CMV infection
Active infection.: evidence of CMV replication regardless of symptoms
CMV disease
…. CMV viral syndrome characterized by presence of fever and or malaise, leucopenia or thrombocytopenia
……Tissue invasive disease the patient presented with clinical symptoms and signs of end-organ damage
CMV disease is determined by the presence of CMV infection (confirmed by CMV positive serology preferably by PCR, culture, biopsy or viral load both qualitative as well as quantitative ) associated by nonspecific clinical symptoms and signs.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
Tissue-invasive CMV disease is the most aggressive form being associated with specific organ involvement commonly gastro-intestinal, pneumonitis, hepatitis, nephritis, cerebritis, myocarditis and retinitis. Among these, the gastrointestinal tract is the commonest organ to be involved.
CMV disease is the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs. CMV disease can be further categorized into : CMV syndrome and tissue-invasive CMV disease (or end-organ disease). CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved. Cytomegalovirus Infections in Solid Organ Transplantation: A Review Poornima Ramanan and Raymund R Razonablehttps://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/corrauth.gifd
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? CMV disease denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs. CMV disease can be further categorized into CMV syndrome and tissue-invasive CMV disease (or end-organ disease). CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved .
reference 31. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004;4:611–620. [PubMed] [Google Scholar]
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
Cytomegalovirus infection is a frequent complication after transplantation. This infection occurs due to – transmission from the transplanted organ. -reactivation of latent infection. – after a primary infection in seronegative patients. This condition occurs mainly between 30 and 90 days after transplantation. can be defined as follows: latent infection, active infection, viral syndrome or invasive disease. latent infection – after the initial immune response, the virus persists in a latent state, mainly in myeloid lineage cells . active infection – the presence of viral replication, diagnosed by growing the virus in vitro; by the discovery of intracytoplasmic and intranuclear inclusions,by viral identification via tissue staining of biopsy material; or by the discovery of evidence of viral replication detected by antigenemia assay or molecular methods. disease – presence of evidence of an infection with symptoms attributed to it. viral syndrome –the presence of signs and symptoms of disease and the confirmation of viral replication in the peripheral blood (detected by antigenemia assay or molecular techniques). invasive disease – the presence of specific symptoms in a target organ and histological findings demonstrating the cytopathic effect of the virus in tissue. In these instances, there may or may not be evidence of viral replication in the peripheral blood. The most common clinical picture in the transplanted host is a viral syndrome: characterized by fever and malaise as well as leukopenia, thrombocytopenia and elevated liver enzymes. These signs appear from the 3rd to 4th week, with a peak from the 6th to 16th week, and become rare after the 6th month. Upper digestive tract symptoms, and mainly pain, are common. Diarrhea, occasionally containing blood, is more uncommon and is suggestive of colonic involvement. Respiratory symptoms indicate more severe disease and may require admission to an intensive care unit.
Reference Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23.
CMV infection :
Detected of virl pcr in blood without clinical symptoms.
CMV syndrome:
Detection of pcr in blood with systemic symptoms such as:
Fever.
Myalgia.
Arthralgia.
Leukopenia.
CMV invasive:
Detection of pcr virl in tissue and end organ damage.
CMV infection refers to the detection of CMV DNA in blood samples with no clinical presentation. CMV syndrome refers to the detection of CMV DNA in blood samples accompanies by the systematic symptoms such as myalgia, arthralgia, fever and leukopenia. Tissue-invasive CMV is referred by the clinical presentation of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
CMV can present in kidney transplant recipients as either CMV infection or CMV disease
CMV infection – Defined as the presence of CMV replication in the blood regardless of whether signs or symptoms are present.
CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. CMV disease may manifest as either CMV syndrome or tissue-invasive CMV disease:
CMV syndrome – Defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of tissue-invasive disease.
• Tissue-invasive CMV disease –Patients withtissue-invasive CMV disease have clinical symptoms and signs of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
CMV infection means the detection of CMV DNA in blood samples, however, there are no clinical manifestations, and would be two types. CMV syndrome: There are viral replication and symptoms such as fever, malaise, myalgia, arthralgia leukopenia, or thrombocytopenia. tissue-invasive CMV: is defined by clinical manifestations of CMV inclusions or CMV by IHC in involved tissues. Involvement tissues include: GI (gastritis, colitis), lung (pneumonitis), liver (hepatitis), eye (retinitis), CNS (meningitis, encephalitis)
CMV infection = CMV vireamia regardless of whether signs or symptoms are present
CMV disease = presence of detectable CMV in a clinical specimen (blood and or tissue) accompanied by other clinical manifestations. It can be either
A) CMV syndrome Defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of tissue-invasive disease.
B) tissue-invasive CMV disease identification of CMV inclusions or positive CMV-specific immunohistochemistry staining on histopathology. (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
CMV Infection is when there is evidence of the cytomegalovirus (human herpes virus 5) being present in the body and it is undergoing a complete replication cycle with new infectious virions being produced. Detection of CMV in the blood (viraemia) is usually quantified by a polymerase chain reaction (PCR) test performed on either whole blood or plasma. The key difference between CMV infection versus CMV syndrome or disease is that the patient is asymptomatic. However, this does not mean that damage is not occurring as indirect effects of CMV virus can start occurring during CMV infection and there is also the potential for rapid expansion in the copies of CMV in the blood leading to CMV syndrome or CMV disease.
Latent CMV can occur after primary CMV infection when the virus remains present in monocytes and other bone marrow progenitor cells. During this time, the viral genome is present in these cells but is not undergoing a complete replication cycle or producing new infective virions. Latent CMV is relevant to solid organ transplant recipients as following heavy immunosuppression they may re-activate this CMV meaning they are at risk of developing CMV disease from 3 different sources: re-activation of their own latent CMV, transfer of CMV from the donor and primary infection from another source.
Symptomatic CMV
When CMV becomes symptomatic this may be as either CMV syndrome or CMV disease
CMV syndrome is when there is evidence of CMV infection being present in the body (viraemia) and in addition to this the patient becomes symptomatic with systemic symptoms such as fever, myalgia, arthralgia and they may also demonstrate leucopenia on blood tests.
CMV disease requires a tissue diagnosis to prove the CMV viraemia is directly causing end-organ damage. CMV can affect multiple organs and the means of diagnosis will therefore depend on the affected organ. A biopsy may be performed to achieve a histopathological diagnosis or a tissue sample may be sent for culture. The classic finding is owl eye inclusion bodies but this will not always be universally present. If CMV is affecting the central nervous system a lumbar puncture may be performed to demonstrate CMV in the cerebrospinal fluid. Alternatively, in cases of CMV-retinitis a diagnosis can be made by an ophthalmologist with experience in CMV disease; however, CMV retinitis is more common in HIV-patients and less commonly seen in CMV-disease affecting solid organ transplant recipients.
Reference:
British Transplantation Society (2022): Prevention and management of CMV disease after solid organ transplantation. Available at: https://bts.org.uk/guidelines-standards/ %5Baccessed April 4, 2023]
The direct effects of CMV are the clinical manifestations occurring as a result of CMV replication, dissemination and tissue invasion of specific organs .
1- CMV disease: denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs.
CMV disease can be further categorized into
A- CMV syndrome :manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
B- Tissue-invasive CMV disease: (or end-organ disease) is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others).
Among these, the gastro-intestinal tract is the commonest organ to be involved .
REFFERENCE:
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521
signs. CMV disease is defined as evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome (eg, fever, malaise, leukopenia, thrombocytopenia) or as tissue invasive disease. CMV syndrome: Patients with a CMV syndrome have evidence of clinical disease, but without end-organ involvement. Typical symptoms include fever, malaise, weakness, myalgias, and arthralgias. Tissue invasive disease: Involves specific organ involvement, such as pneumonitis hepatitis, gastroenteritis, and colitis.
CMV infection refers to the presence of CMV in the blood (viremia); CMV syndrome includes symptoms (fever, malaise, lab findings like leukopenia etc.).
Tissue-invasive CMV refers to organ involvement like pneumonitis, hepatitis, colitis, retinitis etc.
The difference between CMV infection, CMV syndrome and tissue-invasive CMV:
1. CMV infection :
CMV viremia and CMV disease were considered as CMV infection. CMV viremia is defined as any detectable virus in blood or tissues by quantitative PCR (>600 copies/mL) or culture or positive antigenemia testing (CMVpp65 antigen) without clinical symptoms.
2. CMV syndrome:
It is clinical manifestations of flu-like symptoms (fever, malaise, arthralgia, associated with leukopenia and thrombocytopenia) along with detection of CMV in blood. 3. Tissue-invasive CMV disease:
It denotes specific organ involvement (pneumonitis, hepatitis, nephritis, myocarditis and retinitis, gastritis, colitis) with detection of CMV in tissues (by histology / culture / PCR), with or without systemic illness (CMV syndrome).
References:
1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521. 2. Uta Erdbruegger1 , Irina Scheffner2 , Michael Mengel, et al. Advance Access publication 28 June 2011 Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant (2012) 27: 435–443 doi: 10.1093/ndt/gfr306
CMV infection: Presence of the CMV virus in any body fluid or body tissue
The virus may be isolated by culture, viral protein or antigen (CMV pp65 antigen) may be detected within peripheral blood leukocytes or viral nucleic acid in any body fluid by PCR. Body fluids include serum, whole blood, buffy coat, cerebrospinal fluid, bronchoalveolar lavage or urine. The patient may or may not display any symptoms or signs.
CMV syndrome: Presence of the CMV virus in blood along with any 2 of the following symptoms or tests – Fever ≥ 38°C for ≥ 48 hours – Leukopenia or neutropenia – New malaise or New fatigue – Thrombocytopenia – Raised liver enzymes – PBF ≥ 5% atypical lymphocytes
CMV may be detected in blood by viral isolation, rapid culture, antigenemia test, or PCR.
The patient will not display any evidence of localized organ involvement.
CMV disease: Presence of CMV syndrome along with with organ involvement by tissue invasive CMV
Organ involvement includes pneumonia, gastrointestinal disease, hepatitis, pancreatitis, encephalitis, retinitis, nephritis, cystitis and myocarditis. Invasive procedures to obtain tissue from each organ followed by culture or histopathology and immunohistochemistry to demonstrate presence of the virus is necessary. Patients of CMV disease may be PCR negative on blood tests.
Reference:
Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, et al. for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
Presence of CMV in a patient have specific criteria for diagnosis…
CMV Infection: It is defined as the presence of CMV virus, viral protein, or viral antigen in the blood, any bodily fluid or tissue with or without symptoms… CMV replication can be detected by either viral culture, NAT, pp65Ag and CMV viremia (positive culture)
CMV disease: It is defined as CMV infection with the presence of clinical signs and symptoms
CMV syndrome -Fever, malaise, atypical lymphocytes >5% in blood, leukopenia or neutropenia, thrombocytopenia and elevated liver enzymes
Tissue invasive disease/end organ CMV disease – involves CMV syndrome + CMV Detection in the blood + histological demonstration of CMV related disease like colitis,pneuomonitis with typical owl eye inclusion bodies
CMV infection : detection of CMV in blood by cuture , antigen test or PCR
CMV syndrome : Fever , malaise , either leukopenia or thrombocytopenia + detection of CMV in blood
CMV disease : end organ invasive tissue disease + CMV syndrome + CMV detection by histology or culture in affected organs such as retinitis , pnemonititis , colitis … etc
CMV infection : Detection of CMV in blood by culture, antigen test or PCR.
CMV syndrome : CMV infection + presence of fever, malaise, leukopenia or thrombocytopenia.
CMV disease: CMV syndrome + dectection of CMV by histology or culture in affected organs.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? 1. CMV infection
CMV viremia and CMV disease were considered as CMV infection. CMV viremia is defined as any detectable virus in blood or tissues by quantitative PCR (>600 copies/mL) or culture or positive antigenemia testing (CMVpp65 antigen) without clinical symptoms. 2. CMV syndrome is clinical manifestations of flu-like symptoms (fever, malaise, arthralgia, associated with leukopenia and thrombocytopenia) along with detection of CMV in blood. 3. Tissue-invasive CMV diseasedenotes specific organ involvement (pneumonitis, hepatitis, nephritis, myocarditis and retinitis, gastritis, colitis) with detection of CMV in tissues (by histology / culture / PCR), with or without systemic illness (CMV syndrome). References 1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
2. Uta Erdbruegger1 , Irina Scheffner2 , Michael Mengel, et al. Advance Access publication 28 June 2011 Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant (2012) 27: 435–443 doi: 10.1093/ndt/gfr306
CMV infection is indicated by a positive antigenemia, culture, biopsy or viral load
CMV disease denotes the presence of CMV infection accompanied by clinical symptoms and signs.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMC infection.
CMV infection refers to detection of CMV antigenemia by investigation like serology, culture, and PCR regardless of clinical manifestation.
CMV syndrome;
Defined as presence of detectable CMV in a clinical specimen accompanied by other clinical manifestation. Tissue invasive disease;
Defined as invasion of tissue by cmv causing organ specific damage like kidney, GIT, heart etc.
CMV infection: isolation or detection of the virus in body fluid or tissue by culture, antigen test or PCR. CMV syndrome: CMV infection along with constitutional symptoms like fever, malaise, arthralgia, myalgia, leukopenia and or thrombocytopenia. CMV disease: CMV syndrome along with end-organ or invasive tissue disease.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection (indicated by a positive antigenemia, PCR ,culture, or biopsy ) accompanied by clinical symptoms and signs.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia, and detection of virus in blood.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved.
Tissue invasive disease is CMV syndrome + detection of CMV by histology or culture of affected organ .
Reference
Cytomegalovirus Infections in Solid Organ Transplantation: A Review
Poornima Ramanan and Raymund R Razonable
CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
● CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease) or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
Ref . Up to date
defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen.
recommended that both the source of the specimens tested (e.g., plasma, serum, whole blood, peripheral blood leukocytes, CSF, urine, or tissue) and the diagnostic method used be described clearly
CMV syndrome
definition that should only be used in SOT recipients
definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
Fever ≥38°C for at least 2 days.
New or increased malaise (toxicity grade 2) or new or increased fatigue (toxicity grade 3) (National Cancer Institute: Common Terminology Criteria for Adverse Events, version 4.0).
Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count of <3500 cells/µL, if the WBC count prior to the development of clinical symptoms was ≥4000 cells/µL, or a WBC decrease of >20%, if the WBC count prior to the development of clinical symptoms was <4000 cells/µL. The corresponding neutrophil counts are <1500 cells/µL or a decrease of >20% if the neutrophil count before the onset of symptoms was <1500 cells/µL.
Greater than or equal to 5% atypical lymphocytes.
Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL.
Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit of normal (applicable to non–liver transplant recipients).
Tissue-invasive CMV disease
is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others).
References: Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, Andreas Pikis, Raymund R. Razonable, Veronica Miller, Paul D. Griffiths, for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
_ CMV infection means identification or isolation of CMV DNA by PCR in the blood or body fluid.
_ CMV syndrome when the CMV infection has additional clinical manifestations as fever, malaise , cytopenias as leukopenia and thrombocytopenia. _CMV invasive tissue disease means presence of tissue invasion as pneumonitis, gastrointestinal disease (enteritis and colitis), retinitis or encephalitis, hepatitis , pancreatitis and nephritis.plus identification of viral particles or inclusion bodies in tissue biopsy or special immunohistochemical staining.
infection : refers to The virus is detected by antigeniemia test or PCR in body fluids or tissue samples
It is either a primary infection in a previous sero-negative host
or secondary infection (re-infection with a different viral strain)
or (reactivation a latent endogenous virus).
CMV syndrome defined as CMV detection in blood by viral isolation by rapid culture, antigenemia, or NAT together with at least 2 of the following : 1-fever 38 for at least 2 days. 2-new or increased malaise. 3- leukopenia or neutropenia on 2 separate measurements at least 24 hours apart. 4-create than or equal to 5% atypical lymphocyte. 5-thrombocytopenia platelet less than 100000 or decrease less than 25 % from the baseline. 6-elevation of hepatic transaminase 2 to the upper limit.
CMV invasive disease;
The gold standard for diagnosing CMV tissue-invasive disease is identifying CMV inclusions or positive CMV-specific immunohistochemistry staining on histopathology but, since tissue may be contaminated with blood or body secretions and viral shedding can occur from some sites (urine, bronchoalveolar lavage [BAL] fluid, stool) in the absence of clinical disease, ther its better to do both culture and histopathology on the tissue specimen.
Individuals with suspected CMV tissue-invasive disease a negative plasma or whole-blood PCR does not exclude tissue-invasive CMV disease, especially in patients with CMV gastrointestinal disease, pneumonia, or retinitis.
In some patients, obtaining a tissue biopsy may not be possible. When this is the case, viral-load testing or culture of body fluids may be performed.
CMV infection means detection of the virus in blood by culture, antigen test or PCR. CMV syndrome include constitutional symptoms like fever , malaise, arthralgia , myalgia with leukopenia and or thrombocytopenia plus detection of CMV in blood. CMV disease include end-organ , invasive tissue disease and consist of CMV syndrome + detection of CMV by histology or culture in affected organs.
Reference:
Dr.Ahmed Halawa lecture
CMV Infection
Detection of CMV in blood by culture, antigen test or PCR Active CMV infections may be symptomatic or asymptomatic and are characterized by viral replication with expression of a CD4+ and CD8+ T-cell response to CMV. Primary CMV infection represents infection in the previously uninfected seronegative host, whereas secondary CMV infection represents infection in a previously infected seropositive host caused by either reactivation of latent endogenous virus, or superinfection with new virus strain
CMV Syndrome
• Fever, malaise either leukopenia or thrombocytopenia + detection of CMV in blood For patients with suspected CMV syndrome (eg, fever, malaise, leukopenia, and/or lymphocytosis in the absence of end-organ disease), CMV Disease (end-organ, invasive tissue disease)
• CMV syndrome + detection of CMV by histology or culture in affected organs CMV disease refers to symptomatic acute CMV infection and includes CMV syndrome (fever, fatigue, leukopenia or thrombocytopenia, and detectable CMV viremia) and endorgan CMV disease (e.g., pneumonitis, hepatitis, or gastrointestinal involvement such as colitis or enteritis, or involvement of the allograft itself).
1-up to date 2-Lecture of CMV in Kidney Transplantation By Ahmed Halawa Consultant Transplant Surgeon. Associate Professor, University of Liverpool – UK
The difference between CMV infection, CMV syndrome and CMV disease:
CMV establishes latent infection after the resolution of acute (or primary) infection. Patients who are CMV seropositive have latent infection. Secondary, symptomatic disease may present later. The risk of CMV reactivation is highest in the setting of systemic immunosuppression.
CMV can present in kidney transplant recipients as either CMV infection, CMV syndrome or CMV disease:
CMV infection :It is presence of CMV replication in blood regardless of whether signs or symptoms are present. CMV syndrome:meanssymptomatic viremia (symptoms and signs like fever, malaise, arthralgia, leukopenia, thrombocytopeniawithout evidence of tissue-invasive disease. CMV disease :Patients withtissue-invasive CMV disease have clinical symptoms and signs of end-organ disease as enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis.
Patients with tissue-invasive CMV disease may present with any of the following syndromes:
What is the difference between CMV infection, CMV syndrome, and tissue-invasive CMV?CMV infection defines as virus isolation or detection of viral protein (antigen) or nucleic acid in any body fluid or tissue specimen. CMV syndrome
defined as required CMV detection in blood by viral isolation by rapid culture, antigenemia, or NAT together with at least 2 of the following :
1-fever 38 for at least 2 days.
2-new or increased malaise.
3- leukopenia or neutropenia on 2 separate measurements at least 24 hours apart.
4-create than or equal to 5% atypical lymphocyte.
5-thrombocytopenia platelet less than 100000 or decrease less than 25 % from the baseline.
6-elevation of hepatic transaminase 2 to the upper limit. CMV Tissue -invasive CMV
Disease of end- organ disease absence of appropriate clinical symptoms and signs are required together with detection of CMV in the tissue from relevant organ by histopathology ,virus isolation .rapid culture ,immunochemistry, or DNA by hybridization unless there are data supporting that other material can be accepted as having similar significance CMV diseases such as pneumonia, GIT disease , hepatitis,nephritis ,cysitis,
myocarditis and pancreatitis References
Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Multidisciplinary approach to understanding cytomegalovirus disease. Paris, Amsterdam: Excerpta Medica International Congress Series, 1993:233–40.Google ScholarGoogle PreviewWorldCatCOPAC
2Ljungman P. Cytomegalovirus infections in transplant patients. Scand J Infect Dis 1996; Supplementum 100:59–63.Google ScholarWorldCat
3Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34:1094–7.Google ScholarCrossrefPubMedWorldCat
● CMV infection refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs
● CMV Disease : when there is CMV infection and symptoms include feeling or being sick (nausea and vomiting), diarrhoea, fever, muscle aches, fatigue, night sweats and generally feeling unwell
● CMV Syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
● Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis )
Among these, the gastro-intestinal tract is the commonest organ to be involved
P. Ramanan and R. Raymund Cytomegalovirus Infections in Solid Organ Transplantation: A Review . Infection and chemotherapy . 2013 Sep; 45(3):260–271.
Isolation of CMV virus or detection of its protein or nucleic acid in any body fluid or tissue; evidence of virus replication denotes CMV infection.
CMV syndrome includes:
– fever (more than 38C) for at least 2 days within 4 days period.
-Neutropenia or thrombocytopenia.
-CMV viremia..
CMV disease with involvement of specific organ or tissue denotes tissue invasive CMV..
. CMV Infection
CMV infection is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen. CMV Syndrome
CMV syndrome is a disease definition that should only be used in SOT recipients. Because it is impossible to exclude all other causes of the clinical symptomatology described as CMV syndrome, a “proven” category cannot be defined. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
1.Fever ≥38°C for at least 2 days.
2.New or increased malaise or new or increased fatigue .
3.Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart.
4.Greater than or equal to 5% atypical lymphocytes.
5.Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL.
6.Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit of normal . CMV disease
It consists of “end-organ disease” and CMV syndrome. To define “proven CMV end-organ disease,” the presence of appropriate clinical symptoms and/or signs are required together with documentation of CMV in tissue from the relevant organ by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization . It is recognized that high viral DNA levels detected with quantitative NAT, such as polymerase chain reaction (PCR), in tissue from the relevant organ likely represent CMV disease and could therefore be accepted as “possible CMV end-organ disease,” especially when blood sampled at the same time does not contain CMV DNA. Reference:
Per Ljungman, Michael Boeckh et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
CMV Infection CMV infection shows evidence of CMV viral replication. So it can be defined as isolation of CMV virus (detection of viral proteins and nucleic acid in body fluids) in body fluids or tissues. The spectrum can be Infection which can be asymptomatic , viral syndrome or CMV disease. CMV disease is detected by histopathology. Patient may have symptoms or be asymptomatic. CMV syndrome It is defined by presence of- · CMV virus in blood · Neutropenia · Thrombocytopenia · Fever of > 38 C for 2 days · Deranged liver functions · >5% atypical lymphocytes of peripheral blood films. CMV can be detected by viral isolation.
Tissue-invasive CMV CMV disease with specific organ involvement e.g pneumonitis, hepatitis, pancreatitis , encephalitis, cystitis etc
Reference Ljungman P, Boeckh M, Hirsch HH, et al. Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91.
CMV infection: define as isolation of CMV virus or detection of CMV protein or nucleic acid in any body fluid or tissue ( in other ward it mean evidence of virus replication with producing new infectious visions). It can be asymptomatic infection, viral syndrome, or CMV disease (histopathological evidence of CMV).
CMV syndrome: In SOT it define as follow:
documented fever (>38c) for at least 2 days of 4 days period.
Presence of neutropenia or thrombocytopenia.
Presence of CMV in blood.
Tissue invasive CMV: define as CMV disease with involvement of specific organ.
References:
Ljungman P., Griffiths P. and Paya C. Definition of Cytomegalovirus Infection and Disease in Transplant Recipients. Clinical Infectious Disease, 2002;34(8)-1094-1097.
CMV infection: Presence of the CMV virus in any body fluid or body tissue The virus may be isolated by culture, viral protein or antigen (CMV pp65 antigen) may be detected within peripheral blood leukocytes or viral nucleic acid in any body fluid by PCR. Body fluids include serum, whole blood, buffy coat, cerebrospinal fluid, bronchoalveolar lavage or urine. The patient may or may not display any symptoms or signs.
CMV syndrome: Presence of the CMV virus in blood along with any 2 of the following symptoms or tests – Fever ≥ 38°C for ≥ 48 hours – Leukopenia or neutropenia – New malaise or New fatigue – Thrombocytopenia – Raised liver enzymes – PBF ≥ 5% atypical lymphocytes
CMV may be detected in blood by viral isolation, rapid culture, antigenemia test, or PCR. The patient will not display any evidence of localized organ involvement.
CMV disease: Presence of CMV syndrome along with with organ involvement by tissue invasive CMV Organ involvement includes pneumonia, gastrointestinal disease, hepatitis, pancreatitis, encephalitis, retinitis, nephritis, cystitis and myocarditis. Invasive procedures to obtain tissue from each organ followed by culture or histopathology and immunohistochemistry to demonstrate presence of the virus is necessary. Patients of CMV disease may be PCR negative on blood tests.
Reference: Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, et al. for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
CMV infection and disease are not synonymous terms; not all patients with infection develop overt clinical disease. ●CMV infection refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen, regardless of symptoms or signs
●CMV disease refers to evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome (eg, fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, thrombocytopenia) or as a tissue-invasive disease.
CMV invasive disease;
The gold standard for diagnosing CMV tissue-invasive disease is identifying CMV inclusions or positive CMV-specific immunohistochemistry staining on histopathology. A positive culture from a biopsy specimen is also considered consistent with CMV disease, but, since tissue may be contaminated with blood or body secretions and viral shedding can occur from some sites (urine, bronchoalveolar lavage [BAL] fluid, stool) in the absence of clinical disease, it is optimal to perform both culture and histopathology on the tissue specimen.
Individuals with suspected CMV tissue-invasive disease should also have a plasma or whole-blood PCR testing since PCR results are often available prior to the biopsy results and may influence the decision to initiate antiviral therapy. In addition, it is crucial to establish the baseline viral load because serial testing is used to monitor response to therapy.
A negative plasma or whole-blood PCR does not exclude tissue-invasive CMV disease, especially in patients with CMV gastrointestinal disease, pneumonia, or retinitis. The absence of CMV inclusions on histopathology also does not exclude tissue-invasive disease since such inclusions can be missed due to sampling error.
In some patients, obtaining a tissue biopsy may not be possible. When this is the case, viral-load testing or culture of body fluids may be performed. The culture of urine specimens should be avoided since a positive urine culture does not correlate with CMV disease.
◇ What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
▪︎CMV Infection “CMV infection” is defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen. It is recommended that both the source of the specimens tested (e.g., plasma, serum, whole blood, peripheral blood leukocytes, CSF, urine, or tissue) and the diagnostic method used be described clearly (1).
▪︎CMV disease denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs. CMV disease can be further categorized into:
1. CMV syndrome
2. tissue-invasive CMV disease (or end-organ disease).
▪︎CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
▪︎Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others)[2]. Among these, the gastro-intestinal tract is the commonest organ to be involved [3].
___________________
Ref:
(1) Pear L, Paul G. Definitions of Cytomegalovirus Infection and Disease in Transplant Recipients.Clinical Infectious Diseases 2002; , V 34: 1094–1097. (2)Poornima R, Raymund R R. Cytomegalovirus Infections in Solid Organ Transplantation: A Review. Infect Chemother. 2013; 45(3): 260–271.
(3) Freeman RB., Jr The ‘indirect’ effects of cytomegalovirus infection. Am J Transplant. 2009;9:2453–2458.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
1. CMV Infection: is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen. · Primary CMV infection is defined as the first detection of CMV infection in an individual who has no evidence of CMV exposure before transplantation. · Recurrent infection” is defined as new CMV infection in a patient with previous evidence of CMV infection.May result from reactivation of latent virus (endogenous) or reinfection (exogenous). 2. CMV disease: consists of “end-organ disease” and CMV syndrome. CMV disease in SOT: The presence of CMV in the blood, together with symptoms and/or signs. · This is not sufficient for the definition of either proven or probable CMV disease at any other site, with the exception of CMV syndrome in SOT patients(1). · CMV disease refers to manifestation of disease-related signs and symptoms with alterations in blood count or invasive disease in tissue samples(2).
3. Tissue invasive CMV: is an end-organ disease and the presence of appropriate clinical symptoms and/or signs are required together with documentation of CMV in tissue from the relevant organ by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization unless there are data supporting that other materials can be accepted as having similar significance. · High viral DNA levels detected with quantitative NAT in tissue especially when blood sampled at the same time does not contain CMV DNA. · Tissue-invasive disease is defined as appropriate clinical symptoms and signs of end-organ disease (e.g., enteritis, hepatitis, nephritis, pneumonitis, meningoencephalitis, retinitis) with documentation of CMV in tissue from the relevant organ(3). 4. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following(1): a) Fever ≥38°C for at least 2 days. b) New or increased malaise or new or increased fatigue. c) Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count of <3500 cells/µL, if the WBC count prior to the development of clinical symptoms was ≥4000 cells/µL, or a WBC decrease of >20%, if the WBC count prior to the development of clinical symptoms was <4000 cells/µL. The corresponding neutrophil counts are <1500 cells/µL or a decrease of >20% if the neutrophil count before the onset of symptoms was <1500 cells/µL. d) Greater than or equal to 5% atypical lymphocytes. e) Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL. f) Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit of normal (applicable to non–liver transplant recipients).
Reference 1. Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, Andreas Pikis, Raymund R. Razonable, Veronica Miller, Paul D. Griffiths, for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668 2. Osman Kara Ganciclovir in the Prevention of Cytomegalovirus Reactivation in Allogeneic Hematopoietic Stem Cell Transplantation: Non-Eliminative Reduction of Viral Load July 2022, Medical Science and Discovery 9(7):401-405,DOI:10.36472/msd.v9i7.761, License CC BY-NC 4.0,Project: transplant patients quality of life- psychological status………Kotton CN, 3. Kumar D, Caliendo AM, et al The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900–31.
CMV infection : refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen irrespective of the presence of symptoms or signs. The virus is detected by culture , antigeniemia test or PCR.
It is either a primary infection in a previous sero-negative host or a secondary infection (re-infection with a different viral strain) or (reactivation a latent endogenous virus).
CMV syndrome: refers to the presence of CMV in the blood as above coupled with constitutional manifestations like fever, malaise together with either leucopenia, thrombocytopenia or both but without evidence of localized organ involvement.
CMV disease: the presence of CMV syndrome together with tissue invasive CMV (encephalitis, retinitis, nephritis, myocarditis, pneumonitis, colitis, gastritis, hepatitis, pancreatitis and cystitis) evidenced by histology, culture or immunohistochemistry in a specific organ. Blood sample PCR is inconclusive, and a negative PCR in the blood does not exclude tissue-invasive CMV disease.
References:
1. Ljungman P et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91.
2. Lecture of Professor Ahmed Halawa, CMV in Kidney Transplantation.
CMV infection: Detection of CMV in body culture, antigen test or PCR CMV syndrome: presence of fever, malaise , either leukopenia or thrombocytopenia and detection of CMV in blood. CMV disease: CMV syndrome + detection of cmv by histology or culture of the affected organ
including CMV pneumonia, CMV gastroenteritis, CMV hepatitis, CMV nephritis and CMV encephalitis
The difference between CMV infection, CMV syndrome and CMV disease: 1. CMV infection: CMV infection is defined as virus isolation or detection of viral antigens in any body fluid or tissue.eg, plasma, serum, blood, leukocytes , cerebrospinal fluid, broncho-alveolar lavage, urine, or tissue and the diagnostic methods used are culture, antigen detection or PCR. 2 . CMV syndrome: CMV syndrome is a definition that should only be used in SOT recipients. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following: 1. Fever ≥38°C for at least 2 days. 2. New or increased malaise or fatigue. 3. Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart. 4. Atypical lymphocytes more than or equal to 5%. 5. Thrombocytopenia defined as a platelet count of <100 000 cells/µL. 6. Elevation of hepatic aminotransferases to 2 times the upper limit of normal. 3 . CMV disease (end organ, invasive tissue disease): CMV Pneumonia: Clinical symptoms and/or signs of pneumonia such as new infiltrates on imaging, hypoxia, dyspnea combined with CMV documented in lung tissue by virus isolation, rapid culture, histopathology, immunohistochemistry, or DNA hybridization techniques. CMV Gastrointestinal Disease: Proven disease requires upper and/or lower gastrointestinal (GI) symptoms plus macroscopic mucosal lesions plus CMV documented in tissue by the above methods. CMV Hepatitis: Proven disease requires abnormal liver function tests plus CMV documented in tissue by the above methods. CMV Encephalitis and Ventriculitis: Proven disease requires central nervous system symptoms plus detection of CMV in CNS tissue. Nephritis: Proven disease is defined by the detection of CMV in a kidney allograft biopsy obtained from a patient with renal dysfunction together with the identification of histologic features of CMV infection. Worth noting that, the detection of CMV in urine by PCR or culture is not sufficient for the diagnosis of CMV nephritis as asymptomatic viral shedding in urine is common. Other organs that could be involved include, urinary bladder, myocardium and pancreas. REFRENCES: 1.Professor Ahmed Halawa lecture. 2 . Per Ljungman etal, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–9. 3 . Camille N. Kotton etal,I nternational Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation.
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? (1-3)
CMV infection
It is indicated by presence of a positive antigenemia, culture, viral load or biopsy
CMV disease
It denotes presence of CMV infection (i.e., positive antigenemia, viral load, culture or biopsy) in the presence of clinical signs and symptoms.
It can further be classified into CMV syndrome and tissue-invasive CMV disease or end-organ disease.
CMV syndrome
It manifests generally as a flu-like illness with fever and general body malaise. It is frequently associated with thrombocytopenia and leucopenia
Tissue-invasive CMV or end-organ CMV disease
The clinical manifestations that occur are as a result of CMV replication, dissemination and tissue invasion of specific organs e.g., gastritis, colitis, hepatitis, pancreatitis, pneumonitis, myocarditis, cystitis, nephritis, retinitis, CNS involvement.
References
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Mar;13 Suppl 4:93-106. PubMed PMID: 23465003. Epub 2013/03/08. eng.
2. Humar A, Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2006 Feb;6(2):262-74. PubMed PMID: 16426310. Epub 2006/01/24. eng.
3. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2004 Apr;4(4):611-20. PubMed PMID: 15023154. Epub 2004/03/17. eng.
CMV infection is the presence of CMV replication in tissues, blood, or other body fluids, irrespective of symptoms.
CMV replication can be detected by an antigen test, a nucleic acid amplification test (QNAT), & virus culture. Therefore, CMV replication can be termed CMV antigenemia (antigen detection), CMV DNAemia or RNAemia (nucleic acid detection), & CMV viremia (culture) depending on the laboratory method used.
CMV disease refers to viral infection with clinical symptoms & signs.
CMV infection – Presence of CMV replication in the blood irrespective of whether signs or symptoms are present. Thiis usually detected by viral culture, antigen test or PCR.
CMV syndrome – Defined as presence of CMV infection with symptoms such as fever, malaise, leucopenia and/or thrombocytopenia without end organ affectation.
CMV disease – Defined as presence of CMV syndrome and detection or end organ disease by histology or culture in the affected organs.
Presence of CMV replication evidenced by +VE antigenemia, VL, culture or biopsy +/- clinical signs and symptoms.
CMV SYNDROME.
(CMV infection + symptoms)
Non specific flu like illness with HOB,GBM +/- Leukopenia or thrombocytopenia.
CMV TISSUE INVASIVE DISEASE.
CMV DX + organ involvement(Intestinal, pulmonary, liver, cardiac or eye involvement)GIT is the commonest manifestation of tissue invasive disease. Biopsy + histology confirms this.
Tissue invasive disease , (end-organ, invasive tissue disease) Enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis with demonstration of CMV in tissue specimen by histopathology
CMV Viral Syndrome:
*1 of signs With e/o Active infection
-Fever>2day
-Malaise
-Leucopenia
->5%Atypical lymphocytes
-Thrombocytopenia
-Transaminitis (x2)
Reference:
1-The lecture of professor Halawa
2- Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9)
3- Kotton et al. Transplantation 2018;102: 900–931.
CMV infection: Define as a virus isolation or detection of the presence of viral proteins without causing any symptoms or signs. CMV disease: In addition to the viral load and viral protein detection, there are present symptoms and signs and present clinically:
CMV pneumonia, with possible, infiltrate, dyspnea, tachypnea, and hypoxemia.
CMV gastrointestinal disease.
CMV hepatitis.
CMV retinitis.
CMV encephalitis and ventriculitis.
CMV nephritis.
CMV endocarditis.
CNV cystitis.
CMV pancreatitis.
CMV syndrome: Used in SOT recipients, and required detection of CMV viral isolation, rapid culture, antigenemia, with at least 2 of the following:
Fever >/38 c for at least 2 days.
New or increased malaise (toxicity G2), or new or increased fatigue (toxicity G3).
Leukopenia or neutropenia on 2 separate measurements at least 24 hrs apart, define as a WBC count of <3500 cell/ml, or a decrease of cell count by > 20% if cell count before symptoms was <1500 cell/ml.
Greater than or equal to 5% atypical lymphocytes.
Thrombocytopenia is defined as a platelet count <100000 cells/ml prior to the development of symptoms.
Elevation of the hepatic aminotransferase to 2 times the upper limit of normal.
references:
Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Multidisciplinary approach to understanding cytomegalovirus disease. Paris, Amsterdam: Excerpta Medica International Congress Series, 1993:233–40
2Ljungman P. Cytomegalovirus infections in transplant patients. Scand J Infect Dis 1996; Supplementum 100:59–63.
3Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34:1094–7.
4Miller V. The forum for collaborative HIV research: a model for an integrated and inclusive approach to clinical research and drug development. Clin Pharmacol Ther 2009; 86:3
5Hutchison C, Kwong A, Ray S, Struble K, Swan T, Miller V. Accelerating drug development through collaboration: the Hepatitis C Drug Development Advisory Group. Clin Pharmacol Ther 2014; 96:162–5.
What is the difference between CMV infection CMV syndrome and tissue-invasive CMV?
1-Latent CMV infection ;
After the initial immune response, the virus persists in a latent state, mainly in myeloid lineage cells, and employs various mechanisms to evade the immune system and to survive.
2-Active CMV infection;
The presence of viral replication, diagnosed by viral identification via tissue staining of biopsy material; or by the discovery of evidence of viral replication detected by antigenemia assay or molecular methods.
3-CMV disease ;
CMV disease denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs.
CMV disease can be further categorized into CMV syndrome and tissue-invasive CMV disease (or end-organ disease).
4-CMV viral syndrome ;
The presence of signs and symptoms of disease and the confirmation of viral replication in the peripheral blood (detected by antigenemia assay or molecular techniques). CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
5- CMV invasive disease;
The presence of specific symptoms in a target organ and histological findings demonstrating the cytopathic effect of the virus in tissue. In these instances, there may or may not be evidence of viral replication in the peripheral blood.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved .
Reference ;
1-The lecture of professor Halawa
2.Humar A, Michaels M AST ID Working Group on Infectious Disease Monitoring. Humar A American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006;6:262–274. [PubMed] [Google Scholar].
What is the difference between CMV infection, CMV syndrome, and tissue-invasive CMV?
CMV is considered one of the most common viral infections after SOT and impacts the organ transplant outcome as it’s associated with increased morbidity, and mortality.
1. CMV infection (indicated by a positive antigenemia, culture, biopsy, or viral load) is accompanied by clinical symptoms and signs.
2. CMV syndrome flu-like syndrome is associated with fever and malaise frequently associated with leucopenia or thrombocytopenia.
3. CMV disease indicates Tissue-invasive, organ-specific diseases like the intestine retina, lung, pancreas, liver, heart, and gastrointestinal involvement is among the commonest organ infected with CMV disease.
Defects in innate immune responses have been associated with an increased risk of CMV infection and disease in SOT recipients, whose adaptive immune responses are reduced and ineffective by immunosuppressive drugs. Examples of innate or CMV-specific immune defects include Toll-like receptor (TLR) gene polymorphisms, mannose-binding lectin (MBL) deficiency or polymorphism [2,3), chemokine and cytokine defects including increased IL-10 expression [4], deficiency in CMV-specific CD4+ and CD8+ T cells.
Laboratory testing for CMV screening and diagnosis including viral culture, and pp65 antigenemia this test allows for the quantification of positive leukocytes., quantitative nucleic acid tests (QNAT), and histological testing
early diagnostic tools with QNAT and antigenemia that will indicate the extent of the disease and monitor response to treatment (5).
References
1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71.
2.Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation. 2007; 83:359–362.
3.Kwakkel-van Erp JM, Paantjens AW, van Kessel DA, Grutters JC, van den Bosch JM, van de Graaf EA, Otten HG. Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation. Clin Exp Immunol. 2011; 165:410–416.
4. Krishnan A, Zhou W, Lacey SF, Limaye AP, Diamond DJ, La Rosa C. Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high risk for late cytomegalovirus disease. Transpl Infect Dis. 2010;12:363–370.
5.Mallat S, Moukarzel M, Atallah D, Abou Arkoub R, Mourani C. CYTOMEGALOVIRUS INFECTION POST KIDNEY TRANSPLANT: What Should We Know Now? J Med Liban. 2015 Jul-Sep;63(3):164-9. doi: 10.12816/0015841. PMID: 26591198.
CMV infection is refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs ,not all patients with infection develop overt clinical disease. It is recommended that both the source of the specimens tested (eg, plasma, serum, whole blood, peripheral blood leukocytes [PBLs], cerebrospinal fluid [CSF], bronchoalveolar lavage [BAL] fluid, urine, or tissue) and the diagnostic method used be described clearly. CMV syndrome: manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others) with the clinical presentation related to organ involved and the severity of infection , eg respiratory distress or failure ,diarrhea ,ocular pain swelling and redness ,high renal profile, liver failure ,chest pain, shortness of breath and so on . CMV disease : Is CMV infection associated with clinical syndrome and evidence of end organ damage . Reference :
Thank you All. Well done all. Probably the confusion comes from the difference between the terms of CMV infection and CMV disease which are completely different. So detection of viral particles whether by PCR/NAT without the presence of symptoms would be infection. CMV disease will include end organ disease and syndrome where patient has the constitutional symptoms and tissue diagnosis of the affected organ. The only one exception for that and does not need a direct tissue diagnosis would be CMV retinitis.
Be careful that you can have CMV tissue invasive disease with CMV PCR negative in the blood. Diagnosis in these cases would be through the tissue biopsy.
Thank you Prof
I have seen 2 patients with CMV gastritis and colitis with negative CMV PCR. These patients were in the late transplant period. Would the patients presenting late post transplant have negative CMV PCR?
I have seen CMV colitis with massive GI bleeding and persistent negative CMV PCR in two cases of post-kidney transplantation and one with SLE on longstanding IS, the typical endoscopic finding of focal, patchy ulcerations so need multiple biopsies to confirm the diagnosis of the typical tissue invasive CMV with viral inclusion bodies(owl sign )
CMV infection indicated by a positive antigenemia, culture, biopsy or viral load.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. In addition to detect CMV in the blood.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved. This to be proved by detection of CMV by histology in the affected organ.
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
CMV infection
is defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen. CMV syndrome
is a disease definition that should only be used in SOT recipients. Because it is impossible to exclude all other causes of the clinical symptomatology described as CMV syndrome.The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
-Fever ≥38°C for at least 2 days.
-New or increased malaise or new or increased fatigue .
-Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count of <3500 cells/µL, if the WBC count prior to the development of clinical symptoms was ≥4000 cells/µL. The corresponding neutrophil counts are <1500 cells/µL or a decrease of >20% if the neutrophil count before the onset of symptoms was <1500 cells/µL.
-Greater than or equal to 5% atypical lymphocytes.
-Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL.
-Elevation of hepatic aminotransferases to 2 times the upper limit of normal .
Tissue invasive CMV
Is manifested by CMV syndrome in addition to detection of CMV by histology and culture in affected organ.
Tissue-invasive CMV disease is associated with specific organ involvement as gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis where , the gastro-intestinal tract is the commonest organ to be involved. Reference
-Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, Andreas Pikis, Raymund R. Razonable, Veronica Miller, Paul D. Griffiths, for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91.
-Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013;45(3):260-271.
presence of CMV in blood detected by any reliable method like DNA PCR is referred to CMV infection. CMV syndrome;
CMV infection with attributable symptoms like fever, chills or flu like symptoms is called CMV syndrome and when there is organ damage like GI, LUNG, RETINA, CNS or KIDNEY even without detectable PCR but histopathological evidence is tissue invasive disease
CMV infection: CMV virus, viral protein, or viral antigen in blood, body fluids, or tissue, with or without symptoms, indicates CMV replication. CMV replication can be identified by viral culture, nucleic acid test (NAT), or antigen testing as CMV DNAemia, RNAemia, or viremia (positive culture).
CMV disease: CMV infection with symptoms. Two types exist:
CMV syndrome: Fever, malaise, atypical lymphocytosis, leukopenia or neutropenia, thrombocytopenia, and increased hepatic transaminases.
Tissue-invasive disease/end-organ CMV disease: CMV invades tissues and damages organs such the gastrointestinal tract, lungs, liver, kidney, heart, pancreas, neurological system, retina, and others. Histopathology (inclusion bodies) can diagnose tissue-invasive illness even with a negative blood CMV PCR.
Presence of cytomegalovirus (CMV) in a patient warrants fulfilling certain criteria for diagnosing a CMV infection, CMV syndrome, or a tissue-invasive CMV. There are specific definitions for these terms (1).
CMV infection: It is defined as the presence of CMV virus, viral protein, or viral antigen (suggesting CMV replication) in blood, any bodily fluid, or tissue, with or without symptoms. CMV replication can be detected by either a viral culture, a nucleic acid test (NAT), or by antigen testing terming CMV DNAemia or RNAemia (positive NAT), CMV antigenemia (positive antigen testing), and CMV viremia (positive culture) (2,3).
CMV disease: It is defined as CMV infection in presence of clinical signs and symptoms. It is subdivided into 2 forms:
CMV syndrome: Presence of fever, malaise, atypical lymphocytosis, leukopenia or neutropenia, thrombocytopenia, and elevated hepatic transaminases encompasses CMV syndrome.Tissue-invasive disease/ End‐organ CMV disease: It involves invasion of tissues by CMV causing organ specific damage like gastrointestinal tract (gastrointestinal disease), lungs (pneumonitis), liver (hepatitis), kidney (nephritis), heart (myocarditis), pancreas (pancreatitis), nervous system (encephalitis), retina (retinitis) etc. The diagnosis in tissue-invasive disease can be achieved by a histopathological diagnosis (presence of inclusion bodies), and can be seen even in presence of a negative CMV PCR in blood.
References
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28. PMID: 27682069.Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID: 29596116.
I should have mentioned in my answer that CMV invasion of lung causing pneumonitis can be diagnosed by doing a diagnostic BAL. Pulmonary involvement in transplant recipient can also be due to pneumocystis pneumonia (PCP).
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? CMV infection
presence of the CMV within the blood, detected by investigations such as CMV PCR, CMV Ag or culture
CMV Syndrome
CMV infection plus symptomatic presentations including fever, malaise, chills and laboratory findings such as leucopenia, thrombocytopenia
tissue-invasive CMV
CMV syndrome plus identification of the CMV in the affected organs (usually multi-organ ) either by histology or by cultures
CMV can present in kidney transplant recipients as either CMV infection or CMV disease
CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease) or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
The most common clinical manifestation of tissue-invasive CMV disease in kidney transplant recipients is gastrointestinal disease
Among 26 CMV D+/R- kidney transplant recipients who developed CMV disease after completing three months of CMV prophylaxis, 21 (81 percent) had gastrointestinal disease, including one patient who had concurrent pneumonitis Two patients (8 percent) had CMV nephritis, and there was one case (4 percent) each of retinitis, pancreatitis, and hepatitis.
Patients with tissue-invasive CMV disease may present with any of the following syndromes:
Gastrointestinal disease – Esophagitis, enteritis and/or colitis, dysphagia, nausea, vomiting, diarrhea, and/or abdominal pain. In a study of 26 solid organ transplant recipients (including 13 kidney transplant recipients) with CMV gastrointestinal disease, 7 (27 percent) had upper gastrointestinal disease, 16 (62 percent) had lower gastrointestinal disease, and 3 (12 percent) had both
Hepatitis – Aspartate aminotransferase and alanine aminotransferase elevation with CMV viremia in the absence of any other cause.
Pancreatitis – Abdominal pain with elevated amylase and lipase in the setting of CMV viremia.
Pneumonitis – Cough, shortness of breath, and pulmonary infiltrates on radiographic imaging plus CMV in bronchoalveolar lavage fluid.
Meningoencephalitis – Headache, nuchal rigidity, mental status changes, or paralysis, plus CMV in cerebrospinal fluid.
Retinitis – Retinal edema or hemorrhage as reported by an ophthalmologist. CMV retinitis can present with one or more discrete foci of retinal edema or necrosis, with or without retinal hemorrhage or inflammatory sheathing of retinal vessels on funduscopic examination
Nephritis – Kidney dysfunction in the presence of microbiologic and histologic features of CMV infection in a kidney biopsy specimen.
quantitative polymerase chain reaction (PCR) is the preferred test for detecting CMV in blood . Evidence of CMV infection at the affected site is required for other tissue-invasive disease (eg, CMV enteritis)
CMV infection
This refers to the detection of the CMV in the blood either by CMV PCR, CMV Ag or culture
CMV Syndrome
This refers to the symptoms caused by the CMV like fever, malaise, chills and laboratory parameters like leucopenia, thrombocytopenia and CMV infection
CMV Disease
This refers to the CMV syndrome plus detection of the CMV in the affected organ either by histology or by cultures
CMV infection – Is the presence of CMV replication in blood regardless of whether signs or symptoms are present. CMV disease – Is the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. CMV disease may present as either CMV syndrome or tissue invasive CMV disease CMV syndrome: Is the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of evidence of tissue-invasive disease. Tissue-invasive CMV disease: Is the presence of clinical symptoms and signs of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?CMV infection :Detected of CMV in blood by culture or antigen test CMV syndrome :Fever ,malize ,leucopenia Tissue-invasive CMV?Associated with specific organ involvement (hepatitis ,nephritis )
CMV Infection
• Detection of CMV in blood by culture, antigen test or PCR CMV Syndrome
• Fever, malaise either leukopenia or thrombocytopenia + detection of CMV in blood CMV Disease (end-organ, invasive tissue disease)
• CMV syndrome + detection of CMV by histology or culture in affected
*The direct effects of CMV are the clinical manifestations occurring as a result of CMV replication, dissemination and tissue invasion of specific organs.
*CMV infection indicated by a positive antigenemia, culture, biopsy or viral load accompanied by clinical symptoms and signs.
*CMV disease can be further categorized into CMV syndrome and tissue-invasive CMV disease (or end-organ disease).
*CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
*Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis and others). Among these, the gastro-intestinal tract is the commonest organ to be involved.
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
CMV infection
Refers to detection of CMV virus by culture , serological or PCR investigations in blood without clinical manifestations CMV syndrome
Clinical symptoms of fever ,malaise associated with either leucopenia or thrombocytopenia and evidence of CMV infection in blood Tissue invasive CMV :
CMV Clinical syndrome associated with evidence of CMV tissue invasion and end organ dysfunction as CMV pneumonitis and nephritis .
CMV infection is the presence of any markers of the virus or its particles in the body.
CMV syndrome relates to the clinical manifestations of either acute infection or reactivation of CMV.
Tissue-invasive CMV relates to the disseminated CMV infection with multiple organ dysfunction. this condition commonly occurs in immunosuppressed patients, particularly if the CD4 count is less than 50/mm. it will affect multiple organs as pneumonitis, retinitis, encephalitis, hepatitis, colitis, pancytopenia, …..etc
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection: Detection of virus in the blood by culture, serology (antigen test) or PCR.
CMV syndrome: Acute infection by the virus resembling mononucleosis by fever , malaise, but less likely tonsillitis and lymphadenopathy. Hematological presentations:
Lymphocytosis with almost 10% atypical lymphocytes.
Mild-to-moderate anemia
Reduced haptoglobin levels
Cold agglutinins
Elevated levels of rheumatoid factor.
Positive antinuclear antibodies
Thrombocytopenia
Disseminated intravascular coagulation
CMV disease: – end organ damage and invasive tissue disease. Defined as CMV syndrome with specific histopathology (Owl’s eye) and culture from tissue biopsy of the affected organ. Refrences: (1) Prof. Ahmad Halawa presentation CMV in renal transplantation (2) Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
Disease versus infection CMV
Disease and infection are not the same thing; not all infected people experience overt clinical disease.
Regardless of symptoms or signs, CMV infection is defined as the isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue material.
The term “CMV illness” or CMV syndrome; refers to the presence of symptoms or signs that can be linked to a CMV infection.
CMV disease can present as either a viral syndrome (fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, thrombocytopenia, etc.) or as a tissue-invasive disease.
Or in other words CMV disease is a CMV infection + syndrome + organ involvement
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection: complete replication cycle of the virus with production of new infectious virions (Detection of CMV in blood by culture, antigen test or PCR)
CMV syndrome: fever, leucopenia or thrombocytopenia, myalgia or arthralgia + detection of CMV in blood
Tissue-invasive CMV: histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease (CMV syndrome + detection of CMV by histology or culture in affected organs)
References
1. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
2. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
CMV infection:
The presence of CMV replication (NAT, antigen testing, viral culture) in tissue, blood, or other bodily fluids regardless of symptomatology.
CMV DNAemia or RNAemia (NAT); CMV NAT replication in the blood
CMV antigenemia; antigen testing.
CMV viremia; culture.
Asymptomatic CMV infection: CMV replication without clinical signs and symptoms of disease CMV disease:
CMV infection that is accompanied by clinical signs and symptoms. CMV disease is categorized into: (a) CMV syndrome: Detection of CMV in the blood by viral isolation, rapid culture, antigenemia, or QNAT Plus, at least two of the following:
1. Fever ≥38°C for at least 2 d
2. New or increased malaise or fatigue
3. Leukopenia or neutropenia on 2 separate measurements
4. 5% atypical lymphocytes
5. Thrombocytopenia
6. Hepatic aminotransferases increase to two times ULN (except non‐liver transplant recipients)
(b) End‐organ CMV disease: CMV syndrome + detection of CMV by histology or culture in affected organs
The diagnosis of most end‐organ CMV diseases should be confirmed by histopathology. (eg, gastrointestinal disease, pneumonitis, hepatitis, nephritis, myocarditis, pancreatitis, encephalitis, retinitis, others).
References:
– Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
-Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521. -Prof. Halawa Lecture.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? CMV Infection
CMV infection is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen. Both specimen source and methods of identification should be clearly mentioned.
Tissue-invasive CMV:
The proven disease requires clinical symptoms and/or signs of organ involvement( e.g of pneumonia such as new infiltrates on imaging, hypoxia, tachypnea, and/or dyspnea) combined with CMV documented in lung tissue by virus isolation, rapid culture, histopathology, immunohistochemistry, or DNA hybridization techniques.
CMV Syndrome
CMV syndrome is a disease definition that should only be used in SOT recipients. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
1. Fever ≥38°C for at least 2 days.
2. New or increased malaise (toxicity grade 2) or new or increased
fatigue (toxicity grade 3).
3. Leukopenia or neutropenia on 2 separate measurements at
least 24 hours apart, defined as a white blood cell (WBC) count
of <3500 cells/μL, if the WBC count prior to the development of
clinical symptoms was ≥4000 cells/μ.
4. Greater than or equal to 5% atypical lymphocytes.
5. Thrombocytopenia defined as a platelet count of <100 000
cells/μL if the platelet count prior to the development of clinical
symptoms was ≥115 000 cells/μL or a decrease of >20% if the
platelet count prior to the development of clinical symptoms
was <115 000 cells/μL.
6. Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit.
References;
1-Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials CID 2017:64 (1 January).
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
Cytomegalovirus (CMV) can affect allograft function and increase patient morbidity and mortality.
Late-onset CMV disease continues to be a major problem in high-risk patients after completion of antiviral prophylaxis.
Patients may develop asymptomatic viremia, CMV syndrome or tissue-invasive disease.
CMV infection
CMV detection in blood through culture, antigen testing, or PCR .
Syndrome CMV
Blood testing for CMV in addition to a fever, malaise, and either leukopenia or thrombocytopenia
Tissue-invasive CMV
It is possible to diagnose CMV disease (an end-organ, invasive tissue disease) by looking for the CMV virus by histology or culture in the affected organs.
CMV in Renal Transplantation By Ahmed Halawa Associate Professor and Consultant Transplant Surgeon, University of Liverpool, United Kingdom
Definitions of cytomegalovirus (CMV) infection and disease, Multidisciplinary approach to understanding cytomegalovirus disease, 1993 Amsterdam Excerpta Medica International Congress Series, Ljungman, Griffiths, Michelson, and Plotkin, p. 233–7
CMV infection Is defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen. CMV detection
4 definitions are included according to the method used and sample to be examined Viremia. “Viremia” is defined as the isolation of CMV by culture that involves the use of either standard or shell vial techniques.
Antigenemia. “Antigenemia” is defined as the detection of CMV pp65 in leukocytes. DNAemia. “DNAemia” is defined as the detection of DNA in samples of plasma, whole blood, and isolated peripheral blood leukocytes or in buffy-coat specimens. RNAemia. “RNAemia” is defined as the detection of RNA (e.g., by nucleic acid sequence—based amplification or noncommercial reverse transcriptase–PCR) in samples of plasma, whole blood, or isolated peripheral blood leukocytes or in buffy-coat specimens.
Accordingly, CMV infection could be classified as follow Primary CMV Infection is defined as the detection of CMV infection in an individual previously found to be CMV seronegative Recurrent Infection “Recurrent infection” is defined as new detection of CMV infection in a patient who has had previously documented infection and who has not had virus detected for an interval of at least 4 weeks during active surveillance Reinfection. “Reinfection” is defined as detection of a CMV strain that is distinct from the strain that was the cause of the patient’s original infection Reactivation. Reactivation is assumed if the 2 strains are found to be indistinguishable either by sequencing specific regions of the viral genome or by using a variety of molecular techniques that examine genes known to be polymorphic. CMV syndrome In order to define CMV syndrome in SOT the following criteria should be minimally present 1- the documented presence of fever (temperature, >38°C) for at least 2 days within a 4-day period, 2- the presence of neutropenia or thrombocytopenia,
3- and the detection of CMV in blood. CMV tissue invasive disease
Affection of the body organs by active CMV infection as follow :
detected by histpathology exam finding awel eyes signs Gastrointestinal disease • Ulceration affecting any part of the GI tract: • Oesophagus → dysphagia, odynophagia • Gastritis → nausea, vomiting, dyspepsia • Duodenitis, enteritis, colitis → abdominal pain (often severe), diarrhoea,
perforation (especially in colonic disease) • GI bleeding, sometimes torrential, is common Pneumonitis • Presents with cough, fever and breathlessness • Hypoxia, exacerbated by exercise • CXR appearances are variable, including lobar infiltrates, localized or diffuse
nodular infiltrates or diffuse, bilateral interstitial infiltrates • Common in lung and bone marrow transplants, less so in renal transplantation Chorioretinitis • Very unusual in solid organ transplant recipients • May occur following prolonged viraemia (more than 6 months) • Vasculitis of retinal vessels with typical fundoscopic appearance (‘scrambled
eggs with tomato sauce’) Graft dysfunction • CMV infection of graft EC and RTEC → ↓GFR • CMV pancreatitis and hepatitis occurs in pancreas and liver transplant
recipients, but are uncommon in solitary organ renal transplantation
Ref
1- Per Ljungman, Paul Griffiths, Carlos Paya, Definitions of Cytomegalovirus Infection and Disease in Transplant Recipients, Clinical Infectious Diseases, Volume 34, Issue 8, 15 April 2002, Pages 1094–1097,
2- OSH Renal Transplantation, OCT, 2011 page: 324-335
CMV infection and disease are not synonymous terms; not all patients with infection develop overt clinical disease. · CMV infection refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs. · CMV disease refers to evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome (eg, fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, thrombocytopenia) or as tissue-invasive disease. CMV disease consists of “end-organ disease” and CMV syndrome.
· CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. · Tissue-invasive CMV disease isassociated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others).
A negative plasma or whole-blood PCR does not exclude tissue-invasive CMV disease, especially in patients with CMV gastrointestinal disease, pneumonia, or retinitis. The absence of CMV inclusions on histopathology also does not exclude tissue-invasive disease since such inclusions can be missed as a result of sampling error.
Reference: · Angela M Caliendo. Approach to the diagnosis of cytomegalovirus infection. UpToDate. · Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
Thankyou for mentioning the possibility of a negative PCR with tissue invasion which might be more difficult with a neg. histology due to the focal nature.
CMV infection is defined as the presence of detectable CMV in blood with or without symptoms
CMV disease which is defined as the presence of detectable CMV in blood associated with CMV syndrome and /or tissue invasive CMV
CMV syndrome is defined as the presence of detectable CMV in blood together with general manifestations not localized to certain organ such as malaise, fatigue, fever, leuckopenia, thrombocytopenia, arthralgia
Tissue invasive CMV is defined as the presence of detectable CMV in blood associated with manifestations of tissue invasion (enteritis, colitis, pneumonitis, hepatits, meningitis, encephalitis, retinitis and nephritis)
CMV infection is the detection of its DNA in culture, antigen or techniques using PCR without necessarily having clinical manifestations of the disease.
The syndrome is when we have established systemic disease, presenting fever, malaise, jaundice, or cytopenias in the presence of infection.
Invasive or visceral disease is when there is the presence of the syndrome with confirmation of CMV in biopsy, culture, or immunohistochemistry in a specific organ.
CMV infection
Detection of CMV in blood via culture/PCR/antigen test in an asymptomatic patient. CMV syndrome
Presence of CMV in blood plus presentation of constitutional symptoms like malaise, fever, leukopenia and thrombocytopenia. Tissue invasive CMV disease
Presence of CMV syndrome with CMV infected organ evidenced by histology/culture. Reference
Prof Halawa lecture.
-CMV Infection;
Detection of CMV in blood by Culture , Antigen test( PP65) or PCR.
-CMV Syndrome;
Fever,Malaise either leukopenia or thrombocytopenia + Detection of CMV in blood.
-CMV Disease (Tissue Invasive Disease, End-organ);
CMV syndrome + Detection of CMV by histology or culture in affected organs (Nephritis,Hepatitis,Pneumonitis,Colitis,Gastritis,Pancreatitis,Myocarditis,Cystitis,Retinitis,Encephalitis.
-References;
(Prof.Dr.Halawa Lecture:
(kotton et al.Transplantation 2018;102:900-931)
(Razonable and Humar.Clinical Transplantation.2019;33:e13512)
This is the presence and detection of viral protein or nucleic acid in the body fluid tissue irrespective of clinical signs and symptoms. This could be divided into:
Primary CMV infection, which is the infection in the previously seronegative host
Secondary CMV infection represents infection in a previously infected seropositive host caused by either reactivation of the latent endogenous virus, or superinfection with a new virus strain
CMV Syndrome
This CMV infection is detected in the blood with clinical features like fever, malaise, leucopenia, or thrombocytopenia
Tissue invasive CMV
This is the occurrence of CMV syndrome in addition to plus the detection of CMV infection by tissue histology or culture. The clinical manifestation of this is CMV retinitis, CMV pneumonitis, CMV colitis, or the involvement of the allograft.
CMV in Kidney Transplantation Lecture, by Ahmed Halawa
Gabriel M. Danovitch. Handbook of Kidney transplantation. Sixth Edition.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present. CMV Syndrome: Fever, malaise either leukopenia or thrombocytopenia + detection of CMV in blood. CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. References:-
1-Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients, Up To Date 2023.
2- CMV in Kidney Transplantation Lecture By: professor Ahmed Halawa.
CMV infection is defined as a situation in which there is evidence of the virus creating new infectious virions and performing a full replication cycle. This is required for the virus to be considered infectious(detected by PCR analysis of blood or other fluid or tissue specimens reveals the presence of viral proteins or replication of the virus) it is asymptomatic.
CMV syndrome is a disease that occurs when there is detectable PCR CMV and the patient exhibits constitutional symptoms such as flu-like sickness, fever, and malaise. In addition, there must be evidence of CMV infection. Patients may sometimes be diagnosed with cytopenias such as leucopenia and thrombocytopenia.
Tissue-invasive CMV is another name for the end-organ disease that is caused by CMV invasion and results in distinctive clinical symptoms such as hepatitis, retinitis, and gastroenteritis.
Presence of virus i.e.,CMV ,viral proteins or replication of virus detected by PCR in blood or any fluid or tissue specimen without the presence of symptoms or signs in the patient .
CMV syndrome and CMV tissue invasive disease comes under the category of CMV infection tion.CMV syndrome is a condition in which there is detectable PCR CMV and the patient has constitutional symptoms like flu-like illness,fever and malaise .Sometimes patient may have cutopenias like leucopenia and thrombocytopenia. CMV tissue invasive disease -condition in which there is detectable CMV PCR in blood or tissue specimen with organ involvement like encephalitis,retinitis,pneumonitis,colitis etc.
CMV Infection:
Presence of CMV in blood by culture and antigen test and PCR
CMV Syndrome:
Fever/ Malaise with leukopenia or thrombocytopenia and presence of CMV in blood.
Tissue invasive CMV?
CMV syndrome plus detected of virus by histology or cultures in affected organ
It’s CMV infection with end organ damage like Pneumonia and retinitis and colitis
Reference.
Lecture of Pro dr Ahmed Halwa
CMV infection:
Denotes detection of CMV in a patient who used to be negative before.
Its either detection of CMV virus by culture of plasma, or identification of CMV protein PP65, or showing CMV antigen presence in the form of DNA or RNA detected by PCR. CMV syndrome:
Reflects the triad of fever of more than 38 C for 2 days out of 4 in the context of neutropenia or thrombocytopenia and detection of CMV from blood. Tissue-invasive CMV:
Synonym to end organ disease secondary to invasion by CMV, with resultant characteristic clinical features such as hepatitis, retinitis, gastroenteritis etc.
reference:
1]Per Ljungman et al.Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials.Clin Infect Dis. 2017 Jan 1;64(1):87-91.
CMV infection is defined as a state there is evidence of the virus undergoing a complete replication cycle and producing new infectious virions.
Active replication can be further characterised into
asymptomatic infection (no obvious signs of pathologic symptoms).
viral syndrome (fever >38°C for 2 days of unexplained origin and one of leucopenia, myalgia or arthralgia).
CMV disease (histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease or CMV colitis, or CMV pneumonitis)
Isolation of CMV virus, viral proteins, or nucleic acid in any body fluid or tissue specimen- indicated by a positive antigenemia, culture, biopsy or viral load
CMV syndrome
Manifests as flu-like illness, fever, and malaise and are frequently associated with leucopenia or thrombocytopenia.
CMV tissue invasive disease
Associated with specific organ involvement (ie: retinitis, pneumonitis, hepatitis, colitis)
References
1) Poornima Ramanan et al. Cytomegalovirus Infections in Solid Organ Transplantation: A Review. Infect Chemother 2013;45(3):260-271.
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection is diagnosed whenever there is active CMV replication in the blood, regardless of whether signs or symptoms are present.
CMV disease is defined by the presence of detectable CMV in a clinical specimen + clinical symptoms and signs. According to the presentation, CMV disease may be further subdivided into CMV syndrome and CMV tissue-invasive disease.
CMV syndrome describes a detectable viral replication in the blood accompanied by non-specific constitutional symptoms (e.g., fever, malaise, arthralgias, leukopenia, thrombocytopenia) and with the absence of tissue-invasive disease.
CMV tissue-invasive disease (as it can be figured from the name) describes a detectable viral replication in the blood accompanied by symptoms and signs of end-organ disease (e.g., nephritis, colitis, enteritis, hepatitis, pneumonitis, meningitis, encephalitis, and retinitis). The viral antigens may be isolated in tissue biopsy specimens by histopathology.
latent infection – after the initial immune response, the virus persists in a latent state, mainly in myeloid lineage cells and evades the immune system and to survive.
active infection –
the presence of viral replication, diagnosed by –
growing the virus in vitro
by the discovery of intracytoplasmic and intranuclear inclusions, which are characteristics of the virus
by viral identification via tissue staining of biopsy material
by the discovery of evidence of viral replication detected by antigenemia assay or molecular methods.
disease – evidence of an infection with symptoms attributed to it.
viral syndrome –the presence of signs and symptoms of disease and the confirmation of viral replication in the peripheral blood (detected by antigenemia assay or molecular techniques).
invasive disease – the presence of specific symptoms in a target organ and histological findings demonstrating the cytopathic effect of the virus in tissue. In these instances, there may or may not be evidence of viral replication in the peripheral blood.
The most common clinical picture in the transplanted host is a viral syndrome, characterized by fever and malaise as well as leukopenia, thrombocytopenia and elevated liver enzymes.
Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34((8)):1094–7. doi: 10.1086/cid.2002.34.issue-8
CMV infection
Active infection.: evidence of CMV replication regardless of symptoms
CMV disease
…. CMV viral syndrome characterized by presence of fever and or malaise, leucopenia or thrombocytopenia
……Tissue invasive disease the patient presented with clinical symptoms and signs of end-organ damage
CMV disease is determined by the presence of CMV infection (confirmed by CMV positive serology preferably by PCR, culture, biopsy or viral load both qualitative as well as quantitative ) associated by nonspecific clinical symptoms and signs.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
Tissue-invasive CMV disease is the most aggressive form being associated with specific organ involvement commonly gastro-intestinal, pneumonitis, hepatitis, nephritis, cerebritis, myocarditis and retinitis. Among these, the gastrointestinal tract is the commonest organ to be involved.
CMV disease is the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs. CMV disease can be further categorized into :
CMV syndrome and tissue-invasive CMV disease (or end-organ disease).
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved.
Cytomegalovirus Infections in Solid Organ Transplantation: A Review
Poornima Ramanan and Raymund R Razonablehttps://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/corrauth.gifd
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV disease denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs. CMV disease can be further categorized into CMV syndrome and tissue-invasive CMV disease (or end-organ disease). CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved .
reference
31. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, Freeman R, Heaton N, Pescovitz MD Valganciclovir Solid Organ Transplant Study Group. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. 2004;4:611–620. [PubMed] [Google Scholar]
CMV infection :
Isolation of CMV from tissue or fluid without any presentation
CMV syndrome:
CMV infection + general symptoms
CMV Disease:
CMV infection with confirmed histology involvement in organs ( hepatitis, colitis, myocarditis, pneumonitis)
CMV infection: is the presence of cmv in blood detected by PCR with no symptoms.
CMV syndrome: is the presence of general symptoms as myalgia, arthralgia, fever associated with cmv infection.
Tissue-invasive CMV: end organ affection with CMV infection detected by histopathology
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
Cytomegalovirus infection is a frequent complication after transplantation.
This infection occurs due to
– transmission from the transplanted organ.
-reactivation of latent infection.
– after a primary infection in seronegative patients.
This condition occurs mainly between 30 and 90 days after transplantation.
can be defined as follows: latent infection, active infection, viral syndrome or invasive disease.
latent infection – after the initial immune response, the virus persists in a latent state, mainly in myeloid lineage cells .
active infection – the presence of viral replication, diagnosed by growing the virus in vitro; by the discovery of intracytoplasmic and intranuclear inclusions,by viral identification via tissue staining of biopsy material; or by the discovery of evidence of viral replication detected by antigenemia assay or molecular methods.
disease – presence of evidence of an infection with symptoms attributed to it.
viral syndrome –the presence of signs and symptoms of disease and the confirmation of viral replication in the peripheral blood (detected by antigenemia assay or molecular techniques).
invasive disease – the presence of specific symptoms in a target organ and histological findings demonstrating the cytopathic effect of the virus in tissue. In these instances, there may or may not be evidence of viral replication in the peripheral blood.
The most common clinical picture in the transplanted host is a viral syndrome:
characterized by fever and malaise as well as leukopenia, thrombocytopenia and elevated liver enzymes. These signs appear from the 3rd to 4th week, with a peak from the 6th to 16th week, and become rare after the 6th month.
Upper digestive tract symptoms, and mainly pain, are common. Diarrhea, occasionally containing blood, is more uncommon and is suggestive of colonic involvement.
Respiratory symptoms indicate more severe disease and may require admission to an intensive care unit.
Reference
Azevedo LS, Pierrotti LC, Abdala E, Costa SF, Strabelli TM, Campos SV, Ramos JF, Latif AZ, Litvinov N, Maluf NZ, Caiaffa Filho HH, Pannuti CS, Lopes MH, Santos VA, Linardi Cda C, Yasuda MA, Marques HH. Cytomegalovirus infection in transplant recipients. Clinics (Sao Paulo). 2015 Jul;70(7):515-23.
CMV infection :
Detected of virl pcr in blood without clinical symptoms.
CMV syndrome:
Detection of pcr in blood with systemic symptoms such as:
Fever.
Myalgia.
Arthralgia.
Leukopenia.
CMV invasive:
Detection of pcr virl in tissue and end organ damage.
CMV infection refers to the detection of CMV DNA in blood samples with no clinical presentation.
CMV syndrome refers to the detection of CMV DNA in blood samples accompanies by the systematic symptoms such as myalgia, arthralgia, fever and leukopenia.
Tissue-invasive CMV is referred by the clinical presentation of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
CMV can present in kidney transplant recipients as either CMV infection or CMV disease
CMV infection – Defined as the presence of CMV replication in the blood regardless of whether signs or symptoms are present.
CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations. CMV disease may manifest as either CMV syndrome or tissue-invasive CMV disease:
CMV syndrome – Defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of tissue-invasive disease.
•
Tissue-invasive CMV disease – Patients with tissue-invasive CMV disease have clinical symptoms and signs of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
CMV infection means the detection of CMV DNA in blood samples, however, there are no clinical manifestations, and would be two types.
CMV syndrome: There are viral replication and symptoms such as fever, malaise, myalgia, arthralgia leukopenia, or thrombocytopenia.
tissue-invasive CMV: is defined by clinical manifestations of CMV inclusions or CMV by IHC in involved tissues. Involvement tissues include: GI (gastritis, colitis), lung (pneumonitis), liver (hepatitis), eye (retinitis), CNS (meningitis, encephalitis)
●CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
●CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either
○ CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease)
○ or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
infection means detection of CMV DNA in blood and no symptoms
CMV syndrome means fever , malaise arthralgia low WBC AND PLATLETS
CMV disease – above all and presence of CMV in tissue biopsy from colon , stomach or any organ
CMV infection = CMV vireamia regardless of whether signs or symptoms are present
CMV disease = presence of detectable CMV in a clinical specimen (blood and or tissue) accompanied by other clinical manifestations. It can be either
A) CMV syndrome Defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (eg, fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of tissue-invasive disease.
B) tissue-invasive CMV disease identification of CMV inclusions or positive CMV-specific immunohistochemistry staining on histopathology. (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
CMV Infection is when there is evidence of the cytomegalovirus (human herpes virus 5) being present in the body and it is undergoing a complete replication cycle with new infectious virions being produced. Detection of CMV in the blood (viraemia) is usually quantified by a polymerase chain reaction (PCR) test performed on either whole blood or plasma. The key difference between CMV infection versus CMV syndrome or disease is that the patient is asymptomatic. However, this does not mean that damage is not occurring as indirect effects of CMV virus can start occurring during CMV infection and there is also the potential for rapid expansion in the copies of CMV in the blood leading to CMV syndrome or CMV disease.
Latent CMV can occur after primary CMV infection when the virus remains present in monocytes and other bone marrow progenitor cells. During this time, the viral genome is present in these cells but is not undergoing a complete replication cycle or producing new infective virions. Latent CMV is relevant to solid organ transplant recipients as following heavy immunosuppression they may re-activate this CMV meaning they are at risk of developing CMV disease from 3 different sources: re-activation of their own latent CMV, transfer of CMV from the donor and primary infection from another source.
Symptomatic CMV
When CMV becomes symptomatic this may be as either CMV syndrome or CMV disease
CMV syndrome is when there is evidence of CMV infection being present in the body (viraemia) and in addition to this the patient becomes symptomatic with systemic symptoms such as fever, myalgia, arthralgia and they may also demonstrate leucopenia on blood tests.
CMV disease requires a tissue diagnosis to prove the CMV viraemia is directly causing end-organ damage. CMV can affect multiple organs and the means of diagnosis will therefore depend on the affected organ. A biopsy may be performed to achieve a histopathological diagnosis or a tissue sample may be sent for culture. The classic finding is owl eye inclusion bodies but this will not always be universally present. If CMV is affecting the central nervous system a lumbar puncture may be performed to demonstrate CMV in the cerebrospinal fluid. Alternatively, in cases of CMV-retinitis a diagnosis can be made by an ophthalmologist with experience in CMV disease; however, CMV retinitis is more common in HIV-patients and less commonly seen in CMV-disease affecting solid organ transplant recipients.
Reference:
British Transplantation Society (2022): Prevention and management of CMV disease after solid organ transplantation. Available at: https://bts.org.uk/guidelines-standards/ %5Baccessed April 4, 2023]
The direct effects of CMV are the clinical manifestations occurring as a result of CMV replication, dissemination and tissue invasion of specific organs .
1- CMV disease: denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs.
CMV disease can be further categorized into
A- CMV syndrome : manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
B- Tissue-invasive CMV disease: (or end-organ disease) is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others).
Among these, the gastro-intestinal tract is the commonest organ to be involved .
REFFERENCE:
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521
signs.
CMV disease is defined as evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome (eg, fever, malaise, leukopenia, thrombocytopenia) or as tissue invasive disease.
CMV syndrome: Patients with a CMV syndrome have evidence of clinical disease, but without end-organ involvement. Typical symptoms include fever, malaise, weakness, myalgias, and arthralgias.
Tissue invasive disease: Involves specific organ involvement, such as pneumonitis hepatitis, gastroenteritis, and colitis.
CMV infection refers to the presence of CMV in the blood (viremia); CMV syndrome includes symptoms (fever, malaise, lab findings like leukopenia etc.).
Tissue-invasive CMV refers to organ involvement like pneumonitis, hepatitis, colitis, retinitis etc.
The difference between CMV infection, CMV syndrome and tissue-invasive CMV:
1. CMV infection :
CMV viremia and CMV disease were considered as CMV infection.
CMV viremia is defined as any detectable virus in blood or tissues by quantitative PCR (>600 copies/mL) or culture or positive antigenemia testing (CMVpp65 antigen) without clinical symptoms.
2. CMV syndrome:
It is clinical manifestations of flu-like symptoms (fever, malaise, arthralgia, associated with leukopenia and thrombocytopenia) along with detection of CMV in blood.
3. Tissue-invasive CMV disease:
It denotes specific organ involvement (pneumonitis, hepatitis, nephritis, myocarditis and retinitis, gastritis, colitis) with detection of CMV in tissues (by histology / culture / PCR), with or without systemic illness (CMV syndrome).
References:
1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
2. Uta Erdbruegger1 , Irina Scheffner2 , Michael Mengel, et al. Advance Access publication 28 June 2011 Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant (2012) 27: 435–443 doi: 10.1093/ndt/gfr306
CMV infection:
Presence of the CMV virus in any body fluid or body tissue
The virus may be isolated by culture, viral protein or antigen (CMV pp65 antigen) may be detected within peripheral blood leukocytes or viral nucleic acid in any body fluid by PCR. Body fluids include serum, whole blood, buffy coat, cerebrospinal fluid, bronchoalveolar lavage or urine. The patient may or may not display any symptoms or signs.
CMV syndrome:
Presence of the CMV virus in blood along with any 2 of the following symptoms or tests
– Fever ≥ 38°C for ≥ 48 hours – Leukopenia or neutropenia
– New malaise or New fatigue – Thrombocytopenia
– Raised liver enzymes
– PBF ≥ 5% atypical lymphocytes
CMV may be detected in blood by viral isolation, rapid culture, antigenemia test, or PCR.
The patient will not display any evidence of localized organ involvement.
CMV disease:
Presence of CMV syndrome along with with organ involvement by tissue invasive CMV
Organ involvement includes pneumonia, gastrointestinal disease, hepatitis, pancreatitis, encephalitis, retinitis, nephritis, cystitis and myocarditis. Invasive procedures to obtain tissue from each organ followed by culture or histopathology and immunohistochemistry to demonstrate presence of the virus is necessary. Patients of CMV disease may be PCR negative on blood tests.
Reference:
Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, et al. for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
CMV infection:
Detection of CMV in blood by culture, antigen or PCR.
CMV syndrome:
Fever, malaise with either leukopenia or thrombocytopenia.
+
Detection of CMV in blood
Tissue invasive CMV:
CMV syndrome
+
Detection of CMV by histology or culture in affected organ.
Presence of CMV in a patient have specific criteria for diagnosis…
CMV Infection: It is defined as the presence of CMV virus, viral protein, or viral antigen in the blood, any bodily fluid or tissue with or without symptoms… CMV replication can be detected by either viral culture, NAT, pp65Ag and CMV viremia (positive culture)
CMV disease: It is defined as CMV infection with the presence of clinical signs and symptoms
CMV syndrome -Fever, malaise, atypical lymphocytes >5% in blood, leukopenia or neutropenia, thrombocytopenia and elevated liver enzymes
Tissue invasive disease/end organ CMV disease – involves CMV syndrome + CMV Detection in the blood + histological demonstration of CMV related disease like colitis,pneuomonitis with typical owl eye inclusion bodies
References :
1 ) Prof Ahmed Halawa lecture
CMV infection : Detection of CMV in blood by culture, antigen test or PCR.
CMV syndrome : CMV infection + presence of fever, malaise, leukopenia or thrombocytopenia.
CMV disease: CMV syndrome + dectection of CMV by histology or culture in affected organs.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
1. CMV infection
CMV viremia and CMV disease were considered as CMV infection.
CMV viremia is defined as any detectable virus in blood or tissues by quantitative PCR (>600 copies/mL) or culture or positive antigenemia testing (CMVpp65 antigen) without clinical symptoms.
2. CMV syndrome is clinical manifestations of flu-like symptoms (fever, malaise, arthralgia, associated with leukopenia and thrombocytopenia) along with detection of CMV in blood.
3. Tissue-invasive CMV disease denotes specific organ involvement (pneumonitis, hepatitis, nephritis, myocarditis and retinitis, gastritis, colitis) with detection of CMV in tissues (by histology / culture / PCR), with or without systemic illness (CMV syndrome).
References
1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
2. Uta Erdbruegger1 , Irina Scheffner2 , Michael Mengel, et al. Advance Access publication 28 June 2011 Impact of CMV infection on acute rejection and long-term renal allograft function: a systematic analysis in patients with protocol biopsies and indicated biopsies. Nephrol Dial Transplant (2012) 27: 435–443 doi: 10.1093/ndt/gfr306
Ref also
3.Prof Ahmed Halawa Lecture
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
CMV infection: means detection of CMV virus by serology screen, culture, investigation CMV PCR regardless clinical sign.
CMV syndrome: detection of CMV virous in the serological marker with present of sign and symptom like arthralgia , fever, thrombocytopenia.
CMV tissue invasive: invasion of CMV virus to the organs like kidney, heart, small intestine , eyes GIT. however CMV PCR become negative.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMC infection.
CMV infection refers to detection of CMV antigenemia by investigation like serology, culture, and PCR regardless of clinical manifestation.
CMV syndrome;
Defined as presence of detectable CMV in a clinical specimen accompanied by other clinical manifestation.
Tissue invasive disease;
Defined as invasion of tissue by cmv causing organ specific damage like kidney, GIT, heart etc.
CMV infection: isolation or detection of the virus in body fluid or tissue by culture, antigen test or PCR.
CMV syndrome: CMV infection along with constitutional symptoms like fever, malaise, arthralgia, myalgia, leukopenia and or thrombocytopenia.
CMV disease: CMV syndrome along with end-organ or invasive tissue disease.
CMV infection:means viral replication by CMV PCR ,patient has no symptoms
CMV syndrome :means fever ,malaise ,leucopenia ,thrombocytopenia but no tissue invasive disease
CMV disease :it is CMV syndrome plus tissue invasive disease:e.g hepatitis , e-British ,pneumonitis ,colitis ,gastritis .
Hepatitis , nephritis
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection (indicated by a positive antigenemia, PCR ,culture, or biopsy ) accompanied by clinical symptoms and signs.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia, and detection of virus in blood.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved.
Tissue invasive disease is CMV syndrome + detection of CMV by histology or culture of affected organ .
Reference
Cytomegalovirus Infections in Solid Organ Transplantation: A Review
Poornima Ramanan and Raymund R Razonable
Prof Ahmed Halawa lecture
CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
●
CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease) or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
Ref . Up to date
CMV Infection
CMV syndrome
definition that should only be used in SOT recipients
definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
Tissue-invasive CMV disease
References:
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, Andreas Pikis, Raymund R. Razonable, Veronica Miller, Paul D. Griffiths, for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
A– CMV infection = detection of CMV in blood by any method
B-CMV syndrome= A+ constitutional symptoms (fever,malaise) and leukopenia, thrombocytopenia
C- CMV disease = A + B + detection of CMV in the affected organ by culture, tissue biopsy, immunohistochemical staining
_ CMV infection means identification or isolation of CMV DNA by PCR in the blood or body fluid.
_ CMV syndrome when the CMV infection has additional clinical manifestations as fever, malaise , cytopenias as leukopenia and thrombocytopenia.
_CMV invasive tissue disease means presence of tissue invasion as pneumonitis, gastrointestinal disease (enteritis and colitis), retinitis or encephalitis, hepatitis , pancreatitis and nephritis.plus identification of viral particles or inclusion bodies in tissue biopsy or special immunohistochemical staining.
infection : refers to The virus is detected by antigeniemia test or PCR in body fluids or tissue samples
It is either a primary infection in a previous sero-negative host
or secondary infection (re-infection with a different viral strain)
or (reactivation a latent endogenous virus).
CMV syndrome
defined as CMV detection in blood by viral isolation by rapid culture, antigenemia, or NAT together with at least 2 of the following :
1-fever 38 for at least 2 days.
2-new or increased malaise.
3- leukopenia or neutropenia on 2 separate measurements at least 24 hours apart.
4-create than or equal to 5% atypical lymphocyte.
5-thrombocytopenia platelet less than 100000 or decrease less than 25 % from the baseline.
6-elevation of hepatic transaminase 2 to the upper limit.
CMV invasive disease;
The gold standard for diagnosing CMV tissue-invasive disease is identifying CMV inclusions or positive CMV-specific immunohistochemistry staining on histopathology but, since tissue may be contaminated with blood or body secretions and viral shedding can occur from some sites (urine, bronchoalveolar lavage [BAL] fluid, stool) in the absence of clinical disease, ther its better to do both culture and histopathology on the tissue specimen.
Individuals with suspected CMV tissue-invasive disease a negative plasma or whole-blood PCR does not exclude tissue-invasive CMV disease, especially in patients with CMV gastrointestinal disease, pneumonia, or retinitis.
In some patients, obtaining a tissue biopsy may not be possible. When this is the case, viral-load testing or culture of body fluids may be performed.
references
uptodate
CMV infection means detection of the virus in blood by culture, antigen test or PCR.
CMV syndrome include constitutional symptoms like fever , malaise, arthralgia , myalgia with leukopenia and or thrombocytopenia plus detection of CMV in blood.
CMV disease include end-organ , invasive tissue disease and consist of CMV syndrome + detection of CMV by histology or culture in affected organs.
Reference:
Dr.Ahmed Halawa lecture
I like your reply but writing ‘Dr.Ahmed Halawa lecture’ is not good enough as a reference.
CMV Infection
Detection of CMV in blood by culture, antigen test or PCR
Active CMV infections may be symptomatic or asymptomatic and are characterized by viral replication
with expression of a CD4+ and CD8+ T-cell response to CMV. Primary CMV infection represents infection in the previously uninfected seronegative host, whereas secondary CMV infection represents infection in a previously infected seropositive host caused by either reactivation of latent endogenous virus, or superinfection with new virus strain
CMV Syndrome
• Fever, malaise either leukopenia or thrombocytopenia + detection of CMV in blood
For patients with suspected CMV syndrome (eg, fever, malaise, leukopenia, and/or lymphocytosis in the absence of end-organ disease),
CMV Disease (end-organ, invasive tissue disease)
• CMV syndrome + detection of CMV by histology or culture in affected organs
CMV disease refers to symptomatic acute CMV infection and includes CMV syndrome (fever, fatigue, leukopenia or thrombocytopenia, and detectable CMV viremia) and endorgan CMV disease (e.g., pneumonitis, hepatitis, or gastrointestinal involvement such as colitis or enteritis, or involvement of the allograft itself).
1-up to date
2-Lecture of CMV in Kidney Transplantation By Ahmed Halawa Consultant Transplant Surgeon. Associate Professor, University of Liverpool – UK
I like your reply but writing ‘up to date’ is not good enough as a reference.
The difference between CMV infection, CMV syndrome and CMV disease:
CMV establishes latent infection after the resolution of acute (or primary) infection. Patients who are CMV seropositive have latent infection. Secondary, symptomatic disease may present later. The risk of CMV reactivation is highest in the setting of systemic immunosuppression.
CMV can present in kidney transplant recipients as either CMV infection, CMV syndrome or CMV disease:
CMV infection :It is presence of CMV replication in blood regardless of whether signs or symptoms are present.
CMV syndrome:means symptomatic viremia (symptoms and signs like fever, malaise, arthralgia, leukopenia, thrombocytopeniawithout evidence of tissue-invasive disease.
CMV disease :Patients with tissue-invasive CMV disease have clinical symptoms and signs of end-organ disease as enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis.
Patients with tissue-invasive CMV disease may present with any of the following syndromes:
-Gastrointestinal disease :Esophagitis, enteritis and/or colitis, dysphagia, nausea, vomiting, diarrhea, and/or abdominal pain.
-Hepatitis :Aspartate aminotransferase and alanine aminotransferase elevation with CMV viremia in the absence of any other cause.
-Pancreatitis :Abdominal pain with elevated amylase and lipase in the setting of CMV viremia.
-Pneumonitis: Cough, shortness of breath, and pulmonary infiltrates on radiographic imaging plus CMV in bronchoalveolar lavage fluid.
-Meningoencephalitis : Headache, nuchal rigidity, mental status changes, or paralysis, plus CMV in cerebrospinal fluid.
-Retinitis: Retinal edema or hemorrhage . CMV retinitis can present with one or more discrete foci of retinal edema or necrosis.
-Nephritis :Kidney dysfunction in the presence of microbiological and histological features of CMV infection in a kidney biopsy specimen.
References:
Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:93.
Schnitzler MA, Woodward RS, Brennan DC, et al. Impact of cytomegalovirus serology on graft survival in living related kidney transplantation: implications for donor selection. Surgery 1997; 121:563.
What is the difference between CMV infection, CMV syndrome, and tissue-invasive CMV?CMV infection defines as virus isolation or detection of viral protein (antigen) or nucleic acid in any body fluid or tissue specimen.
CMV syndrome
defined as required CMV detection in blood by viral isolation by rapid culture, antigenemia, or NAT together with at least 2 of the following :
1-fever 38 for at least 2 days.
2-new or increased malaise.
3- leukopenia or neutropenia on 2 separate measurements at least 24 hours apart.
4-create than or equal to 5% atypical lymphocyte.
5-thrombocytopenia platelet less than 100000 or decrease less than 25 % from the baseline.
6-elevation of hepatic transaminase 2 to the upper limit.
CMV Tissue -invasive CMV
Disease of end- organ disease absence of appropriate clinical symptoms and signs are required together with detection of CMV in the tissue from relevant organ by histopathology ,virus isolation .rapid culture ,immunochemistry, or DNA by hybridization unless there are data supporting that other material can be accepted as having similar significance CMV diseases such as pneumonia, GIT disease , hepatitis,nephritis ,cysitis,
myocarditis and pancreatitis
References
Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Multidisciplinary approach to understanding cytomegalovirus disease. Paris, Amsterdam: Excerpta Medica International Congress Series, 1993:233–40.Google ScholarGoogle PreviewWorldCatCOPAC
2Ljungman P. Cytomegalovirus infections in transplant patients. Scand J Infect Dis 1996; Supplementum 100:59–63.Google ScholarWorldCat
3Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34:1094–7.Google ScholarCrossrefPubMedWorldCat
Short and precise reply
● CMV infection refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs
● CMV Disease : when there is CMV infection and symptoms include feeling or being sick (nausea and vomiting), diarrhoea, fever, muscle aches, fatigue, night sweats and generally feeling unwell
● CMV Syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
● Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis )
Among these, the gastro-intestinal tract is the commonest organ to be involved
P. Ramanan and R. Raymund Cytomegalovirus Infections in Solid Organ Transplantation: A Review . Infection and chemotherapy . 2013 Sep; 45(3):260–271.
Short and sweet reply
Isolation of CMV virus or detection of its protein or nucleic acid in any body fluid or tissue; evidence of virus replication denotes CMV infection.
CMV syndrome includes:
– fever (more than 38C) for at least 2 days within 4 days period.
-Neutropenia or thrombocytopenia.
-CMV viremia..
CMV disease with involvement of specific organ or tissue denotes tissue invasive CMV..
I agree
. CMV Infection
CMV infection is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen.
CMV Syndrome
CMV syndrome is a disease definition that should only be used in SOT recipients. Because it is impossible to exclude all other causes of the clinical symptomatology described as CMV syndrome, a “proven” category cannot be defined. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
1.Fever ≥38°C for at least 2 days.
2.New or increased malaise or new or increased fatigue .
3.Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart.
4.Greater than or equal to 5% atypical lymphocytes.
5.Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL.
6.Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit of normal .
CMV disease
It consists of “end-organ disease” and CMV syndrome. To define “proven CMV end-organ disease,” the presence of appropriate clinical symptoms and/or signs are required together with documentation of CMV in tissue from the relevant organ by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization . It is recognized that high viral DNA levels detected with quantitative NAT, such as polymerase chain reaction (PCR), in tissue from the relevant organ likely represent CMV disease and could therefore be accepted as “possible CMV end-organ disease,” especially when blood sampled at the same time does not contain CMV DNA.
Reference:
Per Ljungman, Michael Boeckh et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
Any personal experience of managing invasive CMV?
No
CMV Infection
CMV infection shows evidence of CMV viral replication. So it can be defined as isolation of CMV virus (detection of viral proteins and nucleic acid in body fluids) in body fluids or tissues. The spectrum can be Infection which can be asymptomatic , viral syndrome or CMV disease. CMV disease is detected by histopathology. Patient may have symptoms or be asymptomatic.
CMV syndrome
It is defined by presence of-
· CMV virus in blood
· Neutropenia
· Thrombocytopenia
· Fever of > 38 C for 2 days
· Deranged liver functions
· >5% atypical lymphocytes of peripheral blood films.
CMV can be detected by viral isolation.
Tissue-invasive CMV
CMV disease with specific organ involvement e.g pneumonitis, hepatitis, pancreatitis , encephalitis, cystitis etc
Reference
Ljungman P, Boeckh M, Hirsch HH, et al. Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91.
Any personal experience of managing invasive CMV?
Unfortunately not Prof
References:
I like your reply but writing ‘BTA guidelines’ is not good enough as a reference.
BTS, UK Guideline on Prevention and Management of Cytomegalovirus (CMV) Infection and Disease Following Solid Organ Transplantation. 2022
I agree
CMV infection:
Presence of the CMV virus in any body fluid or body tissue
The virus may be isolated by culture, viral protein or antigen (CMV pp65 antigen) may be detected within peripheral blood leukocytes or viral nucleic acid in any body fluid by PCR. Body fluids include serum, whole blood, buffy coat, cerebrospinal fluid, bronchoalveolar lavage or urine. The patient may or may not display any symptoms or signs.
CMV syndrome:
Presence of the CMV virus in blood along with any 2 of the following symptoms or tests
– Fever ≥ 38°C for ≥ 48 hours – Leukopenia or neutropenia
– New malaise or New fatigue – Thrombocytopenia
– Raised liver enzymes
– PBF ≥ 5% atypical lymphocytes
CMV may be detected in blood by viral isolation, rapid culture, antigenemia test, or PCR.
The patient will not display any evidence of localized organ involvement.
CMV disease:
Presence of CMV syndrome along with with organ involvement by tissue invasive CMV
Organ involvement includes pneumonia, gastrointestinal disease, hepatitis, pancreatitis, encephalitis, retinitis, nephritis, cystitis and myocarditis. Invasive procedures to obtain tissue from each organ followed by culture or histopathology and immunohistochemistry to demonstrate presence of the virus is necessary. Patients of CMV disease may be PCR negative on blood tests.
Reference:
Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, et al. for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
I appreciate your reply. Any personal experience of invasive disease?
CMV infection and disease are not synonymous terms; not all patients with infection develop overt clinical disease.
●CMV infection refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen, regardless of symptoms or signs
●CMV disease refers to evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome (eg, fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, thrombocytopenia) or as a tissue-invasive disease.
CMV invasive disease;
The gold standard for diagnosing CMV tissue-invasive disease is identifying CMV inclusions or positive CMV-specific immunohistochemistry staining on histopathology. A positive culture from a biopsy specimen is also considered consistent with CMV disease, but, since tissue may be contaminated with blood or body secretions and viral shedding can occur from some sites (urine, bronchoalveolar lavage [BAL] fluid, stool) in the absence of clinical disease, it is optimal to perform both culture and histopathology on the tissue specimen.
Individuals with suspected CMV tissue-invasive disease should also have a plasma or whole-blood PCR testing since PCR results are often available prior to the biopsy results and may influence the decision to initiate antiviral therapy. In addition, it is crucial to establish the baseline viral load because serial testing is used to monitor response to therapy.
A negative plasma or whole-blood PCR does not exclude tissue-invasive CMV disease, especially in patients with CMV gastrointestinal disease, pneumonia, or retinitis. The absence of CMV inclusions on histopathology also does not exclude tissue-invasive disease since such inclusions can be missed due to sampling error.
In some patients, obtaining a tissue biopsy may not be possible. When this is the case, viral-load testing or culture of body fluids may be performed. The culture of urine specimens should be avoided since a positive urine culture does not correlate with CMV disease.
references
uptodate
I like your reply but writing ‘up to date’ is not good enough as a reference.
◇ What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
▪︎CMV Infection “CMV infection” is defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen. It is recommended that both the source of the specimens tested (e.g., plasma, serum, whole blood, peripheral blood leukocytes, CSF, urine, or tissue) and the diagnostic method used be described clearly (1).
▪︎CMV disease denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs. CMV disease can be further categorized into:
1. CMV syndrome
2. tissue-invasive CMV disease (or end-organ disease).
▪︎CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
▪︎Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others)[2]. Among these, the gastro-intestinal tract is the commonest organ to be involved [3].
___________________
Ref:
(1) Pear L, Paul G. Definitions of Cytomegalovirus Infection and Disease in Transplant Recipients.Clinical Infectious Diseases 2002; , V 34: 1094–1097. (2)Poornima R, Raymund R R. Cytomegalovirus Infections in Solid Organ Transplantation: A Review. Infect Chemother. 2013; 45(3): 260–271.
(3) Freeman RB., Jr The ‘indirect’ effects of cytomegalovirus infection. Am J Transplant. 2009;9:2453–2458.
I wish you could use bold or underline for headings.
Ok, thanks Prof Ajay
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
1. CMV Infection: is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen.
· Primary CMV infection is defined as the first detection of CMV infection in an individual who has no evidence of CMV exposure before transplantation.
· Recurrent infection” is defined as new CMV infection in a patient with previous evidence of CMV infection. May result from reactivation of latent virus (endogenous) or reinfection (exogenous).
2. CMV disease: consists of “end-organ disease” and CMV syndrome.
CMV disease in SOT: The presence of CMV in the blood, together with symptoms and/or signs.
· This is not sufficient for the definition of either proven or probable CMV disease at any other site, with the exception of CMV syndrome in SOT patients(1).
· CMV disease refers to manifestation of disease-related signs and symptoms with alterations in blood count or invasive disease in tissue samples(2).
3. Tissue invasive CMV: is an end-organ disease and the presence of appropriate clinical symptoms and/or signs are required together with documentation of CMV in tissue from the relevant organ by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization unless there are data supporting that other materials can be accepted as having similar significance.
· High viral DNA levels detected with quantitative NAT in tissue especially when blood sampled at the same time does not contain CMV DNA.
· Tissue-invasive disease is defined as appropriate clinical symptoms and signs of end-organ disease (e.g., enteritis, hepatitis, nephritis, pneumonitis, meningoencephalitis, retinitis) with documentation of CMV in tissue from the relevant organ(3).
4. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following(1):
a) Fever ≥38°C for at least 2 days.
b) New or increased malaise or new or increased fatigue.
c) Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count of <3500 cells/µL, if the WBC count prior to the development of clinical symptoms was ≥4000 cells/µL, or a WBC decrease of >20%, if the WBC count prior to the development of clinical symptoms was <4000 cells/µL. The corresponding neutrophil counts are <1500 cells/µL or a decrease of >20% if the neutrophil count before the onset of symptoms was <1500 cells/µL.
d) Greater than or equal to 5% atypical lymphocytes.
e) Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL.
f) Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit of normal (applicable to non–liver transplant recipients).
Reference
1. Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, Andreas Pikis, Raymund R. Razonable, Veronica Miller, Paul D. Griffiths, for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91, https://doi.org/10.1093/cid/ciw668
2. Osman Kara Ganciclovir in the Prevention of Cytomegalovirus Reactivation in Allogeneic Hematopoietic Stem Cell Transplantation: Non-Eliminative Reduction of Viral Load July 2022, Medical Science and Discovery 9(7):401-405,DOI:10.36472/msd.v9i7.761, License CC BY-NC 4.0,Project: transplant patients quality of life- psychological status……… Kotton CN,
3. Kumar D, Caliendo AM, et al The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900–31.
I agree.
CMV can present in kidney transplant recipients as either CMV infection or CMV disease :
●CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
●CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as
REFERENCE
Uptodate
Any personal experience of managing invasive CMV?
CMV infection : refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen irrespective of the presence of symptoms or signs. The virus is detected by culture , antigeniemia test or PCR.
It is either a primary infection in a previous sero-negative host or a secondary infection (re-infection with a different viral strain) or (reactivation a latent endogenous virus).
CMV syndrome: refers to the presence of CMV in the blood as above coupled with constitutional manifestations like fever, malaise together with either leucopenia, thrombocytopenia or both but without evidence of localized organ involvement.
CMV disease: the presence of CMV syndrome together with tissue invasive CMV (encephalitis, retinitis, nephritis, myocarditis, pneumonitis, colitis, gastritis, hepatitis, pancreatitis and cystitis) evidenced by histology, culture or immunohistochemistry in a specific organ. Blood sample PCR is inconclusive, and a negative PCR in the blood does not exclude tissue-invasive CMV disease.
References:
1. Ljungman P et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91.
2. Lecture of Professor Ahmed Halawa, CMV in Kidney Transplantation.
I appreciate your reply. Any personal experience of invasive disease?
CMV infection:
Detection of CMV in body culture, antigen test or PCR
CMV syndrome:
presence of fever, malaise , either leukopenia or thrombocytopenia and detection of
CMV in blood.
CMV disease:
CMV syndrome + detection of cmv by histology or culture of the affected
organ
including CMV pneumonia, CMV gastroenteritis, CMV hepatitis, CMV nephritis and CMV encephalitis
Yes, I agree.
The difference between CMV infection, CMV syndrome and CMV disease:
1. CMV infection:
CMV infection is defined as virus isolation or detection of viral antigens in any body fluid or tissue.eg, plasma, serum, blood, leukocytes , cerebrospinal fluid, broncho-alveolar lavage, urine, or tissue and the diagnostic methods used are culture, antigen detection or PCR.
2 . CMV syndrome:
CMV syndrome is a definition that should only be used in SOT recipients. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
1. Fever ≥38°C for at least 2 days.
2. New or increased malaise or fatigue.
3. Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart.
4. Atypical lymphocytes more than or equal to 5%.
5. Thrombocytopenia defined as a platelet count of <100 000 cells/µL.
6. Elevation of hepatic aminotransferases to 2 times the upper limit of normal.
3 . CMV disease (end organ, invasive tissue disease):
CMV Pneumonia:
Clinical symptoms and/or signs of pneumonia such as new infiltrates on imaging, hypoxia, dyspnea combined with CMV documented in lung tissue by virus isolation, rapid culture, histopathology, immunohistochemistry, or DNA hybridization techniques.
CMV Gastrointestinal Disease:
Proven disease requires upper and/or lower gastrointestinal (GI) symptoms plus macroscopic mucosal lesions plus CMV documented in tissue by the above methods.
CMV Hepatitis:
Proven disease requires abnormal liver function tests plus CMV documented in tissue by the above methods.
CMV Encephalitis and Ventriculitis:
Proven disease requires central nervous system symptoms plus detection of CMV in CNS tissue.
Nephritis:
Proven disease is defined by the detection of CMV in a kidney allograft biopsy obtained from a patient with renal dysfunction together with the identification of histologic features of CMV infection. Worth noting that, the detection of CMV in urine by PCR or culture is not sufficient for the diagnosis of CMV nephritis as asymptomatic viral shedding in urine is common.
Other organs that could be involved include, urinary bladder, myocardium and pancreas.
REFRENCES:
1.Professor Ahmed Halawa lecture.
2 . Per Ljungman etal, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–9.
3 . Camille N. Kotton etal,I nternational Consensus Guidelines on the Management of Cytomegalovirus in Solid Organ Transplantation.
Thank you for your reply
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV? (1-3)
CMV infection
It is indicated by presence of a positive antigenemia, culture, viral load or biopsy
CMV disease
It denotes presence of CMV infection (i.e., positive antigenemia, viral load, culture or biopsy) in the presence of clinical signs and symptoms.
It can further be classified into CMV syndrome and tissue-invasive CMV disease or end-organ disease.
CMV syndrome
It manifests generally as a flu-like illness with fever and general body malaise. It is frequently associated with thrombocytopenia and leucopenia
Tissue-invasive CMV or end-organ CMV disease
The clinical manifestations that occur are as a result of CMV replication, dissemination and tissue invasion of specific organs e.g., gastritis, colitis, hepatitis, pancreatitis, pneumonitis, myocarditis, cystitis, nephritis, retinitis, CNS involvement.
References
1. Razonable RR, Humar A. Cytomegalovirus in solid organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2013 Mar;13 Suppl 4:93-106. PubMed PMID: 23465003. Epub 2013/03/08. eng.
2. Humar A, Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2006 Feb;6(2):262-74. PubMed PMID: 16426310. Epub 2006/01/24. eng.
3. Paya C, Humar A, Dominguez E, Washburn K, Blumberg E, Alexander B, et al. Efficacy and safety of valganciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid organ transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2004 Apr;4(4):611-20. PubMed PMID: 15023154. Epub 2004/03/17. eng.
Thank you for your reply
Welcome, thank you Prof.
References
1.BTS.org.uk/uk-guideline-on-prevention-and-management-of-cytomegalovirus-cmv-infection-and-disease-following-solid-organ-transplantation
2. Hyeyoung Lee and Eun-Jee Oh, Laboratory diagnostic testing for cytomegalovirus infection in solid organ transplant patients, Korean J Transplant 2022;36:15-28 https://doi.org/10.4285/kjt.22.0001
Thank you for your reply
CMV infection – Presence of CMV replication in the blood irrespective of whether signs or symptoms are present. Thiis usually detected by viral culture, antigen test or PCR.
CMV syndrome – Defined as presence of CMV infection with symptoms such as fever, malaise, leucopenia and/or thrombocytopenia without end organ affectation.
CMV disease – Defined as presence of CMV syndrome and detection or end organ disease by histology or culture in the affected organs.
Reference
Up to date
Thank you for your reply
CMV INFECTION
Presence of CMV replication evidenced by +VE antigenemia, VL, culture or biopsy +/- clinical signs and symptoms.
CMV SYNDROME.
(CMV infection + symptoms)
Non specific flu like illness with HOB,GBM +/- Leukopenia or thrombocytopenia.
CMV TISSUE INVASIVE DISEASE.
CMV DX + organ involvement(Intestinal, pulmonary, liver, cardiac or eye involvement)GIT is the commonest manifestation of tissue invasive disease. Biopsy + histology confirms this.
REF;
Cytomegalovirus infections in solid organ transplantation: a reviewP Ramanan, RR Razonable – Infection & chemotherapy, 2013 – synapse.koreamed.org
Thank you for your reply
Thank you.
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection:
-Evidence of CMV replication regardless of symptoms
-CMV DNAemia by nucleic acid testing (NAT), CMV antigenemia (antigen testing) or
CMV viremia (viral culture).
-Primary infection (donor derived), Reinfection (donor derived) or Reactivation (latent recipient infection)
-Donor derived infections are the most common
CMV disease :
-Both evidence of infection as well as symptoms
-CMV syndrome – fever, malaise, arthralgia, leukopenia, thrombocytopenia
Tissue invasive disease , (end-organ, invasive tissue disease)
Enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis with demonstration of CMV in tissue specimen by histopathology
CMV Viral Syndrome:
*1 of signs With e/o Active infection
-Fever>2day
-Malaise
-Leucopenia
->5%Atypical lymphocytes
-Thrombocytopenia
-Transaminitis (x2)
Reference:
1-The lecture of professor Halawa
2- Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9)
3- Kotton et al. Transplantation 2018;102: 900–931.
Thank you for your reply
CMV infection:
Define as a virus isolation or detection of the presence of viral proteins without causing any symptoms or signs.
CMV disease:
In addition to the viral load and viral protein detection, there are present symptoms and signs and present clinically:
CMV syndrome:
Used in SOT recipients, and required detection of CMV viral isolation, rapid culture, antigenemia, with at least 2 of the following:
references:
Ljungman P, Griffiths P. Definitions of cytomegalovirus infection and disease. In: Multidisciplinary approach to understanding cytomegalovirus disease. Paris, Amsterdam: Excerpta Medica International Congress Series, 1993:233–40
2Ljungman P. Cytomegalovirus infections in transplant patients. Scand J Infect Dis 1996; Supplementum 100:59–63.
3Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis 2002; 34:1094–7.
4Miller V. The forum for collaborative HIV research: a model for an integrated and inclusive approach to clinical research and drug development. Clin Pharmacol Ther 2009; 86:3
5Hutchison C, Kwong A, Ray S, Struble K, Swan T, Miller V. Accelerating drug development through collaboration: the Hepatitis C Drug Development Advisory Group. Clin Pharmacol Ther 2014; 96:162–5.
Thank you for your reply
What is the difference between CMV infection CMV syndrome and tissue-invasive CMV?
1-Latent CMV infection ;
After the initial immune response, the virus persists in a latent state, mainly in myeloid lineage cells, and employs various mechanisms to evade the immune system and to survive.
2-Active CMV infection;
The presence of viral replication, diagnosed by viral identification via tissue staining of biopsy material; or by the discovery of evidence of viral replication detected by antigenemia assay or molecular methods.
3-CMV disease ;
CMV disease denotes the presence of CMV infection (indicated by a positive antigenemia, culture, biopsy or viral load) accompanied by clinical symptoms and signs.
CMV disease can be further categorized into CMV syndrome and tissue-invasive CMV disease (or end-organ disease).
4-CMV viral syndrome ;
The presence of signs and symptoms of disease and the confirmation of viral replication in the peripheral blood (detected by antigenemia assay or molecular techniques). CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
5- CMV invasive disease;
The presence of specific symptoms in a target organ and histological findings demonstrating the cytopathic effect of the virus in tissue. In these instances, there may or may not be evidence of viral replication in the peripheral blood.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved .
Reference ;
1-The lecture of professor Halawa
2.Humar A, Michaels M AST ID Working Group on Infectious Disease Monitoring. Humar A American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant. 2006;6:262–274. [PubMed] [Google Scholar].
I appreciate your reply. Any personal experience of invasive disease?
What is the difference between CMV infection, CMV syndrome, and tissue-invasive CMV?
CMV is considered one of the most common viral infections after SOT and impacts the organ transplant outcome as it’s associated with increased morbidity, and mortality.
1. CMV infection (indicated by a positive antigenemia, culture, biopsy, or viral load) is accompanied by clinical symptoms and signs.
2. CMV syndrome flu-like syndrome is associated with fever and malaise frequently associated with leucopenia or thrombocytopenia.
3. CMV disease indicates Tissue-invasive, organ-specific diseases like the intestine retina, lung, pancreas, liver, heart, and gastrointestinal involvement is among the commonest organ infected with CMV disease.
Defects in innate immune responses have been associated with an increased risk of CMV infection and disease in SOT recipients, whose adaptive immune responses are reduced and ineffective by immunosuppressive drugs. Examples of innate or CMV-specific immune defects include Toll-like receptor (TLR) gene polymorphisms, mannose-binding lectin (MBL) deficiency or polymorphism [2,3), chemokine and cytokine defects including increased IL-10 expression [4], deficiency in CMV-specific CD4+ and CD8+ T cells.
Laboratory testing for CMV screening and diagnosis including viral culture, and pp65 antigenemia this test allows for the quantification of positive leukocytes., quantitative nucleic acid tests (QNAT), and histological testing
early diagnostic tools with QNAT and antigenemia that will indicate the extent of the disease and monitor response to treatment (5).
References
1. Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71.
2.Manuel O, Pascual M, Trendelenburg M, Meylan PR. Association between mannose-binding lectin deficiency and cytomegalovirus infection after kidney transplantation. Transplantation. 2007; 83:359–362.
3.Kwakkel-van Erp JM, Paantjens AW, van Kessel DA, Grutters JC, van den Bosch JM, van de Graaf EA, Otten HG. Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation. Clin Exp Immunol. 2011; 165:410–416.
4. Krishnan A, Zhou W, Lacey SF, Limaye AP, Diamond DJ, La Rosa C. Programmed death-1 receptor and interleukin-10 in liver transplant recipients at high risk for late cytomegalovirus disease. Transpl Infect Dis. 2010;12:363–370.
5.Mallat S, Moukarzel M, Atallah D, Abou Arkoub R, Mourani C. CYTOMEGALOVIRUS INFECTION POST KIDNEY TRANSPLANT: What Should We Know Now? J Med Liban. 2015 Jul-Sep;63(3):164-9. doi: 10.12816/0015841. PMID: 26591198.
Thank you for your reply
CMV infection is refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs ,not all patients with infection develop overt clinical disease.
It is recommended that both the source of the specimens tested (eg, plasma, serum, whole blood, peripheral blood leukocytes [PBLs], cerebrospinal fluid [CSF], bronchoalveolar lavage [BAL] fluid, urine, or tissue) and the diagnostic method used be described clearly.
CMV syndrome: manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others) with the clinical presentation related to organ involved and the severity of infection , eg respiratory distress or failure ,diarrhea ,ocular pain swelling and redness ,high renal profile, liver failure ,chest pain, shortness of breath and so on .
CMV disease : Is CMV infection associated with clinical syndrome and evidence of end organ damage .
Reference :
Thank you for your reply
Thank you All. Well done all. Probably the confusion comes from the difference between the terms of CMV infection and CMV disease which are completely different. So detection of viral particles whether by PCR/NAT without the presence of symptoms would be infection. CMV disease will include end organ disease and syndrome where patient has the constitutional symptoms and tissue diagnosis of the affected organ. The only one exception for that and does not need a direct tissue diagnosis would be CMV retinitis.
Be careful that you can have CMV tissue invasive disease with CMV PCR negative in the blood. Diagnosis in these cases would be through the tissue biopsy.
Thank you Prof
I have seen 2 patients with CMV gastritis and colitis with negative CMV PCR. These patients were in the late transplant period. Would the patients presenting late post transplant have negative CMV PCR?
Thanks for sharing your experience, Dr Bagha
I have seen CMV colitis with massive GI bleeding and persistent negative CMV PCR in two cases of post-kidney transplantation and one with SLE on longstanding IS, the typical endoscopic finding of focal, patchy ulcerations so need multiple biopsies to confirm the diagnosis of the typical tissue invasive CMV with viral inclusion bodies(owl sign )
Thanks for sharing your experience, Dr SAJA.
CMV infection indicated by a positive antigenemia, culture, biopsy or viral load.
CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia. In addition to detect CMV in the blood.
Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others). Among these, the gastro-intestinal tract is the commonest organ to be involved. This to be proved by detection of CMV by histology in the affected organ.
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
Short and precise reply.
CMV infection
is defined as virus isolation or detection of viral antigens or nucleic acid in any body fluid or tissue specimen.
CMV syndrome
is a disease definition that should only be used in SOT recipients. Because it is impossible to exclude all other causes of the clinical symptomatology described as CMV syndrome.The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
-Fever ≥38°C for at least 2 days.
-New or increased malaise or new or increased fatigue .
-Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, defined as a white blood cell (WBC) count of <3500 cells/µL, if the WBC count prior to the development of clinical symptoms was ≥4000 cells/µL. The corresponding neutrophil counts are <1500 cells/µL or a decrease of >20% if the neutrophil count before the onset of symptoms was <1500 cells/µL.
-Greater than or equal to 5% atypical lymphocytes.
-Thrombocytopenia defined as a platelet count of <100 000 cells/µL if the platelet count prior to the development of clinical symptoms was ≥115 000 cells/µL or a decrease of >20% if the platelet count prior to the development of clinical symptoms was <115 000 cells/µL.
-Elevation of hepatic aminotransferases to 2 times the upper limit of normal .
Tissue invasive CMV
Is manifested by CMV syndrome in addition to detection of CMV by histology and culture in affected organ.
Tissue-invasive CMV disease is associated with specific organ involvement as gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis where , the gastro-intestinal tract is the commonest organ to be involved.
Reference
-Per Ljungman, Michael Boeckh, Hans H. Hirsch, Filip Josephson, Jens Lundgren, Garrett Nichols, Andreas Pikis, Raymund R. Razonable, Veronica Miller, Paul D. Griffiths, for the Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum, Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials, Clinical Infectious Diseases, Volume 64, Issue 1, 1 January 2017, Pages 87–91.
-Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013;45(3):260-271.
Do you think these numbers are distinctive for diagnosis?
As per the reference
CMV infection;
presence of CMV in blood detected by any reliable method like DNA PCR is referred to CMV infection.
CMV syndrome;
CMV infection with attributable symptoms like fever, chills or flu like symptoms is called CMV syndrome and when there is organ damage like GI, LUNG, RETINA, CNS or KIDNEY even without detectable PCR but histopathological evidence is tissue invasive disease
Short and precise reply. I wish you could write references
UpToDate
CMV infection: CMV virus, viral protein, or viral antigen in blood, body fluids, or tissue, with or without symptoms, indicates CMV replication. CMV replication can be identified by viral culture, nucleic acid test (NAT), or antigen testing as CMV DNAemia, RNAemia, or viremia (positive culture).
CMV disease: CMV infection with symptoms. Two types exist:
CMV syndrome: Fever, malaise, atypical lymphocytosis, leukopenia or neutropenia, thrombocytopenia, and increased hepatic transaminases.
Tissue-invasive disease/end-organ CMV disease: CMV invades tissues and damages organs such the gastrointestinal tract, lungs, liver, kidney, heart, pancreas, neurological system, retina, and others. Histopathology (inclusion bodies) can diagnose tissue-invasive illness even with a negative blood CMV PCR.
Short and precise reply. I wish you could write references
Presence of cytomegalovirus (CMV) in a patient warrants fulfilling certain criteria for diagnosing a CMV infection, CMV syndrome, or a tissue-invasive CMV. There are specific definitions for these terms (1).
CMV infection: It is defined as the presence of CMV virus, viral protein, or viral antigen (suggesting CMV replication) in blood, any bodily fluid, or tissue, with or without symptoms. CMV replication can be detected by either a viral culture, a nucleic acid test (NAT), or by antigen testing terming CMV DNAemia or RNAemia (positive NAT), CMV antigenemia (positive antigen testing), and CMV viremia (positive culture) (2,3).
CMV disease: It is defined as CMV infection in presence of clinical signs and symptoms. It is subdivided into 2 forms:
CMV syndrome: Presence of fever, malaise, atypical lymphocytosis, leukopenia or neutropenia, thrombocytopenia, and elevated hepatic transaminases encompasses CMV syndrome.Tissue-invasive disease/ End‐organ CMV disease: It involves invasion of tissues by CMV causing organ specific damage like gastrointestinal tract (gastrointestinal disease), lungs (pneumonitis), liver (hepatitis), kidney (nephritis), heart (myocarditis), pancreas (pancreatitis), nervous system (encephalitis), retina (retinitis) etc. The diagnosis in tissue-invasive disease can be achieved by a histopathological diagnosis (presence of inclusion bodies), and can be seen even in presence of a negative CMV PCR in blood.
References
Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.Ljungman P, Boeckh M, Hirsch HH, Josephson F, Lundgren J, Nichols G, Pikis A, Razonable RR, Miller V, Griffiths PD; Disease Definitions Working Group of the Cytomegalovirus Drug Development Forum. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis. 2017 Jan 1;64(1):87-91. doi: 10.1093/cid/ciw668. Epub 2016 Sep 28. PMID: 27682069.Kotton CN, Kumar D, Caliendo AM, Huprikar S, Chou S, Danziger-Isakov L, Humar A; The Transplantation Society International CMV Consensus Group. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. 2018 Jun;102(6):900-931. doi: 10.1097/TP.0000000000002191. PMID: 29596116.
I wish you could mention BAL for CMV pneumonitis. In such patients, one needs to look for PCP as well.
Ajay
Thank you Professor.
I should have mentioned in my answer that CMV invasion of lung causing pneumonitis can be diagnosed by doing a diagnostic BAL. Pulmonary involvement in transplant recipient can also be due to pneumocystis pneumonia (PCP).
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection
presence of the CMV within the blood, detected by investigations such as CMV PCR, CMV Ag or culture
CMV Syndrome
CMV infection plus symptomatic presentations including fever, malaise, chills and laboratory findings such as leucopenia, thrombocytopenia
tissue-invasive CMV
CMV syndrome plus identification of the CMV in the affected organs (usually multi-organ ) either by histology or by cultures
Short and precise reply. I wish you could write references
CMV can present in kidney transplant recipients as either CMV infection or CMV disease
CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either CMV syndrome (symptomatic viremia without evidence of tissue-invasive disease) or tissue-invasive CMV disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis)
The most common clinical manifestation of tissue-invasive CMV disease in kidney transplant recipients is gastrointestinal disease
Among 26 CMV D+/R- kidney transplant recipients who developed CMV disease after completing three months of CMV prophylaxis, 21 (81 percent) had gastrointestinal disease, including one patient who had concurrent pneumonitis Two patients (8 percent) had CMV nephritis, and there was one case (4 percent) each of retinitis, pancreatitis, and hepatitis.
Patients with tissue-invasive CMV disease may present with any of the following syndromes:
Gastrointestinal disease – Esophagitis, enteritis and/or colitis, dysphagia, nausea, vomiting, diarrhea, and/or abdominal pain. In a study of 26 solid organ transplant recipients (including 13 kidney transplant recipients) with CMV gastrointestinal disease, 7 (27 percent) had upper gastrointestinal disease, 16 (62 percent) had lower gastrointestinal disease, and 3 (12 percent) had both
Hepatitis – Aspartate aminotransferase and alanine aminotransferase elevation with CMV viremia in the absence of any other cause.
Pancreatitis – Abdominal pain with elevated amylase and lipase in the setting of CMV viremia.
Pneumonitis – Cough, shortness of breath, and pulmonary infiltrates on radiographic imaging plus CMV in bronchoalveolar lavage fluid.
Meningoencephalitis – Headache, nuchal rigidity, mental status changes, or paralysis, plus CMV in cerebrospinal fluid.
Retinitis – Retinal edema or hemorrhage as reported by an ophthalmologist. CMV retinitis can present with one or more discrete foci of retinal edema or necrosis, with or without retinal hemorrhage or inflammatory sheathing of retinal vessels on funduscopic examination
Nephritis – Kidney dysfunction in the presence of microbiologic and histologic features of CMV infection in a kidney biopsy specimen.
quantitative polymerase chain reaction (PCR) is the preferred test for detecting CMV in blood . Evidence of CMV infection at the affected site is required for other tissue-invasive disease (eg, CMV enteritis)
REFERENCES
UpToDate
I appreciate that you would get BAL for CMV pneumonitis. In such patients, one needs to look for PCP as well.
Ajay
THANK YOU .
CMV infection
This refers to the detection of the CMV in the blood either by CMV PCR, CMV Ag or culture
CMV Syndrome
This refers to the symptoms caused by the CMV like fever, malaise, chills and laboratory parameters like leucopenia, thrombocytopenia and CMV infection
CMV Disease
This refers to the CMV syndrome plus detection of the CMV in the affected organ either by histology or by cultures
Short and precise reply. I wish you could write references
Thank you Prof
Will include them
CMV infection – Is the presence of CMV replication in blood regardless of whether signs or symptoms are present.
CMV disease – Is the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
CMV disease may present as either CMV syndrome or tissue invasive CMV disease
CMV syndrome: Is the presence of detectable viral replication in blood accompanied by attributable symptoms and signs (fever, malaise, arthralgia, leukopenia, thrombocytopenia) in the absence of evidence of tissue-invasive disease.
Tissue-invasive CMV disease: Is the presence of clinical symptoms and signs of end-organ disease (eg, enteritis, colitis, hepatitis, nephritis, pneumonitis, meningitis, encephalitis, retinitis).
Short and precise reply. I wish you could write references
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV disease :
is the presence of detectable CMV test plus clinical manifestation .which
can be presented as either CMV syndrome or tissue invasive disease .
CMV syndrome:
For a determination of CMV syndrome, CMV in plasma (quantitative PCR CMV DNA
(PCR)) and the presence of at least one of the following symptoms and signs of disease
are necessary: fever ≥38°C, general signs (malaise, myalgia, arthralgias), leukopenia
(≤3.5 × 109/L), atypical lymphocytosis (≥5%), and thrombocytopenia (≤100 × 109/L). In a
case of suspected CMV nephritis in KTRs, kidney graft rejection should always be ruled
out
2.2.2. Tissue-invasive disease:
In a case of tissue-invasive CMV disease, evidence of particular tissue/organ
involvement (hepatitis, colitis, pancreatitis, pneumonitis, nephritis, cystitis, etc.) is based
on clinical symptoms and signs associated with a particular organ, positive quantitative
PCR CMV DNA in plasma, and, in particular, on the presence of CMV in a given organ or
tissue (detected by methods of isolation, histopathology, immunohistochemistry, or
hybridization in situ).
CMV invasive disease can be most frequently :
intestine (40%) followed by the liver (20%), lungs (10%), kidneys (5%), and eyes/brain
(1%) .
For CMV encephalitis, it is sufficient to prove the presence of CMV in the liquor (PCR)
and for CMV pneumonitis in bronchoalveolar flushing (PCR).
References:
1-Ramanan P,Razonable RR. Cytomegalovirus infection in solid organ transplantation: A
review .Infection and Chemotherapy.2013;45(3):260-271.
I am looking for BAL for CMV pneumonitis. In such patients, one needs to look for PCP as well.
Ajay
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?CMV infection :Detected of CMV in blood by culture or antigen test CMV syndrome :Fever ,malize ,leucopenia Tissue-invasive CMV?Associated with specific organ involvement (hepatitis ,nephritis )
References :”
hand book of kidney transplant
Short and precise reply. I wish you could write references.
CMV Infection
• Detection of CMV in blood by culture, antigen test or PCR
CMV Syndrome
• Fever, malaise either leukopenia or thrombocytopenia + detection of CMV in blood
CMV Disease (end-organ, invasive tissue disease)
• CMV syndrome + detection of CMV by histology or culture in affected
Short and precise reply. I wish you could write references.
*The direct effects of CMV are the clinical manifestations occurring as a result of CMV replication, dissemination and tissue invasion of specific organs.
*CMV infection indicated by a positive antigenemia, culture, biopsy or viral load accompanied by clinical symptoms and signs.
*CMV disease can be further categorized into CMV syndrome and tissue-invasive CMV disease (or end-organ disease).
*CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
*Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis and others). Among these, the gastro-intestinal tract is the commonest organ to be involved.
Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
Thankyou
CMV infection
Refers to detection of CMV virus by culture , serological or PCR investigations in blood without clinical manifestations
CMV syndrome
Clinical symptoms of fever ,malaise associated with either leucopenia or thrombocytopenia and evidence of CMV infection in blood
Tissue invasive CMV :
CMV Clinical syndrome associated with evidence of CMV tissue invasion and end organ dysfunction as CMV pneumonitis and nephritis .
Thankyou
Short and precise reply. I wish you could write references.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection:
Detection of virus in the blood by culture, serology (antigen test) or PCR.
CMV syndrome:
Acute infection by the virus resembling mononucleosis by fever , malaise, but less likely tonsillitis and lymphadenopathy.
Hematological presentations:
CMV disease: – end organ damage and invasive tissue disease.
Defined as CMV syndrome with specific histopathology (Owl’s eye) and culture from tissue biopsy of the affected organ.
Refrences:
(1) Prof. Ahmad Halawa presentation CMV in renal transplantation
(2) Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
I agree
Disease versus infection CMV
Disease and infection are not the same thing; not all infected people experience overt clinical disease.
Regardless of symptoms or signs,
CMV infection is defined as the isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue material.
The term “CMV illness” or CMV syndrome; refers to the presence of symptoms or signs that can be linked to a CMV infection.
CMV disease can present as either a viral syndrome (fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, thrombocytopenia, etc.) or as a tissue-invasive disease.
Or in other words CMV disease is a CMV infection + syndrome + organ involvement
· Razonable RR, Humar A, AST Infectious Diseases Community of Practice. Cytomegalovirus in solid organ transplantation. Am J Transplant 2013; 13 Suppl 4:93.
· Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials. Clin Infect Dis 2017; 64:87.
Thank You
1- CMV infection is detection of CMV in the blood by culture, antigen test or PCR.
2-CMV syndrome fever and malaise (clinical symptoms and signs) + leucopenia or thrombocytopenia+ detection of CMV in the blood
3-tissue invasive CMV is CMV syndrome + detection of CMV by histology or culture in the affected organs
reference lecture of prof. Ahmed Halawa
Thank You
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection:
CMV syndrome:
Tissue-invasive CMV:
Source ; prof Halawa lecture
Thankyou.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection: complete replication cycle of the virus with production of new infectious virions (Detection of CMV in blood by culture, antigen test or PCR)
CMV syndrome: fever, leucopenia or thrombocytopenia, myalgia or arthralgia + detection of CMV in blood
Tissue-invasive CMV: histopathological evidence of CMV, CMV retinitis diagnosed by an ophthalmologist, or CMV in the CSF indicative of CNS disease (CMV syndrome + detection of CMV by histology or culture in affected organs)
References
1. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
2. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
Thankyou
CMV infection:
The presence of CMV replication (NAT, antigen testing, viral culture) in tissue, blood, or other bodily fluids regardless of symptomatology.
CMV DNAemia or RNAemia (NAT); CMV NAT replication in the blood
CMV antigenemia; antigen testing.
CMV viremia; culture.
Asymptomatic CMV infection: CMV replication without clinical signs and symptoms of disease
CMV disease:
CMV infection that is accompanied by clinical signs and symptoms. CMV disease is categorized into:
(a) CMV syndrome: Detection of CMV in the blood by viral isolation, rapid culture, antigenemia, or QNAT Plus, at least two of the following:
1. Fever ≥38°C for at least 2 d
2. New or increased malaise or fatigue
3. Leukopenia or neutropenia on 2 separate measurements
4. 5% atypical lymphocytes
5. Thrombocytopenia
6. Hepatic aminotransferases increase to two times ULN (except non‐liver transplant recipients)
(b) End‐organ CMV disease: CMV syndrome + detection of CMV by histology or culture in affected organs
The diagnosis of most end‐organ CMV diseases should be confirmed by histopathology. (eg, gastrointestinal disease, pneumonitis, hepatitis, nephritis, myocarditis, pancreatitis, encephalitis, retinitis, others).
References:
– Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
-Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
-Prof. Halawa Lecture.
Well done.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV Infection
CMV infection is defined as virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen. Both specimen source and methods of identification should be clearly mentioned.
Tissue-invasive CMV:
The proven disease requires clinical symptoms and/or signs of organ involvement( e.g of pneumonia such as new infiltrates on imaging, hypoxia, tachypnea, and/or dyspnea) combined with CMV documented in lung tissue by virus isolation, rapid culture, histopathology, immunohistochemistry, or DNA hybridization techniques.
CMV Syndrome
CMV syndrome is a disease definition that should only be used in SOT recipients. The definition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid culture, antigenemia, or NAT together with at least 2 of the following:
1. Fever ≥38°C for at least 2 days.
2. New or increased malaise (toxicity grade 2) or new or increased
fatigue (toxicity grade 3).
3. Leukopenia or neutropenia on 2 separate measurements at
least 24 hours apart, defined as a white blood cell (WBC) count
of <3500 cells/μL, if the WBC count prior to the development of
clinical symptoms was ≥4000 cells/μ.
4. Greater than or equal to 5% atypical lymphocytes.
5. Thrombocytopenia defined as a platelet count of <100 000
cells/μL if the platelet count prior to the development of clinical
symptoms was ≥115 000 cells/μL or a decrease of >20% if the
platelet count prior to the development of clinical symptoms
was <115 000 cells/μL.
6. Elevation of hepatic aminotransferases (alanine aminotransferase or aspartate aminotransferase) to 2 times the upper limit.
References;
1-Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials CID 2017:64 (1 January).
BAL could be very helpful in pneumonitis.
Yes, agree.. Thanks prof Dawlat
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection
Syndrome CMV
Tissue-invasive CMV
===================================================================
Reference
Thankyou.
Many thanks Prof.Dawlat
CMV infection
Is defined as isolation of the CMV virus or detection of viral proteins or nucleic acid in any body fluid or tissue specimen.
CMV detection
4 definitions are included according to the method used and sample to be examined
Viremia. “Viremia” is defined as the isolation of CMV by culture that involves the use of either standard or shell vial techniques.
Antigenemia. “Antigenemia” is defined as the detection of CMV pp65 in leukocytes.
DNAemia. “DNAemia” is defined as the detection of DNA in samples of plasma, whole blood, and isolated peripheral blood leukocytes or in buffy-coat specimens.
RNAemia. “RNAemia” is defined as the detection of RNA (e.g., by nucleic acid sequence—based amplification or noncommercial reverse transcriptase–PCR) in samples of plasma, whole blood, or isolated peripheral blood leukocytes or in buffy-coat specimens.
Accordingly, CMV infection could be classified as follow
Primary CMV Infection
is defined as the detection of CMV infection in an individual previously found to be CMV seronegative
Recurrent Infection
“Recurrent infection” is defined as new detection of CMV infection in a patient who has had previously documented infection and who has not had virus detected for an interval of at least 4 weeks during active surveillance
Reinfection.
“Reinfection” is defined as detection of a CMV strain that is distinct from the strain that was the cause of the patient’s original infection
Reactivation.
Reactivation is assumed if the 2 strains are found to be indistinguishable either by sequencing specific regions of the viral genome or by using a variety of molecular techniques that examine genes known to be polymorphic.
CMV syndrome
In order to define CMV syndrome in SOT the following criteria should be minimally present
1- the documented presence of fever (temperature, >38°C) for at least 2 days within a 4-day period,
2- the presence of neutropenia or thrombocytopenia,
3- and the detection of CMV in blood.
CMV tissue invasive disease
Affection of the body organs by active CMV infection as follow :
detected by histpathology exam finding awel eyes signs
Gastrointestinal disease
• Ulceration affecting any part of the GI tract:
• Oesophagus → dysphagia, odynophagia
• Gastritis → nausea, vomiting, dyspepsia
• Duodenitis, enteritis, colitis → abdominal pain (often severe), diarrhoea,
perforation (especially in colonic disease)
• GI bleeding, sometimes torrential, is common
Pneumonitis
• Presents with cough, fever and breathlessness
• Hypoxia, exacerbated by exercise
• CXR appearances are variable, including lobar infiltrates, localized or diffuse
nodular infiltrates or diffuse, bilateral interstitial infiltrates
• Common in lung and bone marrow transplants, less so in renal transplantation
Chorioretinitis
• Very unusual in solid organ transplant recipients
• May occur following prolonged viraemia (more than 6 months)
• Vasculitis of retinal vessels with typical fundoscopic appearance (‘scrambled
eggs with tomato sauce’)
Graft dysfunction
• CMV infection of graft EC and RTEC → ↓GFR
• CMV pancreatitis and hepatitis occurs in pancreas and liver transplant
recipients, but are uncommon in solitary organ renal transplantation
Ref
1- Per Ljungman, Paul Griffiths, Carlos Paya, Definitions of Cytomegalovirus Infection and Disease in Transplant Recipients, Clinical Infectious Diseases, Volume 34, Issue 8, 15 April 2002, Pages 1094–1097,
2- OSH Renal Transplantation, OCT, 2011 page: 324-335
So in the different situations it is the PCR that is routinely used to assess the viremia.
CMV infection and disease are not synonymous terms; not all patients with infection develop overt clinical disease.
· CMV infection refers to virus isolation or detection of viral proteins (antigens) or nucleic acid in any body fluid or tissue specimen regardless of symptoms or signs.
· CMV disease refers to evidence of CMV infection with attributable symptoms or signs; CMV disease may manifest as either a viral syndrome (eg, fever, malaise, leukopenia, neutropenia, atypical lymphocytosis, thrombocytopenia) or as tissue-invasive disease.
CMV disease consists of “end-organ disease” and CMV syndrome.
· CMV syndrome manifests generally as flu-like illness, fever and malaise frequently associated with leucopenia or thrombocytopenia.
· Tissue-invasive CMV disease is associated with specific organ involvement (gastro-intestinal, pneumonitis, hepatitis, nephritis, myocarditis and retinitis, among others).
A negative plasma or whole-blood PCR does not exclude tissue-invasive CMV disease, especially in patients with CMV gastrointestinal disease, pneumonia, or retinitis. The absence of CMV inclusions on histopathology also does not exclude tissue-invasive disease since such inclusions can be missed as a result of sampling error.
Reference:
· Angela M Caliendo. Approach to the diagnosis of cytomegalovirus infection. UpToDate.
· Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother. 2013 Sep;45(3):260-71. doi: 10.3947/ic.2013.45.3.260. Epub 2013 Sep 27. PMID: 24396627; PMCID: PMC3848521.
Thankyou for mentioning the possibility of a negative PCR with tissue invasion which might be more difficult with a neg. histology due to the focal nature.
References
1- up-to-date
CMV infection is the detection of its DNA in culture, antigen or techniques using PCR without necessarily having clinical manifestations of the disease.
The syndrome is when we have established systemic disease, presenting fever, malaise, jaundice, or cytopenias in the presence of infection.
Invasive or visceral disease is when there is the presence of the syndrome with confirmation of CMV in biopsy, culture, or immunohistochemistry in a specific organ.
Well done
CMV infection
Detection of CMV in blood via culture/PCR/antigen test in an asymptomatic patient.
CMV syndrome
Presence of CMV in blood plus presentation of constitutional symptoms like malaise, fever, leukopenia and thrombocytopenia.
Tissue invasive CMV disease
Presence of CMV syndrome with CMV infected organ evidenced by histology/culture.
Reference
Prof Halawa lecture.
Well done.
-CMV Infection;
Detection of CMV in blood by Culture , Antigen test( PP65) or PCR.
-CMV Syndrome;
Fever,Malaise either leukopenia or thrombocytopenia + Detection of CMV in blood.
-CMV Disease (Tissue Invasive Disease, End-organ);
CMV syndrome + Detection of CMV by histology or culture in affected organs (Nephritis,Hepatitis,Pneumonitis,Colitis,Gastritis,Pancreatitis,Myocarditis,Cystitis,Retinitis,Encephalitis.
-References;
(Prof.Dr.Halawa Lecture:
(kotton et al.Transplantation 2018;102:900-931)
(Razonable and Humar.Clinical Transplantation.2019;33:e13512)
Well done
CMV Infection
This is the presence and detection of viral protein or nucleic acid in the body fluid tissue irrespective of clinical signs and symptoms. This could be divided into:
CMV Syndrome
This CMV infection is detected in the blood with clinical features like fever, malaise, leucopenia, or thrombocytopenia
Tissue invasive CMV
This is the occurrence of CMV syndrome in addition to plus the detection of CMV infection by tissue histology or culture. The clinical manifestation of this is CMV retinitis, CMV pneumonitis, CMV colitis, or the involvement of the allograft.
CMV in Kidney Transplantation Lecture, by Ahmed Halawa
Gabriel M. Danovitch. Handbook of Kidney transplantation. Sixth Edition.
Well done.
What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection – Defined as the presence of CMV replication in blood regardless of whether signs or symptoms are present.
CMV Syndrome: Fever, malaise either leukopenia or thrombocytopenia + detection of CMV in blood.
CMV disease – Defined as the presence of detectable CMV in a clinical specimen accompanied by other clinical manifestations.
References:-
1- Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant patients, Up To Date 2023.
2- CMV in Kidney Transplantation Lecture By: professor Ahmed Halawa.
tissue invasive!!!!
Lecture Prof. Halawa
Well done
CMV infection
Presence of virus i.e.,CMV ,viral proteins or replication of virus detected by PCR in blood or any fluid or tissue specimen without the presence of symptoms or signs in the patient .
CMV syndrome and CMV tissue invasive disease comes under the category of CMV infection tion.CMV syndrome is a condition in which there is detectable PCR CMV and the patient has constitutional symptoms like flu-like illness,fever and malaise .Sometimes patient may have cutopenias like leucopenia and thrombocytopenia.
CMV tissue invasive disease -condition in which there is detectable CMV PCR in blood or tissue specimen with organ involvement like encephalitis,retinitis,pneumonitis,colitis etc.
REFERENCE:
Prof Halawa presentation
Histological tissue diagnosis is diagnostic in tissue invasion.
CMV Infection:
Presence of CMV in blood by culture and antigen test and PCR
CMV Syndrome:
Fever/ Malaise with leukopenia or thrombocytopenia and presence of CMV in blood.
Tissue invasive CMV?
CMV syndrome plus detected of virus by histology or cultures in affected organ
It’s CMV infection with end organ damage like Pneumonia and retinitis and colitis
Reference.
Lecture of Pro dr Ahmed Halwa
CMV infection:
Denotes detection of CMV in a patient who used to be negative before.
Its either detection of CMV virus by culture of plasma, or identification of CMV protein PP65, or showing CMV antigen presence in the form of DNA or RNA detected by PCR.
CMV syndrome:
Reflects the triad of fever of more than 38 C for 2 days out of 4 in the context of neutropenia or thrombocytopenia and detection of CMV from blood.
Tissue-invasive CMV:
Synonym to end organ disease secondary to invasion by CMV, with resultant characteristic clinical features such as hepatitis, retinitis, gastroenteritis etc.
reference:
1]Per Ljungman et al.Definitions of Cytomegalovirus Infection and Disease in Transplant Patients for Use in Clinical Trials.Clin Infect Dis. 2017 Jan 1;64(1):87-91.
Thankyou
CMV infection is defined as a state there is evidence of the virus undergoing a complete replication cycle and producing new infectious virions.
Active replication can be further characterised into
references
Thankyou
CMV infection
CMV syndrome
CMV tissue invasive disease
References
1) Poornima Ramanan et al. Cytomegalovirus Infections in Solid Organ
Transplantation: A Review. Infect Chemother 2013;45(3):260-271.
Well done.
In tissue invasion the sure sign will be detection of the inclusion bodies by histology .
2. What is the difference between CMV infection, CMV syndrome and tissue-invasive CMV?
CMV infection is diagnosed whenever there is active CMV replication in the blood, regardless of whether signs or symptoms are present.
CMV disease is defined by the presence of detectable CMV in a clinical specimen + clinical symptoms and signs. According to the presentation, CMV disease may be further subdivided into CMV syndrome and CMV tissue-invasive disease.
CMV syndrome describes a detectable viral replication in the blood accompanied by non-specific constitutional symptoms (e.g., fever, malaise, arthralgias, leukopenia, thrombocytopenia) and with the absence of tissue-invasive disease.
CMV tissue-invasive disease (as it can be figured from the name) describes a detectable viral replication in the blood accompanied by symptoms and signs of end-organ disease (e.g., nephritis, colitis, enteritis, hepatitis, pneumonitis, meningitis, encephalitis, and retinitis). The viral antigens may be isolated in tissue biopsy specimens by histopathology.
References:
Santos CAQ, Vella J, Brennan DC. Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant recipients. ©2023 UpToDate® (accessed on 4 February 2023).
Well done.
CMV infection can be-
the presence of viral replication, diagnosed by –
growing the virus in vitro
by the discovery of intracytoplasmic and intranuclear inclusions, which are characteristics of the virus
by viral identification via tissue staining of biopsy material
by the discovery of evidence of viral replication detected by antigenemia assay or molecular methods.
The most common clinical picture in the transplanted host is a viral syndrome, characterized by fever and malaise as well as leukopenia, thrombocytopenia and elevated liver enzymes.
Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. 2002;34((8)):1094–7. doi: 10.1086/cid.2002.34.issue-8