does not help to differentiate between them. This review assesses several respiratory viruses in relation to organ transplant recipients.
Diagnosis:
Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has high sensitivity. Rapid antigen tests are available for influenza and RSV, but have low sensitivity.
Influenza Virus
Influenza virus is a RNA virus, single stranded from the Orthomyxoviridae family. They are seasonal and see more commonly during winter. The incidence rate depends on age, likelihood of exposure, level of immunity, degree of immune suppression and nature of the epidemic.
The most common symptom seen are cough, fever, rhinorrhea, myalgia, gastrointestinal symptoms, sore throat, and headache in transplant recipients. Transplant recipients are at an increased risk of complications, such as viral pneumonia, bacterial superinfection, fungal infections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Risk factors associated with severe disease include older age, diabetes and use of mycophenolate mofetil. The most important form of prevention in transplant patients is vaccination. There are three groups of drugs that can be used for the treatment of influenza. These include M2 inhibitors, neuromunidase inhibitors and baloxavir. It is recommended that all symptomatic transplant recipient should be treated irrespective of symptom duration.
Respiratory Syncytial Virus (RSV)
RSV is a single stranded RNA virus. It belongs to the pneumoviridae family. It’s OK it’s mainly among young children and during winter. Children are a significant source of transmission. The virus has been identified in upper and lower respiratory tract specimen. It is a cause of significant morbidity and mortality. Risk factors include young children, recent transplant and recent rejection of transplant. Common symptoms include fever, cough, dyspnea and rhinorrhea. Lower respiratory tract infection symptoms include bronchitis, bronchiolitis and pneumonia. Hospitalized patients should be placed under contacts precautions. Palivizumab can be used as prophylaxis during the RSV season in children who are immune compromised. Ribavirin can be used for treatment. Unfortunately, data for transplant recipients is scarce.
Human Metapneumovirus (HMPV)
It is a single stranded RNA virus. It belongs to the pneumoviridae family. It resembles RSV. Most cases are identified in winter and spring. Ribavirin also has activity against HMPV. Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients.
Parainfluenza Virus (PIV)
It belongs to the paramyxoviridae family. It is a single stranded RNA virus. No season has been associated with its outbreaks. It may also cause lower respiratory tract disease and respiratory failure. The mainstay of treatment for PIV infections is supportive care and prevention in hospital settings based on adherence to contact precautions.
Rhinovirus
Rhinoviruses are single stranded RNA viruses. They belong to the picornaviridae family. They are the predominant cause of the common cold. They are usually found as part of coinfection with other viruses and bacteria symptoms are usually those of a common cold, although some cases of lower respiratory tract infections have been noted in transplant recipients. I study suggested a correlation between higher viral load and more symptoms. Treatment is based on supportive care and prevention in the hospital setting (droplet precautions).
Coronaviruses (CoVs)
They are single stranded RNA viruses of the Coronaviridae family. They may because upper respiratory tract infection, however some forms are associated with outbreaks of severe respiratory disease. The SARS-CoV1 infection emerged in late 2002 and was associated with high rate of lower respiratory tract infection and high mortality. MERS-CoV infection was first identified in Saudi Arabia, and was associated with severe respiratory illness and high mortality rates. Two cases in kidney transplant recipient have been described and only one of the two patients survived. Treatment options include ribavirin, interferon and steroids.
Adenovirus
It is a double stranded DNA virus of the Adenoviridae family. It’s establishes latency in lymphoid tissue. Therefore, infection can represent reactivation or de novo acquisition. They are known to cause viremia without obvious symptoms. Rates of infection differ with age and the transplanted organ. Higher rates are seen among children. They are also seen in intestinal transplantation, possibly due to the high amount of lymphoid tissue in the allograft and greater immune suppression. Adenovirus can manifest with conjunctivitis, upper and lower respiratory tract infections, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis. It has a predilection for the transplanted organ. Adenovirus should be considered as a cause of pyelonephritis when a kidney transplant recipient presents with fever of unknown origin and arising creatinine.
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal-oral route. Prevention is based on maintaining droplet and contact precautions in hospitals. Treatment involves supportive care, reduction in immune suppression medications, cidofovir, brincidofovir, IVIG and adenovirus-specific cytotoxic T lymphocytes.
Bocavirus
It is a single stranded DNA virus. It belongs to the parvoviridae family. They are known for their viral persistence. They usually occur in coinfection with other respiratory viruses. Since they have a high co-infection rate, it makes their true contribution to respiratory tract infections unknown.
KI and WU polyomaviruses
They are double stranded DNA viruses of the Polyomaviridae family. They have been detected in transplant recipients, unfortunately it is unclear whether they present any clinical significance.
Respiratory viruses and rejection in lung transplantation
Lung transplant recipients are at an increased risk for respiratory tract infections, especially lower respiratory tract infections. This may be related to continuous contact of the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and higher levels of immune suppression compared to other organ transplants. Studies have been inconclusive regarding respiratory viruses and incidence of rejection of lung transplants.
Summary
Respiratory viruses are a significant cause of mobility and mortality among solid organ transplant recipients. Effective therapies are only available for some of the respiratory viruses such as influenza. Preventative measures are also lacking as vaccination is only available against influenza currently. Development of new antivirals in vaccines is needed, especially given the severe implications that respiratory viral infections have on immune compromised patients.
Level Of Evidence:
It is a narrative review. The LOE is level V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
Introduction
There are numerous respiratory viruses that have a significant impact on the health of immunocompromised organ transplant recipients, and new viruses and serotypes are continuously being discovered.
All organ types will be discussed, the vast majority of data comes from studies of lung transplant recipients.
The incidence of respiratory viral infection in transplant ranges between 0.76–0.91 episodes per patient-year part of the studies included asymptomatic infections.
The incidence appears to be higher among lung transplant recipients (LTRs), but is not affected by time from transplant.
Respiratory viruses are present throughout the year, but there is a higher incidence in the autumn and winter, and patterns differ between viruses,
Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on.
98 LTRs found an attributable mortality of 5.1% [2]
Diagnosis
Viral culture, direct fluorescent antibody (DFA) staining and serology were used to diagnose respiratory viral infection
DFA staining is available for only a limited number of respiratory viruses and requires expertise in interpreting the results.
Nucleic acid testing (NAT) for respiratory viruses is the gold standard for diagnosis and has a sensitivity of 72–100%.
In a study of 93 LTRs, 5/93 had respiratory viruses identified in bronchoalveolar lavage using viral culture and DFA staining, whereas 48/93 had respiratory viruses identified by NAT on the same samples.
Using multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h.
Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity.
Epidemiology and Risk Factors
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
There are multiple strains, only influenza A and B are generally associated with disease in humans.
Circulate mainly in the winter, and cause a significant proportion of RTIs during that time.
The influenza attack rate depends on several factors, including age, likelihood of exposure, level of immunity, degree of immunosuppression and the nature of the epidemic .
A study evaluating incidence of influenza infections in.
3569 SOT recipients between the years 1990 and 2000 calculated an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively.
Clinical Presentation
Immunocompromised patients may not fit the classic definition of influenza-like illness.
In a prospective multicenter study including 477 SOT recipients and 139 patients after hematopoetic stem cell transplantation with confirmed influenza infection, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
Immunocompromised individuals are at increased risk for complications
These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis, etc.
Compiling data from four studies with a total of 947 SOT recipients with influenza, hospitalization, intensive care unit admission, pneumonia and mortality rates were 57–71%, 11–16%, 22–35% and 4–7.8%, respectively.
Univariate analysis identified multiple comorbidities, use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission.
Prevention
Patients diagnosed with influenza should be placed under droplet precautions [18 ], as outbreaks in the hospital setting have been described.
Another small study conducted during an influenza outbreak in a kidney transplant unit revealed that the unvaccinated population had significantly high rates of influenza infection.
Several studies have shown that patients on mycophenolate have a worse antibody response compared to other immunosuppressive drugs, there is no recommendation to withhold treatment around vaccination
Another measure to prevent influenza infection would be using antiviral prophylaxis.
Post-exposure prophylaxis has been evaluated in the non-immunocompromised population and can be given in cases of exposure to influenza among transplant recipients who have contraindications to receiving the influenza vaccine or who are not expected to mount an immune response.
Similar management can be pursued for an outbreak on a transplant ward
Treatment
There are three groups of drugs approved for the treatment of influenza.
Favipiravir may be promising as it seems to have low resistance rates and is synergistic when combined with oseltamivir
It is currently licensed only in Japan for use in influenza unresponsive or insufficiently responsive to current antivirals.
Several monoclonal antibodies targeting various hemagglutinins of influenza virus have been developed.
These were tested in phase two studies as monotherapy or in combination with antiviral drugs, showing mixed results.
NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals.
Resistance has been documented in 9.7% of patients treated with baloxavir; this was associated with prolonged shedding of the virus and longer time to alleviation of symptoms.
Epidemiology and Risk Factors
RSV is a single-stranded RNA virus of the Pneumoviridae family and has two strains: RSV-A and RSV-B.
It is a seasonal virus with peak incidence in the winter and spring and circulates mainly among young children, who are a significant source of transmission.
In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens and is a cause of significant morbidity and mortality due to the development of lower RTIs.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children, recent transplant, lung or multivisceral transplant and recent rejection.
Clinical Manifestations
The clinical presentation of RSV is similar to other respiratory viruses, as it commonly presents with fever, cough, dyspnea and rhinorrhea.
Compared to other respiratory viruses, RSV more frequently causes lower RTI.including bronchitis, bronchiolitis and pneumonia.
This is especially true for LTRs, where lower RTI rates can be as high as
Prevention
Hospitalized patients should be placed under contact precautions as RSV droplets form large particles and are transmitted by contact.
The American Academy of Pediatrics recommends consideration of palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised, acknowledging that this recommendation is not evidence based.
Since prophylaxis is given on a monthly basis during the RSV season and dosing is weight-based, costs of treatment in adults are extremely high.
Due to its extended half-life, it can be given once per season and has shown favorable results in a recently published randomized trial conducted on preterm infants.
There are currently multiple vaccines under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based.
These vaccines are recommended for elderly persons, pregnant women or the pediatric population.
The most advanced is ResVax, which is a nanoparticlebased vaccine; a recent phase three trial of this vaccine in pregnant women did not reduce RSV infections in infants after birth.
Treatment
A survey conducted in 11 transplant centers in the United States revealed differences in treatment regimens in lung transplant compared to other organs.
Among 11 non-lung transplant centers 7/11 treat lower RTI with ribavirin and only one center adds IVIG , whereas in upper RTI no center gives treatment.
Data on treatment for RSV infection in SOT recipients are limited to case series in lung transplants.
In a combined analysis of trials done in HSCT, ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
A study on 10 lung transplant recipients with lower RTI due to RSV showed good outcomes with mainly supportive care.
All trials failed to show significant improvements in clinical and virologic outcomes in the presatovir group, except for a possible decrease in progression to lower RTI in lymphopenic HSCT recipients.
These drugs can be divided into fusion inhibitors (RV521, AK0529/ziresovir) and replication inhibitors (PC786, EDP-938)
Human Metapneumovirus
Studies conducted on LTRs identified HMPV in 3.6–6.8% of positive respiratory samples.
In a study that included 139 LTRs with infections due to either RSV. HMPV or PIV, ribavirin was associated with significantly less chronic lung allograft disease (CLAD, OR 0.24, 95% CI 0.1–0.59).
Two other small series of 15 and 19 lung transplant recipients with HMPV infection demonstrated favorable outcomes on graft function among patients treated with ribavirin with or without steroids.
These data may suggest some benefit from ribavirin in lung transplants, controlled studies are lacking, and current treatment is primarily based on supportive care.
Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients.
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family.
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower.
A systematic review on antiviral treatment for PIV infection in HSCT recipients showed no benefit in this population.
Studies in SOT recipients are limited to small case series describing the use of ribavirin with and without immunomodulators in LTRs with mixed viral infection ( PIV and RSV with/without HMPV) These studies showed mixed responses to the treatments used.
DAS 181 was evaluated in an RCT among immunocompromised patients with lower RTI secondary to PIV infection.
The mainstay of treatment for PIVinfection is supportive care and prevention in the hospital setting is based on adherence to contact precautions.
Rhinovirus
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, which is part of the Enterovirus genus.
Serotypes A–C circulate year-round and are the predominant cause for the common cold.
As such, these viruses are isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients.
In studies among LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6% of the positive samples.
One study compared infection rates in 36 LTRs with a cohort of 235 immunocompromised and immunocompetent patients, and showed a higher infection rate among LTRs (41.7% vs. 14.5%, p < 0.001).
Symptoms of rhinovirus infection are usually those of the common cold, there have been case reports of lower RTI in LTRs. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses
CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human.
SARS-CoV1 infection emerged in southern China in late 2002, and was associated with high rates of lower RTI and mortality as high as 20% .
SARS-CoV1 infection was described in two transplant recipients; the first was a liver transplant patient that was exposed in the healthcare setting and infected several healthcare workers.
He was treated with ribavirin, but eventually succumbed.
MERS-CoV infection was first identified in Saudi Arabia, and is associated with severe respiratory illness and mortality rates as high as 50%.
Human to human transmission is associated with healthcare settings, and in one of the cohorts studied, 25% of the people infected were healthcare workers.
MERS-CoV still causes sporadic infections, mainly in the Middle East.
Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes.
Adenoviruses establish latency in lymphoid tissue; infection can represent reactivation or de novo community.
Adenoviruses are known to cause viremia without obvious symptoms; differentiating infection and disease may be more appropriate.
In a study of 263 SOT recipients, adenovirus in blood was checked at regular intervals during the first year posttransplant.
As much as 7.2% (19/263) developed viremia; only 4/19 (21%) were symptomatic.
Rates of adenovirus infection differ with age and the transplanted organ.
Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression.
Clinical Manifestations
Adenovirus infection can manifest with conjunctivitis, upper RTI lower RTI. hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis [105 ].
Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
In most cases there are no long term sequelae, development of bronchiolitis obliterans has been described in lung transplant recipients.
Prevention
Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
Prevention in the hospital setting is based on maintaining droplet and contact precautions.
Brincidofovir is an orally bioavailable lipid conjugate of cidofovir that lacks the nephrotoxicity associated with cidofovir.
It was tested in a phase two RST for preemptive treatment of adenovirus viremia in HSCT recipients and showed benefits. it is not FDA approved and the appropriate dose for treatment of adenovirus is not established
Treatment
Data on treatment modalities for adenovirus disease are derived from case reports and small case series.
Aside from supportive care, treatment options include reduction of immunosuppression, cidofovir, brincidofovir, IVIG and adenovirusspecific cytotoxic T lymphocytes.
Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression.
Contemporary data, the largest series being 13 liver transplant recipients, show promising results with the use of brincidofovir as well as with its use in combination with the reduction of immunosuppression.
Some may use IVIG , usually in addition to an antiviral drug.
Using virus-specific cytotoxic T lymphocytes for the treatment of cytomegalovirusand Epstein–Barr virus infections in HSCT recipients shows great promise.
Data regarding adenovirus infections are scarce in HSCT, and still lacking in SOT
10. Bocavirus
Bocavirus is a single-stranded DNA virus of the Parvoviridae family.
It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses.
Among LTRs, bocaviruses were isolated from only 0.5–1% of the positive respiratory samples.
B19, bocaviruses are known for their viral persistence.
This, combined with the high co-infection rate, makes their true contribution to RTIs unknown
11. KI and WU Polyomaviruses
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family that were discovered in 2007.
Studies in HSCT recipients suggested a higher frequency of infection with these viruses.
A study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively.
It is still unclear whether this has any clinical significance
12. Respiratory Viruses and Rejection in Lung Transplantation
LTRs are at increased risk for RTIs in general and lower RTIs.
Numerous studies have evaluated the association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS) showing conflicting data.
A systematic review and meta-analysis published in 2011 demonstrated no association between respiratory viral infection and acute rejection, only four studies were included in the analysis
It showed a non-significant trend towards association with.
It seems, that there is no definitive association between rhinoviruses and CoVs and rejection or CLAD.
Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV , HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD .
Findings
A large prospective multicenter study on 616 transplant recipients, mostly SOT, showed that vaccination in the same influenza season was associated with a reduction in odds for pneumonia (odds ratio (OR) 0.51, 95% CI 0.21–0.55).
Another small study conducted during an influenza outbreak in a kidney transplant unit revealed that the unvaccinated population had significantly high rates of influenza infection.
In a study that included 139 LTRs with infections due to either RSV , HMPV or PIV,ribavirin was associated with significantly less chronic lung allograft disease (CLAD, OR 0.24, 95% CI 0.1–0.59).
In LTRs with RSV, HMPV and PIV infections, as shown in a study on 139 LTRs where ribavirin was associated with a lower risk of CLAD .
13. Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
With the introduction of molecular diagnostic methods, they are detected at a greater frequency and diversity.
Effective therapies are available only for influenza, and to some extent for RSV infection; new drug classes show some promise.
Preventive measures are lacking, as vaccination is only available against influenza at this time.
Given the severe implications respiratory viral infection have on the immunocompromised population, development of new antivirals and vaccines is needed
Level of evidence is 5
Thank you, I appreciate your effort.
Respiratory Viruses in Solid Organ Transplant Recipients.
Introduction.
Organ transplant recipient are higher risk for respiratory viral infection due to their immunocompromised status specially post lung transplant with the incidence ranges between 0.76–0.91 episodes per patient-year, one study on 98 LTRs found an attributable mortality of 5.1% and usually sharing same clinical manifestation.
Diagnosis is mainly depends on Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%, for short turnaround time diagnosis rapid antigen tests, allowing results within minutes, and suffer from low sensitivity.
1-Influenza Virus.
Epidemiology and Risk Factors:
A study evaluating incidence of influenza infections in 3569 SOT recipients between the years 1990 and 2000 calculated an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants, respectively and 39% of all respiratory infections were caused by influenza and 32% of all viral infections were observed among LTRs.
Clinical presentation:
Usually different in immunocompromised patient, one study shown that the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%).
Risk factors for severe disease include: recent use of high-dose steroids, recent rejection, lymphocyte depletion, and lung transplantation.
Treatment:
Annual influenza vaccination is the most effective strategy to prevent infection and is currently recommended for all patients, their families, and healthcare personnel, three drugs currently approved by the FDA for use in the USA and approved by the CDC for the treatment of influenza infections include: oseltamivir, zanamivir, and peramivir, which have activity against influenza A and B virus, as opposed to the M2 protein inhibitors which are only effective against influenza A and this antivirals must be initiated within 48 h of symptom onset for maximum benefit, but should be initiated in this population regardless of the duration of symptoms also early treatment with oseltamivir may prevent progression to pneumonia in about 70% of the patients and reduce mortality to <10%.
2-Respiratory Syncytial Virus
Epidemiology, clinical picture and Risk Factors:
Has two strains: RSV-A and RSV-B, it is a seasonal virus with peak incidence in the winter and spring, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens in LTR. Has many risk factors such as young children (less than two years old), recent transplant, lung or multivisceral transplant and recent rejection and presented as all respiratory viruses but Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
Prevention:
Isolation of infected patient is a great step in preventing the transmission, palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised which is given monthly and still need more studies also Nirsevimab is a novel monoclonal that shown strong preventive effect in RCTs.
Treatment.
Early diagnosis of infection and timely institution of antiviral therapy is critical to prevent progression to LRTI and to achieve a favourable outcome, aerosolized ribavirin is logistically difficult to administer and has teratogenic potential, some studies shown that systemic oral and intravenous ribavirin has been effective, but with no available evidence to strongly recommend a specific route of administration and several reports describe combining ribavirin with intravenous immunoglobulin (IVIG) or RSV-specific immune globulin.
3-Human Metapneumovirus.
Most cases identified in the winter and spring, LTRs identified HMPV in 3.6–6.8%, prevention is better than cure as still no specific therapy identified for this viral infection and mainly depends on supportive treatment and Ribavirin that also not based on robust evident.
4-Parainfluenza Virus.
PIV is a single-stranded RNA virus of the Paramyxoviridae family, there are four serotypes of PIV (1–4), LTRs, where it accounts for 3.6–20.9% of the respiratory viruses isolated, the mainstay of treatment for PIV infection is supportive care and prevention in the hospital setting is based on adherence to contact precautions.
5-Rhinovirus.
Most infections are limited to the upper respiratory tract, but involvement of the lower respiratory tract is observed among patients with profound immunosuppression, in a prospective study performed among LTRs, 14.7% of patients had rhinovirus identified in respiratory specimens. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
6-Adenovirus.
The American Society of Transplantation defines ADV infections based on symptoms, detection of virus by PCR or culture, and the presence of tissue invasive disease, the incidence of ADV infections ranges from 2.5-14% among autologous HSCT recipients and from 5-47% among allogeneic HSCT recipients. The incidence is highest during the first 100 days following transplantation.
Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft, mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
General precautions to prevent Adenovirus infection are required and regarding the treatment supportive care and treatment options include reduction of immunosuppression, Cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational) might has a role.
Respiratory Viruses and Rejection in Lung Transplantation.
Lung transplant recipients are considered higher risk for these viruses because the allograft with the environment, impaired mucociliary clearance, impaired cough reflex and a relatively greater immunosuppression compared to other organ transplants, some studies demonstrated that there are significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections, and other shown that treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections.
Conclusion:
Respiratory viruses are significant factors for morbidity and mortality in overall population and particularly for SOT recipients whose are immunocompromised specially LTR and HSCT, need more studies to find vaccines for them and mainly their treatment depends on supportive therapy.
Level of evidence: V (Narrative article).
Thank you, I appreciate your effort.
Summary
Introduction
Incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-years.
Incidence is higher among lung transplant recipients.
They cause similar symptoms and the clinical presentation does not differentiate between the viruses.
Rate of progression to lower respiratory tract infection ranges between 6.2–40% in LTRs.
Diagnosis
Viral culture has a long turnaround time of 10 days for standard viral culture and two days for shell vial culture.
Direct fluorescent antibody (DFA) staining is available for only a limited number of respiratory viruses and requires expertise in interpreting the results.
Nucleic acid testing (NAT) is now the gold standard for diagnosis and has a sensitivity of 72–100%.
Influenza virus
Single-stranded RNA virus of the Orthomyxoviridae family.
There are multiple strains, although only influenza A and B are generally associated with disease in humans.
They are seasonal, circulate mainly in the winter.
Immunocompromised individuals are also at increased risk for complications- viral pneumonia, bacterial superinfection, fungal co-infections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Risk factors associated with severe disease include older age, diabetes and use of MMF, multiple co-morbidities, use of anti-lymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia.
Most important means for prevention is vaccination of the transplant recipient and close contacts.
Only inactivated influenza vaccines should be given, live attenuated intranasal vaccine is contraindicated in SOT.
American Society of Transplantation (AST) guidelines recommend vaccinating with an inactivated influenza vaccine as soon a one month post-transplant, acknowledging the fact that vaccine immunogenicity up to six months post-transplant can be poor.
Immunogenicity in SOT is variable, but generally lower compared to a non-immunocompromised population.
Still, influenza vaccine has been shown to decrease influenza infection rates, complications and mortality in the SOT population.
American Society of Transplantation 2019 guidelines recommend that high-dose vaccination is the preferred strategy where available, although two doses of standard vaccine could also be used.
Infectious Diseases Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak to patients in the affected wards.
An outbreak is defined as two healthcare-associated cases diagnosed within 72 h in the same ward, and prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case.
The neuraminidase inhibitors (NAIs) are the group most commonly used for treatment- oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
All symptomatic patients should be treated, irrespective of symptom duration.
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes sub-therapeutic (as in post-exposure prophylaxis).
Respiratory Syncytial Virus
Single-stranded RNA virus of the Pneumoviridae family.
Two strains: RSV-A and RSV-B.
Seasonal virus with peak incidence in the winter and spring.
Young children are a significant source of transmission.
Risk factors for lower RTI and mortality in the SOT population are poorly defined, but include young children (less than two years old), recent transplant, lung or multi-visceral transplant and recent rejection.
Clinical presentation is similar to other respiratory viruses.
Frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia.
Multiple vaccines under development, including live-attenuated, viral-recombinant, subunit and nanoparticle-based.
Data on treatment for RSV infection in SOT recipients are limited to case series in lung transplants.
Human Metapneumovirus
Single-stranded RNA virus of the Pneumoviridae family, closely resembling RSV.
Most cases identified in the winter and spring.
Current treatment is primarily based on supportive care.
Prevention is mainly based on infection control practices, including implementation of contact precautions in hospitalized patients .
Parainfluenza Virus
Single-stranded RNA virus of the Paramyxoviridae family.
Four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter.
Utility of antivirals in SOT is unknown.
Rhinovirus
Single-stranded RNA viruses that are members of the Picornaviridae family.
Serotypes A–C circulate year-round and are the predominant cause for the common cold.
Coronaviruses
Second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8%.
Symptoms are generally similar to other respiratory viruses.
Adenovirus
Double-stranded DNA virus of the Adenoviridae family.
Latency is in lymphoid tissue thus, infection can represent reactivation or de novo community acquisition.
No seasonal variability and have been associated with institutional outbreaks.
May cause viremia without obvious symptoms; therefore, differentiating infection and disease is important.
Manifestation include conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
Kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis.
Mortality is high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Transmission by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route.
Prevention is by maintaining droplet and contact precautions.
Treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus- specific cytotoxic T lymphocytes (investigational).
Respiratory Viruses and Rejection in Lung Transplantation.
Associations have also been reported for specific respiratory viruses, including influenza, HMPV and RSV, PIV and adenovirus. However there is no definitive association between rhinoviruses and CoVs and rejection.
Level of evidence:V
Thank you, I appreciate your effort.
Respiratory Viruses in Solid Organ Transplant Recipients
Please summarise this article.
Introduction
Incidence of respiratory viral infection among organ transplant recipients range from 0.76-0.91episode/patient-year.
Incidence higher in LTR, but it is not affected by time from transplantation.
Can occur all over the year, but higher incidence in autumn & winter.
The symptoms are similar in all respiratory viruses.
Progression to lower RTI range 6.2%-40% I LTR & mortality in 5.1%.
New respiratory viruses and serotypes are found often, affecting immunocompromised organ transplant patients. This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, as they relate to organ transplant recipients. Lung transplant research will dominate the discussion. This evaluation does not concentrate on hematopoietic stem cell transplantation, however, findings from this group will guide organ transplant therapy. This series will cover the SARS-CoV-2 epidemic.
Diagnosis:
viral culture: need long time (10days for standard viral culture & 2 days for shell viral culture).
DFA staining available only in limited number of respiratory centers & need expertise in interpretation of data.
Serology: useful only for epidemiological studies & not for diagnosis of acute infection.
NAT: gold standard for diagnosis with sensitivity 72%-100%. Multiplex NAT can test several viruses simultaneously in only 12-24hours.
Rapid antigen test: results within minutes, low sensitivity, available for influenza virus & RSV.
Influenza Virus:
cinical manifestation
Immunocompromised people may not have influenza. Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms.
Complications are also more common in immunocompromised people. They include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis.
Treatment:
M2 inhibitors (amantadine and rimantadine) are not utilized since they are inactive against influenza B while circulating influenza A strains are resistant. The most regularly used NAIs are oseltamivir, zanamivir, peramivir, and laninamivir (available only in Japan and South Korea). Recently licensed baloxavir provides a unique method of action. The single-dose oral medicine selectively inhibits influenza cap-dependent endonuclease. It works for uncomplicated influenza in non-immunocompromised people.
Baloxavir may work better than NAIs against influenza B strains.
Respiratory Syncytial Virus:
Symptoms
RSV, like other respiratory viruses, causes fever, cough, dyspnea, and rhinorrhea. RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses. LTRs have decreased RTI rates as much as possible.
Therapy
Lung transplant care differed from other organs in a US assessment of 11 transplant hospitals. All 10 lung transplant facilities treat lower RTI with ribavirin, and three add IVIG, whereas only 6/10 treat upper RTI and none offer IVIG.
Human Metapneumonia:
HMPV, a Pneumoviridae virus, is similar to RSV. Like RSV, most occurrences occur in winter and spring. LTRs found HMPV in 3.6–6.8% of positive respiratory samples. 8/18 (44%) of these individuals had a lower RTI.
Ribavirin fights HMPV in vitro. Antivirals and immunomodulators do not reduce mortality in HSCT patients.
Parainfluenza:
PIV is a single-stranded RNA paramyxoviridae virus.
PIV has four serotypes (1–4): serotype 3 is the most frequent, has no seasonality, and has caused outbreaks, whereas serotypes 1 and 2 occur in the autumn and winter. In LTRs, PIV infection accounts for 3.6–20.9% of respiratory viruses isolated.
After post hoc analysis, the highly immunocompromised category had better results. DAS 181 is FDA-unapproved. Therefore, supportive care is the core of PIV infection therapy, and hospital prevention relies on adherence to protocols.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses of the Picornaviridae family of enteroviruses. Serotypes A–C produce most colds year-round.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviride viruses are single-stranded RNA. Established human CoVs (229E, NL63, OC43, and HKU1) induce upper respiratory tract infections (RTI), whereas others (SARS-CoV1, MERS-CoV, and SARS-CoV-2) produce outbreaks.
One kidney transplant recipient recovered. Ribavirin, interferon, and steroids were administered in case reports. MERS-CoV still produces some Middle Eastern illnesses.
Adenovirus:
Adenoviridae’s double-stranded DNA virus Adenovirus contains seven subgroups (A-G) and over 90 serotypes. Latency in lymphoid tissue allows adenoviruses to reactivate or create a new colony.
IVIG is sometimes used with antivirals. HSCT patients with cytomegalovirus and Epstein–Barr virus infections may benefit from virus-specific cytotoxic T cells.
HSCT adenovirus data is sparse.
Lung Transplant Rejection and Respiratory Viruses:
LTRs are at higher risk for RTIs, especially lower RTIs. Continuous contact with the environment, decreased mucociliary clearance, cough reflex, and more immunosuppression than other organ transplants may cause this. Many studies have examined the relationship between respiratory viral infection and acute rejection, or CLAD/bronchiolitis obliterans syndrome (BOS), with inconsistent results.
What is the level of evidence provided by this article?
Level of evidence is V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.Please use sub-headings ins addition to headings to make easier to read your write-up. Please use bold or underline to highlight sub-headings as well.
Respiratory Viruses in Solid Organ Transplant Recipients :incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year – a higher incidence in the autumn and winter. All respiratory viruses generally cause similar symptoms and the clinical presentation does not differentiate between the viruses – Rate of progression to lower respiratory tract infection (RTI) varies between the different studies and ranges between 6.2–40% in LTRs -Data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking, but a study on 98 LTRs found an attributable mortality of 5.1%
DIAGNOSIS Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100% -multiplex NAT allows testing for several viruses simultaneously with a turnaround time of only 12–24 h .-Rapid antigen tests, allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus is a single-stranded RNA virus of the Orthomyxoviridae family. influenza A and B associated with disease in humans. are seasonal, mainly in the winter . In a prospective multicenter study including 477 SOT recipients and 139 patients after hematopoietic stem cell transplant (HSCT) with confirmed influenza infection, the most common symptom was cough (85%), followed by fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%) increased risk for complications. These include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis,
Risk factors older age, diabetes and use of mycophenolate mofetil. use of antilymphocyte globulin in the past six months, lymphopenia, hypogammaglobulinemia, patients diagnosed with influenza should be placed under droplet precautions the most important means for prevention is vaccination of the transplant recipient and close contacts. Only inactivated influenza vaccines should be given to transplant recipients. The inactivated influenza vaccine has now been developed in a quadrivalent formulation and includes two A strains (H1N1 and H3N2) and two B strains..
Pre-exposure prophylaxis using low-dose oseltamivir can be given in cases of exposure to influenza among transplant recipients who have contraindications to receiving the influenza vaccine or who are not expected to mount an immune response
drugs approved for the treatment of influenza The neuraminidase inhibitors (NAIs) are the group most commonly used, and include oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) -Baloxavir may also be more effective against influenza B strains than NAIs
Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure, which is sometimes subtherapeutic (as in post-exposure prophylaxis). NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals. Treatment options include changing to a different NAI, changing to a different antiviral class, or combination antivirals.
Respiratory Syncytial Virus a single-stranded RNA virus of the Pneumoviridae family has two strains: RSV-A and RSV-B. It is a seasonal virus with peak incidence in the winter and spring ] and circulates mainly among young children, who are a significant source of transmission . In LTRs, RSV accounts for 2.4–6.2% of respiratory viruses identified in upper and lower respiratory tract specimens and is a cause of significant morbidity and mortality due to the development of lower RTI . Compared to other respiratory viruses, RSV more frequently causes lower RTI, including bronchitis, bronchiolitis and pneumonia
ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI. Patients who received a combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) had significantly lower mortality when treated for lower RTI, and a nonsignificant reduction in progression to lower RTI
.Presatovir is a new antiviral with specific anti-RSV activity that inhibits fusion of the virus with possible decrease in progression to lower RTI in lymphopenic HSCT recipients.
Human Metapneumovirus HMPV is a single-stranded RNA virus of the Pneumoviridae family, . Its seasonality also follows that of RSV, with most cases identified in the winter and spring . had symptoms of RTI,Data in SOT are based solely on lung transplants and are limited to small case series. In a study that included 139 LTRs with infections due to either RSV, HMPV or PIV
ribavirin (mostly given using oral preparation) was associated with significantly less chronic lung allograft disease -some benefit from ribavirin in lung transplants,
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family. There are four serotypes of PIV serotype 3 is the most common and shows no seasonality and has been associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter in LTRs is associated with a high rate of symptomatic disease and lower RTI A systematic review on antiviral treatment for PIV infection in HSCT recipients showed no benefit in this population Studies in SOT recipients are limited to small case series describing the use of ribavirin with and without immunomodulators in LTRs with mixed viral infections (PIV and RSV with/without HMPV)
Rhinovirus Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, isolated most frequently in respiratory samples taken from immunocompetent patients as well as SOT recipients. In studies among LTRs evaluating respiratory viruses found in respiratory samples by PCR, rhinoviruses accounted for 41.8–61.6% of the positive samples -are frequently found as part of coinfection with other viruses or bacteria, rendering the relative part of rhinoviruses unknown -Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs Treatment is based on supportive measures and droplet precautions prevention in the hospital.
Coronaviruses CoVs are single-stranded RNA viruses of the Coronaviridae family. Established human CoVs (229E, NL63, OC43, HKU1) cause upper RTI, whereas other CoVs (severe acute respiratory syndrome (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, SARS-CoV-2) are associated with outbreaks of severe respiratory disease. Human coronaviruses are second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8% of the positive samples . Symptoms are generally similar to other respiratory viruses. ribavirin and interferon as active against the virus although no clear clinical benefit of ribavirin was seen. MERS-CoV infection was first identified in Saudi Arabia and is associated with severe respiratory illness and mortality rates as high as 50% . Human to human transmission is associated with healthcare settings, and in one of the cohorts studied, 25% of the people infected were healthcare workers -Treatment options used in published case reports include ribavirin, interferon and steroids . MERS-CoV still causes sporadic infections, mainly in the Middle East
Adenovirus. is a double-stranded DNA virus of the Adenoviridae family that has seven subgroups (A-G) and almost currently known 90 serotypes Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition -no seasonal variability – associated with institutional outbreaks Rates of adenovirus infection differ with age and the transplanted organ. Rates are higher among children, probably because they are more likely to be non-immune, and in intestinal transplantation, presumably because of the higher amount of lymphoid tissue in the allograft and greater immunosuppression-Clinical Manifestations Adenovirus infection can manifest with conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft
In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection . Prevention Adenovirus infections are transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route. Therefore, prevention in the hospital setting is based on maintaining droplet and contact precautions -treatment options include reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific cytotoxic T lymphocytes (investigational). Earlier case reports described favorable outcomes when combining cidofovir with reduction of immunosuppression
.Bocavirus a single-stranded DNA virus of the Parvoviridae family. It is rarely isolated from respiratory specimens, and in positive specimens, there is often co-infection with other respiratory viruses . similar to the closely related parvovirus B19, bocaviruses are known for their viral persistence . This, combined with the high co-infection rate, makes their true contribution to RTIs unknown
KI and WU Polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family Studies in HSCT recipients suggested a higher frequency of infection with these viruses A study done in kidney transplant recipients identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively However, it is still unclear whether this has any clinical significance
Respiratory Viruses and Rejection in Lung Transplantation . A systematic review and meta-analysis published in 2011 demonstrated no association between respiratory viral infection and acute rejection, although only four studies were included in the analysis. It also showed a non-significant trend towards association with BOS, but that was limited by small numbers A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections – Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections,
level of evidence provided by this article Level V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.Please use sub-headings ins addition to headings to make easier to read your write-up. Please use bold or underline to highlight sub-headings as well.
Please summarise this article.
Introduction:
This review covers both RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), humanmetapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV),adenovirus, bocavirus and KI and WU polyomaviruses, specifically as they relate to organ transplant recipients. In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76-0.91 episodes per patient-year, with higher incidence in the autumn and winter. Rates of progression to lower respiratory tract infection (RTI) vary between 6.2-40% in LTRs, and data on mortality associated with viral pneumonia in solid organ transplant (SOT) recipients are lacking.
Diagnosis:
By viral culture, direct fluorescent antibody (DFA) staining, and serology, although each technique has drawbacks of its own. NAT, which has a sensitivity range of 72–100%, is currently the gold standard for diagnosis. A turnaround time of only 12 to 24 hours is possible with multiplex NAT when testing for many viruses at once. The sensitivity of rapid antigen tests is poor and they are only available for RSV and influenza.
Influenza virus:
Influenza virus is a single-stranded RNA virus of the Orthomyxoviridae family.
Only influenza A and B are typically linked to illness in people.
Influenza viruses are seasonal and circulate mainly in the winter, with an incidence of 41.8, 2.8 and 4.3 per 1000 patient years in lung, liver and kidney transplants.
Clinical features:
Cough was the most frequent symptom (85%), followed by fever (63%), rhinorrhea (48%), Myalgia, gastrointestinal issues, a sore throat, and a headache all made up 40% of the list.
Immunocompromised patients may not fit the classic definition of influenza-like illness, but are at increased risk for complications such as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis.
Prevention:
In the hospital setting, patients diagnosed with influenza should be placed under droplet precautions and vaccination of the transplant recipient and close contacts is the most important means for prevention. Inactivated influenza vaccines should be given to transplant recipients, as there is a theoretical risk of dissemination of virus contained in the live attenu-Viruses 2021, 13, 2146 3 of 16ated intranasal influenza vaccine, which is therefore contraindicated for SOT recipients. Immunogenicity of influenza vaccine in SOT is variable, but generally lower compared to a non-immunocompromised population. Vaccination has been shown to decrease influenza infection rates, complications and mortality in the SOT population, with a large prospective multicenter study on 616 transplant recipients showing that vaccination in the same influenza season wasassociated with a reduction in odds for pneumonia (odds ratio (OR) 0.51, 95% CI 0.21–0.55) and admission to the ICU (OR 0.49). However, several studies have evaluated different vaccination strategies and had variable outcomes.
Treatment:
Amantadine and rimantadine, M2 inhibitors, are no longer utilized because they are naturally inert against influenza B and circulating influenza. High levels of resistance are present in strain A. The most widely used class of drugs are neuraminidase inhibitors (NAIs), and include zanamivir (inhaled and intravenous), peramivir, and oseltamivir (oral) (intravenous).
Influenza A strains are so highly resistant, M2 inhibitors are not advised.
Early treatment within 48 hours of illness controls the disease complication rate, and ICU admissions.
Respiratory Syncytial Virus:
RSV is a single-stranded RNA virus of the Pneumoviridae family, has two strains: RSV-A and RSV-B.
Peak incidence on winter, RSV accounts for 2.4–6.2% of respiratory viruses.
Risk factors: include young children, recent transplant, lung or multivisceral transplant, and recent rejection.
Clinical manifestation:
fever, cough, dyspnea and rhinorrhea, but more frequently causes lower RTI.
Prevention:
Nirsevimab is a novel monoclonal that targets an epitope of the RSV fusion protein.
Vaccination: under development, including live-attenuated, viral-recombinant, subunit and
nanoparticle-based, ResVax being the most advanced.
Treatment:
Ribavirin treatment was associated with reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
Presatovir is a new antiviral with specific anti-RSV activity, but two phase 2b RCTs failed to show significant improvements in clinical and virologic outcomes, and 20% of patients developed resistance.
Human Metapneumovirus:
HMPV is a single-stranded RNA virus of the Pneumoviridae family, more at winter and spring. Isolated in 3.6–6.8% of positive respiratory samples, 44 % presents with LRTI.
Ribavirin has in vitro activity against HMPV, but data from HSCT recipients do not demonstrate a mortality benefit, and current treatment is primarily based on supportive care. Prevention is mainly based on infection control practices.
Parainfluenza Virus:
(PIV) is a single-stranded RNA virus of the Paramyxoviridae family, with 4 genotypes, type 3 is the most common , types 1+2 occurs in fall and winter.
PIV infection in LTRs is associated with a high rate of symptomatic disease and lower RTI, with 21% experiencing respiratory failure.
Antivirals for PIV infection in SOT are unknown, and DAS 181 is a novel, inhaled sialidase that cleaves sialic acid from the host’s respiratory epithelium, but does not reach statistical significance. Treatment is based on adherence to contact precautions.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses that are members of the Picornaviridae family, Serotypes A–C, the predominant cause for the common cold.
Rhinoviruses accounted for 41.8-61.6% of the positive respiratory PCR samples.
Symptoms of rhinovirus infection are usually those of the common cold, although there have been case reports of lower RTI in LTRs. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
CoVs are single-stranded RNA viruses of the Coronaviridae family, the second prevalent respiratoy virus post rhinoviruses.
Symptoms are generally similarto other respiratory viruses.
SARS-CoV1 infection emerged in southern China in 2002 and was associated with lower RTI and mortality. In-vitro studies identified ribavirin and interferon as active against the virus, but of no clear benefit.
MERS-CoV is associated with severe respiratory illness and mortality rates, and is spread through healthcare settings, camels, and kidney transplant recipients. Treatment options include ibavirin, interferon, and steroids.
Adenovirus:
Adenovirus is a double-stranded DNA virus of the Adenoviridae family, of 7 subgroups, Adenoviruses establish latency in lymphoid tissue; thus, infection can represent reactivation or de novo community acquisition.
Adenoviruses can cause viremia without obvious symptoms, and rates vary with age and organ transplantation.
Clinical features:
Adenovirus infection can cause conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and can be fatal in kidney transplant recipients.
Adenovirus is transmitted through respiratory droplets, direct conjunctivalinoculation, person-to-person contact, infected fomites, and fecal-oral routes.
Treatment options include reduction of immunosuppression, brincidofovir, IVIG, and adenovirusspecific cytotoxic T lymphocytes. Data is scarce in HSCT and still lacking in SOT.
Bocavirus:
Bocavirus is a single-stranded DNA virus of the Parvoviridae family, there is often co-infection with other respiratory viruses, isolated from only 0.5–1% of the positive respiratory samples.
KI and WU Polyomaviruses:
KI and WU polyomaviruses are double-stranded DNA viruses of the Polyomaviridae family, discovered in 2007.
KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens.
Respiratory Viruses and Rejection in Lung Transplantation:
Risk factors of LRTI are: continuous contact with the environment, impaired mucociliary clearance, impaired cough reflex, and greater immunosuppression.
There is a higher rate of rejection in viral LRTI.
reatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections.
Summary:
Respiratory viruses are a significant cause of morbidity and mortality among SOT
recipients. Detected more frequently by molecular diagnostic methods, effective therapies are available only for influenza, and some of RSV infection
What is the level of evidence provided by this article?Level of evidence V- erratic review
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.Please use sub-headings ins addition to headings to make easier to read your write-up. Please use bold or underline to highlight sub-headings as well.
Thank you, Prof. Ajay
your advice noted
Please summarise this article.
Introduction
o Respiratory viruses are a cause of significant morbidity and mortality among SOT recipients
o The incidence of respiratory viral infections in SOT recipients is 0.76–0.91 episodes per patient-year (higher among lung transplant recipients)
o All respiratory viruses generally cause similar symptoms and similar clinical presentations
o Rate of progression to lower respiratory tract infection (LTRs) ranges between 6.2–40% in LTRs
o Mortality associated with viral pneumonia in SOT recipients is 5.1%
Aim of the study: review the epidemiology, clinical manifestations, therapies and preventive measures for clinically significant respiratory viruses (both RNA and DNA) with the exception of SARS-CoV-2. The vast majority of data comes from studies of lung transplant recipients
Diagnosis
1. viral culture: 10 days for standard viral culture and two days for shell vial culture
2. direct fluorescent antibody (DFA) staining: available for only a limited number of respiratory viruses and requires expertise
3. serology: useful only for epidemiological studies and not for diagnosing acute infection
4. Nucleic acid testing (NAT) for respiratory viruses: the gold standard for diagnosis and has a sensitivity of 72-100%. Use multiplex NAT with time only of 12–24h
5. Rapid antigen tests: allowing results within minutes, are clinically available for influenza and RSV only and suffer from low sensitivity
Influenza Virus
Epidemiology and Risk Factors
o It is a single-stranded RNA virus (Orthomyxoviridae family)
o Only influenza A and B are generally associated with disease in humans
o Is seasonal, mainly in the winter (months November to May in the Northern Hemisphere and May to October in the Southern Hemisphere), and cause a significant proportion of RTIs
Clinical Presentation
o The most common symptom are cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%) and headache (30%)
o Immunocompromised individuals are at increased risk for complications (viral pneumonia, bacterial super infection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis)
Risk factors for severe disease:
1. older age
2. diabetes
3. use of mycophenolate mofetil
4. multiple comorbidities
5. use of antilymphocyte globulin in the past six months
6. lymphopenia
7. hypogammaglobulinemia
8. influenza A and nosocomial acquisition as risk factors for pneumonia or ICU admission
Prevention
1. Droplet precautions
2. Vaccination of the transplant recipient (the inactivated influenza vaccine includes two A strains (H1N1 and H3N2) and two B strains) and close contacts
3. Pre-exposure and post-exposure antiviral prophylaxis: should be given in the case of a hospital outbreak to patients in the affected wards. An outbreak is defined as two healthcare-associated cases diagnosed within 72 h in the same ward, and prophylaxis should be given for 14 days and at least 7 days after symptom onset in the last identified case
Treatment
o Early antiviral treatment (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates
o Patients who have symptoms > 48 h also benefit from treatment (SOT recipients and general population)
o All symptomatic patients should be treated, irrespective of symptom duration
Antiviral resistance:
o Immunocompromised patients are at increased risk for antiviral resistance due to prolonged viral replication combined with antiviral exposure
o NAI resistance should be suspected in a transplant patient with a prolonged illness and persistent viral replication, or in those who developed influenza while on or shortly after receiving low dose antivirals
o Treatment options include changing to a different NAI, changing to a different antiviral class, or combination antivirals
Neuraminidase inhibitors (NAIs):
1. oseltamivir (oral): 75 mg q12h (5 days), prophylactic Dose is 75 mg q24h
2. zanamivir (inhaled and intravenous): 10 mg q12h (5 days), prophylactic Dose is 10 mg q24h
3. peramivir (intravenous): 600 mg once
4. laninamivir (available only in Japan and South Korea):
5. Baloxavir: recently approved. It is a selective inhibitor of influenza cap-dependent endonuclease and is a single dose oral medication. It is effective in uncomplicated influenza in the non-immunocompromised population. It may also be more effective against influenza B strains than NAIs. Dose is 40 mg (<80 kg), 80 mg (>80 kg) and prophylactic dose is 40 mg (<80 kg), 80 mg (>80 kg)
Respiratory Syncytial Virus
Epidemiology and Risk Factors
o Single-stranded RNA virus (pneumoviridae family)
o Have two strains (RSV-A and RSV-B)
o Seasonal virus with peak incidence in the winter and spring
o Mainly affects young children (a significant source of transmission)
o In LTRs, accounts for 2.4–6.2% of respiratory viruses and is a cause of significant morbidity and mortality
o Risk factors for lower RTI include young children (<2 years old), recent transplant, lung or multivisceral transplant and recent rejection
Clinical Presentation
o Commonly presents with fever, cough, dyspnea and rhinorrhea
o More frequently causes lower RTI (bronchitis, bronchiolitis and pneumonia): 72%
Prevention
1. Contact precautions
2. Palivizumab for age < 2 years
Treatment
Ribavirin ± IVIG/steroids
Human Metapneumovirus (HMPV)
o Single-stranded RNA virus (Pneumoviridae family) closely resembling RSV
o Accounts for 3.6–6.8% of LTRs causes
o Treatment: Ribavirin ± IVIG/steroids?
o Prevention: contact precautions
Parainfluenza Virus
o A single-stranded RNA virus (Paramyxoviridae family)
o Four serotypes of PIV (1–4); serotype 3 is the most common and shows no seasonality associated with outbreaks, whereas serotypes 1 and 2 appear in the fall and winter
o Accounts for 3.6–20.9% of LTRs
o Treatment: Ribavirin ± IVIG/steroids?
o Prevention: contact precautions
Rhinovirus
o Single-stranded RNA viruses (Picornaviridae family)
o Serotypes A–C circulates year-round and are the predominant cause for the common cold
o Accounts for 41.8–61.6% of LTRs
o Symptoms: common cold
o Treatment: supportive
o Prevention: droplet precautions
Coronaviruses (CoVs)
o Single-stranded RNA viruses (coronaviridae family)
o Are second only to rhinoviruses for prevalence among LTRs (12.4–17.8% of the positive samples)
o Symptoms are generally similar to other respiratory viruses
o SARS-CoV1 infection emerged in southern China in late 2002 and was associated with high rates of lower RTI and mortality as high as 20%
o MERS-CoV infection was first identified in Saudi Arabia [92] and is associated with severe respiratory illness and mortality rates as high as 50%
o Treatment: Ribavirin, interferon, steroids
o Prevention: airborne & contact & droplet precautions
Adenovirus
Epidemiology
o Double-stranded DNA virus (Adenoviridae) family
o Have seven subgroups (A-G) and currently 90 serotypes
o Infection can be reactivation or de novo
o No seasonal variability
o Can cause viremia without obvious symptoms (differentiating infection and disease may be more appropriate)
o Rates are higher among children
Clinical Manifestations
o Conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis
o In a kidney transplant recipient with fever of unknown origin and rise in creatinine, adenovirus should be considered as a cause of pyelonephritis
o Mortality can be as high as 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection
o Cause bronchiolitis obliterans in lung transplant recipients
Prevention
o Transmitted by respiratory droplets, direct conjunctival inoculation, person-to-person contact, infected fomites and the fecal–oral route
o Prevention: droplet & contact precautions
Treatment
o Cidofovir, brincidofovir (investigational), IVIG
Bocavirus
o Single-stranded DNA virus (parvoviridae family)
o In LTRs, isolated from only 0.5–1%
o There is often co-infection with other respiratory viruses
o Prevention: Standard precautions
KI and WU Polyomaviruses
o Are double-stranded DNA viruses (Polyomaviridae family)
o In kidney transplant recipient’s identified KI and WU polyomaviruses in 14.3% and 9.1% of respiratory specimens, respectively
Respiratory Viruses and Rejection in Lung Transplantation
o A study on 100 LTRs, half with RTIs and half without, showed significantly higher rates of acute rejection (16% vs. 0%) and biopsy-proven bronchiolitis obliterans (10% vs. 0%) among those with respiratory infections
Conclusions
o Respiratory viruses cause a significant morbidity among SOT recipients
o With the introduction of molecular diagnostic methods, now can be detected easily
o Effective therapies are available only for influenza (and to some extent for RSV infection)
o Vaccination is only available for influenza virus
o New antivirals and vaccines is needed due to severe implications of respiratory viral infections on the immunocompromised population
What is the level of evidence provided by this article?Level V
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
DX.:
Preventions:
general measures for all such as mask , hand hygiene, distance and vaccination
treatment:
supportive treatment
there is no specific treatment for majority except influenza virus
some time may get benefit from intravenous IVIG
I like your well-structured summary, and conclusions.Please use headings and sub-headings to make easier to read your write-up. Please use bold or underline to highlight headings and sub-headings.
Introduction:
-Respiratory viruses have a significant impact on the health of immunocompromised individuals.
-It incidence in SOTR between 0.76–0.91 episodes per patient-year, and it is highest among lung transplant recipients LTR.
-It does not affected by the transplantation time, It occurs throughout the year with some seasonal variation.
– It can progress to lower respiratory tract infection in 6.2–40% in LTRs with reported mortality 5.1 % in LTR.
Diagnosis
-Viral culture, direct fluorescent antibody (DFA) staining and serology were used for diagnosis.
– NAT for respiratory viruses is now the gold standard with sensitivity of 72–100%
-Multiplex NAT; testing for several viruses simultaneously with a turnaround time of only 12–24 h.
– Rapid antigen tests, allowing results within minutes, available for influenza and RSV only and has low sensitivity.
Influenza Virus
Epidemiology and Risk Factors
-Single-stranded RNA virus with different stain, A&B cause disease in human.
-Seasonal virus, mainly in the winter.
– Attack rate affected by; age, immunity ( previous vaccination), degree of immunosuppresion.
-Incidence in higher among LTR.
Clinical Presentation
-The most common symptom: cough, fever, rhinorrhea, myalgia, GIT symptoms, sore throat and headache.
– SOTR at high risk of complications: viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and
myocarditis, myositis, encephalopathy and encephalitis.
– Risk factors increase disease severity: old age, comorbidities DM, use of MMF, ATG, lymphopenia, low Ig, Influenza A and nosocomial infection.
Prevention
– Droplet precautions for hospitalized persons.
– Vaccination of SOTR and close contacts, only inactivated vaccine , the live attenuated one is contraindicated.
– Variable immunogenicity and lower compared to immunocompetent, however, it is still decrease infection & complication.
– AST recommend that high-dose vaccination is the preferred strategy
– Antiviral prophylaxis; pre-exposure or post-exposure, concern about risistance.
– ID Society of America recommend that antiviral prophylaxis should be given in the case of a hospital outbreak.
Treatment
Three groups of drugs:
–M2 inhibitors (amantadine and rimantadine) are not used today
–Neuraminidase inhibitors (NAIs) most commonly used, oseltamivir (oral), zanamivir (inhaled and intravenous), peramivir (intravenous) and laninamivir (available only in Japan and South Korea).
– Selective inhibitor of cap-dependent endonuclease; Baloxavir ; recently approved, more effective against influenza B strains than NAIs
-Early initiation (within 24–48 h) is associated with a decrease in influenza complications and lower ICU admission rates, should be started before the availability of results.
-It is recommended that all symptomatic patients should be treated, irrespective of symptom duration.
-SOTR have prolong viral shedding, therefore, extend treatment duration in symptomatic individuals.
– Several monoclonal antibodies targeting various hemagglutinins of influenza virus have been developed
– NAI resistance has been reported.
– Treatment options include changing to different NAI, changing to a different antiviral class, or combination antivirals.
Respiratory Syncytial Virus
Epidemiology and Risk Factors
-Single-stranded RNA virus and has two strains: RSV-A and RSV-B.
– It is a seasonal virus with peak incidence in the winter and spring
– Mainly among young children (significant source of transmission)
– Accounts for 2.4–6.2% of respiratory viruses
– Cause a significant morbidity and mortality due to the development of lower RTI.
Clinical Manifestations
– Commonly presents with fever, cough, dyspnea and rhinorrhea.
– RSV more frequently causes lower RTI (up to 72%); bronchitis, bronchiolitis and pneumonia.
Prevention
– Hospitalized person should be under contact precautions.
– AAP recommended Palivizumab prophylaxis during the RSV season in children under 24 months of age who are severely immunocompromised.
– Nirsevimab ; monoclonal antibody with extended half-lives against RSV can be give once per season and showed favorable results on preterm infants
– Multiple type of vaccine underdevelopment.
Treatment
– Lower RTI treated with ribavirin +/- (IVIG).
– Data on treatment in SOT are limited to case series in LTR.
– Oral ribavirin treatment in LTR is associated with improvement in graft function and reduction in bronchiolitis obliterans syndrome
– Inhaled and systemic IV ribavirin are not preferred for the side effects systemic hemolytic anemia, leukopenia, neuropsychiatric, and teratogenic.
– Several new drugs are under development.
Human Metapneumovirus
– Closely similar to RSV. Its seasonality also follows that of RSV.
– Account for 3.6–6.8% of positive respiratory samples and cause Lower RTI in 44%.
– Ribavarin in LTR showed favorable outcomes on graft function, less chronic lung allograft disease.
– Prevention is mainly based on infection control practices.
Parainfluenza Virus
– Single-stranded RNA virus with four serotypes of PIV (1–4).
– PIV3 3 is the most common and shows no seasonality, whereas PIV-1& 2 appear in the fall and winter.
– Accounts for 3.6–20.9% of the respiratory viruses isolated.
– In LTRs is associated with a high rate of symptomatic disease and lower RTI, 21% respiratory failure.
– Utility of antivirals for PIV infection in SOT is unknown, mixed result with ribavirin.
– DAS 181 is a novel, inhaled sialidase, not yet FDA approved.
– Treatment is supportive care and preventive measures, contact precautions.
Rhinovirus
– Single-stranded RNA, serotypes A–C are the predominant cause for the common cold.
– Accounted for 41.8–61.6% of the positive samples.
– Seen frequently as part of coinfection with other viruses or bacteria.
– Symptoms of common cold, and in LRT cause lower RTI .
– Treatment is supportive care and preventive measures, droplet precautions.
Coronaviruses
-Single-stranded RNA viruses cause URTI, can cause outbreak of severe respiratory disease SARS-CoV1 (China in 2002, mortality 20 % ), MERS-CoV (Saudi Arabia 2012, mortality 50%), and SARS-CoV-2.
– CoVs second only to rhinoviruses for prevalence among LTRs, accounting for 12.4–17.8%.
– Immunocompromised group had a significantly higher rate of severe lower RTI.
– Treatment options include ribavirin, interferon and steroids
Adenovirus
Epidemiology
-Double-stranded DNA virus 7 subgroups (A-G) and 90 serotypes.
– Establish latency in lymphoid tissue; can be reactivated or de novo infection.
– No seasonal variability.
– Can cause viremia without obvious symptoms.
– Rates of infection differ with age (higher in children) and the transplanted organ ( higher in intestinal Tx).
Clinical Manifestation:
-Can present with conjunctivitis, upper or lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis, and has a predilection for the transplanted allograft.
-KTR: fever of unknown origin and rise in creatinine.
-Mortality 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
-LTR can be complicated with bronchiolitis obliterans.
Prevention
-Droplet and contact precautions.
– Brincidofovir not yet approved by FDA.
Treatment
-Supportive care.
– Treatment options include reduction of IS, cidofovir, brincidofovir (investigational), IVIG and adenovirusspecific
cytotoxic T lymphocytes (investigational).
Bocavirus
– Single-stranded DNA, rarely isolated.
– Often co-infection with other respiratory viruses.
– Closely related parvovirus B19, known for their viral persistence.
KI and WU Polyomaviruses
– Double-stranded DNA viruses.
– Their clinical significance is still unclear.
Respiratory Viruses and Rejection in Lung Transplantation
-The are conflicting for association between respiratory viral infection and acute rejection or CLAD/bronchiolitis obliterans syndrome (BOS).
– Associations have also been reported for influenza, HMPV and RSV, PIV and adenovirus
– No definitive association with rhinoviruses and CoVs
-Treatment with ribavirin was associated with lower rates of CLAD/BOS in LTRs with RSV, HMPV and PIV
Summary:
-Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
-Effective therapies are available only for influenza, and also to some extent for RSV infection
-Development of new antivirals and vaccines is needed.
Level of evidence: V Narrative review.
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
III. Respiratory Viruses in Solid Organ Transplant Recipients
Please summarise this article.
Introduction
Influenza virus:
Clinical manifestations
Complications:
Risk factors for severe disease:
Prevention
=======================
RSV
Epidemiology & risk factors
Clinical features
Prevention
=======================
HMPV
=======================
Parainfluenza virus (PIV)
=======================
Rhinoviruses
=======================
Coronaviruses (CoVs)
=======================
Adenovirus
=======================
Treatment
1.Influenza virus: Neuraminidase inhibitors
2.RSV: Ribavirin +/- IVIG/steroids
3.Parainfluenza: Virus Ribavirin +/- IVIG/steroids?
DAS 181-investigational
4.Human metapneumovirus: Ribavirin +/-IVIG/steroids?
5.Rhinovirus: None
6.Human Coronaviruses: None
7.SARS-CoV1, MERS-CoV: Ribavirin, interferon, steroids
8.Adenovirus: Cidofovir, brincidofovir (investigational), IVIG
9.Bocavirus: None
Dosing of antivirals
Investigational antivirals for influenza:
Antiviral resistance
Summary
=========================
What is the level of evidence provided by this article?
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
Respiratory Viruses in SOT recipients
Introduction
Respiratory viruses
Influenza virus
Epidemiology and risk factors
I) Age.
II) Exposure.
III) Level of immunity.
IV) Degree of immunosuppressants.
V) Nature of the epidemic.
Clinical presentation
I) Viral pneumonia.
II) Bacterial superinfection.
III) Fungal co-infection.
IV) Pericarditis, myocarditis, and myositis.
V) Encephalopathy and encephalitis.
I) Older age.
II) DM.
III) MMF
Prevention
I) Low-dose oseltamivir in outbreak condition.
Treatment
Respiratory Syncytial Virus
Epidemiology and risk factors
Clinical manifestation
Prevention
Treatment
Human metapneumovirus
Parainfluenza virus
Rhinovirus
Coronaviruses
Adenovirus
Epidemiology
Clinical manifestation
Prevention
Treatment
Bocavirus
KI and WU polyomaviruses
Respiratory virus and rejection in lung transplantation
Summary
Respiratory viruses are a significant cause of morbidity and mortality among SOT recipients.
Detection is at the great frequency with the introduction of molecular diagnostic methods.
Effective therapy is available only for influenza and to some extent RSV.
Development of new antivirals and vaccines is warranted as the respiratory viral infection have a n implications in immunocompromised patients
Level of evidence
Level ((V)) review article
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
Thank you Prof
SUMMARY
Introduction
It has been proven beyond doubt that solid organ transplantation offers a better long quality of life for those with organ failure. However, there is a challenge of increased tendency to develop infection especially respiratory tract infection which sometimes can be fatal. The incidence of respiratory tract infection is 0.76-0.91 per patient per year, and the majority of these viruses have similar clinical signs and symptoms. Diagnosis is usually through virus culture, DFA, serology, rapid antigen test, and NAT which is the gold standard
Influenza Virus
Respiratory syncytial virus
Coronaviruses
Adenovirus
Respiratory Viruses and Rejection in Lung Transplantation
The level of evidence is 5
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this narrative article on respiratory viruses in transplant recipients.
-SUMMARY
Introduction
In organ transplant recipients, the incidence of respiratory viral infections
among lung transplant recipients (LTRs) supposed to be higher.
Clinical picture is not different from one virus to another.
The progression to lower respiratory tract infection (RTI) is variable and ranges 6.2–40% in LTRs
Diagnosis
Historically viral culture was used but it takes a long time ,Direct fluorescent antibody (DFA) staining which is available for limited viruses and serology was used in epidemiological studies.
Nucleic acid testing (NAT) for respiratory viruses is the gold standard for diagnosis and has a sensitivity of 72–100%
Influenza virus
Epidemiology
It is a single-stranded RNA virus of the Orthomyxoviridae family. There are many strains but A ,B can cause disease in humans. The infection rate varies according to age and immunity.
Clinical picture
A study on SOT and HSCT recipients demonstrated that cough ,fever ,rhinorrhea, gastrointestinal symptoms ,sore throat and headache
Immunosuppressed specially those who are old age , diabetics and on MMF therapy ,cases are liable to more severe complications as viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis and myocarditis, myositis, encephalopathy and encephalitis
Prevention
Involves isolation and vaccination , only inactivated influenza vaccines need to be given to transplant recipients.
The vaccine include quadrivalent formulation of 2 A strains (H1N1 and H3N2) and 2 B strains.
It is administered as soon as 1month post-transplant, as immunogenicity till 6 months post-transplant can be decreased.
The influenza vaccine can lower influenza infection rates, complications and mortality in the SOT.
One study revealed that high-dose intramuscular vaccine provide high rate of seroconversion of once strain compared to a standard-dose vaccine.
American Society of Transplantation 2019 guidelines recommend that high dose vaccination is better meanwhile 2 doses of standard vaccine can be used.
Antiviral prophylaxis using low-dose oseltamivir pre or post exposure.
Treatment
Neuraminidase inhibitors (NAIs) including oseltamivir , zanamivir, peramivir and laninamivir. Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease ,taken as a single dose oraly, specialy in uncomplicated non-immunocompromised cases against influenza B virus .
Favipiravir has low resistance rate and can potentiate oseltamivir effect.
Monoclonal antibodies showed variable results.
Immunocompromised patients are liable for antiviral resistance .
NAIs resistance occurs in the A/H1N1 strain, the common mutation is H275Y, found in A/ /H1N1, maintaining susceptibility to zanamivir.
And in A/H3N2 the common mutation is R292K, with decreased response to oseltamivir and zanamivir
Respiratory Syncytial Virus
Epidemiology and Risk Factors
It is a single-stranded RNA virus of the Pneumoviridae family and has 2 strains: RSV-A and RSV-B.
Risk factor include young age, recent transplant, lung or multivisceral transplant and recent rejection.
Clinical manifestations
Similar to other respiratory viruses ,RSV is more liable to cause Lower RTIs reaching 72%
Prevention
Contact precautions are needed. Palivizumab prophylaxis during the RSV season for children younger than 24 months whom are severely immunocompromised although that is not evidence based. Palivizumab is not given to adult SOT recipients.
Nirsevimab is a novel monoclonal that targets RSV fusion protein epitope
Vaccines are underdevelopment and is recommended for elderly , pregnant women or the pediatrics
Treatment
Lung transplant centers use ribavirin with or without intravenous immunoglobulin (IVIG) for LRTI treatment.
For HSCT cases , ribavirin reduced progression of upper RTI to lower RTI and decreased mortality among patients with lower RTI.
A combination of ribavirin and an immunomodulator (IVIG, RSV-IVIG or palivizumab) decreased mortality when used for LRTI, and did not significantly reduce progression to LRTI.
Presatovir a new antiviral but did not show promising results.
New drugs targeting RSV are under development including fusion inhibitors
and replication inhibitors.
Human Metapneumovirus
HMPV is a single-stranded RNA virus of the Pneumoviridae family, similar to RSV.
Ribavirin has antiviral activity towards HMPV. HSCT recipients did not show a mortality benefit with antivirals or immunomodulators
Current treatment is based on supportive care.
Prevention is based on infection control.
Parainfluenza Virus
Parainfluenza virus (PIV) is a single-stranded RNA virus of the Paramyxoviridae family including 4 serotypes of PIV ,serotype 3 is the most common
A study showed that PIV infection, mostly PIV3, lead to respiratory failure in 21 % of the cases .
Antivirals effectiveness for PIV infection in SOT is unknown
DAS 181 prevents attachment and entry of the virus ,it was assessed in immunocompromised patients with lower RTI secondary to PIV infection with a trend towards better outcome ,it did not reach statistical significance
Treatment for PIV infection is supportive care and prevention involves contact
precautions.
Rhinoviruses
They are single-stranded RNA viruses that are members of the Picornaviridae
family.
Rhinoviruses accounted for 41.8–61.6% of Lung transplant recipient cases in a study.
Rhinoviruses are usually associated with coinfection with other viruses or bacteria, the symptoms are similar to common cold symptoms .
Treatment is supportive measures and prevention includes droplet precautions.
Coronaviruses
They are single-stranded RNA viruses of the Coronaviridae family.Human CoVs (229E, NL63, OC43, HKU1) can lead to upper RTI, other CoVs (SARS)-CoV1, Middle Eastern respiratory syndrome (MERS)-CoV, (SARS-CoV-2) can lead to outbreaks of severe respiratory disease.
It can cause severe LRTI in immunocompromised cases.
Studies showed that interferon , high-dose steroids and supportive care treatment for SARS- COVID 1 have favourable outcomes
MERS-CoV infection can lead to severe respiratory illness and mortality rates as high as 50%.Treatment include ribavirin, interferon and steroids
Adenovirus
Epidemiology
Adenovirus is a double-stranded DNA virus of the Adenoviridae family with 7 subgroups (A-G) and 90 serotypes.
Infection can be due to reactivation or de novo infection ,commonly cause viremia which is asymptomatic .
Risk factors include younger age and intestinal transplantation.
Clinical picture
Includes conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis and allografts affection.
In renal transplant recipients it presents with rising creatinine and fever of unknown origin.
Mortality can reach 50% for adenoviral pneumonia and 80% for disseminated adenoviral infection.
Prevention
Through droplet and contact precautions . Brincidofovir without nephrotoxicity showed benefits in treatment of adenovirus viremia in HSCT.
Treatment
include supportive therapy ,reduction of immunosuppression, cidofovir, brincidofovir (investigational), IVIG and adenovirus specific cytotoxic T lymphocytes (investigational).
Bocavirus
It is a single-stranded DNA virus of the Parvoviridae family. The co infection rate is high rendering it’s actual role unknown.
KI and WU Polyomaviruses
Both are double-stranded DNA viruses of the Polyomaviridae family . HSCT recipients had higher infection rate with these viruses
Respiratory Viruses and Rejection in Lung Transplantation
LTRs are at high risk for RTIs especially lower RTIs due to impaired mucociliary clearance, impaired cough reflex and greater immunosuppression compared to other organ transplants.
A systematic review demonstrated lack of association between respiratory viral infection and acute rejection.
Another study showed significantly high acute rejection rate and biopsy-proven bronchiolitis obliterans among cases having respiratory infections
Ribavirin decreased rates of CLAD/BOS in LTRs with RSV, HMPV and PIV infections .
-level of evidence is V
Disease burden
Diagnosis
Influenza virus
Respiratory Syncytial Virus
Human Metapneumovirus
Parainfluenza Virus
Rhinovirus
Coronaviruses
Adenovirus
Introduction
· Soild organ transplantation is the standard of care for those individuals who suffer from end-stage organ failure. One of the problems associated with this procedure is infections especially respiratory viral infections. This issue is more common among lung transplant recipients and it is important cause of morbidity and mortality.
· The incidence ranges from 0.76 to 0.97 /patient/year throughout the year but mainly in the autumn and winter.
· It may progress to lower respiratory tract infection in up to 40% of cases with mortality around 5%
· All the viruses present with the same clinical picture
· The gold stranded for the diagnosis is Nucleic Acid Testing (NAT)
· The following are examples of respiratory viruses in solid organ transplantation
1.Infuenza virus
· Single stranded RNA virus of Orthomyxoviridae family
· Influenza A & B are responsible for human disease
· Seasonal viruses
· Risk factors are age (Extreme of age), immune suppression, and response to vaccination
· May present with fever, rhinorrhea, myalgia, GIT symptoms, sore throat and headache.
· Complications include viral pneumonia, superimpose bacterial infections, fungal infections, myopericarditis, myositis and encephalitis
· Prevention is mainly by inactivated vaccine in transplant population within one post-transplantation. The alternative is pre-exposure anti-viral prophylaxis by low dose oseltamivir.
· Treatment: The neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, and laninamivir) and the cap-dependent endonuclease inhibitor (baloxavir). The treatment should be started as early as possible even before the lab results and continued for 10 days.
2.Respiratory Synthcytial Virus (RSV)
· Single stranded RNA virus of pneumoviridae/paramyxoviridae family
· Two strains; A & B
· Seasonal mainly in winter & spring
· Largely affects children and they are the main source of transmission
· May progress to LRTI specially in children < 2 years, lung recipients, multi-visceral transplant and rejection. This is important cause of morbidity and mortality.
· Clinical picture is similar to other viruses but it has tendency to cause more LRTi
· Prevention: Avoid contacts, palivizumab in immunecompromised chidren < 2 years, Nirsevimab in preterm infants, and vaccine e.g., ResVax
· Treatment: Limited data in lung transplant, oral ribavirin has been used with some degree of success. New treatment on pipelines e.g., presatovir
3.Human Metapeumovirus (HMPV)
· This virus is similar to RSV
· LRTI occur in 3.6 to 6.8%
· Treatment: Ribavirin showed some benefit but in lung transplant , but these were small studies with limited data
4.Parainfuenza Virus (PIV)
· Single-stranded RNA virus of paramyoviridae family
· 4 Serotypes (serotype 3 is more prevalent)
· No seasonality
· Mainly LRTI resulting in respiratory failure in up to 20% of cases
· Treatment: no clear data, supportive and preventive measures are the best do
5.Rhinovirus
· Single-stranded RNA virus of the picornaviridae family (Enterovirus)
· Serotype A-C are the causes of common cold
· Occur in association with other viruses or bacteria
· Treatment is mainly supportive
6.Coronaviruses
· Single-stranded RNA of the corovaviridae family
· Associated with outbreaks of severe respiratory disease e.g., SARS-CoV1 (Southern China), MERS-CoV (Saudia Arabia, zoonotic transmission from Camels), SARS-CoV2 (Recent pandemic)
· LRTI in up to 17%
· High mortality rates 20 to 50%
7.Adenovirus
· Double-stranded DNA virus of the adenoviridae family
· May be dormant in lymphoid tissue
· No seasonality
· Common in children, intestinal transplant, and heavy immune-suppression
· May lead to pyelonephritis in renal recipient
· High mortality up to 80% in disseminated adenoviral disease
· Prevention is mainly by avoiding contacts
· Treatment: supportive, reduction of immune-suppression, and combination of cidofovir and IVIG.
8.Boca-virus
· Single-stranded DNA virus of parvoviridae family
· Rare
· Closely related to parvovirus B-19
9.KI and WU polyomaviruses
· Double-stranded DNA viruses of polyomaviridae family
· Discovered in 2007
· Found in 14% and 9% of kidney recipients respiratory specimen respectively
Respiratory viruses and Rejection in Lung transplant
*LTR are at LRTI but the relationship between acute respiratory infection and rejection may not be linear. Conflicting data here and there.
*Risk factors for respiratory infections in LTRs are:
1. The allograft is open to the environment
2. Impaired mucociliary clearance
3. Impaired cough reflex
4. Higher amount of immune-suppression compared to other SOT
Conclusion
· Respiratory infections are important causes of morbidity and mortality in SOT particularly LTRs. Treatment is only limited to influenza and no prevention such as vaccination in most cases except for influenza. Therefore, the development of new antiviral treatment and vaccination are badly needed.
-Narrative review, level 5
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this very good article on respiratory viruses in transplant patients.
Thnxs Prof
Many thanks Dr Ben to have taken note of my comments.
Most welcome prof
Summary
Introduction
This article is about respiratory viral infections in SOT recipients. It is important to address this because of the significant morbidity and mortality that can caused by these infections. Added to this is the effect on the graft leading to acute rejection and chronic lung allograft dysfunction in lung transplant recipients. These infections can appear at any time post transplant, no just during hospital stay, but mainly from the community.
In this article, we are going to discuss a few of the major respiratory viruses and the impact caused by them on the graft and the patient.
Discussion
Traditional methods of diagnosis included viral culture, direct fluorescent antibody staining (DFA) and serology. The time frame for these tests were long, from a week to 10 days. In addition, it was difficult to accurately diagnose acute infection with these methods.
However, molecular techniques have changed these shortcomings, rendering traditional testing methods mostly obsolete. NAT for respiratory viruses are now the gold standard for diagnosis. Nucleic acid testing (NAT) has a sensitivity of 72-100%. Rapid antigen tests allow results within minutes, but are only clinically available fro influenza and RSV and have low sensitivity.
Influenza virus
Influenza virus is a single stranded RNA virus with multiple strains. These viruses are seasonal, mainly in winter. Infection rates are higher among children and degree of immunosuppression as wells likelihood of exposure all play a role in disease incidence.
Most common symptoms include cough, fever, sore throat, headache, rhinorrhoea, myalgia, GI symptoms. Immunocompromised patients are at increased risk of complications such as viral pneumonia, fungal confections, pericarditis, myocarditis, myositis, and encephalitis.
Risk factors included older age, diabetes, and use of MMF. Prevention includes vaccination of transplant recipients and close contacts. Live attenuated intranasal influenza vaccine is contraindicated for solid organ transplant recipients because of the risk of dissemination of virus. American society of Transplantation recommends vaccinating with inactivated influenza vaccine one month post transplant.
Treatment includes neuraminidase inhibitors(NAIs) such as oseltamivir, zanamivir, peramivir, and laninamivir.
Respiratory syncytial virus
RSV is a single stranded RNA virus with two strains – RSV A and RSV B. It is a seasonal virus, infecting mainly in winter and spring. Young children are affected the most and they also serve to disseminate the virus.
Clinical features include cough, fever, dyspnoea, and rhinnorhea. RSV is more effective in causing lower RTI such as bronchitis, bronchiolitis, and pneumonia, in comparison with other respiratory viruses.
Prevention include palivizumab prophylaxis around the RSV season in children under 24 months of age.
Treatment includes ribavirin and IVIG. Newer antivirals includes presatovir and ziresovir.
Human Metapneumovirus
HMPV is a single stranded RNA virus, affecting mostly in the winter and spring. Antivirals and immunomodulators are not enough to treat.
However, favorable outcomes can be seen with ribavirin with or without steroids. Current treatment is based primarily on supportive care.
Prevention is mainly based on infection control such as implementation of contact precautions among hospitalized patients.
Parainfluenza virus
Parainfluenza virus is a single stranded virus and does not show any seasonality. PIV infection is associated with a high rate of symptomatic disease and lower RTI.
There is mixed response when it comes to the use of antivirals for this infection. Currently, the mainline treatment for PIV involves supportive care and prevention in the hospital setting based on adherence to contact precautions.
Rhinovirus
Rhinoviruses are single stranded RNA viruses and are the cause for the common cold. Symptoms are similar to common cold, but case reports suggest lower RTI in LTRs. More symptoms may indicate higher viral load. Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronavirus
Coronaviruses are single stranded RNA viruses. The virus is associated with lower RTI and high mortality. In vitro studies identify that ribavirin and interferon can give better outcome along with supportive care.
Adenovirus
Adenovirus can cause viremia without obvious clinical symptoms, with rates of infection higher among children, perhaps because they are likely to be non-immune. Intestinal transplant recipients also have a higher risk of infection due to the higher amount of lymphoid tissue in the allograft and more intensive immunosuppressive regimen.
Clinical symptoms include conjunctivitis, upper RTI, lower RTI, hemorrhagic cystitis, pyelonephritis, hepatitis and enterocolitis. Infection transmission routes include respiratory droplets, direct conjunctival inoculation, person to person contact, infected somites, and faeco-oral route. Prevention includes maintenance of droplet and contact precautions.
Treatment includes supportive care, and reduction of immunosuppression, along with cidofovir, brincidofovir, IVIG and adenovirus specific cytotoxic T lymphocytes.
Bocavirus
Bocavirus is a single stranded DNA virus that usually appears in conjunction with other respiratory viruses. These viruses are very persistent and their contribution to RTIs is unknown.
KI and WU polyomaviruses
These viruses are double stranded DNA viruses that have a higher rate of infection among HSCT recipients. Clinical significance is unclear.
Respiratory virus and lung transplant
Lung transplant recipients are at increased risk for RTIs in general and lower RTIs in specific. This could be attributed to continuous contact of allograft with the environment, impaired mucociliary clearance, impaired cough reflex, and a relatively greater level of immunosuppression compared to other organ transplants.
Treatment with ribavirin is associated with lower rates of CLAD/Bronchilitis obliterates syndrome (BOS).
Conclusion
Respiratory viruses can cause significant morbidity and mortality among solid organ transplant recipients. Although traditional testing methods have worked in the past, molecular testing provides more quicker and accurate results which allow the transplant team to identify problems in a timely fashion and treat the patient appropriately so that both th patient and the graft are adequately protected. Preventive measures need to be developed further so that the incidence of respiratory infection is lower in immunosuppressed patients. Vaccination seems to be the only major preventive measure for most of these viruses, along with contact precautions in the hospital setting. Further studies are needed to standardize preventive measures and develop newer and more effective prevention. Development of new antivirals and vaccines is needed.
Level of evidence
This is a narrative review, and thus level of evidence is 5.
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this very good article on respiratory viruses in transplant patients.
III. Respiratory Viruses in Solid Organ Transplant Recipients
===================================================================
Please summarise this article.
——————————————————————————————————————-
Diagnosis
—————————————————————————————————————
Influenza virus
Clinical Presentation
Prevention
Treatment
====================================================================
Respiratory Syncytial Virus
Epidemiology and Risk Factors
Clinical Manifestations
Prevention
Treatment
===================================================================\
Human Metapneumovirus
=================================================================
Parainfluenza Virus
====================================================================
Rhinovirus
===================================================================
Coronaviruses
====================================================================
Adenovirus
Epidemiology
Clinical Manifestations
Prevention
Treatment
====================================================================
Bocavirus
===================================================================
KI and WU Polyomaviruses
===================================================================
Respiratory Viruses and Rejection in Lung Transplantation
====================================================================
Summary
====================================================================
What is the level of evidence provided by this article?
The level of evidence is V
I like your well-structured detailed summary. I appreciate level of evidence that you have allocated to this very good article on respiratory viruses in transplant patients.
Typing whole sentence in bold amounts to shouting.
Summary
Introduction:
New respiratory viruses and serotypes are found often, affecting immunocompromised organ transplant patients. This review covers RNA and DNA respiratory viruses, including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, coronavirus (CoV), adenovirus, bocavirus, and KI and WU polyomaviruses, as they relate to organ transplant recipients. Lung transplant research will dominate the discussion. This evaluation does not concentrate on hematopoietic stem cell transplantation, however, findings from this group will guide organ transplant therapy. This series will cover the SARS-CoV-2 epidemic.
Influenza Virus:
cinical manifestation
Immunocompromised people may not have influenza. Cough (85%), fever (63%), rhinorrhea (48%), myalgia (40%), gastrointestinal symptoms (40%), sore throat (35%), and headache (30%) were the most prevalent symptoms.
Complications are also more common in immunocompromised people. They include viral pneumonia, bacterial superinfection, fungal coinfections, pericarditis, myocarditis, myositis, encephalopathy, and encephalitis.
Treatment:
M2 inhibitors (amantadine and rimantadine) are not utilized since they are inactive against influenza B while circulating influenza A strains are resistant. The most regularly used NAIs are oseltamivir, zanamivir, peramivir, and laninamivir (available only in Japan and South Korea). Recently licensed baloxavir provides a unique method of action. The single-dose oral medicine selectively inhibits influenza cap-dependent endonuclease. It works for uncomplicated influenza in non-immunocompromised people.
Baloxavir may work better than NAIs against influenza B strains.
Respiratory Syncytial Virus:
Symptoms
RSV, like other respiratory viruses, causes fever, cough, dyspnea, and rhinorrhea. RSV causes bronchitis, bronchiolitis, and pneumonia more often than other respiratory viruses. LTRs have decreased RTI rates as much as possible.
Therapy
Lung transplant care differed from other organs in a US assessment of 11 transplant hospitals. All 10 lung transplant facilities treat lower RTI with ribavirin, and three add IVIG, whereas only 6/10 treat upper RTI and none offer IVIG.
Human Metapneumonia:
HMPV, a Pneumoviridae virus, is similar to RSV. Like RSV, most occurrences occur in winter and spring. LTRs found HMPV in 3.6–6.8% of positive respiratory samples. 8/18 (44%) of these individuals had a lower RTI.
Ribavirin fights HMPV in vitro. Antivirals and immunomodulators do not reduce mortality in HSCT patients.
Parainfluenza:
PIV is a single-stranded RNA paramyxoviridae virus.
PIV has four serotypes (1–4): serotype 3 is the most frequent, has no seasonality, and has caused outbreaks, whereas serotypes 1 and 2 occur in the autumn and winter. In LTRs, PIV infection accounts for 3.6–20.9% of respiratory viruses isolated.
After post hoc analysis, the highly immunocompromised category had better results. DAS 181 is FDA-unapproved. Therefore, supportive care is the core of PIV infection therapy, and hospital prevention relies on adherence to protocols.
Rhinovirus:
Rhinoviruses are single-stranded RNA viruses of the Picornaviridae family of enteroviruses. Serotypes A–C produce most colds year-round.
Treatment is based on supportive measures and prevention in the hospital setting mandates droplet precautions.
Coronaviruses:
Coronaviride viruses are single-stranded RNA. Established human CoVs (229E, NL63, OC43, and HKU1) induce upper respiratory tract infections (RTI), whereas others (SARS-CoV1, MERS-CoV, and SARS-CoV-2) produce outbreaks.
One kidney transplant recipient recovered. Ribavirin, interferon, and steroids were administered in case reports. MERS-CoV still produces some Middle Eastern illnesses.
Adenovirus:
Adenoviridae’s double-stranded DNA virus Adenovirus contains seven subgroups (A-G) and over 90 serotypes. Latency in lymphoid tissue allows adenoviruses to reactivate or create a new colony.
IVIG is sometimes used with antivirals. HSCT patients with cytomegalovirus and Epstein–Barr virus infections may benefit from virus-specific cytotoxic T cells.
HSCT adenovirus data is sparse.
Lung Transplant Rejection and Respiratory Viruses:
LTRs are at higher risk for RTIs, especially lower RTIs. Continuous contact with the environment, decreased mucociliary clearance, cough reflex, and more immunosuppression than other organ transplants may cause this. Many studies have examined the relationship between respiratory viral infection and acute rejection, or CLAD/bronchiolitis obliterans syndrome (BOS), with inconsistent results.
Excellent, Weam
The review highlights the severity of respiratory viral infections in SOT recipients and their significant impact on morbidity and mortality.In organ transplant recipients, the incidence of respiratory viral infections in transplant ranges between 0.76–0.91 episodes per patient-year
Dignosis with Nucleic acid testing (NAT) for respiratory viruses is now the gold standard for diagnosis and has a sensitivity of 72–100%
The article has very good table attached in pic with the treatment options and drug dosing for common viruses
Level of evidence: Level V
Thanks, Ahmed
This is a very short summary, please expand.
Introduction:
Diagnosis:
Influenza virus:
RSV:
Human Metapneumonia:
Parainfluenza virus (PIV):
Rhinovirus:
Coronavirus:
Adenovirus:
Bocavirus:
KI & WU polyomavirus:
Respiratory viruses & rejection in lung transplant recipients:
Level of evidence is 5
Thanks, Ban