1. A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
What is the differential diagnosis?
The patient presented with high grade fever, lethargic, unwell and on immunosuppressive therapy.
The main differential diagnoses are:
Viral infection
(COVID 19, RSV, Influenza/Parainfuenza virus, CMV, BK, EBV, Adenovirus, HSV and dengue fever)
Bacterial infection
Pneumonia, TB
Parasitic infection
Malaria
Fungal infection
PTLD
UTI
Rejection
How would you manage this case?
Admit the patient and the criteria for the ICU admission are:
low partial pressure of arterial oxygen, the inspiratory oxygen fraction (PaO2 / FiO2) ratio less than 300, oxygen saturation less than 90%, and PaO2 below 70 mm Hg despite 5 L/minute oxygen therapy, and persistent hypotension (systolic blood pressure < 90 mm Hg or mean arterial pressure < 65 mm Hg).
MDT should be involved
Full history
Clinical examination
Investigation: CBC, CRP, LFT, RFT and electrolytes, Virology PCR, (RT-PCR) testing performed on nasopharyngeal swab, blood culture, urine analysis and culture, CXR and CT, screen for DM, ECG, CNI trough level, interleukin-6, markers of myocardial damage (creatine kinase, troponin I, lactate dehydrogenase), tests of secondary hemostasis profile (prothrombin time, activated partial thromboplastin time), procalcitonin, fibrinogen, d-dimer and e-GFR
Supportive management: Control the BP and good hydration and antipyretic
Oxygen treatment was provided to patients whose oxygen saturation was below 92%
Antimetabolites were discontinued.
Trough levels were adjusted as 4–6 ng/dL for tacrolimus for stable and were stopped in hypoxemic patients. The calcineurin inhibitor levels were also monitored twice a week in hospitalized patients, once a week in outpatients.
Antibiotic therapy was administered based on the infection specialist’s decision in the presence of confirmed or suspected invasive bacterial infection
Prophylactic-dose low-molecular-weight heparin was used for inpatients unless there were contraindications.
Demir E, Ucar ZA, Dheir H, Danis R, Yelken B, Uyar M, Parmaksiz E, Artan AS, Sinangil A, Merhametsiz O, Yadigar S, Dirim AB, Akin B, Garayeva N, Safak S, Turkmen A. COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic. BMC Nephrol. 2022 May 12;23(1):183. doi: 10.1186/s12882-022-02784-w. PMID: 35550025; PMCID: PMC9097147.
High grade fever and lethargy 4 months post kidney transplant could be any type of infection viral,bacterial or fungal; in spite the time is short but malignancy could be one of the diagnosis
we need to investigate more by doing ESR,HRCT chest ,Abdominal ultrasound,CMV PCR ,TB screening
How would you manage this case?
A. Detailed history
B. Physical examination
C. Investigations:
– CBC, CRP
– RFT, LFT
– Nasopharyngeal swab for covid-19 RT- PCR
– CMV PCR
– HRCT of chest
– Renal allograft biopsy
– May need BAL assessment
D. Treatment
– Modification of immunosuppression( Stop MMF, Reduction of CNI dose, increase dose of steroid)
– Supportive treatment (oxygen, I/V fluid)
– Specific treatment according to diagnosis.
What are differentials?
Usually we divide the post-transplant infection according to duration, and the most common and less common infection, like,
a. The initial first six month we face bacterial infection,
b. Viral infections,
c. Fungal infections,
d. Tuberculosis
e. otheres
How would you manage the case?
The detailed history,
Detailed examination,
Baseline investigation.
X-ray chest,
galactomanone if needed,
Viral serology.
HRCT,
And last but not the least allograft biopsy. Management;
General management,
Treat the cause according to evidence.
What are differentials? We divide the transplant related infection according to the most common and less common with duration of transplantation. 1. In first six months the most common infections are and differentials will be, A. Bacterial infections, B. Viral infections, like CMV, BKVAP, COVID-19, dengue. C. Fungal infection, D. Malaria, E. Tuberculosis. How would you manage this case? A detailed history, Detailed examination, Baseline investigation, Radiological examination, Viral serology, CRP, procalcitonine, May need BAL, Sputum for GS, C/S, and AFB, geneXpert. With treat according to the concluded diagnosis,
What is the differential diagnosis? Common Causes of fever in early post-transplant Most common cause 1- Viral infections: account for 50-70% of febrile episodes a. CMV is the most common viral infection b. COVID-19 is also suspected – due to highly contagious PANDEMIC, although respiratory symptoms, hypoxia are common c. EBV related PTLD d. RSV, influenza, parainfluenza virus – depending on community infection e. Dengue fever – severe myalgia 2- Malaria – blood transfusion and endemicity 3- M-TB 4- Fungal infections – PCP 5- Bacterial infections – Enteric Fever How would you manage this case? 1. Detailed clinical history – pattern of fever, associated Chill & Rigor – CMV and EBV sero-status (donor and recipient) – CMV- and PCP-prophylaxis – history of contact with covid patient. 2. Clinical examination – respiratory rate, SPO2, lymphadenopathy, graft site tenderness
3-Lab investigations – Viral screening: COVID-19 rtPCR, PCR for CMV-DNA, EBV-DNA – CBC with PBF, ESR, MP, Widal-test – RFT, LFT, CRP, Procalcitonin – Sputum (induced) culture & sensitivity – TB-skin test, IGRA – HRCT Chest and CECT Abdomen & Pelvis – Graft biopsy / Lymph-node biopsy Treatment – Antipyretics (PCM) SOS – Temperature monitoring – supportive treatment including good hydration and antipyretics – Reduce MMF; minimize Tacrolimus dose, steroid – same dose / increase
Specific treatment according to underling cause – Covid – isolation, observation, SPO2-monitoring, multivitamin. – CMV – Valgancyclovir 900mg PO bid x 3weeks – PCP – Bactrim-DS 2tab bid x 3weeks (dose adjusted to GFR) – Malaria – Chloroquine / Quinine / Artesunate, depending on subtype – Enteric fever – IV Ciprofloxacin / Inj Ceftriaxone – Dengue – monitoring Platelet (transfusion SOS) – EBV – reduction of IS, monitoring DNA, RFT – PTLD – Biopsy of Graft / lymph-node reduction of IS, can try Retuximab, Ref: 1-Peterson PK, Balfour HH Jr, Fryd DS, et al. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med. 1981 Sep;71(3):345-51
fever early post transplant with nrgative blood and urine culture and no localizing symptoms or signs during COVID 19 period. Differential inculdes: COVID 19 infection Other viral infection (CMV, EBV, PCP, Influenza etc) Atypical bacterial infection and mycobactria Also: still bacterial UTI( not appearing in first culture) could be.
· How would you manage this case? · Detailed history of symptoms, duration, recent infection, travel history, contact with sick person, antibiotics, prophylaxis history). · Admission, repeat septic work up,COVID 19 swab, · Vitals signs monitoring specially, BP and SPO2, and reduction of antihypertensive if BP on the lower side. · Broad spectrum antibiotics. · Reduction of MMF by 50%and discontinuation if signs of sever sepsis or desaturation with change of prednisone to stress dose. · Tailing antibiotics according to culture result and involvement of ID if needed.
The first six months period is associated with maximum immune suppression with increasing risk of opportunistic infection; hence our approach has to include searching for different infectious agents.
I would recommend liver function test looking for significantly elevated liver enzymes consistent with hepatitis or cholestatic pattern reflective of infiltrative lesions. CAT scan with contrast looking for thoracic or abdominal lymphadenopathy, pulmonary infiltrate or other intra abdomenal lesions, finding of which would be an indication to proceed with PET scan to differentiate lymphoma or other malignant lesions {which is reported to increase in incidence in the same period post transplantation}. Opportunistic infections screening:
1]PCP, although no respiratory symptoms were reported, extra pulmonary infection might be happening in patients who are on nebulized pentamidine. PCR of sputum and blood is indicative in this patient.
2] Herpesviruses such as VZV, HSV, CMV particularly in the presence of skin rash or presence of abnormal liver function test. PCR test
3] EBV particularly in the context of lymphadenopathy. PCR test.
4] Fungal infection, Toxoplasma, Nocardia, strongyloidiasis, Listeria, leishmania and trypanosomiasis
5] hepatitis viruses: HBV, HCV and HEV.
6] BKV especially in the context of hydronephrosis or allograft function impairment.
7] most importantly TB has to be ruled out by tuberculin skin test and QuantiFERON gold test.
In case all evidences are falling short of probable diagnosis, then next step would be
1] liver biopsy.
2] Bone marrow aspirates and biopsy.
3] CSF examination.
reference:
1} N. Sarabu et al. Fever of Unknown Origin in a Kidney Transplant Recipient.American Journal of Transplantation Images in Transplantation – Continuing Medical Education (CME).Volume15, Issue7,July 2015, Pages 2006-2008.
Q2: lab tests including COVID PCR, CMV, and other viruses PCR if needed. Virus and blood cultures are negative. Hence, viral infections especially covid-19 should be considered. CBC.diff, ferritin, LDH, CRP, and D-dimer to follow up with the patient. Supportive measures such as IV fluids hydration and antipyrotic are good. O2 saturation should be regularly performed and if O2 sat <= 93% oxygen support and hospitalization are needed. For these cases, dexamethasone 6 mg/day and remdesivir or paxlovid could be used. Reduction of immunosuppression with holding MMF and reduction of CNIs with measurement of their level is part of the treatment. Other infections will need specific treatment if their PCR is positive.
Transplanted patient presented with fever with no other localizing symptoms diagnosis require full history ,examination including LN and investigations to reach diagnosis putting into considerations the most common infection prevalent in this specific population and reactivation of old latent infections with immunosuppression as SOT recipients are highly susceptible to conventional and opportunistic infections, which represent a major cause of morbidity, graft dysfunction and mortality. . the differential diagnosis COVID-19. PCP CMV EBV UTI . Hidden abscess. Respiratory Syncytial virus and Influenza virus infection. Bacterial infection although absence of symptoms is not typical. Fungal infection. Hepatitis A,B and c infection. Drug induce as sirolimus pneumonitis.
Management Symptomatic treatment: -Antipyretic. – IV fluid to keep good hydration. -CBC, CRB, LDH, FERRITIN, procalcitonin. – Kidney function test.
-Liver function test-AST, ALT, hepatitis, B and C , -Pan cultures (blood, urine, sputum if available). -throat swab. -PCR for Covid-19 , CMV, EBV . -tacrolimus level. -Stop of MMF. -Stress dose steroids with shift to dexamesazone. -Antiviral therapy remdisivir or cidofovir. -empirical bread spectrum antibiotics. -Specific treatment if other viral diagnosis. -IVIG could be used. Reference Timsit, JF., Sonneville, R., Kalil, A.C. et al. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med45, 573–591 (2019).
What is the differential diagnosis?
Infectious causes :
Viral infections.
Bacterial infections.
Parasite.
Lymphoproliferative disorder.
Drug induced.
How would you manage this case?Investigations after detailed history to konw the right place of infection
Blood cultures.
Viral screening
Ct scan of body to look for any abscess.
Reduce immuosuppresion.
After the first month of Transplant, we can worry less about care-related Bacterial Infections and start to worry about opportunistic infections. Among the infections we can mainly investigate:
Once the patient has no signs or symptoms to target a more specific site, a screnning with imaging exam would be necessary:
– CT of the chest, abdomen, spine
Associated with serological tests or molecular markers and biomarkers in the blood:
– Galactomannan and B-Glucan
– Serologies for hepatitis, EBV, HIV, Epstein-Barr
– CMV PCR, COVID19
– Blood culture and urine culture
– IGRA
– rK39
With the result of these exams, there would be a direction for the follow-up, as biopsy or lumbar or abdominal or joint punctures may be necessary
At the same time, I would evaluate the possibility of changing immunosuppressants (MMF)
Patient is renal transplant recipient with fever after 3 months of transplant ….Patient is on triple immunosuppression…
Patient needs to get evaluated for fever in a transplant patient after 3 months….
The most common reasons for fever in this time frame are CMV infection, PCP infection, PTLD, Bacterial infections like UTI, abscess…I would also like to get COVID RT PCR and RSV infection….
If all other septic causes are negative, patient could have rejection which needs to be kept in mind…
I would get a basic workup for the fever…CBC, RFT, LFT, Procalcitonin, CRP, blood cultures and urine cultures…..CT chest and CT abdomen needs to be done to rule out infections….I could show features of COVID, CMV, PCP and any lymphadenopathy…
If there is any lymph node i would proceed with biopsy….CMV DNA PCR and bronchoscopy for PCP lavage staining is needed if there is a suspiscion of pneumonia or other CMV specific organ involvement…
I would start the patient on IV cefaperazone sulbactum (1.5gm IV BD) ad IV teicoplannin 400mg IV…Later i would taper or stop them based on the culture results…\\
Whole body PET CT scan is indicated if there is no obvious cause of fever to rule out other malignancies and may give a clue to diagnose PTLD…
I would reduce or stop the antimetabolite till we find the cause of the fever and continue low dose MMF and steroids…
Causes of fever in early post transplant
1- Viral infections: are the most common causes of early fever post transplant respponsable for more than 50% of febrile episodes ,including
a- CMV ( is the most common viral infection) ,EBV, RSV, influenza and parainfluenza virus
b- COVID 19 is also highly suspected.
2- Bacterial infections specially PCP.
3- Fungal infections
4- Non infectious causes as graft rejection.
How would you manage this case?
1-Detailed history specially CMV , EBV status of both donor and recipient and previous CMV prophylaxis , history of contact with covid patient.
2-Clinical examination.
3-Lab investigations
-CBC,ESR, CRP ,procalcitonon
– S Cr, BUN ,LFT
-Serum electrolytes.
-Sputum culture &sensitivity .
-Viral screen : COVID 19 PCR ,CMV PCR , EBV PCR.
4-Radiological investigation :
-Abdomen ultrasonography
-CXR
-Chest ,abdomen and pelvis CT Treatment
-supportive measurements including good hydration and antipyretics
– Decrease dose of MMF and increase steroid .
– Specific treatment according to underling cause
Ref :
1-Peterson PK, Balfour HH Jr, Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med. 1981 Sep;71(3):345-51
1) Monitor vital sign, may need to withhold anti-hypertensive therapy
2) Bring down the fever with paracetamol (anti-pyretic)
3) COVID-PCR
4) To reduce/withhold anti-metabolite
5) WCC (? lymphopenia or predominantly neutrophils), CRP, procalcitonin
6) SPO2 monitoring
7) Throat and nasal swab for viral panel
8) Treatment according to the organism
The current presentation favors the differential diagnosis of either viral infections or PTLD.
Differential diagnosis:
CMV
EBV
COVID-19
Influenza
Parainfluenza
RSV
Adenovirus
Rhinovirus
Bacterial infection is less likely in this clinical context and negative cultures.
Management of the case starts with diagnostic studies:
PCR COVID19
PCR BLOOD FOR EBV
PCR CMV
Nasal and throat swab for viral panel
Inflammatory markers
Abdominal imaging
Renal and liver function test
Treatment depends on the etiology based on the results of diagnostic tests
Fever in early transplant may be infectious or non infectious
infectious causes:
Viral as CMV, EBV, influenza, COVID
Bacterial PCP
Fungal
non infectious as rejection
How would you manage this case?
full history especially donor details as virology status
clinical examination
labs
routine labs plus CMV PCR, EBV PCR, COVID
radiology as abdominal USG
Treatment
supportive measures with good hydration
decrease dose of MMF
specific treatment according the cause
Causes of fever in early post transplant 1- Viral infections: are the most common causes of early fever post transplant respponsable for more than 50% of febrile episodes ,including a- CMV ( is the most common viral infection) ,EBV, RSV, influenza and parainfluenza virus b- COVID 19 is also highly suspected. 2- Bacterial infections specially PCP. 3- Fungal infections 4- Non infectious causes as graft rejection.
How would you manage this case?
1-Detailed history specially CMV , EBV status of both donor and recipient and previous CMV prophylaxis , history of contact with covid patient. 2-Clinical examination. 3-Lab investigations -CBC,ESR, CRP ,procalcitonon – S Cr, BUN ,LFT -Serum electrolytes. -Sputum culture &sensitivity . -Viral screen : COVID 19 PCR ,CMV PCR , EBV PCR. 4-Radiological investigation : -Abdomen ultrasonography -CXR -Chest ,abdomen and pelvis CT Treatment -supportive measurements including good hydration and antipyretics – Decrease dose of MMF and increase steroid . – Specific treatment according to underling cause
Ref :
1-Peterson PK, Balfour HH Jr, Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med. 1981 Sep;71(3):345-51.
· What is the differential diagnosis?Viral infections such as CMV , Infleunza. Rhino virus, Covid 19, EBV
Bacterial infections such as TB.
· How would you manage this case?Further detailed history and examinations
Supportive measures , Hydration, antipyretics.
Following test to be collected :CBC, renal function, liver function test. Respiratory cultures and sputum culture, stool cultures, CMV PCR, EBV PCR. AFB culture. CXR.
If any virus reported positive the case is treated accordingly.
Reduce or stop antimetabolites if the infection progress.
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
What is the differential diagnosis?
Early fever post transplant
Viral infections are the most common causes of early fever post transplant such as CMV ,EBV ,influenza , respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, adenovirus, polyomaviruses BK virus,herpes, hepatitis,COVID
as the period mentioned above Dec.2019 COVID 19 is highly suspected.
Bacterial infections, fungal infections and rejection were other important causes of fever.
How would you manage this case?
History and clinical examination
Labs including CBC,BUN,creatinine,serum electrolytes,LDH,AST,ALT,albumin,total protein,PT,PTT,INR,CRP,RBS,ferritin
urine analysis and culture
Blood culture
Sputum culture ,AFB
COVID 19 PCR
Hepatitis ,CMV PCR and IgM
Abdomen ultrasonography
Cxr
Chest ,abdomen and pelvis CT
Treatment of COVID 19
As our mentioned above patient consider stable so supportive measurements at the top of treatment including increase fluid intake ,antipyretics ,reduction of immunosuppressive and in some cases stopping MMF.
Since remdisivir was approved for the treatment of COVID-19 and its in- teraction with CNI is yet unknown, we recommend treat- ment with remdisivir in a hospital setting where CNI drug level monitoring is available.
if severe respiratory symptoms dexamethasone should be considered
Differential diagnosis:
This patient presented with fever, lethargy no other specific clinical symptoms CXR normal, blood and urine culture negative.
Differentials are: · Viral- Covid 19, CMV, influenza, adenovirus, parainfluenza · Bacterial (Atypical)- Tuberculosis · Parasitic- Malaria, Kala azar · Fungal infection · Malignancy: Non-Hodgkin lymphoma, Hodgkin lymphoma, Solid organ Tumour Management: · Detailed history and clinical examination. · Multi-disciplinary approach along with infectious disease specialist. · Workups will includes: CBC, PCR for Covid 19, CMV, influenza, parainfluenza and adenovirus, CRP, procalcitonin levels, D dimer levels, UECS, blood slide for malaria, LDH, ESR. · Supportive treatment: Anti-pyretics for fever, adequate hydration, oxygen if SPO2<92%. · Reduction/ modification of IS: Stop MMF, Reduce CNI by 50% in severe disease., Oral steroids switched to IV dexamethasone in those requiring oxygen supplementation or mechanical ventilation. Specific treatment according to confirm diagnosis.
Fever after SOT in intermediate period 1-6 mo
infective etiology is likely and list is exhaustive viral, bacterial , parasitic and fungal
past medical History , epidemiology , vaccination , personal history, exposure are all vital to pin point the infection
multidisciplinary approach
serology is less likely to be positive so direct evidence in culture of bacteria , identification of virus , imaging suggestive of any lesion is looked for
microscopy and histology is gold standard for diagnosis
particular transplant unit may have some protocol to investigate such scenario based on prior experiences
reactivation of prior viral infection is also likely so history is very important
A careful history need to be taken including the recipient ‘s vaccination history and viral infection history , or any past medical history of importance and travelling history as well as the deceased donor’s available history and virological and medical data available .
Physical examination including lymph node assessment.
Initial Septic workout for fever FBC, CRP, PCT, Urinalysis ,
Other investigations:
CMV PCR ,COVID 19 nasal swab,
Antigen detection tests for adenovirus, influenza A, respiratory syncytial virus, and rotavirus;
Chest X ray to look for lung infections.
Blood culture and urine culture
If still unable to locate infection or cause- CT TAP is indicated
To start IV hydration and antipyretic
For antibiotic if CRP/PCT high
Stop MMF and monitor trough level of CNI
Vigilant monitoring of renal profile
References
Buxeda A, Arias-Cabrales C, Pérez-Sáez MJ, et al. Use and Safety of Remdesivir in Kidney Transplant Recipients With COVID-19. Kidney Int Rep. 2021;6(9):2305-2315. doi:10.1016/j.ekir.2021.06.023
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi:10.1159/000512329
Worby CJ, Chaves SS, Wallinga J, Lipsitch M, Finelli L, Goldstein E. On the relative role of different age groups in influenza epidemics. Epidemics. 2015;13:10–6.
Renal graft from a decreased donor and presented with fever 3 months post-transplant without respiratory symptoms.
Blood, urine cultures and chest Xray are Negative for finding.
Currently on maintenance therapy Tac,MMF , prednisolone
Differential diagnosis
Viral infection
Cytomegalovirus (CMV) ,
Herpes simplex (HSV),
Varicella zoster virus (VZV),
Epstein Barr virus (EBV),
Polyomaviruses (BK, JC, SV-40) ,
Human herpes virus 6,7,8 (HHV),
Human T-lymphotropic virus 1 and 2 (HTLV),
Hepatitis B and C viruses (HBV, HCV),
Human immunodeficiency virus (HIV),
Human papillomavirus (HPV),
Adenovirus,
Respiratory syncytial virus (RSV),
Influenza and parainfluenza viruses,
Human metapneumovirus,
Rhinovirus,Coronavirus (COVID19)
Bacterial infection such as
TB ,mycobacterium avium
Community aquired infections
Fungal infection Acute Rejection
Different Malignancies such as
non-Hodgkin lymphoma,
Hodgkin lymphoma,
Kaposi sarcoma,
cancers of the liver, stomach, oropharynx, anus, vulva, and penis.
-Management
A careful history is needed including the recipient ‘s vaccination history and viral infection history or travelling history and medical data available.
Physical examination including lymph node, Hepatosplenomegaly and any Rash or lesion on Skin. Initial investigations include.
Urinalysis, CMV PCR, QuantiFERON testing using interferon gamma assays, COVID 19 nasal swab, Antigen detection tests for adenovirus, influenza A, respiratory syncytial virus, and rotavirus. Treatment options CMV
multiple approaches included reduction in immunosuppressives, then addition of antiviral agents (oral valganciclovir or ganciclovir) , and in some cases adjuvant therapy. HSV,VZV (Diagnosed by direct fluorescence antibody for HSV and VZV from vesicular lesions or PCR from CSF or visceral tissue samples). Treated with oral acyclovir, valacyclovir, or famciclovir and for disseminated infections IV acyclovir, EBV EBV infection causes a mononucleosis-type syndrome and can lead to PTLD which can be treated by significant reduction in IS along with R CHOP and adoptive immunotherapy with stimulated T cells . Polyomaviruses Urine cytology for monitoring polyomavirus infection after transplantation. Reduction of immunosuppression is the main therapy with monitoring for rejection is challenging HHV-6 , HHV-7 and HHV-8 (Diagnosed by qualitative and quantitative molecular assays, by tissue immunohistochemistry or peripheral blood mononuclear cell culture). Treatment includes reducing immunosuppression and antiviral agents. HHV 8 can be associated with Kaposi sarcoma treated by reducing the immunosuppressive regimen and chemotherapy or foscarnet HTLV-1 It can progress to HTLVI-associated myelopathy or to adult T cell leukemia/lymphoma. Optimal treatment yet to be defined. HBV Diagnosed by HB s Ag , HB c Ab , HB s Ab ,HBV PCR
Treatment involves reduction of immunosuppression and antiviral as entecavir or tenofovir. HCV Diagnosed by HCV PCR Treated by DAAT HIV Main challenges are the pharmacologic interactions between immunosuppressives agents and some antiretroviral drugs and a higher rate of acute rejection HPV Treatment requires decreasing immunosuppression, topical, or surgical treatment. Respiratory infection viruses
Treatment includes supportive care and use of antiviral medications for some cases . Influenza can be treated with oseltamivir or zanamivir for influenza A and B. Influenza vaccine should be administered pretransplant and every year after transplant. Ribavirin for treatment of lower respiratory infection with RSV respiratory syncytial virus. Reference 1. Unal E, Topcu A, Demirpolat MT, Özkan ÖF (2018) Viral Infections after Kidney Transplantation: An Updated Review. Int J Virol AIDS 5:040. 2. Jani A A. Infections After Solid Organ Transplantation.Medscape 2022. 3. Arasaratnam RJ (2015) Lower-dose valganciclovir for the prevention of cytomegalovirus after solid organ transplantation: An important tradeoff. Transpl Infect Dis 17: 623-624. · .
1. A 21-year-old female who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
Issues/ concerns
– 21yo female, DD KTx in December 2019
– March 2020 presents with fever 39.2, lethargic, generally unwell, no respiratory symptoms
– clinical exam unremarkable apart from being febrile
– CXR clear, urine and blood culture negative
– medication: CCB and BB for HTN, Tacrolimus 2mg BD, MMF 250mg BD, Prednisone 5mg OD
– this patient is in the intermediate post-transplant period (1-6 months post-transplant)
– during this period, patients face the greatest impact of immunosuppression and are at the greatest risk for development of OIs
– risk of activation of latent infections, relapsed, residual and opportunistic infections is high
– differential diagnosis: SARS-CoV-2 pneumonia, CMV, TB, other pneumonia (viral, bacterial, fungal), acute rejection, BKV, PTLD are high on my differential list
– history of treatment for rejection since the intensive antirejection therapy increases the risk of reactivation of viral and fungal infections
– baseline investigations: CBC, ESR, CRP, procalcitonin, ferritin levels, nasopharyngeal swabs for SARS-CoV-2 RT-PCR and influenza, blood slide for malaria, stool m/c/s, IGRA, sputum gene xpert, sputum m/c/s, urine LAM, BAL for PCP and aspergillosis, CMV quantitative PCR, BKV quantitative PCR, EBV quantitative PCR, CSF analysis, serum LDH, serum CrAg, fungal markers (BDG, galactomannan), HBsAg, HCV Ab, HIV Ab, UECs, LFTs, coagulation profile, D-dimers, BGA, tacrolimus trough levels, graft biopsy
– imaging: abdominopelvic and graft ultrasound, CT (Chest, Abdomen) as indicated, screen for undrained fluid collections, blockage or leaks of anastomoses
– microbiology and tissue histology: remain the gold standard
– ELISA, direct immunofluorescence, quantitative molecular assays like NAAT in place of serologic tests since immunosuppressed patients do not reliably develop antibodies during an active infection
– supportive treatment: hydration, antipyretics
– early drainage of any fluid collections, debridement of devitalized tissues if present
– modification of immunosuppressive regimen to elicit an improved host immune response but this must be done cautiously to avoid precipitating IRIS or graft rejection
– hold MMF, she is already on a small dose at 250mg BD, maintain tacrolimus and prednisone
– specific treatment depending on the results obtained from the investigations done:
SARS-CoV-2 – mainly supportive treatment, isolation, oxygen as required, in case of severe disease consider increasing steroid dose, adding remdesivir
CMV – ganciclovir 5days followed by 3 weeks treatment with valganciclovir and 3 months prophylaxis
TB – anti-tuberculous drugs for at least 6-9 months but may be extended depending on the site of the infection
BKV – reduce immunosuppression
acute rejection – intensify immunosuppression
References
1. Peterson PK, Balfour HH, Jr., Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. The American journal of medicine. 1981
Sep;71(3):345-51. PubMed PMID: 6269425. Epub 1981/09/01. eng.
2. Roberts MB, Fishman JA. Immunosuppressive Agents and Infectious Risk in Transplantation: Managing the “Net State of Immunosuppression”. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021 Oct 5;73(7):e1302-e17. PubMed PMID: 32803228. Pubmed Central PMCID: PMC8561260. Epub 2020/08/18. eng.
3. Nair V, Jandovitz N, Hirsch JS, Nair G, Abate M, Bhaskaran M, et al. COVID-19 in kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2020 Jul;20(7):1819-25. PubMed PMID: 32351040. Pubmed Central PMCID: PMC7267603. Epub 2020/05/01. eng.
4. de Matos SB, Meyer R, Lima FWM. Cytomegalovirus Infection after Renal Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil. Infection & chemotherapy. 2017 Dec;49(4):255-61. PubMed PMID: 29299892. Pubmed Central PMCID: PMC5754335. Epub 2018/01/05. eng.
5. Christiadi D, Karpe KM, Walters GD. Interventions for BK virus infection in kidney transplant recipients: Cochrane Database Syst Rev. 2019 May 28;2019(5):CD013344. doi: 10.1002/14651858.CD013344. eCollection 2019.
6. Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clinical journal of the American Society of Nephrology : CJASN. 2020 Mar 6;15(3):430-8. PubMed PMID: 32066593. Pubmed Central PMCID: PMC7057293. Epub 2020/02/19. eng.
Differential diagnosis
Fever, lethargy no clinical symptoms CXR normal, blood and urine culture negative.
High on the differential lists will be Covid 19 due to the non-specific clinical presentation and the current worldwide conditions.
Other differentials will include:
Viral- CMV, influenza, adenovirus, parainfluenza
Bacterial- TB,
Parasitic-malaria
Fungal infection
Management
Starts with a detailed history and through physical examination.
In consultation with an infectious disease specialist.
Workups will include:CBC, PCR for Covid 19, CMV, influenza, parainfluenza and adenovirus, CRP, procalcitonin levels, D dimer levels, UECS, blood slide for malaria, LDH, ESR.
Empiric treatment for covid 19 as awaits workups due to the global pandemic.
Anti-pyretics for fever.
Adequate rehydration.
Oxygen supplementation if SPO2<92%.
Stop MMF this will be adequate in mild to moderate disease.
Reduce CNI by 50% in severe disease.
Oral steroids switched to IV dexamethasone in those requiring oxygen supplementation or mechanical ventilation.
Antivirals like remdesvir can be used in though with caution since their drugs interaction in transplant recipients is not well studied.
Other medication that can be used: tocilizumab, IVIG
References
Respiratory Viruses in Solid Organ Transplant Recipients Roni Bitterman
and Deepali Kumar
Halawa et al;COVID 19 in KTR ;Case series and brief review of current evidence.Nephron 2021;145(2);192-198
Horby P et al; Recovery collaboration group; Dexamethasone in hospitalized pts with covid 19.N Eng j med .2021 feb 25;384(8).693-704
Differential diagnosis in the above post transplant case with fever and unremarkable systemic examination with no identifiable focus of infection are likely viral causes with COVID 19 as the top differential due to the current situation worldwide -other viral.infections which can be considered include CMV,influenza and parainfluenza virus.
Fungal infections
Tuberculosis
Bacterial infections
After detailed history and examination,tests which should be carried out to confirm diagnosis include:Complete blood picture,liver and renal function test,serum ldh,inflammatory markers like serum CRP,ferritin , D dimers and procalcitonin,IL-6.PCR for COVID 19,PCR for CMV DNA,and influenza virus.Tacrolimus level should also be done to detect early rejection.
Treatment
Patient should be admitted and antipyretics ,hydration with intravenous fluids and empirical antibiotics should be started.Antimetabolite I.e.,MMF should be stopped and treatment should be according to specific cause ..If Covid likely the oral steroids should be switched to I/V dexamethasone and other drugs like remdesivir ,Paxlovid, molnupiravir, favipiravir,Sotrovimab can be tried according to their availability and center protocol .But physician should be cautious while using these drugs as have many drug-drug interaction and graft function closely monitored
REFERENCES:
1-Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511
2-Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8.
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD) DDX;
Infectious
Viral – COVID 19,CMV,EBV,RSV,Adenovirus,Parainfluenza virus etc.
Bacterial – Pneumonia, TB, HAI, UTI.
Fungal.
Parasitic – Malaria.
Non infectious.
Drugs – MMF/AZA.
Endocrine -Thyrotoxicosis.
Ca -PTLD,KS.
How would you manage this case?
Good hx taking including pre transplant workup results, vaccination status pre transplant, contact with any pts with PTB, travel to malaria endemic area, any UTI features etc.
MDT approach including an infectious dx person and transplant nephrologist.
Order for lab tests ; FHG,UECS,LFTS,COVID 19 PCR,CMV PCR,BGAS,MRDT, sputum for gene xpert and PCP, Blood and urine cultures,urinalysis,Spo2 levels ,tac levels, BKV PCR etc.
Rehydrate adequately.
Fever control with antipyretic.
Covid 19 mgt to be instituted considering we are in a pandemic as we await other results.
Stop MMF.
In severe cases or critical cases we decrease CNI by 50%,monitor graft function and give stress doses of steroids.
IV dexamethasone on those in need of resp support.
Oxygen supplementation or resp support on those in need of.
Antivirals to be considered ; remdesevir /cidofovir.
Other meds to decrease inflammation and improve outcome ;IVIG/Tocilizumab.
The labs results to guide any further t.
Appropriate post transplant vaccinations to be given a s per protocol.
REF;
Halawa et al;COVID 19 in KTR ;Case series and brief review of current evidence.Nephron 2021;145(2);192-198
Horby P et al; Recovery collaboration group; Dexamethasone in hospitalized pts with covid 19.N Eng j med .2021 feb 25;384(8).693-704
Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms and muted clinical and radiologic findings. Fever is neither a sensitive nor a specific predictor of infection Viral: · influenza, parainfluenza, respiratory syncytial virus, adenovirus, human metapneumovirus, coronavirus –
· parvovirus –
· herpes simplex virus (HSV), CMV, varicella-zoster virus (VZV; shingles), Bacterial: urinary tract infection Fungal infection Opportunistic infection Management
History • Recent hospitalizations or illnesses • Social/exposure history • Immunization status • Comorbid conditions • Current degree of immunosuppression • Exposure history indicative of possible pathogen Labs and Studies • Complete blood count with differential-CRP-Procalcitonin • Electrolyte and kidney function evaluation • Liver function testing • Influenza testing and other respiratory viral • Blood culture – (bacterial and fungal ) Urine exam and culture 4-Antibacterial therapy is the cornerstone of the initial empiric therapy.
5- if patient is sick we may reduce MMF or even stop
Reference: UpToDate: Infection in the solid organ transplant recipient
👉 Differential diagnosis of transplant recipient with high grade fever and sense of being unwell without localizing symptoms is highly suggestive of viral infections;
1_ COVID 19.
2.other viral infection s as influenza, para influenza , RSV.
3_ CMV infection (although it is difficult in 1st 3 months with typical prophylactic therapy, but identification of V status and CMV IgG prior to transplant in both the donor and recipient is essential.
👉 Management:
_COVID PCR from nasal and throat swab to confirm diagnosis.
_CMV PCR.
_As blood and urine culture are negative, so viral infections as COVID 19 should be suspected.
_Serum LDH, ferritin, CBC for lymphopneia and CRP are used for follow up of the patient.
_isolation of the patient with caution during dealing with PPE.
_supportive measures as IV fluids, good hydration and antipyretics.
_Follow up progress of the case, If any SOB or desaturation oxygen support can be used.
_for severe cases,requiring respiratory support, we can add high dose dexamethasone 6mg/day to shorten hospital stay and fasten the recovery.
_In case of severe cases, antiviral as remdisivir and paxlovid can be used.
_IVIG can be used in case of multisystem affection as immunomodulatory. _Reduction of IS (start with stoppage of MMF in mild cases ) and UpTo reduction of CNI in severe cases.
_in case of AKI, CVVHF can be used to remove the circulating cytokines in case of cytokine storm.
_In case of influenza virus…ribavirin and oseltamivir can be used.
_CMV infection also treated by reduction of IS plus use of ganciclovir.
· What is the differential diagnosis?
Fever more than 3years post transplant with no localizing symptom or sign.
Common cause:
1-Viral infection, like, COVID 19, influenza, CMV, PCP, RSV, etc
2-Bacterial infection
3-fungal infection,
· How would you manage this case?Detailed history of presenting complains, duration, recent travel, vaccination, prophylactic medications, contact with sick persons.
Previous infectious complications.
Rejection history and immunosuppression given.
After that, septic workup including sputum, blood culture, urine culture, ESR and CRP.
I will hold his MMF during the peak of his symptoms.
Empiric antibiotics coverage,till we have culture result back.
If confirmed COVID 19, then will keep holding MMF, give dexamethasone 8mg iv daily, ID consultation to consider anti viral and new monoclonal anti bodies like Remdesivir and Paxlovid.
Timetable of infections in renal transplant recipients 0–1 month Bacterial: wound infection, pneumonia, urinary tract infection, pyelitis, bacteremia Viral: herpes simplex, hepatitis 1–6 months Viral: CMV, Epstein–Barr, varicella zoster Fungal: Candida, Aspergillus, Cryptococcus Bacterial: Listeria, Legionella, Nocardia Prortozoa: Pneumocystis carinii > 6 months Bacterial: community micro-organism, mycobacteriosis Viral: hepatitis B or C, CMV chorioretinitis References;
1-Medical Complications of Kidney Transplantation Claudio Ponticelli first edition 2007
The cuases of fever in post-RTX were many
we need to know the status of CMV ,EBV,TB PRETRANSPLANt.
Early fever post-RTX could be viral or bacterial
we need to check for other causees a part from infection, like malignancy like PTLD Urinary tract infections are the most common form of bacterial infection in the renal transplant recipient. · gastrointestinal infections manifest with fever may be caused by CMV and other viruses or bacterial infection.
We need to look for the drug cause as well
How would you manage this case?
this patient need full history and clinical examination
need full CBC and CMP
need full sepsis work up including blood and urine culteur
need to send full viral panel including CMV,EBV,BV. Full supportive measures; hydration, antipyretic and appropriate antibiotics for infectious agent if needed.
Three month fever post transplant with no localizing symtpoms, CXR, urine and blood culture negative.
I would like to know CMV.EBV, TB status pre transplant to narrow my DD.
DD can include:
Infection causes like CMV, EBV, PCP, COVID, reactivation of latent TB, Resp viral like influenze and RSV.
Non infection: like PTLD and haposi sarcoma, autoimmune dse (less likely given the heavy burden of immunosupression)
What is the differential diagnosis?
KTR presented with high grade fever, which is a nonspecific but sensitive indicator of disease. The differential diagnosis for fever in the post-transplant period is as follows:
1. Infectious causes:
· Viral infection, bacterial infection or bungal infection.
· 87% of the febrile episodes occurring in the transplant patients hospitalized in the ICU were due to infections(1).
· Infections detected in the first month after transplantation are usually hospital-acquired bacterial complications related to surgical or technical problems. Bloodstream infections, catheter-related infections, nosocomial pneumonia, and surgical site infections predominate.
· Reactivation of latent infections and early fungal and viral infections account for a smaller proportion of febrile episodes during this period.
· Opportunistic infections will appear later unless an expected exposure has occurred.
· Urinary tract infections are the most common form of bacterial infection in the renal transplant recipient.
· gastrointestinal infections manifest with fever may be caused by CMV and other viruses or bacterial infection.
As a result of immunosuppression, solid organ transplant recipients are at risk of neurologic opportunistic infections that include cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), L. monocytogenes, Nocardia spp., mycobacteria, C. neoformans, Aspergillus, zygomycetes, and toxoplasmosis.
2. Non-infectious causes
a) Drugs:
· Antimetabolite immunosuppressive drugs, such as mycophenolate mofetil and azathioprine are associated with significantly lower maximum temperatures and leukocyte counts(2).
b) Metabolic causes like thyrotoxicosis.
c) Malignancy; PTLD, Kaposi sarcoma and other SOT-related malignancy.
How would you manage this case?
1. Detailed patient history and physical examination, with careful attention to skin, joints, lymph nodes, medication history (including antibiotics), travel, dietary exposure (e.g., unpasteurized milk), and animal exposure(3).
2. Basic laboratory testing (e.g., CBC, complete metabolic panel), blood cultures (2 sets), serologic tests for HIV, echocardiography, and CT of the chest, abdomen, pelvis, and other regions on the basisof symptoms and examination; ESR and CRP are commonly obtained.
3. Additional testing should be performed on the basis of the patient history, physical examination, epidemiology, exposures, imaging, and the results of the laboratory assays ordered as part of the minimal fever(FUO) evaluation (e.g., serologic or PCR testing for zoonotic or tickborne illness or endemic mycoses, evaluation for hepatitis viruses); include workup for tuberculosis or testing for rheumatologic and thyroid disorders (e.g., RF, ANA, TSH)(3).
4. I will onsider biopsy (rash, temporal artery, lymph nodes, masses, other lesions) as appropriate.
5. I will consider temporary discontinuation of new and potentially offending medications.
6. Screening for viruses if appropriate; HIV, HBV &HCV, CMV, EBV, HSV,VZV and HHV8.
7. Full supportive measures; hydration, antipyretic and appropriate antibiotics for infectious agent if needed.
References
1. Singh N, Chang FY, Gayowski T, Wagener M, Marino IR. Fever in liver transplant recipients in the intensive care unit. Clin Transplant 1999;13(6):504-11.
2. Sawyer RG, Crabtree TD, Gleason TG, Antevil JL, Pruett TL. Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections. Clin Transplant 1999;13(3):260-5. [PubMed]
COVID-19 is highly considered in the differential diagnosis of fever in this era of COVID pandemic.
of course , I will consider the possibility of COVID-19 infection in this case scenario and further adjust the dose of immunosuppression. I will adjust the dose of TAC to be in the range of 4-6 ng/ml. I will reduce the anti-metabolite dose(MMF) by 50% or even to be discontinued when there is severe leucopenia or a need to respiratory support( the patient already on a reduced dose of MMF). I will keep him on prednisolone.
A post transplant patient has presented with high grade fever with no associated symptoms and unremarkable examination.
Differential could be very vast
COVID can be considered and in prevailing circumstances it’s mandatory to do Covid PCR
Bacterial infections though no obvious focus which makes it less likely
Viral infections could present this way
CMV
Adeno virus
para influenza virus etc
Tuberculosis
Fungal infections
Further investigations can narrow down the diagnosis
Management
Definitive management would depend upon final diagnosis. In our country where infectious diseases are most common presentation of these patients we always cover them with broad spectrum antibiotics
Adequate hydration
If patient looks sick usually we stop MMF .All basic labs will be sent which included
BloodCP, Rfts Electrolytes, Lfts. Blood and urine culture, Viral PCRs if available and strongly indicated.
Antivirals can be considered like Remdesivir and Paxlovid etc
Covid-19 test, viral load , culture and detection test for possible curative organism.
Stop of MMF.
If sever cases we considered reduction of CNIs with target drug level 50-100 in CyA, 3-5- in TAC.
Antiviral therapy remdisivir or cidofovir.
Dexamethazone.
Tocilizumab.
Specific treatment if other viral diagnosis.
IVIG.
Vaccination according tp protocol after cure of the disease.
References
1 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565–74. 2 Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020 Mar;579(7798):265–9. 3 Zhu L, Xu X, Ma K, Yang J, Guan H, Chen S, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am J Transplant. 2020 Jul;20(7):1859–63.
Bridevaux, P.O.; Aubert, J.D.; Soccal, P.M.; Mazza-Stalder, J.; Berutto, C.; Rochat, T.; Turin, L.; Van Belle, S.; Nicod, L.; Meylan, P.; et al. Incidence and outcomes of respiratory viral infections in lung transplant recipients: A prospective study. Thorax 2014, 69, 32–38. [CrossRef] 2. Peghin, M.; Hirsch, H.H.; Len, Ó.; Codina, G.; Berastegui, C.; Sáez, B.; Solé, J.; Cabral, E.; Solé, A.; Zurbano, F.; et al. Epidemiology and Immediate Indirect Effects of Respiratory Viruses in Lung Transplant Recipients: A 5-Year Prospective Study. Am. J. Transplant. 2017, 17, 1304–1312. [CrossRef]
What is the differential diagnosis?This patient is at high risk of infections due to hypertension, kidney disease and immune suppression.. The differentials will include 1. Viral infections- Adeno virus , CMV, COVID 19, influenza virus 2. Bacterial infections 3. Fungal infections
How would you manage this case?The first step will be detailed history, including travel history, history of contact, Detailed physical examination Measurement of Oxygen saturations Investigations- Blood test like Blood CP, CRP, Renal Functions. Liver Functions COVID 19PCR CMV PCR In case off COVID 19 , Serum ferritin and D Dimer levels.
The patient will require hospital admission and supportive care. Watching the renal functions and drug levels and reducing the MF dose will be required. I case of COVID 19 Remdesivir can achieve early recovery. In case of drop of oxygen levels, dexamethsone can be used.
Ahmad Z, Bagchi S, Naranje P, Agarwal SK, Das CJ. Imaging spectrum of pulmonary infections in renal transplant patients. Indian J Radiol Imaging. 2020 Jul-Sep;30(3):273-279. Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198.
Your reply is too limited. It does not address all the concerns. I agree that investigating for COVID19 as the first step. I appreciate your clinical approach that includes that includes commencing anti-virals. I would be stopping MMF (typed as MF by yourself) for few days rather than reducing as you suggest.
Thank you All
I can see that you all referred to COVID 19 as one of the differential although presenting symptom of pyrexia is very non specific. For the sake of discussion, I did not see a comment on the use of neutralizing antibody Sotrovimab when can be used in these cases or not to be used at all. What about the role of other antivirals such as Remdisvir, Paxolivid and Molnuprivir in these cases and risks of drug drug interactions with immunosuppression. More comments in this area are highly recommended.
drug-drug interaction COVID-19 and organ transplantation
Reference:
Elens L, Langman LJ, Hesselink DA, Bergan S, Moes DJAR, Molinaro M, Venkataramanan R, Lemaitre F. Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug-Drug Interactions. Ther Drug Monit. 2020 Jun;42(3):360-368. doi: 10.1097/FTD.0000000000000761. PMID: 32304488; PMCID: PMC7188032.
1.Sotrovimab: investigational drug used only for mild to moderate cases may be useful here, but not recommended for hospitalized patients and may be associated with worse out come. 2.Remdesvir:It has antiviral activity and my be use for inpatent and outpatient COIV-19 positive patients, not advised in cases of eGFR < 30 ml/min 3.Molnuprivir: It is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has shown antiviral activity against SARS-CoV-2 in vitro and in clinical trials. Recommended in mild to moderate COVID-19 who are at high risk of disease progression ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available 3.Paxolivid: Nirmatrelvir is an oral protease inhibitor that is active against MPRO, a viral protease that plays an essential role in viral replication by cleaving the 2 viral polyproteins.1 It has demonstrated antiviral activity against all coronaviruses that are known to infect humans.2 Nirmatrelvir is packaged with ritonavir(as Paxlovid), a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent that has been used to boost HIV protease inhibitors. This will results in significant drug-drug interactions with immune suppression particularly CNIs
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
What is the differential diagnosis?3 months post transplant fever, is due to latent infection reactivation, relapsed infections, opportunistic infections, or community acquired infections. Viral infections: – RNA Viruses: influenza viruses, parainfluenza virus, respiratory syncytial virus, human metapneumovirus, rhinovirus, coronavirus,HCV, HEV, HAV, and HIV. – DNA Viruses: adenovirus, bocavirus, KI and WU polyomaviruses, CMV, EBV, HBV. Bacterial infections: atypical infections – mycoplasma, leigenalla, TB, E.coli, C.diificile…others. Fungal infections:PJP Noninfectious: drugs, myeloablative conditions, PTLD…etc
How would you manage this case? Full history, contact with sick people, history of recent travel, occupational history. Full clinical examination. Full blood count, urinalysis, CRP, ESR, hepatitis B,C,E,A serology. NAT-PCR for all the above mentioned viruses. Blood, urine and throat swab culture. Kidney function test- creatinine, BUN, Na,k. Liver function test-AST, ALT, bilirubins, albumin, INR. LDH, Ferritin Tacrolimus level. Identify Risk factors: HLA miss match, use of ATG, History of rejection. Evaluate the hemodynamic status, volume status of the patient.
Medications: IV hydration, antipyretics (NSAIDS should not be used). Remdisivir for COVID-19 Ribavirin for influenza and other respiratory viruses IVIG may be an option. Stress dose prednisolone /steroid. If the fever continue, can reduce immunosuppressive medications References: (1) Timsit, JF., Sonneville, R., Kalil, A.C. et al. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med45, 573–591 (2019). (2) Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511. doi: 10.1111/ctr.13511. Epub 2019 Mar 22. PMID: 30817023; PMCID: PMC7162209. (3) Infectiosn in solid organ transplantation recipient- UpToDate.
I appreciate your clinical approach that includes anti-viral drugs, You mention steroids for stress response, that is excellent. However, that is not same as Dexamethasone if patient require respiratory support. You have NOT mentioned stopping MMF. Your reply is well-referenced.Typing whole sentence in bold or typing in capitals amounts to shouting.
In this young patient with only fever and lethargy with no other symptoms (till that time), mostly viral infection. A detailed history and review of the systems is essential. Followup with serial evaluation (clinical and laboratory) is needed. Because of new high-dose immunosuppression, opportunistic infections should be considered.
Simple URTI of viral etiology usually has a low-grade fever though it can be serious in immunocompromised patients. Influenza usually leads to fever and muscle aches. COVID-19 may cause such a table.
We need to have CBC with differential. Lymphopenia is usually seen in viral infections.
CRP and procalcitonin may help in the differentiation of viral vs bacterial infections.
Management of this patient depends on the aetiology, but in general, we need to hydrate and give symptomatic analgesic and antipyretic. We have to be alert keeping in respect to secondary bacterial infections.
Being generally unwell, I will treat as an inpatient. Monitor for additional symptoms. I have to consider decreasing the immunosuppression in case of definitive CMV/COVİD etc. especially decreasing or stopping antiproliferative therapy.
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
What is the differential diagnosis? Differential diagnoses of fever Post transplantation include: Our Case Received a deceased donor kidney transplant in December 2019 in early period of outbreak of Covid-19, So the Covid 19 infection is the 1st DD. Other Viral infections, CMV, EBV …. infections. Bacterial infections, including urinary tract infections. Fungal Infections, PJP…. This transplant patient is at a high risk of infection due to: Immunosuppression Underlying CKD Hypertension, DM How would you manage this case? Detailed history and comprehensive clinical examination Any history of contact with SARS2-CoV positive patients. CT thorax without iv contrast (To confirm if there is any chest findings) CBC, (lymphopenia may be seen) Kidney function tests. Urine Analysis, Urine and Blood C/S CNIs level C-reactive protein Nasal and throat swab for COVID-19/PCR. Sr. Ferritin, IL-6. CMV viral load. sputum for PCP If confirmed to be COVID-19 (mild infection):
Admission in isolation room, under observation
Supportive medical therapy,good hydration (IV fluids and acetaminophen as needed). Reduction of immunosuppressive medications or even discontinued. Discontinued MMFor decrease 50% and continue CNIswith close graft monitoring the patient (immunosuppression treatment should be individualized based on the careful assessment of each patient) Drugs targeting immune response regulation: Interferons And Dexamethasone. Dexamethasone in those receiving respiratory support (invasive mechanical ventilation or oxygen alone): resulted in lower 28-day mortality (3) Drugs that preventing viral replicatation: Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, & Kaletra. Remdesivir:The Adaptive COVID-19 Treatment Trial proved that remdesivir-treated patients had 31% faster time to recovery when compared to control (1) Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care (2) References
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8. PMID: 33291120; PMCID: PMC7801980. Bitterman R, Kumar D. Respiratory Viruses in Solid Organ Transplant Recipients. Viruses. 2021 Oct 25;13(11):2146. doi: 10.3390/v13112146. PMID: 34834953; PMCID: PMC8622983.
D. K. Brady et al. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection, The FEBS Journal (2022) Federation of European Biochemical Societies. doi: 10.1111/febs.16662 RECOVERY Collaborative Group; Horby P, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
I appreciate your clinical approach that includes anti-viral drugs, Dexamethasone if patient require respiratory support, and stopping MMF. Your reply is well-referenced.Typing whole sentence in bold or typing in capitals amounts to shouting.
-Differential diagnosis
In the current case ,the recipient is 21 y old female hypertensive whom received renal graft from a decreased donor and she presented with fever 3 months post transplant without respiratory symptoms .
Blood ,urine cultures and chest xray are free
Currently on maintenance therapy Tac,MMF ,prednisolone
Differential diagnosis include
Viral infection as
Cytomegalovirus (CMV) ,Herpes simplex (HSV),Varicella zoster virus (VZV),Epstein Barr virus (EBV),Polyomaviruses (BK, JC, SV-40) ,Human herpes virus 6,7,8 (HHV),Human T-lymphotropic virus 1 and 2 (HTLV),Hepatitis B and C viruses (HBV, HCV),Human immunodeficiency virus (HIV),Human papillomavirus (HPV),Adenovirus,Respiratory syncytial virus (RSV),Influenza and parainfluenza viruses,Human metapneumovirus,Rhinovirus,Coronavirus (COVID19)
Bacterial infection as TB ,mycobacterium avium
Fungal infection
Rejection
Malignancy as non-Hodgkin lymphoma, Hodgkin lymphoma, and Kaposi sarcoma, as well as cancers of the liver, stomach, oropharynx, anus, vulva, and penis. -Management
A careful history need to be taken including the recipient ‘s vaccination history and viral infection history , or any past medical history of importance and travelling history as well as the deceased donor’s available history and virological and medical data available .
Physical examination including lymph node assessment
Initial investigations for fever without localizing findings include Urinalysis ,CMV PCR ,QuantiFERON testing using interferon gamma assays,COVID 19 nasal swab, Antigen detection tests for adenovirus, influenza A, respiratory syncytial virus, and rotavirus; PCR may also be available
Regarding each viral infection specifically CMV
For treatment of the established disease multiple approaches are needed involving reduction of immunosuppressives , antiviral agents as oral valganciclovir or ganciclovir , and in some cases adjuvant therapy. HSV,VZV
Diagnosed by direct fluorescence antibody for HSV and VZV from vesicular lesions or PCR from CSF or visceral tissue samples.
Treated with oral acyclovir, valacyclovir, or famciclovir and for disseminated infections IV acyclovir, EBV
EBV infection causes a mononucleosis-type syndrome and can lead to PTLD treated by R CHOP and adoptive immunotherapy with stimulated T cells . Polyomaviruses
Urine cytology for monitoring polyomavirus infection after transplantation.
Reduction of immunosuppression is the main therapy meanwhile differentiating between the BKVN and rejection is challenging and crucial as it affects the outcome HHV-6 , HHV-7 and HHV-8
Diagnosed by qualitative and quantitative molecular assays, by tissue immunohistochemistry or peripheral blood mononuclear cell culture. Treatment includes reducing immunosuppression and antiviral agents.
HHV 8 can be associated with Kaposi sarcoma treated by reducing the immunosuppressive regimen and chemotherapy or foscarnet HTLV-1
It can progress to HTLVI-associated myelopathy or to adult T cell leukemia/lymphoma.Optimal treatment to be defined HBV
Diagnosed by HB s Ag , HB c Ab , HB s Ab ,HBV PCR
Treatment involve reduction of immunosuppression and antiviral as entecavir or tenofovir HCV
Diagnosed by HCV PCR
Treated by DAAT HIV
Main challenges are the pharmacologic interactions between immunosuppressives agents and some antiretroviral drugs and a higher rate of acute rejection HPV
Treatment requires decreasing immunosuppression, topical, or surgical treatment. Respiratory infection viruses
Treatment include supportive care and use of antiviral medications for some cases .
Influenza can be treated with oseltamivir or zanamivir for influenza A and B.
Influenza vaccine should be administered pretransplant and every year after transplant
Ribavirin for treatment of lower respiratory infection with RSV respiratory syncytial virus. Reference
· Chhabra D . Assessment and Management of the Kidney Transplant Patient.Medscape 2022
· Unal E, Topcu A, Demirpolat MT, Özkan ÖF (2018) Viral Infections after Kidney Transplantation: An Updated Review. Int J Virol AIDS 5:040.
· Jani A A. Infections After Solid Organ Transplantation.Medscape 2022.
· Arasaratnam RJ (2015) Lower-dose valganciclovir for the prevention of cytomegalovirus after solid organ transplantation: An important tradeoff. Transpl Infect Dis 17: 623-624.
· Cowan FM, Copas A, Johnson AM, Ashley R, Corey L, et al. (2002) Herpes simplex type 1 infection: A sexually transmitted infection of adolescence? Sex Transm Infect 78: 346-348.
What is the differential diagnosis?The index patient is a hypertensive with recent (3 month back) deceased renal transplant recipient on tacrolimus based triple drug maintenance immunosuppressive drugs, now presenting with fever and lethargy without any respiratory symptoms and having a negative chest x ray and blood and urine cultures.The differential diagnosis of such a scenario having fever in 1-6 months post-transplant include (1,2):
Viral infections: Cytomegalovirus (CMV), Herpes simplex virus (HSV), varicella zoster virus (VZV), BK polyomavirus, relapsed Hepatitis B and C virus, community-acquired viruses (adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, metapneumonia virus) and human herpes virus- (HHV-) 6,7,and 8. In view of the timing of the presentation (March 2020), possibility of COVID-19 should also be considered in this scenario.Opportunistic infections: Pneumocystis jirovecii, Listeria, Toxoplasma, Nocardia, Aspergillus, Endemic fungi, Strongyloidiasis, reactivation of tuberculosis.Community acquired infections: Urinary tract infections, pneumonia, C. difficile colitis.Graft rejection, especially in absence of induction therapy, and non-adherence to medications, or subtherapeutic levels of calcineurin inhibitors.Lingering infections from the peri-surgical period, due to empyema, residual pneumonia, infected hematoma, etc.
How would you manage this case?The patient needs to be evaluated in details with respect to presentation of fever and lethargy (3,4).
Detailed history regarding symptoms, including any respiratory symptoms (cough and expectoration, shortness of breath), urinary symptoms (dysuria, oliguria or hematuria), weight loss, night sweats, diarrhea etc. Travel history, and exposure to someone with symptoms suggestive of COVID-19 should also be elicited. History of the deceased donor should also be elicited (to detect any donor-derived infections), and check if other recipients of organs from same donor have developed any infectious complications. History regarding induction therapy, and CMV prophylaxis should also be elicited.Complete physical examination including temperature and SpO2 for hypoxia.Laboratory testing: a) Complete blood count, Renal function test, C reactive protein, Liver function tests, urine routine microscopic examination, blood culture, urine culture, chest x ray, ultrasound abdomen including graft kidney, tacrolimus trough levels, CMV PCR quantitative.
b) Nasopharyngeal swab test for SARS-COV2 virus: Antigen and RT-PCR testing as per availability (in March 2020).
c) Sputum examination (if expectoration present) for AFB, gram stain, and cultures.
d) High resolution computed tomogram (HRCT) chest in presence of hypoxia or respiratory symptoms.
e) If diagnostic uncertainty persists, and there is clinical and radiological evidence of lower respiratory tract involvement, then invasive testing in form of bronchoalveolar lavage may be required (4).
4. Management includes:
1. Supportive: Antipyretics, maintenance of adequate hydration.
2. Specific: depending on etiology. As the timeline in the case is specifically mentioned as March 2020, the most likely diagnosis in this scenario is COVID-19.
a) COVID-19: With respect to the time of presentation, COVID-19 would be at the top of differential diagnosis. As the patient is having no respiratory symptoms at present, only observation and supportive management is required. If the patient worsens (develops respiratory symptoms and hypoxia), then further imaging and hospitalization might be required. Further treatment, depending on the severity of illness (used in March 2020) included reduction in immunosuppression (stopping MMF and reducing dose of tacrolimus), dexamethasone, hydroxycholoroquine, and ivermectin (5,6). Over 2021-2022, many more therapeutic measures for SARS-COV2 infection have been used with variable results, including remdesivir and tocilizumab.
b) CMV: CMV infection is a possibility in this scenario, especially if history of lymphocyte depleting agent use and if CMV prophylaxis not given. Treatment should be started with valganciclovir 900 mg twice a day and continued till negative CMV PCR quantitative, minimum 2 weeks (7).
References:
Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017 Apr;17(4):856-879. doi: 10.1111/ajt.14208. Epub 2017 Mar 10. PMID: 28117944.Agrawal A, Ison MG, Danziger-Isakov L. Long-Term Infectious Complications of Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Feb;17(2):286-295. doi: 10.2215/CJN.15971020. Epub 2021 Apr 20. PMID: 33879502; PMCID: PMC8823942.Timsit JF, Sonneville R, Kalil AC, Bassetti M, Ferrer R, Jaber S, Lanternier F, Luyt CE, Machado F, Mikulska M, Papazian L, Pène F, Poulakou G, Viscoli C, Wolff M, Zafrani L, Van Delden C. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med. 2019 May;45(5):573-591. doi: 10.1007/s00134-019-05597-y. Epub 2019 Mar 25. PMID: 30911807; PMCID: PMC7079836.Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511. doi: 10.1111/ctr.13511. Epub 2019 Mar 22. PMID: 30817023; PMCID: PMC7162209.RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.Brady DK, Gurijala AR, Huang L, Hussain AA, Lingan AL, Pembridge OG, Ratangee BA, Sealy TT, Vallone KT, Clements TP. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection. FEBS J. 2022 Oct 20:10.1111/febs.16662. doi: 10.1111/febs.16662. Epub ahead of print. PMID: 36266238; PMCID: PMC9874604.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.
Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017 Apr;17(4):856-879. doi: 10.1111/ajt.14208. Epub 2017 Mar 10. PMID: 28117944.
Agrawal A, Ison MG, Danziger-Isakov L. Long-Term Infectious Complications of Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Feb;17(2):286-295. doi: 10.2215/CJN.15971020. Epub 2021 Apr 20. PMID: 33879502; PMCID: PMC8823942.
Timsit JF, Sonneville R, Kalil AC, Bassetti M, Ferrer R, Jaber S, Lanternier F, Luyt CE, Machado F, Mikulska M, Papazian L, Pène F, Poulakou G, Viscoli C, Wolff M, Zafrani L, Van Delden C. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med. 2019 May;45(5):573-591. doi: 10.1007/s00134-019-05597-y. Epub 2019 Mar 25. PMID: 30911807; PMCID: PMC7079836.
Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511. doi: 10.1111/ctr.13511. Epub 2019 Mar 22. PMID: 30817023; PMCID: PMC7162209.
RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
Brady DK, Gurijala AR, Huang L, Hussain AA, Lingan AL, Pembridge OG, Ratangee BA, Sealy TT, Vallone KT, Clements TP. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection. FEBS J. 2022 Oct 20:10.1111/febs.16662. doi: 10.1111/febs.16662. Epub ahead of print. PMID: 36266238; PMCID: PMC9874604.
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.
The index case 4 months post-KT, on triple IS, presented with history of fever without focus and lethargy.
Blood and urine c/s negative, CXR normal.
Fever in early post-transplant period could be resulted from:
-Infection both common and opportunistic infection
– Viral illness:
– Respiratory viruses (infuenza , PIV, RSV, HMNV, adenovirus and COVID-19 ( early during the pandemic),
– CMV, EBV, HSV, VZV
– Bacterial infection: UTI, infected hematoma.
– Fungal infection: candida, aspergillus.
– Protozoal : PCP.
– Malignancy; can present only with fever.
– Rejection also fever can the only presentation ( Noting mentioned about graft function)
Management:
-Detailed history about: contact with any one with COVID, febrile illness, travelling, induction IS, urine output, review prophylaxis therapy and compliance to it. EBV& CMV donor/ recipient status.
– Thorough physical examination: including throat, lymph node, skin rash, graft tenderness.
Work up:
-CBC; lymphopenia or
-Inflammatory markers; CRP, ESR, ferritin
– Coagulation profile
– Cultures: repeat blood culture ( could have culture negative sepsis), urine.
– Respiratory multiples; test wide range of respiratory viruses
– COVID-19 Rapid antigen test, fast result with hour and COVID-19 PCR
– Liver function test: transaminitis.
– Evaluate graft function: kidney function test , urine analysis and culture.
– Abdominal US.
– Viral load PCR: CMV, EBV, BKv and other if history was suggestive.
– Tacrolimus level.
The management will be guided by the result of the tests, may need anti-microbial therapy.
Infectious disease team opinion. If confirmed to be COVID-19:
-The presentation during the peak of COVID.
-The clinical manifestations of SARS-CoV-2 infection in SOTR are highly variable.
– Normal CXR does not exclude the diagnosis, CT has better sensitivity to detect changes, however; it may be unnecessary if patient has no respiratory symptoms and no hypoxemia.
In mild infection the treatment will be supportive, with home isolation, ensure hospital access is available.
As the patient is febrile, and lethargic better to admit her.
– Isolation precautions.
– IVF for hydration.
– Control fever try to avoid Ibuprofen.
– Discontinue MMF
-Dexamethasone if patient require respiratory support, reduce mortality.
– Remdesivir; the first drug approved by the FDA for COVID-19 treatment,
On 21 January 2022, its use was expanded to include COVID-19 treatment in non-hospitalized patients with positive results of direct viral testing who are at high risk for progression to severe COVID-19 RCT showed 87% reduction in risk of hospitalization or death among high-risk, non-hospitalized patients who received a 3-day course of remdesivir compared to those who received the placebo.
References
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8. PMID: 33291120; PMCID: PMC7801980.
Bitterman R, Kumar D. Respiratory Viruses in Solid Organ Transplant Recipients. Viruses. 2021 Oct 25;13(11):2146. doi: 10.3390/v13112146. PMID: 34834953; PMCID: PMC8622983.
RECOVERY Collaborative Group; Horby P, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
Brady, D.K., Gurijala, A.R., Huang, L., Hussain, A.A., Lingan, A.L., Pembridge, O.G., Ratangee, B.A., Sealy, T.T., Vallone, K.T. and Clements, T.P. (2022), A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection. FEBS J. https://doi.org/10.1111/febs.16662
I appreciate your clinical approach that includes anti-viral (Remdesivir), Dexamethasone if patient require respiratory support, and stopping MMF. Your reply is well-referenced.
This patient developed febrile illness 4 months after undergoing kidney transplantation with negative blood and urine culture besides unremarkable CXR , the differential diagnosis will be which may be due to viral infections like COVID 19 infection ,herpesviruses (HSV, VZV, CMV, EBV) HBV infection ,Infection with listeria, nocardia, toxoplasma, , leishmania.Pneumocystis Infection
============================
How would you manage this case
Start with proper history (especially contact with febrile or patients with respiratory symptoms )and clinical examination putting in mined that immunosuppressed patients .may have deceiving symptoms and signs
-Full blood counts ,graft function ,,inflammatory markers CRP -Throat Swab for COVID 19, and herpes viruses . -CMV IgM and PCR -HRCT -Prograf level
Treatment
Start with supportive measures ( oxygen, antipyretics ,IV fluids) as needed .
Reduction of immunosuppressive medications or even discontinuation may be needed . However, there is no consensus on how to adjust immunosuppression & there is the risk of rejection due to reduction of immunosuppression
Antiviral medications: Patients with mild or moderate symptoms of COVID-19 infection and have risk factors for progression to severe illness have three FDA-approved antiviral treatments which have been shown to reduce the risk of hospitalization and death in this population. They include:
A combination of nirmatrelvir and ritonavir (Paxlovid)
Molnupiravir (Lagevrio)
Remdesivir (Veklury)
Paxlovid and Lagevrio can be taken at home, by mouth to avoid hospital admtion and risk of nosocomial infections,they must be started within five days of developing symptoms. Veklury is given intravenously (IV) on three consecutive days , it should be started within seven days of developing symptoms.
Reference :
D. K. Brady et al. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection, The FEBS Journal (2022) Federation of European Biochemical Societies. doi: 10.1111/febs.16662
Fishman, Jay A. “Infection in solid-organ transplant recipients.” New England Journal of Medicine 357.25 (2007): 2601-2614.
viral pneumonia including covid 19,H1N1 influenzas parainfluenza , adeno and CMV pnemonititis , Mycoplasma pneumonia, PTLD (1-6 months IF EBV +ve D /R-ve )
As she is presenting during the pandemic period of covid 19 on back ground of kidney transplant (4months ) on triple IS including tacrolimus and MMF,High grade fever with normal CXR and no URT still does not rule out the possibility of covid 19 ,as its presentation quite variable and even CXR in the early presentation with lethargy and poor oral intake, ask about history of sick contact with URT symptoms
How would you manage this case?
Assess hydration status ask about diarrhea nausea vomiting with poor oral intake , AKI more common in KTX a nd covid pneumonia ,its multifactorial including pre renal ,renal SARS-CoV-2’s direct attack of tubular cells via ACE2 receptors, other factors that may contribute to kidney injury include hypoxia, CRS, and a hypercoagulable state, drug nephrotoxicity , super added sepsis with bacteria or fungal infection. Laboratory tests
Covid SAR-PCR, RSV screen, urine for legionella and pneumococcal antigen, CRP, FBC looking for lymphopenia, high CRP, ferritin, LDH, CMV, EBV, Adenoviral screen, RFT, LFT , Urine proteins ,electrolytes , tacrolimus trough level
isolation of the patient, monitor oxygen saturation with IVF and other supportive care with hydration paracetamol, DVT prophylaxes
Immunosuppression medication
stop MMF or reduced by 50% based on the severity of symptoms, continue on same dose tacrolimus and stress dose prednisolone 10 mg , monitor RFT and proteinuria , the use of antiviral like Remdesivir only to hasten the recovery in moderate to severe covid 19 infection and its FDA approved.
predictors for sever covid pneumonia includes high inflammatory markers like high CRP , high ferritin or IL6 , persistent lymphopenia ,thrombocytopenia are indicators of sever inflammatory response and carry high risk of ARDS with high mortality and indicate the need for antiviral course plus dexamethasone 6-10mg for 10 days , assess for the need of o2 therapy , if patient stable normal CXR and no high inflammatory markers , saturation in RA can be advised for self-isolation and treat as op with other supportive care and instruction to come back in case of persistent fever worsening respiratory symptoms , CT no indicate in such case but should be considered in case of worsening respiratory symptoms and desaturation.
Data from a very large cohort of 17 million patients showed that organ transplant recipients had an adjusted 3.55-fold higher risk of death, whereas those GFR < 30 mL/min had a 2.5-fold increased risk (2). And another study also confirm that covid 19 with AKI carry high in hospital mortality by33.7% compared to non AKI group (3).
References
1.Caillard S, Chavarot N, Francois H, Matignon M, Greze C, Kamar N, Gatault P, Thaunat O, Legris T, Frimat L, Westeel PF, Goutaudier V, Jdidou M, Snanoudj R, Colosio C, Sicard A, Bertrand D, Mousson C, Bamoulid J, Masset C, Thierry A, Couzi L, Chemouny JM, Duveau A, Moal V, Blancho G, Grimbert P, Durrbach A, Moulin B, Anglicheau D, Ruch Y, Kaeuffer C, Benotmane I, Solis M, LeMeur Y, Hazzan M, Danion F; French SOT COVID Registry. Is COVID-19 infection more severe in kidney transplant recipients? Am J Transplant. 2021 Mar;21(3):1295-1303.
2. Williamson EJ, Walker AJ, Bhaskanan K. OpenSAFELY: factors associated with COVID-19 death in 17 million patients [published online ahead of print July 8, 2020]. Nature. 10.1038/s41586-020-2521-4
3. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829–838.
21 year 3 months post Tx, 2019, fever and being unwell, no resp. symptoms, O/E: unremarkable, ONLY HIGH TEMP, CXR, urine and blood cultures were negative.
What is your differential diagnosis?
This is a case of a typical presentation of a febrile illness in an immunocompromised patient in the early post-transplant period.
1. Viral infection including COVID 19 (the illness occurred during the pan epidemic of COVID 19), CMV, herpes viruses.
2. Other respiratory viruses such as RSV, parainfluenza virus, adenovirus, etc..
3. PJN
4. Bacterial infection, culture is negative, but could be a culture negative infection.
5. Fungal infections
6. PTLD, is a possibility since it can be seen in the first few months post Tx, when the IS therapy is at the highest doses. History of risk factors is important.
7. TB, needs to get history of high risk such as country of origin, travel to an endemic area, latent TB in donor and recipient.
Investigations:
1. NP sample for RT PCR for COVID 19.
2. HRCT chest since CXR is normal
· IF 1 and 2 are positive this would confirm the diagnosis of COVID 19.
· CBC and serum CRP, interleukin-6, CK, troponin I, LDH
· PT, activated PTT
· RFT and LFT, and electrolytes),
· Procalcitonin, fibrinogen.
· d-dimer
· Tacrolimus level
Follow up of new occurrence of symptoms and signs May need:
PCR for CMV and herpes viruses
Samples stained for PJ
Culture for a typical bacteria including TB.
May go for molecular testing for TB
Pelviabominal US looking for the graft perigraft area, any LNs
For COVID 19 Assess the severity of the disease per national guidelines
· Asymptomatic patients and patients with mild disease (oxygen saturation above 93%, no lung involvement on chest computed tomography) follow up as outpatient (This may be the index case) for recovery or deterioration.
Moderate disease (oxygen saturation above 90%, respiratory rate under 30 breaths/min) may be hospitalized and later on followed up in as outpatient if overcrowding during the panepidemic.
· Severe disease (oxygen saturation under 90%, respiratory rate above 30 breaths/min), cytokine storm (persistent fever, high or increasing CRP, ferritin, and D-dimer, abnormalities in liver function tests, hypofibrinogenemia with cytopenia in the forms of lymphopenia and thrombocytopenia) admit for ICU management. IS medications
· If mild to moderate we can maintain IS dose (index case) as it appears that temporary withdrawal of IST was not beneficial for survival.
· If severe we can reduce the dose of MMF by 50 % as recommended in severe viral infections by the KDIGO guidelines,
· Needs to adjust Tacrolimus level to the minimum accepted level.
· Follow up of RFT for fear of AR or AKI due to the virus. Antiviral therapy: Were considered later on:
· Remdesivir is the only FDA approved antivirus for the treatment of COVID-19 References
1. Erol Demir, COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic, BMC Nephrology (2022) 23:183
2. Maruhum Bonar H, Management of COVID-19 in Kidney Transplant Recipients: A Single-Center Case Series,
3. NIH, COVID -19 treatment guidelines March 6 2023, International Journal of Nephrology, 18 August 2022.
Non-specific presentation of only fever in such scenario ( require work up such as for pyrexia of unknown origin /despite not fulfilling all criteria !) make the possibility of
infections: different viral, fungal, TB , bacterial and parasitic infections
allergy to some thing !
side effects or drug interactions !
rejections
metabolic , rheumatological, autoimmune causes
malignancy
so required a more detailed history about the donor especially any history of infectious diseases & revising comprehensive history of recipient and complete physical examination from head to toe and discussion with in an MDT discussion
Laboratory investigations:
FBC, CRP,ESR,LDH
RFT,LFT, TFT
UA, early morning urine & respiratory samples or BAL for AFB and PCR for virals
I appreciate that your list of DD includes acute rejection (though mistyped in your reply) malignancies and autoimmune disease. I am not sure if these explain high grade fever. But a temperature of 39.2 degree centigrade would make me consider possibilities that you mention in the sub-heading of ‘Infections’.
A case of fever in a generally unwell immunocompromised patient with negative blood and urine culture put the following differential diagnosis in consideration
Infections including covid, influenza, CMV, tuberculosis, fungal infection
Immune cause such as acute rejection
Malignancy such as PTLD
Other causes such as hyperthyroidism
I will perform the following investigations
Tacrolimus level
Renal function tests and urine analysis
SGPT, TSH and complete blood count
C reactive protein, procalcitonin and beta dglucan
Virology if there is elevation of liver enzymes
Serum LDH
Covid and influenza swab
CMV and EBV PCR
If the cause is not evident I will perform CT chest and abdomen with contrast
If there is unexplained graft dysfunction I will perform renal biopsy
I will start treatment in the form of
Good hydration
Symptomatic treatment including paracetamol on need
Adjust the trough level of tacrolimus
Once the diagnosis is steeled treatment should be initiated according to the cause
I appreciate that your list of DD includes acute rejection or hyperthyroidism. I am sure these would NOT explain high grade fever. But a temperature of 39.2 degree centigrade would make me consider first 2 among the possibilities that you mention among ‘Infections’.
There are many spelling errors, a I quote, “biobsy to be conidered if her creat is trending up.”
I appreciate that your list of DD includes malignancies and autoimmune disease. I am not sure if these explain high grade fever. But a temperature of 39.2 degree centigrade would make me consider first 2 among the possibilities that you mention in the heading of ‘Infections’.
Four months after receiving a kidney transplant from a deceased donor, this patient is experiencing feverish symptoms.
D/D
1-Infections caused by viruses include those caused by COVID 19, influenza, varicella zoster, herpes simplex, EBV, paramyxovirus, and CMV.
2-Bacterial infections: Immunocompromised transplant recipients are susceptible to any bacterial infections that can infect immunocompetent people.
When there is a fever and negative blood and urine cultures, TB is one of the possible diagnoses.
3-Candida infections, aspergillosis, and cryptococcosis
4-Fever can also be a symptom of malignancy, albeit in this case it is doubtful that the transplant and anti-rejection medicines are to blame.
Management
A more thorough history, including travel and contact information for any patients or kids who may have been ill and more thorough examination that looks for any rashes, redness, swelling, or tenderness in the lymph nodes or the graft.
Investigation;
Blood test
complete blood count, ESR, CRP, LFTs, and lactate dehydrogenase tests.
PCR for CMV, EBV, HSV, influenza, Adenivirus.
Nasal & pharyngeal swap for COVID-10 PCR.
As there is no emergency; and the Patient might receive treatment at home with an emphasis on staying well-hydrated and in regular contact with medical professionals.
Immunosupression need to monitor and dosage should be adjusted according to lab result and patient condition.
Graft function monitoring required
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron.
Comprehensive Clinical Nephrology John Feehally, DM, FRCP
Do you think an immuncompromised patient with high grade fever with the list of investigations you referred to would be managed at home? You probably think of this once you have a confirmed diagnosis!
thnak you prof.
invetigation i wrote are the general investigation in case of high fever but this patient can be manage at home, as he has no respiratory distress and saturation is maintained, but in case thing get worse, admission option can be used.
1. A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
Other viral or bacterial respiratory infections(Adenovirus and Mycoplasma should be considered in clusters of pneumonia patients, especially in closed settings such as military camps and schools.).
Aspiration pneumonia
Pneumocystis jirovecii pneumonia
Middle East respiratory syndrome (MERS)
Avian influenza A (H7N9) virus infection
Avian influenza A (H5N1) virus infection
Pulmonary tuberculosis
Febrile neutropenia
Other
COVID-19 should be considered a differential diagnosis for many conditions. The differential is very broad and includes many common respiratory, infectious, cardiovascular, oncological, and gastrointestinal diseases.
Take a detailed history to assess risk of COVID-19.
Suspect the diagnosis based on travel history and risk factors.
Pulse oximetry
Can reveal low oxygen saturation, but the cut-offs used to define disease severity vary.Hypoxia (hypoxemia) is defined as oxygen saturation <94%, or <88% in the presence of chronic lung disease.
• Inflammatory markers (e.g., serum C-reactive protein, erythrocyte sedimentation rate, interleukins, lactate dehydrogenase, procalcitonin, amyloid A, and ferritin)
• Cardiac biomarkers
• Serum creatine kinase and myoglobin.
Swap of the nasal and pharynx for COVID-19 PCR.
Molecular tests are expensive and require specialized skills and instruments, while rapid antigen tests are faster, easier, and cheaper.
Serologic tests may be used to establish a late or retrospective diagnosis or inform public policy.
IN our pateint Cheast Xray was clear
Mild symptom as fever
Urine and blood cultures were negative.
IF suspected COVID19
Managing a home.
An immunocompromised patient who does not receive immediate hospital care may develop further nosocomial infections.
Good fluid and paracetamol .
Discontinuation of MMF and vigilant patient monitoring.
Those getting respiratory support should take dexamethasone( 7-10 days).
Remdesivir has antiviral activity against coronavirus, shortening recovery in COVID-19, but severe adverse events have been reported( acute kidney injury).
Health-education the pateint to prevent COVID-19 .
Buxeda A, Arias-Cabrales C, Pérez-Sáez MJ, et al. Use and Safety of Remdesivir in Kidney Transplant Recipients With COVID-19. Kidney Int Rep. 2021;6(9):2305-2315. doi:10.1016/j.ekir.2021.06.023
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi:10.1159/000512329
Worby CJ, Chaves SS, Wallinga J, Lipsitch M, Finelli L, Goldstein E. On the relative role of different age groups in influenza epidemics. Epidemics. 2015;13:10–6.
Thank you for the detailed discussion about potential causes. Is there any risk factor for this young patient to have aspiration pneumonia?
Do you think common cold present with such high grade temperature?
This patient is presenting 4 months after a kidney transplant from a deceased donor with symptoms of an infection with no clear focus
The differential diagnosis includes: Viral infection:
CMV infection
COVID 19 infection
Adenovirus infection
Herpes simplex virus
Varicella zoster infection
EBV
Paramyxovirus
Influenza
Bacterial Infections:
Any bacterial infections that can affect immunocompetent individuals can also affect immunocompromised transplant recipients
TB is one of the differential diagnosis of fevers and negative blood and urine cultures
Fungal infections:
Candidiasis
Aspergillosis
Cryptococcosis
Malignancy:
Malignancies can also present with fevers although in this patient it would be unlikely related to the transplant and anti-rejection medications
Management:
A more detailed history including history of travel, history of contact with any sick patients or children
A more detailed exam including assessing for any rash, lymph nodes
Investigations:
Complete blood count – To check for lymphocytosis/lymphopenia, neutrophilia
ESR
CRP
UECs
LFTs – To check for transaminitis – if present: to check for Hepatitis B , C and E
Lactate dehydrogenase
CMV PCR
EBV PCR – although it can be elevated after the transplant
HSV PCR
Adenovirus PCR
Influenza PCR
Parainfluenza PCR
As the blood and urine cultures are negative and there is no focus of infection, the patient does not warrant antibiotics
He is hemodynamically stable and not in respiratory distress – he can be managed conservatively with supportive care as the other investigations are awaited
His inflammatory markers and graft function should be monitored closely while awaiting the results
Viral Infections In renal Transplant Recipients. The Scientific World Journal. Volume 2012, Article ID 820621, 18 pages
Fever of Unknown Origin in Solid Organ Transplant Recipients. Infect Dis Clin North Am. 2007;21(4):1033-54
Thank you for the comprehensive review of investigations of pyrexial immuncompromised patient. I take this sentence from your review ‘Malignancies can also present with fevers although in this patient it would be unlikely related to the transplant and anti-rejection medications’ Why malignancy unlikely and what about B symptoms in PTLD including pyrexia?
Thank you Professor Mohsen
The duration of exposure to the CNIs is only 4 months. That’s why, if it was a malignancy, it would be less likely to be directly related to the transplant and anti-rejection medications. However, if it was a missed malignancy prior to transplant, then it can present in a similar way
The B symptoms in PTLD will present in a very similar way
Viral infection including COVID-19, influenza virus, adenovirus, CMV
Bacterial infection (although urine & blood culture negative but possibility of bacterial infection should be considered)
fungal infection.
Because transplantation happened in early period of COVID-19 pandemic, COVID-19 infection should be on the top of differential diagnosis.
Management:
Detailed history of contact with suspected or confirmed COVID-19 patient, travel history.
Measure O2 saturation
CBC (lymphopnea), CRP, ferritin, renal function.
Nasal & pharyngeal swap for COVID-10 PCR.
CMV PCR
If COVID-19 PCR result positive, and according the result of O2 saturation, CRP & ferritin the severity of disease can be determined.
The patient need to be admitted to hospital, stop MMF (close monitoring of renal function) and supportive care.
The patient may be treated at home if she feared from hospital admission due to COVID-19 outbreak, with emphasis on good hydration and close contact with health care personnel.
References:
Elhadedy M., Marie Y. and Halawa A. COVI-19 in Renal Transplant Recipient: Case series and a Brief Review of Current Evidence.Nephron,2021;145:192-198.
Well done for considering (in this index case ) home management.
Not urgent hospitalization in an immunocompromised patient can lead to other nosocomial infections.
What is the differential diagnosis?
A case of fever in post transplant patient on immunosuppression 3 months post transplant with negative blood and urine cultures,no respiratory symptoms and chest x ray is clear:Most causes of fever in post transplant patients are infections, Transplant patients are susceptible to both common and opportunistic infections. The risk of a particular infection is related to several factors including the degree of immunosuppression.The incidence of Infections are usually occur between the first and third months following transplant where in immune suppression is at its maximum during this time due to induction therapy.
DD in the current scenario can be (we will need to know regarding graft function):
The presentation of fever in TX patient in March 2019 at the time of era of COVID 19 pandemic. COVID 19 infection initially may be presented with only fever. The other DD still there:
1-CMV,BKV nephropathy.
2-Nocardia asteroides.
3-Listeria monocytogenes
4-Aspergillus fumigatus.
5-Pneumocystis jirovecii pneumonia
6-Hepatitis B and C viruses
7-Herpes simplex virus.
8-Varicella-zoster virus.
9-Epstein-Barr virus and PTLDs
10-Mycobacterium tuberculosis
How would you manage this case?
Early, specific diagnosis and rapid, aggressive treatment are essential to optimal clinical outcomes since Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms, clinical and radiologic findings. Fever is neither a sensitive nor a specific predictor of infection; up to 40 percent of infections cause no fever (especially fungal infections).
Management:
-Full proper history
-Clinical examination of transplant surgery wound and check for any physical sign that can help to diagnose cause of fever like rashes,skin redness,skin changes,enlarged lymph nodes.
-Investigations including blood tests and imaging:
Serological tests, microbiological cultures, nasal and buccal swabs and even tissue diagnosis as BAL.
-The choice of antimicrobial regimens is complex than in general population due to the urgency of therapy and the frequency of drug toxicities and drug interactions.
What is the differential diagnosis? Differential diagnoses of fever after transplantation include:
1. Infection: viral (responsible for over half of the febrile episodes, especially CMV), bacterial, fungal and parasitic infection
2. Acute rejection (less likely here)
3. Malignancy
How would you manage this case?Detailed history and comprehensive clinical examination
CBC, RFT & electrolytes, ESR, CRP, LFT, RBS, urine analysis, urine and blood C/S
CNI (tacrolimus) level
CMV serology/PCR
Nasal and throat swab for COVID-19/PCR, s.ferritin, IL-6, lymphopenia
This transplant patient is at a high risk of infection due to:
1. Immunosuppression
2. Underlying CKD
3. Hypertension
In 2020, 3 months post transplant presenting with only with fever and lethargy (no respiratory symptoms), normal clinical examination, clear chest x-ray, and negative urine and blood culture, COVID-19 is a high possibility especially with this high risk patient. In COVID-19, fever was reported (two large studies) to be the most common symptom (82–87%) followed by cough (44 to 65.7%)
If confirmed to be COVID-19 (mild infection):
o Admission
o Supportive medical therapy (IV fluids and paracetamol)
o Discontinued MMF with close monitoring the patient (immunosuppression treatment should be individualized based on the careful assessment of each patient)
o Remdesivir: the Adaptive COVID-19 Treatment Trial proved that remdesivir-treated patients had 31% faster time to recovery when compared to control (1)
o Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care (2)
o Dexamethasone in those receiving respiratory support (invasive mechanical ventilation or oxygen alone): resulted in lower 28-day mortality (3)
References
1. Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8. PMID: 33291120; PMCID: PMC7801980.
2. Bitterman R, Kumar D. Respiratory Viruses in Solid Organ Transplant Recipients. Viruses. 2021 Oct 25;13(11):2146. doi: 10.3390/v13112146. PMID: 34834953; PMCID: PMC8622983.
3. RECOVERY Collaborative Group; Horby P, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
1.What is the differential diagnosis?-She is 3 months posttransplant according to the history
-This bring us to the differential diagnosis of infections 1 to 6 months posttransplant:
A.With PCP & Antiviral prophylaxis(CMV,HBV)
Infection with listeria,nocardia,toxoplasma,strongyloides, leishmania, T.cruzi
-However, this patient presented at early days of COVID-19 pandemic and therefore has symptoms are likely due to COVID-19 pneumonia. COVID-19 has re-shaped the roadmap of infections in transplant population as it can happen any time without respect to the postulated time lines of infection post transplant.
2.How would you manage this case?
Ask for COVID-19 swab
Ask for WCC & differential
Ask for inflammatory markers including serum ferritin
Once the infection is confirmed, the management is generally supportive
She is stable and not in any respiratory distress
Keep in isolation ward
Antipyretics
Rehydration by oral /IV fluids
Monitoring & observation of SPO2, VBG, respiratory rate
MMF might continue, she is already getting a low dose and in early posttransplant period(my personal view), some people may stop it.
References
Nephrology secrets, 4th edition
COVID-19 in Renal transplant Recipients by Muhammed Ahmed Elhadedy et al.
How can in this index case HCV present with fever as the first symptom.
What do you mean by anastomotic complications!!
What would be your choice as a gold standard test.?
What is the differential diagnosis?
Upper respiratory tract infection possible bacterial infection/ COVID-19 / respiratory syncytial virus/ Influenza virus/ Aspirogliosis
CMV infection
EBV infection
Pnumocystic Jiorvecii
Also possible urinary tract infection which may appear with fever only
How would you manage this case?
History and Examination
Lab test of CBC for lymphopenia / high ESR and CRP/ high ferritin and d. dimmer/ procalcitonin level if there’s hypoxia
ABG
COVID-19 PCR and igG/ igM
CMV PCR/ serology
Urine routine and culture/ blood culture/ sputum culture if available
CT chest
Good hydration
Antipyretic agents
Antibiotic
Antiviral ( remdesivir )
Dexamethazone if there’s decrease oxygen saturation reduce anti metabolites dose to half
How fast would the index case develop ANTIBODIES (except if she had a preTX infection).ANTIGEN PCR will be more informative .
NAT is the best but more expensive.
1-What is the differential diagnosis:
-SARS-COV-2 infection (Most likely COVID-19)
–Viral and bacterial respiratory infections (eg, influenza, respiratory syncytial virus, adenovirus, Haemophilus influenzae pneumonia, Mycoplasma pneumoniae pneumonia) -CMV infection -Aspergillosis 2-How would you manage this case? Evaluation & Hospitalization;
-Patient should be admitted in isolation room,
-Monitoring her vital signs , Po2 Sat. (keep Po2 sat ≥94% ),
-ABG , Prophylaxis for venous thromboembolism
-Supportive medical in the form of IV fluids and antipyretics, and symptomatic treatment with or without ward-based oxygen therapy based on the oxygen saturation ,
-Discontinued MMF and monitoring Graft functions, FK level, Further investigations;
-CBC (lymphopenia) , CRP , Ferritin,
-Full septic screen (CMV PCR ,Respiratory Multiplex, Pneumonia Multiplex, Sputum c/s ,N.P. sample for COVID-19 PCR) ,
-Bronchoalveolar lavage for aspergillosis , PCP ,
-Repeat CXR +/- HRCT scan on chest . Use of remdesivir;
-Remdesivir (a broad-spectrum antiviral nucleotide prodrug) can be effective against MERS-CoV and SARSCoV infections,
–In the United States, the FDA approved remdesivir for hospitalized children ≥12 years and adults with COVID-19, regardless of disease severity. -The suggested adult dose is 200 mg intravenously on day 1 followed by 100 mg daily for 5 days total (with extension to 10 days if there is no clinical improvement). -If a patient is otherwise ready for discharge prior to completion of the course, remdesivir can be discontinued,
-F/U her as Outpatient and advised her to self-isolate at home. References; –Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; 382:1708. –Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ 2020; 368:m1086. –Veklury. US FDA approved product information; Foster City, CA: Bristol Gilead Sciences, Inc; October 2020.
Differential diagnosismost likely cause of pyrexia would be;
COVID-19( march -2020 but depends on geographical location)
CMV infection
Other respiratory viral infection
Bacterial infections
PTLD early onset
How would you manage this case?Owing to immunosuppressed condition of SOT recipient it would be difficult to ascertain the focus of infection on symptoms, it would rather need to have thorough investigation.
Contact history
RT PCR covid
HRCT chest
Complete blood count with differential
Renal function
Tacrolimus C0 level.
CMV PCR
EBV PCR if prior values are known
CRP and procalcitonin
Management;
In case of COVID treatment with
Antipyretics
Reduction/ stop MMF depending on severity
With hold MMF foe 4-6 weeks and restart after 6 weeks
What is the differential diagnosis?
Infections caused by viruses: infections due to Pneumocystis jirovecii, Nocardia asteroids, Aspergillus spp, Cryptococcus neoformans, cytomegalovirus, varicella-zoster virus, community-acquired respiratory viruses (influenza, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2), or Legionella spp.Infections are caused by bacteria, such as those that affect the urinary tract. How would you manage this case?Take a look at the complete history of the cadaveric kidney. and physical examination of the recipient.
Conventional radiography shows less infection in these hosts. Consequently, more sensitive imaging methods like computed tomography, magnetic resonance imaging, and positron emission tomography are needed to detect infectious and malignant processes.
Microbiology and histology are the “gold standard” for diagnosis. No radiologic discovery is adequate to replace clinical samples. Multi-infections are prevalent. Thus, transplant patients with infectious disorders must have frequent invasive operations to obtain tissues or fluids for culture and histology. Invasive diagnostics may be needed for non-responders.
Serologic assays, which reveal prior pathogen exposure, are helpful pretransplant to predict disease activation risk with immunosuppression but not after transplantation. Consequently, quantitative tests that directly detect protein products or nucleic acids of organisms should be used, such as enzyme-linked immunosorbent assays, direct immunofluorescence, or quantitative molecular assays (nucleic acid amplification tests).
Acute infection may increase host response by changing immunosuppressive regimen components. Reduced immunosuppression may cause immunological reconstitution syndromes or allograft rejection.
Fishman, Jay A. “Infection in solid-organ transplant recipients.” New England Journal of Medicine 357.25 (2007): 2601-2614.
Thankyou for emphasizing the clinical presentation of the index case ,progression of her clinical course.
The golden quick confirmation in this index case would be NAT or Antigen tests (if you are testing for COVID.
What is the differential diagnosis? How would you manage this case?
Patient with few specific symptoms, only fever and malaise with solid organ transplantation with triple immunosuppression (there is no information on the use of lymphocyte depletion).
The possibilities are: 1. Infection
For the period considering COVID-19, there were no community restrictions or the use of masks.
The period from December to March is winter-spring in the northern hemisphere, we must consider respiratory viral diseases.
CMV is also a possibility and needs to be considered, due to its high frequency in transplant patients.
Fungal infections, mycobacteria, and other viral illnesses need to be evaluated.
It is important to seek information about the donor, including serology and post-mortem diagnosis to consider the possibility that an infectious agent may have been transmitted.
Respiratory viral panel, quantitative viral load for CMV, presence of Epstein Baar, chest CT scan (high risk of respiratory disease with few symptoms and not visible on radiography).
2. Rejection
Inadequate immunosuppression may be related to fever and malaise, so it is important to measure immunosuppressants and assess their serum values. Calcineurin inhibitors present greater drug interaction and greater difficulty for serum levels.
Assessing graft function is important and, if altered, consider graft biopsy.
3. Malignancy
Risk of PTLD (main) and Polyomavirus infections.
In March 2020, all immunosuppressed patients with fever should undergo hospitalization and respiratory isolation for investigation of COVID-19. At the time, we did not have medications for proper treatment.
Arterial blood gas analysis and computed tomography are necessary, if there is a need for oxygen therapy, dexamethasone should be started at a dose of 6mg for ten days or total suppression of symptoms.
Bronchoalveolar lavage was not indicated at the time due to the risk of the team, which is why the respiratory viral panel was so important.
If Influenza, start Osentalmivir; COVID 19, start dexamethasone; For other respiratory viruses, evaluate inhaled ribavirin and IVIg; CMV, start Ganciclovir.
Thanks, Filipe Any indication from the presentation to think it is a rejection? I agree that it could be COVID-19 or other viral infections including CMV and PTLD. Please explain why you put rejection in the differential diagnosis.
Donor deceased less than three months ago with low doses of immunosuppressants without respiratory symptoms.
He would evaluate the renal function, if altered, the investigation would progress.
Measurement of serum levels of immunosuppressants.
There was no description of the use of lymphocyte depletion.
I thought it prudent to initiate an investigation, despite viral diseases being the most prevalent in this case.
The differential diagnosis of fever in kidney transplant recipient includes (1):
· Infection.
· Acute rejection (less common with modern immune suppression).
· Systemic inflammatory response.
· May occur during treatment with biological agents.
· How would you manage this case?
The data, in this case scenario, is missing a lot of essential points that will affect the decision-making (e.g. the allograft functions at the time of discharge and at the time of presentation, degree of HLA mismatch, presence of signs of rejection like haematuria or oliguria).
My suggested approach:
– I will start by careful history taking, with special conidiation to any recent contact with any patient with a fever, history of travelling, or living in an area with known endemic disease (like TB). I will also ask about a sore throat or change in the bowel habit.
– Due to the COVID-19 pandemic during that time and the negative culture results, I will consider this case to be COVID-positive until appropriate investigations exclude this highly communicable disease (The patient should be isolated, and I will consider the reduction of immune suppression if possible).
– Detailed clinical examination (special attention to chest auscultation and palpation of the allograft for any tenderness).
– Routine laboratory examination (CBC, Full chemistry, Urine analysis, CRP and ESR).
– If she develops any respiratory symptoms, I will proceed directly to CT scan chest.
– General supportive care will be applied (fluid resuscitation and paracetamol) until the underlying cause is accurately defined.
Appropriate treatment will be started after identifying the cause (according to the relevant guidelines).
References:
1) Steddon S, Ashman N, Chesser A, et al. Oxford Handbook of Nephrology and Hypertension. Second edition, Oxford University Press, ISBN 978–0–19–965161–0, 2014.
Thanks, Ahmed Any indication from the presentation to think it is a rejection? I agree that it could be COVID-19 or other viral infections including CMV and PTLD. Please explain why you put rejection in the differential diagnosis.
The differential diagnosis I mentioned in reply to the first question was a general differential diagnosis for causes of fever in a kidney allograft recipient.
The presented case scenario did not mention any data regarding serum Cr, urine analysis or allograft biopsy. Therefore, there was no data suggestive of allograft rejection in the presented case.
Another rare cause of unexplained fever (with negative culture results) is an undetected haematoma. I have counted a few cases in our centre, which were published as a case series (1). the exact cause of this phenomenon is still unknown to me.
References:
1) Fever in ESRD; Does it Worth a Second Look?. Ahmed Yehia, Omar Ballut and Alaa A Sabry. ARC Journal of Nephrology. 2016; Volume 1, Issue 1, PP 11-15.
The patient had a DBD donor and currently feels lethargic and generally unwell. The patient has no respiratory symptoms. Clinical exam was unremarkable. Urine and blood culture negative. Patient has hypertension and takes calcium channel and beta blockers.
Possible differential diagnosis :
Bacterial infection, especially UTI
Fungal infection
Malignancy, especially PTLD
CMV or EBV
COVID 19 since this disease has symptoms similar to flu and feeling of general being unwell.
TB
Graft rejection
BKV
Management
CBC
Serum creatinine and BUN
Repeat chest X ray, CT
CMV viral load, EBV viral load and administer valgancyclovir if positive
CRP levels can indicate infection
Tac trough level
If found to be COVID positive, then adjust IS dosage with reduction. Supportive treatment needs to be given along with isolation.
Monitor body temperature for fever
IGRA and Mantoux, culture to check for TB and if positive, then anti TB medication for 6 months with review and monitoring and repeat testing.
Consider shifting MMF to everolimus and check if patient feels better
Check if patient is hydrating adequately, and adhering to medication regimen.
References :
Peterson P, Balfour H, et al. Fever in renal transplant recipients : causes, prognostic significance and changing patterns at the university of Minnesota hospital. Am J Med. 1981; 71(3) : 345-351. https://doi.org/10.1016/0002-9343(81)90149-2
Demir, E., Ucar, Z.A., Dheir, H. et al. COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic. BMC Nephrol 23, 183 (2022). https://doi.org/10.1186/s12882-022-02784-w
Garces J, Oschner J. BK virus associated nephropathy in kidney transplant recipients. 2010; 10(4) : 245-249.
Wojciechowski D, Chandran S, Webber A, Hirose R, Vincenti F. Everolimus conversion to treat BK virus infection in kidney transplant recipients.Transplantation proceedings. 2017, 49(8), 1773‐1778. https://doi.org/10.1016/j.transproceed.2017.06.030
What is the differential diagnosis?
A case of post kidney transplant felt lethargic, feverish and generally unwell, chest X-ray was clear, Urine and blood cultures were negative all these were on COVID 19 pandemic time.
So, on top of my differential diagnosis list is (COVID 19 infection) which should be excluded by RT-PCR. Other causes on my list will be suspected as apart of common infection that occurred between 1- 6 months post KTX such as :
1-Graft rejection
2-CMV infection.
3-Donor derived infection.
4-BK virus infection.
5-TB (reactivation or donor derived).
6-HCV, HIV and /or HBV.
7-PJP infection.
8-Respiratory Virus Infections.
9-Herpesvirus infection(EBV,HSV and VZV). How would you manage this case?
1-Send COVID-19 RT-PCR.(if came positive send Laboratory investigations included a complete blood count and serum C-reactive protein, interleukin-6, markers of myocardial damage (creatine kinase, troponin I, lactate dehydrogenase), tests of secondary hemostasis profile (prothrombin time, activated partial thromboplastin time), serum biochemical tests (including renal and liver function, and electrolytes), procalcitonin, fibrinogen, d-dimer.
2-Send CMV, BKV, HCV, HBV, and EBV PCR.
3-Respiratory panel .
4-IGRA, Manteaux, and TB culture.
5-KUB/USG for graft. 6-DSA .
6-Graft biopsy to exclude rejection. =Hospitalization with supportive treatment (indications for hospitalization were severe disease (oxygen saturation under 90%, respiratory rate above 30 breaths/min), cytokine storm (persistent fever, high or increasing CRP, ferritin, and D-dimer, abnormalities in liver function tests, hypofibrinogenemia with cytopenia in the forms of lymphopenia and thrombocytopenia). =Isolation if COVID 19 came positive and planning for vaccination later on.
=Stop Mycophenolate mofetil and continue CNI and shift steroid to IV, if worsening and our patient being in sever condition , will stop CNI and increase the steroid dose.
=Using anti-viral treatment for COVID 19 and keep in mind drug-drug interaction.
=Treatment according to the cause (for example Valgancyclovir for CMV , anti-tuberculous and so on). References:
1-Nambiar P, Silibovsky R, Belden KA. Infection in Kidney Transplantation. Contemporary Kidney Transplantation. 2018;307-327. Published 2018 Jun 27. doi:10.1007/978-3-319-19617-6_22.
2-Demir, E., Ucar, Z.A., Dheir, H. et al. COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic. BMC Nephrol23, 183 (2022). https://doi.org/10.1186/s12882-022-02784-w.
Thanks, Mohamed Any indication from the presentation to think it is a rejection? I agree that it could be COVID-19 or other viral infections including CMV. Could it be PTLD?
Thanks professor, Halawa.
Our patient has been felt lethargic, feverish and generally unwell.(which is broad and not specific presentation and may be we are stretching our D.D list but this should kept in mind).
So rejection should be one of our differential diagnosis .
Causes of fever in post-kidney transplant patients include:
Viral infections, including CMV & COVID-19 infections.
Bacterial infections, including urinary tract infections.
The patient in this scenario underwent kidney transplantation in early period of outbreak of Covid-19. Therefore, I will put Covid 19 infection on the top of the list.
============================ How would you manage this case?
Evaluation of infections in immunosuppressed hosts is challenging. It’s possible that none of the typical symptoms, signs, radiologic, serologic, or hematologic changes would manifest.
Ask about history of contact with SARS2-CoV positive patients.
Repeat chest X-Ray (the initial one was normal) +/-CT chest.
A complete blood count (lymphopenia may be seen)
Kidney function tests (creatinine & BUN)
Tacrolimus trough level
C-reactive protein (CRP)
A SARS-CoV2 PCR swab.
CMV viral load.
Treatment of Covid-19 is mainly supportive:
Reduction of immunosuppressive medications or even discontinued. However, there is no consensus on how to adjust immunosuppression & there is the risk of rejection due to reduction of immunosuppression.
Antipyretics as needed.
Intravenous fluids as needed.
Antivirals:(N.B-most of these agents were made available late after the outbreak) Drugs targeting virus entry into the cell:
Drugs interfering with protein trafficking & post-translational processing:
Nitazoxanide and ivermectin.
Drugs targeting immune response regulation:
Interferons & dexamethasone.
References
D. K. Brady et al. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection, The FEBS Journal (2022) Federation of European Biochemical Societies. doi: 10.1111/febs.16662
The only positive finding in the index case is fever in 3 months post-kidney transplantation, absence of respiratory symptoms, and no culture growth in blood and urine
CMV syndrome
Acute allograft rejection
Mycobacterium TB
PTLD
BK virus
How would you manage this case?
Investigations
Review of prior clinical history and pre-transplant investigations e.g donor status for CMV, TB, and EBV. The results of the sample collected for investigations from disease donor can be reviewed again
CMV serology (IgG, IgM), and CMV DNA
Tacrolimus level
Review drug-drug interaction
Allograft biopsy for histology
IGRA, Mantou, and preferably TB culture
EBV viral load
BK viral load in the urine and blood
Treatment
Specific treatment will be the outcome of the investigations
Antiviral agent gancyclovir or Valganciclovir can be used for CMV infection
AntiTB drugs for a minimum of six months can be used if is TB
Immunosuppression reduction should be the first line if is either PTLD or BK virus
Also, change of MMF to mTOR like sirolimus is advised for BK virus infection.
References
CMV in Kidney Transplantation. Lecture by Ahmed Halawa.
TB in Kidney Transplantation. Lecture by Ahmed Shoker
BKV in Kidney Transplantation. Lecture by Ahmed Halawa
Agrawal, Akansha, Ison, Michael G, Danziger-Isakov, Lara. Long Term Infectious Complications of Kidney Transplantaion. CJASN; 17(2): 286-295
Thanks, Isaac Any indication from the presentation to think it is a rejection? I agree that it could be COVID-19 or other viral infections including CMV. Could it be PTLD? Does BKV infection present in a similar picture?
DD:
1- acute rejection is important cause of fever in transplant recipient, may be alone orr with any infection
2- viral infection is responsible for half cases of fever in renal allograft recipients like community-acquired respiratory viruses (influenza, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2), or Legionella spp, CMV.
3- bacterial infection
4-fungal infection aspergillus, PCP
5-malignancy like PTLD
management :
1- hospitalization
2-good hydration
3-nasopharyngeal swab for influnza virus and COVID 19
4-induced sputum for PCP
5- CT chest to confirm if there is any chest findings
6-stop MMF or decreased to 50%
7-continue CNI and steroid and manage according to the clinical course
8-monitor graft function, CBC for lymphopenia
Jay A Fishman. Infection in the solid organ transplant recipient. uptodate. 2022
Thanks, Riham Any indication from the presentation to think it is a rejection? I agree that it could be COVID-19 or other viral infections including CMV. Could it be PTLD?
Thanks, Mina Any indication from the presentation to think it is a rejection? Does BKV infection present in a similar picture? Could it be a case of COVID-19 infection?
■ Regarding rejection
I thought of rejection as a differential being having high grade fever above 38 degrees
The pain or tenderness or even heaviness are not mentioned , though they are good positive signs but there absence is unreliable being a denervated graft.
■ Regarding Bk
It present with fever of Bk induced nephropathy that is mostly due to rejection, in addition there are obstructive symptoms in the form of ureteric stenosis as well, yet no evidence in the stem about obstruction.
■ Regarding The Covid I missed this very important point.
Sure it could be covid infection ,that mist be diagnosed as soon as possible by Covid pcr to adjust the myfortic dose if pOsitive swab result as well monitor Covid effect on the kidney, either by GN or tubular injury.
What is the differential diagnosis?
The patient presented with high grade fever, lethargic, unwell and on immunosuppressive therapy.
The main differential diagnoses are:
Viral infection
(COVID 19, RSV, Influenza/Parainfuenza virus, CMV, BK, EBV, Adenovirus, HSV and dengue fever)
Bacterial infection
Pneumonia, TB
Parasitic infection
Malaria
Fungal infection
PTLD
UTI
Rejection
How would you manage this case?
Admit the patient and the criteria for the ICU admission are:
low partial pressure of arterial oxygen, the inspiratory oxygen fraction (PaO2 / FiO2) ratio less than 300, oxygen saturation less than 90%, and PaO2 below 70 mm Hg despite 5 L/minute oxygen therapy, and persistent hypotension (systolic blood pressure < 90 mm Hg or mean arterial pressure < 65 mm Hg).
MDT should be involved
Full history
Clinical examination
Investigation: CBC, CRP, LFT, RFT and electrolytes, Virology PCR, (RT-PCR) testing performed on nasopharyngeal swab, blood culture, urine analysis and culture, CXR and CT, screen for DM, ECG, CNI trough level, interleukin-6, markers of myocardial damage (creatine kinase, troponin I, lactate dehydrogenase), tests of secondary hemostasis profile (prothrombin time, activated partial thromboplastin time), procalcitonin, fibrinogen, d-dimer and e-GFR
Supportive management: Control the BP and good hydration and antipyretic
Oxygen treatment was provided to patients whose oxygen saturation was below 92%
Antimetabolites were discontinued.
Trough levels were adjusted as 4–6 ng/dL for tacrolimus for stable and were stopped in hypoxemic patients. The calcineurin inhibitor levels were also monitored twice a week in hospitalized patients, once a week in outpatients.
Antibiotic therapy was administered based on the infection specialist’s decision in the presence of confirmed or suspected invasive bacterial infection
Prophylactic-dose low-molecular-weight heparin was used for inpatients unless there were contraindications.
Demir E, Ucar ZA, Dheir H, Danis R, Yelken B, Uyar M, Parmaksiz E, Artan AS, Sinangil A, Merhametsiz O, Yadigar S, Dirim AB, Akin B, Garayeva N, Safak S, Turkmen A. COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic. BMC Nephrol. 2022 May 12;23(1):183. doi: 10.1186/s12882-022-02784-w. PMID: 35550025; PMCID: PMC9097147.
High grade fever and lethargy 4 months post kidney transplant could be any type of infection viral,bacterial or fungal; in spite the time is short but malignancy could be one of the diagnosis
we need to investigate more by doing ESR,HRCT chest ,Abdominal ultrasound,CMV PCR ,TB screening
Viral ,bacterial or fungal pneumonia
What is the differential diagnosis?
Immunosuppressed patient with high grade temperature should have following differentials-
1. Covid-19 infection
2. Respiratory syncytial virus
3. Adenovirus, influenza and parainfluenza viral infection
4. HSV, HZV
5. CMV infection
6. BK viral infection
7. Acute rejection
8. Bacterial infection
How would you manage this case?
A. Detailed history
B. Physical examination
C. Investigations:
– CBC, CRP
– RFT, LFT
– Nasopharyngeal swab for covid-19 RT- PCR
– CMV PCR
– HRCT of chest
– Renal allograft biopsy
– May need BAL assessment
D. Treatment
– Modification of immunosuppression( Stop MMF, Reduction of CNI dose, increase dose of steroid)
– Supportive treatment (oxygen, I/V fluid)
– Specific treatment according to diagnosis.
What are differentials?
Usually we divide the post-transplant infection according to duration, and the most common and less common infection, like,
a. The initial first six month we face bacterial infection,
b. Viral infections,
c. Fungal infections,
d. Tuberculosis
e. otheres
How would you manage the case?
The detailed history,
Detailed examination,
Baseline investigation.
X-ray chest,
galactomanone if needed,
Viral serology.
HRCT,
And last but not the least allograft biopsy.
Management;
General management,
Treat the cause according to evidence.
What are differentials?
We divide the transplant related infection according to the most common and less common with duration of transplantation.
1. In first six months the most common infections are and differentials will be,
A. Bacterial infections,
B. Viral infections, like CMV, BKVAP, COVID-19, dengue.
C. Fungal infection,
D. Malaria,
E. Tuberculosis.
How would you manage this case?
A detailed history,
Detailed examination,
Baseline investigation,
Radiological examination,
Viral serology,
CRP, procalcitonine,
May need BAL,
Sputum for GS, C/S, and AFB,
geneXpert.
With treat according to the concluded diagnosis,
What is the differential diagnosis?
Common Causes of fever in early post-transplant
Most common cause
1- Viral infections: account for 50-70% of febrile episodes
a. CMV is the most common viral infection
b. COVID-19 is also suspected – due to highly contagious PANDEMIC, although respiratory symptoms, hypoxia are common
c. EBV related PTLD
d. RSV, influenza, parainfluenza virus – depending on community infection
e. Dengue fever – severe myalgia
2- Malaria – blood transfusion and endemicity
3- M-TB
4- Fungal infections – PCP
5- Bacterial infections – Enteric Fever
How would you manage this case?
1. Detailed clinical history – pattern of fever, associated Chill & Rigor
– CMV and EBV sero-status (donor and recipient)
– CMV- and PCP-prophylaxis
– history of contact with covid patient.
2. Clinical examination – respiratory rate, SPO2, lymphadenopathy, graft site tenderness
3-Lab investigations
– Viral screening: COVID-19 rtPCR, PCR for CMV-DNA, EBV-DNA
– CBC with PBF, ESR, MP, Widal-test
– RFT, LFT, CRP, Procalcitonin
– Sputum (induced) culture & sensitivity
– TB-skin test, IGRA
– HRCT Chest and CECT Abdomen & Pelvis
– Graft biopsy / Lymph-node biopsy
Treatment
– Antipyretics (PCM) SOS
– Temperature monitoring
– supportive treatment including good hydration and antipyretics
– Reduce MMF; minimize Tacrolimus dose, steroid – same dose / increase
Specific treatment according to underling cause
– Covid – isolation, observation, SPO2-monitoring, multivitamin.
– CMV – Valgancyclovir 900mg PO bid x 3weeks
– PCP – Bactrim-DS 2tab bid x 3weeks (dose adjusted to GFR)
– Malaria – Chloroquine / Quinine / Artesunate, depending on subtype
– Enteric fever – IV Ciprofloxacin / Inj Ceftriaxone
– Dengue – monitoring Platelet (transfusion SOS)
– EBV – reduction of IS, monitoring DNA, RFT
– PTLD – Biopsy of Graft / lymph-node reduction of IS, can try Retuximab,
Ref:
1-Peterson PK, Balfour HH Jr, Fryd DS, et al. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med. 1981 Sep;71(3):345-51
What is the differential diagnosis?Fever in a renal transplant recipient may indicate an infectious or noninfectious cause. Important noninfectious causes of fever are allograft rejection, malignancy, drug fever, and pulmonary emboli. When a renal transplant patient has a fever, the clinician should initiate an exhaustive evaluation to determine any clues to its cause.
https://medtextfree.wordpress.com/2010/09/15/fever-and-the-renal-transplant-recipient/#:~:text=Fever%20in%20a%20renal%20transplant%20recipient%20may%20indicate,evaluation%20to%20determine%20any%20clues%20to%20its%20cause.
fever early post transplant with nrgative blood and urine culture and no localizing symptoms or signs during COVID 19 period.
Differential
inculdes:
COVID 19
infection
Other viral
infection (CMV, EBV, PCP, Influenza etc)
Atypical
bacterial infection and mycobactria
Also: still
bacterial UTI( not appearing in first culture) could be.
· How would you manage this case?
· Detailed history of symptoms, duration, recent infection, travel history, contact with sick person, antibiotics, prophylaxis history).
· Admission, repeat septic work up,COVID 19 swab,
· Vitals signs monitoring specially, BP and SPO2, and reduction of antihypertensive if BP on the lower side.
· Broad spectrum antibiotics.
· Reduction of MMF by 50%and discontinuation if signs of sever sepsis or desaturation with change of prednisone to stress dose.
· Tailing antibiotics according to culture result and involvement of ID if needed.
this case is answered for second time by mistake
The first six months period is associated with maximum immune suppression with increasing risk of opportunistic infection; hence our approach has to include searching for different infectious agents.
I would recommend liver function test looking for significantly elevated liver enzymes consistent with hepatitis or cholestatic pattern reflective of infiltrative lesions.
CAT scan with contrast looking for thoracic or abdominal lymphadenopathy, pulmonary infiltrate or other intra abdomenal lesions, finding of which would be an indication to proceed with PET scan to differentiate lymphoma or other malignant lesions {which is reported to increase in incidence in the same period post transplantation}.
Opportunistic infections screening:
1]PCP, although no respiratory symptoms were reported, extra pulmonary infection might be happening in patients who are on nebulized pentamidine. PCR of sputum and blood is indicative in this patient.
2] Herpesviruses such as VZV, HSV, CMV particularly in the presence of skin rash or presence of abnormal liver function test. PCR test
3] EBV particularly in the context of lymphadenopathy. PCR test.
4] Fungal infection, Toxoplasma, Nocardia, strongyloidiasis, Listeria, leishmania and trypanosomiasis
5] hepatitis viruses: HBV, HCV and HEV.
6] BKV especially in the context of hydronephrosis or allograft function impairment.
7] most importantly TB has to be ruled out by tuberculin skin test and QuantiFERON gold test.
In case all evidences are falling short of probable diagnosis, then next step would be
1] liver biopsy.
2] Bone marrow aspirates and biopsy.
3] CSF examination.
reference:
1} N. Sarabu et al. Fever of Unknown Origin in a Kidney Transplant Recipient.American Journal of Transplantation Images in Transplantation – Continuing Medical Education (CME).Volume15, Issue7,July 2015, Pages 2006-2008.
Q1: the differential diagnosis includes:
Viral infections: covid-19, influenza virus, RSV, parainfluenza virus, HBV, HCV, HEV
Bacterial infections: UTI, Listeria, Legionella, Nocardia
Fungal: candida, aspergillus, cryptococcus
Protozoal: pneumocystis Jirovani,
Malignancy especially PTLD
Q2: lab tests including COVID PCR, CMV, and other viruses PCR if needed. Virus and blood cultures are negative. Hence, viral infections especially covid-19 should be considered.
CBC.diff, ferritin, LDH, CRP, and D-dimer to follow up with the patient. Supportive measures such as IV fluids hydration and antipyrotic are good. O2 saturation should be regularly performed and if O2 sat <= 93% oxygen support and hospitalization are needed. For these cases, dexamethasone 6 mg/day and remdesivir or paxlovid could be used.
Reduction of immunosuppression with holding MMF and reduction of CNIs with measurement of their level is part of the treatment.
Other infections will need specific treatment if their PCR is positive.
Differential diagnosis
The patient could have
Management
Transplanted patient presented with fever with no other localizing symptoms diagnosis require full history ,examination including LN and investigations to reach diagnosis putting into considerations the most common infection prevalent in this specific population and reactivation of old latent infections with immunosuppression as SOT recipients are highly susceptible to conventional and opportunistic infections, which represent a major cause of morbidity, graft dysfunction and mortality. .
the differential diagnosis
COVID-19.
PCP
CMV
EBV
UTI .
Hidden abscess.
Respiratory Syncytial virus and Influenza virus infection.
Bacterial infection although absence of symptoms is not typical.
Fungal infection.
Hepatitis A,B and c infection.
Drug induce as sirolimus pneumonitis.
Management
Symptomatic treatment:
-Antipyretic.
– IV fluid to keep good hydration.
-CBC, CRB, LDH, FERRITIN, procalcitonin.
– Kidney function test.
-Liver function test-AST, ALT, hepatitis, B and C ,
-Pan cultures (blood, urine, sputum if available).
-throat swab.
-PCR for Covid-19 , CMV, EBV .
-tacrolimus level.
-Stop of MMF.
-Stress dose steroids with shift to dexamesazone.
-Antiviral therapy remdisivir or cidofovir.
-empirical bread spectrum antibiotics.
-Specific treatment if other viral diagnosis.
-IVIG could be used.
Reference
Timsit, JF., Sonneville, R., Kalil, A.C. et al. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med 45, 573–591 (2019).
What is the differential diagnosis?
Infectious causes :
Viral infections.
Bacterial infections.
Parasite.
Lymphoproliferative disorder.
Drug induced.
How would you manage this case?Investigations after detailed history to konw the right place of infection
Blood cultures.
Viral screening
Ct scan of body to look for any abscess.
Reduce immuosuppresion.
After the first month of Transplant, we can worry less about care-related Bacterial Infections and start to worry about opportunistic infections. Among the infections we can mainly investigate:
– Fungal infection: Cryptococcosis, PPC, histoplasmosis
– Bacterial infection: tuberculosis
– Viral infection: CMV, EBV, COVID19
– Infection by parasites: Leishmaniasis
Among non-infectious causes:
– Cancer: PTLD
– Drugs: MMF/AZA
Once the patient has no signs or symptoms to target a more specific site, a screnning with imaging exam would be necessary:
– CT of the chest, abdomen, spine
Associated with serological tests or molecular markers and biomarkers in the blood:
– Galactomannan and B-Glucan
– Serologies for hepatitis, EBV, HIV, Epstein-Barr
– CMV PCR, COVID19
– Blood culture and urine culture
– IGRA
– rK39
With the result of these exams, there would be a direction for the follow-up, as biopsy or lumbar or abdominal or joint punctures may be necessary
At the same time, I would evaluate the possibility of changing immunosuppressants (MMF)
Patient is renal transplant recipient with fever after 3 months of transplant ….Patient is on triple immunosuppression…
Patient needs to get evaluated for fever in a transplant patient after 3 months….
The most common reasons for fever in this time frame are CMV infection, PCP infection, PTLD, Bacterial infections like UTI, abscess…I would also like to get COVID RT PCR and RSV infection….
If all other septic causes are negative, patient could have rejection which needs to be kept in mind…
I would get a basic workup for the fever…CBC, RFT, LFT, Procalcitonin, CRP, blood cultures and urine cultures…..CT chest and CT abdomen needs to be done to rule out infections….I could show features of COVID, CMV, PCP and any lymphadenopathy…
If there is any lymph node i would proceed with biopsy….CMV DNA PCR and bronchoscopy for PCP lavage staining is needed if there is a suspiscion of pneumonia or other CMV specific organ involvement…
I would start the patient on IV cefaperazone sulbactum (1.5gm IV BD) ad IV teicoplannin 400mg IV…Later i would taper or stop them based on the culture results…\\
Whole body PET CT scan is indicated if there is no obvious cause of fever to rule out other malignancies and may give a clue to diagnose PTLD…
I would reduce or stop the antimetabolite till we find the cause of the fever and continue low dose MMF and steroids…
Causes of fever in early post transplant
1- Viral infections: are the most common causes of early fever post transplant respponsable for more than 50% of febrile episodes ,including
a- CMV ( is the most common viral infection) ,EBV, RSV, influenza and parainfluenza virus
b- COVID 19 is also highly suspected.
2- Bacterial infections specially PCP.
3- Fungal infections
4- Non infectious causes as graft rejection.
1-Detailed history specially CMV , EBV status of both donor and recipient and previous CMV prophylaxis , history of contact with covid patient.
2-Clinical examination.
3-Lab investigations
-CBC,ESR, CRP ,procalcitonon
– S Cr, BUN ,LFT
-Serum electrolytes.
-Sputum culture &sensitivity .
-Viral screen : COVID 19 PCR ,CMV PCR , EBV PCR.
4-Radiological investigation :
-Abdomen ultrasonography
-CXR
-Chest ,abdomen and pelvis CT
Treatment
-supportive measurements including good hydration and antipyretics
– Decrease dose of MMF and increase steroid .
– Specific treatment according to underling cause
Ref :
1-Peterson PK, Balfour HH Jr, Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med. 1981 Sep;71(3):345-51
Differential diagnosis
1) COVID-19 infection
2) Other viruses – CMV, EBV, influenza, para influenza, RSV, Adenovirus, Rhinovirus
3) Bacterial infection
4) Tuberculosis
5) Fungal infection
Management
1) Monitor vital sign, may need to withhold anti-hypertensive therapy
2) Bring down the fever with paracetamol (anti-pyretic)
3) COVID-PCR
4) To reduce/withhold anti-metabolite
5) WCC (? lymphopenia or predominantly neutrophils), CRP, procalcitonin
6) SPO2 monitoring
7) Throat and nasal swab for viral panel
8) Treatment according to the organism
The current presentation favors the differential diagnosis of either viral infections or PTLD.
Differential diagnosis:
CMV
EBV
COVID-19
Influenza
Parainfluenza
RSV
Adenovirus
Rhinovirus
Bacterial infection is less likely in this clinical context and negative cultures.
Management of the case starts with diagnostic studies:
PCR COVID19
PCR BLOOD FOR EBV
PCR CMV
Nasal and throat swab for viral panel
Inflammatory markers
Abdominal imaging
Renal and liver function test
Treatment depends on the etiology based on the results of diagnostic tests
Fever in early transplant may be infectious or non infectious
infectious causes:
Viral as CMV, EBV, influenza, COVID
Bacterial PCP
Fungal
non infectious as rejection
How would you manage this case?
full history especially donor details as virology status
clinical examination
labs
routine labs plus CMV PCR, EBV PCR, COVID
radiology as abdominal USG
Treatment
supportive measures with good hydration
decrease dose of MMF
specific treatment according the cause
Causes of fever in early post transplant
1- Viral infections: are the most common causes of early fever post transplant respponsable for more than 50% of febrile episodes ,including
a- CMV ( is the most common viral infection) ,EBV, RSV, influenza and parainfluenza virus
b- COVID 19 is also highly suspected.
2- Bacterial infections specially PCP.
3- Fungal infections
4- Non infectious causes as graft rejection.
1-Detailed history specially CMV , EBV status of both donor and recipient and previous CMV prophylaxis , history of contact with covid patient.
2-Clinical examination.
3-Lab investigations
-CBC,ESR, CRP ,procalcitonon
– S Cr, BUN ,LFT
-Serum electrolytes.
-Sputum culture &sensitivity .
-Viral screen : COVID 19 PCR ,CMV PCR , EBV PCR.
4-Radiological investigation :
-Abdomen ultrasonography
-CXR
-Chest ,abdomen and pelvis CT
Treatment
-supportive measurements including good hydration and antipyretics
– Decrease dose of MMF and increase steroid .
– Specific treatment according to underling cause
Ref :
1-Peterson PK, Balfour HH Jr, Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. Am J Med. 1981 Sep;71(3):345-51.
· What is the differential diagnosis?Viral infections such as CMV , Infleunza. Rhino virus, Covid 19, EBV
Bacterial infections such as TB.
· How would you manage this case?Further detailed history and examinations
Supportive measures , Hydration, antipyretics.
Following test to be collected :CBC, renal function, liver function test. Respiratory cultures and sputum culture, stool cultures, CMV PCR, EBV PCR. AFB culture. CXR.
If any virus reported positive the case is treated accordingly.
Reduce or stop antimetabolites if the infection progress.
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
Early fever post transplant
Viral infections are the most common causes of early fever post transplant such as CMV ,EBV ,influenza , respiratory syncytial virus (RSV), human metapneumovirus (HMPV), parainfluenza virus (PIV), rhinovirus, adenovirus, polyomaviruses BK virus,herpes, hepatitis,COVID
as the period mentioned above Dec.2019 COVID 19 is highly suspected.
Bacterial infections, fungal infections and rejection were other important causes of fever.
History and clinical examination
Labs including CBC,BUN,creatinine,serum electrolytes,LDH,AST,ALT,albumin,total protein,PT,PTT,INR,CRP,RBS,ferritin
urine analysis and culture
Blood culture
Sputum culture ,AFB
COVID 19 PCR
Hepatitis ,CMV PCR and IgM
Abdomen ultrasonography
Cxr
Chest ,abdomen and pelvis CT
Treatment of COVID 19
As our mentioned above patient consider stable so supportive measurements at the top of treatment including increase fluid intake ,antipyretics ,reduction of immunosuppressive and in some cases stopping MMF.
Since remdisivir was approved for the treatment of COVID-19 and its in- teraction with CNI is yet unknown, we recommend treat- ment with remdisivir in a hospital setting where CNI drug level monitoring is available.
if severe respiratory symptoms dexamethasone should be considered
Differential diagnosis:
This patient presented with fever, lethargy no other specific clinical symptoms CXR normal, blood and urine culture negative.
Differentials are:
· Viral- Covid 19, CMV, influenza, adenovirus, parainfluenza
· Bacterial (Atypical)- Tuberculosis
· Parasitic- Malaria, Kala azar
· Fungal infection
· Malignancy: Non-Hodgkin lymphoma, Hodgkin lymphoma, Solid organ Tumour
Management:
· Detailed history and clinical examination.
· Multi-disciplinary approach along with infectious disease specialist.
· Workups will includes: CBC, PCR for Covid 19, CMV, influenza, parainfluenza and adenovirus, CRP, procalcitonin levels, D dimer levels, UECS, blood slide for malaria, LDH, ESR.
· Supportive treatment: Anti-pyretics for fever, adequate hydration, oxygen if SPO2<92%.
· Reduction/ modification of IS: Stop MMF, Reduce CNI by 50% in severe disease., Oral steroids switched to IV dexamethasone in those requiring oxygen supplementation or mechanical ventilation.
Specific treatment according to confirm diagnosis.
Fever after SOT in intermediate period 1-6 mo
infective etiology is likely and list is exhaustive viral, bacterial , parasitic and fungal
past medical History , epidemiology , vaccination , personal history, exposure are all vital to pin point the infection
multidisciplinary approach
serology is less likely to be positive so direct evidence in culture of bacteria , identification of virus , imaging suggestive of any lesion is looked for
microscopy and histology is gold standard for diagnosis
particular transplant unit may have some protocol to investigate such scenario based on prior experiences
reactivation of prior viral infection is also likely so history is very important
Differential diagnosis:
Viral infection :
Bacterial infection :
Fungal infection
PCP, cryptococcus neoformans, aspergillus, candida
Malignancy:
Management
References
Case
Differential diagnosis
Viral infection
Bacterial infection such as
Fungal infection
Acute Rejection
Different Malignancies such as
-Management
A careful history is needed including the recipient ‘s vaccination history and viral infection history or travelling history and medical data available.
Physical examination including lymph node, Hepatosplenomegaly and any Rash or lesion on Skin.
Initial investigations include.
Urinalysis, CMV PCR, QuantiFERON testing using interferon gamma assays, COVID 19 nasal swab, Antigen detection tests for adenovirus, influenza A, respiratory syncytial virus, and rotavirus.
Treatment options
CMV
multiple approaches included reduction in immunosuppressives, then addition of antiviral agents (oral valganciclovir or ganciclovir) , and in some cases adjuvant therapy.
HSV,VZV
(Diagnosed by direct fluorescence antibody for HSV and VZV from vesicular lesions or PCR from CSF or visceral tissue samples). Treated with oral acyclovir, valacyclovir, or famciclovir and for disseminated infections IV acyclovir,
EBV
EBV infection causes a mononucleosis-type syndrome and can lead to PTLD which can be treated by significant reduction in IS along with R CHOP and adoptive immunotherapy with stimulated T cells .
Polyomaviruses
Urine cytology for monitoring polyomavirus infection after transplantation.
Reduction of immunosuppression is the main therapy with monitoring for rejection is challenging
HHV-6 , HHV-7 and HHV-8
(Diagnosed by qualitative and quantitative molecular assays, by tissue immunohistochemistry or peripheral blood mononuclear cell culture).
Treatment includes reducing immunosuppression and antiviral agents.
HHV 8 can be associated with Kaposi sarcoma treated by reducing the immunosuppressive regimen and chemotherapy or foscarnet
HTLV-1
It can progress to HTLVI-associated myelopathy or to adult T cell leukemia/lymphoma. Optimal treatment yet to be defined.
HBV
Diagnosed by HB s Ag , HB c Ab , HB s Ab ,HBV PCR
Treatment involves reduction of immunosuppression and antiviral as entecavir or tenofovir.
HCV
Diagnosed by HCV PCR
Treated by DAAT
HIV
Main challenges are the pharmacologic interactions between immunosuppressives agents and some antiretroviral drugs and a higher rate of acute rejection
HPV
Treatment requires decreasing immunosuppression, topical, or surgical treatment.
Respiratory infection viruses
Treatment includes supportive care and use of antiviral medications for some cases .
Influenza can be treated with oseltamivir or zanamivir for influenza A and B.
Influenza vaccine should be administered pretransplant and every year after transplant.
Ribavirin for treatment of lower respiratory infection with RSV respiratory syncytial virus.
Reference
1. Unal E, Topcu A, Demirpolat MT, Özkan ÖF (2018) Viral Infections after Kidney Transplantation: An Updated Review. Int J Virol AIDS 5:040.
2. Jani A A. Infections After Solid Organ Transplantation.Medscape 2022.
3. Arasaratnam RJ (2015) Lower-dose valganciclovir for the prevention of cytomegalovirus after solid organ transplantation: An important tradeoff. Transpl Infect Dis 17: 623-624.
· .
1. A 21-year-old female who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
Issues/ concerns
– 21yo female, DD KTx in December 2019
– March 2020 presents with fever 39.2, lethargic, generally unwell, no respiratory symptoms
– clinical exam unremarkable apart from being febrile
– CXR clear, urine and blood culture negative
– medication: CCB and BB for HTN, Tacrolimus 2mg BD, MMF 250mg BD, Prednisone 5mg OD
What is the differential diagnosis? (1)
– this patient is in the intermediate post-transplant period (1-6 months post-transplant)
– during this period, patients face the greatest impact of immunosuppression and are at the greatest risk for development of OIs
– risk of activation of latent infections, relapsed, residual and opportunistic infections is high
– differential diagnosis: SARS-CoV-2 pneumonia, CMV, TB, other pneumonia (viral, bacterial, fungal), acute rejection, BKV, PTLD are high on my differential list
– other diagnoses to consider include:
How would you manage this case? (2-6)
– multidisciplinary approach: infectious disease team
– early, definitive diagnosis and rapid, aggressive treatment are key to optimal clinical outcomes
– detailed history and physical examination: history of contact (TB, SARS-CoV-2)
– identify and correct any modifiable risk factors: epidemiologic exposures and the net state of immunosuppression
– pre-transplant CMV, BKV, EBV serostatus
– drug history: induction therapy, use of antimicrobial prophylaxis i.e., TMP-SMX, isoniazid, nystatin, valganciclovir
– vaccination history: pneumococcal, influenza, SARS-CoV-2, meningococcal, VZV
– history of treatment for rejection since the intensive antirejection therapy increases the risk of reactivation of viral and fungal infections
– baseline investigations: CBC, ESR, CRP, procalcitonin, ferritin levels, nasopharyngeal swabs for SARS-CoV-2 RT-PCR and influenza, blood slide for malaria, stool m/c/s, IGRA, sputum gene xpert, sputum m/c/s, urine LAM, BAL for PCP and aspergillosis, CMV quantitative PCR, BKV quantitative PCR, EBV quantitative PCR, CSF analysis, serum LDH, serum CrAg, fungal markers (BDG, galactomannan), HBsAg, HCV Ab, HIV Ab, UECs, LFTs, coagulation profile, D-dimers, BGA, tacrolimus trough levels, graft biopsy
– imaging: abdominopelvic and graft ultrasound, CT (Chest, Abdomen) as indicated, screen for undrained fluid collections, blockage or leaks of anastomoses
– microbiology and tissue histology: remain the gold standard
– ELISA, direct immunofluorescence, quantitative molecular assays like NAAT in place of serologic tests since immunosuppressed patients do not reliably develop antibodies during an active infection
– supportive treatment: hydration, antipyretics
– early drainage of any fluid collections, debridement of devitalized tissues if present
– modification of immunosuppressive regimen to elicit an improved host immune response but this must be done cautiously to avoid precipitating IRIS or graft rejection
– hold MMF, she is already on a small dose at 250mg BD, maintain tacrolimus and prednisone
– specific treatment depending on the results obtained from the investigations done:
References
1. Peterson PK, Balfour HH, Jr., Fryd DS, Ferguson RM, Simmons RL. Fever in renal transplant recipients: causes, prognostic significance and changing patterns at the University of Minnesota Hospital. The American journal of medicine. 1981
Sep;71(3):345-51. PubMed PMID: 6269425. Epub 1981/09/01. eng.
2. Roberts MB, Fishman JA. Immunosuppressive Agents and Infectious Risk in Transplantation: Managing the “Net State of Immunosuppression”. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2021 Oct 5;73(7):e1302-e17. PubMed PMID: 32803228. Pubmed Central PMCID: PMC8561260. Epub 2020/08/18. eng.
3. Nair V, Jandovitz N, Hirsch JS, Nair G, Abate M, Bhaskaran M, et al. COVID-19 in kidney transplant recipients. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. 2020 Jul;20(7):1819-25. PubMed PMID: 32351040. Pubmed Central PMCID: PMC7267603. Epub 2020/05/01. eng.
4. de Matos SB, Meyer R, Lima FWM. Cytomegalovirus Infection after Renal Transplantation: Occurrence, Clinical Features, and the Cutoff for Antigenemia in a University Hospital in Brazil. Infection & chemotherapy. 2017 Dec;49(4):255-61. PubMed PMID: 29299892. Pubmed Central PMCID: PMC5754335. Epub 2018/01/05. eng.
5. Christiadi D, Karpe KM, Walters GD. Interventions for BK virus infection in kidney transplant recipients: Cochrane Database Syst Rev. 2019 May 28;2019(5):CD013344. doi: 10.1002/14651858.CD013344. eCollection 2019.
6. Cooper JE. Evaluation and Treatment of Acute Rejection in Kidney Allografts. Clinical journal of the American Society of Nephrology : CJASN. 2020 Mar 6;15(3):430-8. PubMed PMID: 32066593. Pubmed Central PMCID: PMC7057293. Epub 2020/02/19. eng.
Differential diagnosis
Fever, lethargy no clinical symptoms CXR normal, blood and urine culture negative.
High on the differential lists will be Covid 19 due to the non-specific clinical presentation and the current worldwide conditions.
Other differentials will include:
Viral- CMV, influenza, adenovirus, parainfluenza
Bacterial- TB,
Parasitic-malaria
Fungal infection
Management
Starts with a detailed history and through physical examination.
In consultation with an infectious disease specialist.
Workups will include:CBC, PCR for Covid 19, CMV, influenza, parainfluenza and adenovirus, CRP, procalcitonin levels, D dimer levels, UECS, blood slide for malaria, LDH, ESR.
Empiric treatment for covid 19 as awaits workups due to the global pandemic.
Anti-pyretics for fever.
Adequate rehydration.
Oxygen supplementation if SPO2<92%.
Stop MMF this will be adequate in mild to moderate disease.
Reduce CNI by 50% in severe disease.
Oral steroids switched to IV dexamethasone in those requiring oxygen supplementation or mechanical ventilation.
Antivirals like remdesvir can be used in though with caution since their drugs interaction in transplant recipients is not well studied.
Other medication that can be used: tocilizumab, IVIG
References
Respiratory Viruses in Solid Organ Transplant Recipients Roni Bitterman
and Deepali Kumar
Halawa et al;COVID 19 in KTR ;Case series and brief review of current evidence.Nephron 2021;145(2);192-198
Horby P et al; Recovery collaboration group; Dexamethasone in hospitalized pts with covid 19.N Eng j med .2021 feb 25;384(8).693-704
Differential diagnosis in the above post transplant case with fever and unremarkable systemic examination with no identifiable focus of infection are likely viral causes with COVID 19 as the top differential due to the current situation worldwide -other viral.infections which can be considered include CMV,influenza and parainfluenza virus.
Fungal infections
Tuberculosis
Bacterial infections
After detailed history and examination,tests which should be carried out to confirm diagnosis include:Complete blood picture,liver and renal function test,serum ldh,inflammatory markers like serum CRP,ferritin , D dimers and procalcitonin,IL-6.PCR for COVID 19,PCR for CMV DNA,and influenza virus.Tacrolimus level should also be done to detect early rejection.
Treatment
Patient should be admitted and antipyretics ,hydration with intravenous fluids and empirical antibiotics should be started.Antimetabolite I.e.,MMF should be stopped and treatment should be according to specific cause ..If Covid likely the oral steroids should be switched to I/V dexamethasone and other drugs like remdesivir ,Paxlovid, molnupiravir, favipiravir,Sotrovimab can be tried according to their availability and center protocol .But physician should be cautious while using these drugs as have many drug-drug interaction and graft function closely monitored
REFERENCES:
1-Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511
2-Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8.
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD)
DDX;
How would you manage this case?
REF;
Halawa et al;COVID 19 in KTR ;Case series and brief review of current evidence.Nephron 2021;145(2);192-198
Horby P et al; Recovery collaboration group; Dexamethasone in hospitalized pts with covid 19.N Eng j med .2021 feb 25;384(8).693-704
DD :
Infectious causes :CMV, EBV, PCP, COVID 19, reactivation of latent TB, other viral like influenza.
Non infectious: PTLD and Kaposi sarcoma.
Management :targeting underlying cause
-supportive care: hydration, antipyretic.
-Drug modifications like doubling steroid, hold MMF.
-Clinical examination & search for lymph nodes.
-Lab testing: viral PCR CMV, EBV, LFTs, LDH, TFT, blood c/s ,Tac trough levels
-Viral swab for COVID and other viruses.
-Radiology: CT chest and ECHO.
What is the differential diagnosis? Possible differentials include:
How would you manage this case?
History:
Examination:
Investigations:
Treatment:
References:
Nair V, Jandovitz N, Hirsch JS, Nair G, Abate M, Bhaskaran M, Grodstein E, Berlinrut I, Hirschwerk D, Cohen SL, Davidson KW, Dominello AJ, Osorio GA, Richardson S, Teperman LW, Molmenti EP. COVID-19 in kidney transplant recipients. Am J Transplant. 2020 Jul;20(7):1819-1825. doi: 10.1111/ajt.15967. Epub 2020 May 27. PMID: 32351040; PMCID: PMC7267603.
Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms and muted clinical and radiologic findings. Fever is neither a sensitive nor a specific predictor of infection
Viral:
· influenza, parainfluenza, respiratory syncytial virus, adenovirus, human metapneumovirus, coronavirus –
· parvovirus –
· herpes simplex virus (HSV), CMV, varicella-zoster virus (VZV; shingles),
Bacterial: urinary tract infection
Fungal infection
Opportunistic infection
Management
1. Hospitalization
2. Stabilization
3. Infectious disease consultation
4. Initial Evaluation include
History
• Recent hospitalizations or illnesses
• Social/exposure history
• Immunization status
• Comorbid conditions
• Current degree of immunosuppression
• Exposure history indicative of possible pathogen
Labs and Studies
• Complete blood count with differential-CRP-Procalcitonin
• Electrolyte and kidney function evaluation
• Liver function testing
• Influenza testing and other respiratory viral
• Blood culture – (bacterial and fungal )
Urine exam and culture
4-Antibacterial therapy is the cornerstone of the initial empiric therapy.
5- if patient is sick we may reduce MMF or even stop
Reference: UpToDate: Infection in the solid organ transplant recipient
👉 Differential diagnosis of transplant recipient with high grade fever and sense of being unwell without localizing symptoms is highly suggestive of viral infections;
1_ COVID 19.
2.other viral infection s as influenza, para influenza , RSV.
3_ CMV infection (although it is difficult in 1st 3 months with typical prophylactic therapy, but identification of V status and CMV IgG prior to transplant in both the donor and recipient is essential.
👉 Management:
_COVID PCR from nasal and throat swab to confirm diagnosis.
_CMV PCR.
_As blood and urine culture are negative, so viral infections as COVID 19 should be suspected.
_Serum LDH, ferritin, CBC for lymphopneia and CRP are used for follow up of the patient.
_isolation of the patient with caution during dealing with PPE.
_supportive measures as IV fluids, good hydration and antipyretics.
_Follow up progress of the case, If any SOB or desaturation oxygen support can be used.
_for severe cases,requiring respiratory support, we can add high dose dexamethasone 6mg/day to shorten hospital stay and fasten the recovery.
_In case of severe cases, antiviral as remdisivir and paxlovid can be used.
_IVIG can be used in case of multisystem affection as immunomodulatory.
_Reduction of IS (start with stoppage of MMF in mild cases ) and UpTo reduction of CNI in severe cases.
_in case of AKI, CVVHF can be used to remove the circulating cytokines in case of cytokine storm.
_In case of influenza virus…ribavirin and oseltamivir can be used.
_CMV infection also treated by reduction of IS plus use of ganciclovir.
· What is the differential diagnosis?
Fever more than 3years post transplant with no localizing symptom or sign.
Common cause:
1-Viral infection, like, COVID 19, influenza, CMV, PCP, RSV, etc
2-Bacterial infection
3-fungal infection,
· How would you manage this case?Detailed history of presenting complains, duration, recent travel, vaccination, prophylactic medications, contact with sick persons.
Previous infectious complications.
Rejection history and immunosuppression given.
After that, septic workup including sputum, blood culture, urine culture, ESR and CRP.
I will hold his MMF during the peak of his symptoms.
Empiric antibiotics coverage,till we have culture result back.
If confirmed COVID 19, then will keep holding MMF, give dexamethasone 8mg iv daily, ID consultation to consider anti viral and new monoclonal anti bodies like Remdesivir and Paxlovid.
Timetable of infections in renal transplant recipients
0–1 month
Bacterial: wound infection, pneumonia, urinary tract infection, pyelitis, bacteremia
Viral: herpes simplex, hepatitis
1–6 months
Viral: CMV, Epstein–Barr, varicella zoster
Fungal: Candida, Aspergillus, Cryptococcus
Bacterial: Listeria, Legionella, Nocardia
Prortozoa: Pneumocystis carinii
> 6 months
Bacterial: community micro-organism, mycobacteriosis
Viral: hepatitis B or C, CMV chorioretinitis
References;
1-Medical Complications of Kidney Transplantation Claudio Ponticelli first edition 2007
The cuases of fever in post-RTX were many
we need to know the status of CMV ,EBV,TB PRETRANSPLANt.
Early fever post-RTX could be viral or bacterial
we need to check for other causees a part from infection, like malignancy like PTLD
Urinary tract infections are the most common form of bacterial infection in the renal transplant recipient.
· gastrointestinal infections manifest with fever may be caused by CMV and other viruses or bacterial infection.
We need to look for the drug cause as well
How would you manage this case?
this patient need full history and clinical examination
need full CBC and CMP
need full sepsis work up including blood and urine culteur
need to send full viral panel including CMV,EBV,BV.
Full supportive measures; hydration, antipyretic and appropriate antibiotics for infectious agent if needed.
Three month fever post transplant with no localizing symtpoms, CXR, urine and blood culture negative.
I would like to know CMV.EBV, TB status pre transplant to narrow my DD.
DD can include:
Infection causes like CMV, EBV, PCP, COVID, reactivation of latent TB, Resp viral like influenze and RSV.
Non infection: like PTLD and haposi sarcoma, autoimmune dse (less likely given the heavy burden of immunosupression)
Manage:
What is the differential diagnosis?
KTR presented with high grade fever, which is a nonspecific but sensitive indicator of disease. The differential diagnosis for fever in the post-transplant period is as follows:
1. Infectious causes:
· Viral infection, bacterial infection or bungal infection.
· 87% of the febrile episodes occurring in the transplant patients hospitalized in the ICU were due to infections(1).
· Infections detected in the first month after transplantation are usually hospital-acquired bacterial complications related to surgical or technical problems. Bloodstream infections, catheter-related infections, nosocomial pneumonia, and surgical site infections predominate.
· Reactivation of latent infections and early fungal and viral infections account for a smaller proportion of febrile episodes during this period.
· Opportunistic infections will appear later unless an expected exposure has occurred.
· Urinary tract infections are the most common form of bacterial infection in the renal transplant recipient.
· gastrointestinal infections manifest with fever may be caused by CMV and other viruses or bacterial infection.
As a result of immunosuppression, solid organ transplant recipients are at risk of neurologic opportunistic infections that include cytomegalovirus (CMV), herpes simplex virus (HSV), varicella zoster virus (VZV), L. monocytogenes, Nocardia spp., mycobacteria, C. neoformans, Aspergillus, zygomycetes, and toxoplasmosis.
2. Non-infectious causes
a) Drugs:
· Antimetabolite immunosuppressive drugs, such as mycophenolate mofetil and azathioprine are associated with significantly lower maximum temperatures and leukocyte counts(2).
b) Metabolic causes like thyrotoxicosis.
c) Malignancy; PTLD, Kaposi sarcoma and other SOT-related malignancy.
How would you manage this case?
1. Detailed patient history and physical examination, with careful attention to skin, joints, lymph nodes, medication history (including antibiotics), travel, dietary exposure (e.g., unpasteurized milk), and animal exposure(3).
2. Basic laboratory testing (e.g., CBC, complete metabolic panel), blood cultures (2 sets), serologic tests for HIV, echocardiography, and CT of the chest, abdomen, pelvis, and other regions on the basisof symptoms and examination; ESR and CRP are commonly obtained.
3. Additional testing should be performed on the basis of the patient history, physical examination, epidemiology, exposures, imaging, and the results of the laboratory assays ordered as part of the minimal fever(FUO) evaluation (e.g., serologic or PCR testing for zoonotic or tickborne illness or endemic mycoses, evaluation for hepatitis viruses); include workup for tuberculosis or testing for rheumatologic and thyroid disorders (e.g., RF, ANA, TSH)(3).
4. I will onsider biopsy (rash, temporal artery, lymph nodes, masses, other lesions) as appropriate.
5. I will consider temporary discontinuation of new and potentially offending medications.
6. Screening for viruses if appropriate; HIV, HBV &HCV, CMV, EBV, HSV,VZV and HHV8.
7. Full supportive measures; hydration, antipyretic and appropriate antibiotics for infectious agent if needed.
References
1. Singh N, Chang FY, Gayowski T, Wagener M, Marino IR. Fever in liver transplant recipients in the intensive care unit. Clin Transplant 1999;13(6):504-11.
2. Sawyer RG, Crabtree TD, Gleason TG, Antevil JL, Pruett TL. Impact of solid organ transplantation and immunosuppression on fever, leukocytosis, and physiologic response during bacterial and fungal infections. Clin Transplant 1999;13(3):260-5. [PubMed]
3. REVIEW ARTICLE Fever of Unknown Origin.Ghady Haidar, M.D., and Nina Singh, M.D.https://www.nejm.org/doi/full/10.1056/NEJMra2111003
Thank you, Safi
You have not specifically mentioned COVID-19. Also, how would you manage the immunosuppression during infection?
COVID-19 is highly considered in the differential diagnosis of fever in this era of COVID pandemic.
of course , I will consider the possibility of COVID-19 infection in this case scenario and further adjust the dose of immunosuppression. I will adjust the dose of TAC to be in the range of 4-6 ng/ml. I will reduce the anti-metabolite dose(MMF) by 50% or even to be discontinued when there is severe leucopenia or a need to respiratory support( the patient already on a reduced dose of MMF). I will keep him on prednisolone.
A post transplant patient has presented with high grade fever with no associated symptoms and unremarkable examination.
Differential could be very vast
COVID can be considered and in prevailing circumstances it’s mandatory to do Covid PCR
Bacterial infections though no obvious focus which makes it less likely
Viral infections could present this way
CMV
Adeno virus
para influenza virus etc
Tuberculosis
Fungal infections
Further investigations can narrow down the diagnosis
Management
Definitive management would depend upon final diagnosis. In our country where infectious diseases are most common presentation of these patients we always cover them with broad spectrum antibiotics
Adequate hydration
If patient looks sick usually we stop MMF .All basic labs will be sent which included
BloodCP, Rfts Electrolytes, Lfts. Blood and urine culture, Viral PCRs if available and strongly indicated.
Antivirals can be considered like Remdesivir and Paxlovid etc
Thank you
The differential diagnosis
Management
References
1 Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020 Feb 22;395(10224):565–74. 2 Wu F, Zhao S, Yu B, Chen YM, Wang W, Song ZG, et al. A new coronavirus associated with human respiratory disease in China. Nature. 2020 Mar;579(7798):265–9. 3 Zhu L, Xu X, Ma K, Yang J, Guan H, Chen S, et al. Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression. Am J Transplant. 2020 Jul;20(7):1859–63.
Bridevaux, P.O.; Aubert, J.D.; Soccal, P.M.; Mazza-Stalder, J.; Berutto, C.; Rochat, T.; Turin, L.; Van Belle, S.; Nicod, L.; Meylan, P.; et al. Incidence and outcomes of respiratory viral infections in lung transplant recipients: A prospective study. Thorax 2014, 69, 32–38. [CrossRef] 2. Peghin, M.; Hirsch, H.H.; Len, Ó.; Codina, G.; Berastegui, C.; Sáez, B.; Solé, J.; Cabral, E.; Solé, A.; Zurbano, F.; et al. Epidemiology and Immediate Indirect Effects of Respiratory Viruses in Lung Transplant Recipients: A 5-Year Prospective Study. Am. J. Transplant. 2017, 17, 1304–1312. [CrossRef]
Thank you, Kamal
Well done
What is the differential diagnosis?This patient is at high risk of infections due to hypertension, kidney disease and immune suppression..
The differentials will include
1. Viral infections- Adeno virus , CMV, COVID 19, influenza virus
2. Bacterial infections
3. Fungal infections
How would you manage this case?The first step will be detailed history, including travel history, history of contact,
Detailed physical examination
Measurement of Oxygen saturations
Investigations-
Blood test like Blood CP, CRP, Renal Functions. Liver Functions
COVID 19PCR
CMV PCR
In case off COVID 19 , Serum ferritin and D Dimer levels.
The patient will require hospital admission and supportive care. Watching the renal functions and drug levels and reducing the MF dose will be required.
I case of COVID 19 Remdesivir can achieve early recovery.
In case of drop of oxygen levels, dexamethsone can be used.
Ahmad Z, Bagchi S, Naranje P, Agarwal SK, Das CJ. Imaging spectrum of pulmonary infections in renal transplant patients. Indian J Radiol Imaging. 2020 Jul-Sep;30(3):273-279.
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198.
Your reply is too limited. It does not address all the concerns.
I agree that investigating for COVID19 as the first step.
I appreciate your clinical approach that includes that includes commencing anti-virals. I would be stopping MMF (typed as MF by yourself) for few days rather than reducing as you suggest.
Thank you Prof
Thank you All
I can see that you all referred to COVID 19 as one of the differential although presenting symptom of pyrexia is very non specific. For the sake of discussion, I did not see a comment on the use of neutralizing antibody Sotrovimab when can be used in these cases or not to be used at all. What about the role of other antivirals such as Remdisvir, Paxolivid and Molnuprivir in these cases and risks of drug drug interactions with immunosuppression. More comments in this area are highly recommended.
drug-drug interaction COVID-19 and organ transplantation
Reference:
1.Sotrovimab: investigational drug used only for mild to moderate cases may be useful here, but not recommended for hospitalized patients and may be associated with worse out come.
2.Remdesvir:It has antiviral activity and my be use for inpatent and outpatient COIV-19 positive patients, not advised in cases of eGFR < 30 ml/min
3.Molnuprivir: It is the oral prodrug of beta-D-N4-hydroxycytidine (NHC), a ribonucleoside that has shown antiviral activity against SARS-CoV-2 in vitro and in clinical trials. Recommended in mild to moderate COVID-19 who are at high risk of disease progression ONLY when ritonavir-boosted nirmatrelvir (Paxlovid) and remdesivir are not available
3.Paxolivid: Nirmatrelvir is an oral protease inhibitor that is active against MPRO, a viral protease that plays an essential role in viral replication by cleaving the 2 viral polyproteins.1 It has demonstrated antiviral activity against all coronaviruses that are known to infect humans.2 Nirmatrelvir is packaged with ritonavir(as Paxlovid), a strong cytochrome P450 (CYP) 3A4 inhibitor and pharmacokinetic boosting agent that has been used to boost HIV protease inhibitors. This will results in significant drug-drug interactions with immune suppression particularly CNIs
source; NIH COVID-19 treatment guidelines
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
What is the differential diagnosis?3 months post transplant fever, is due to latent infection reactivation, relapsed infections, opportunistic infections, or community acquired infections.
Viral infections:
– RNA Viruses: influenza viruses, parainfluenza virus, respiratory syncytial virus, human metapneumovirus, rhinovirus, coronavirus,HCV, HEV, HAV, and HIV.
– DNA Viruses: adenovirus, bocavirus, KI and WU polyomaviruses, CMV, EBV, HBV.
Bacterial infections: atypical infections – mycoplasma, leigenalla, TB, E.coli, C.diificile…others.
Fungal infections:PJP
Noninfectious: drugs, myeloablative conditions, PTLD…etc
How would you manage this case?
Full history, contact with sick people, history of recent travel, occupational history.
Full clinical examination.
Full blood count, urinalysis, CRP, ESR, hepatitis B,C,E,A serology.
NAT-PCR for all the above mentioned viruses.
Blood, urine and throat swab culture.
Kidney function test- creatinine, BUN, Na,k.
Liver function test-AST, ALT, bilirubins, albumin, INR.
LDH, Ferritin
Tacrolimus level.
Identify Risk factors: HLA miss match, use of ATG, History of rejection.
Evaluate the hemodynamic status, volume status of the patient.
Medications:
IV hydration, antipyretics (NSAIDS should not be used).
Remdisivir for COVID-19
Ribavirin for influenza and other respiratory viruses
IVIG may be an option.
Stress dose prednisolone /steroid.
If the fever continue, can reduce immunosuppressive medications
References:
(1) Timsit, JF., Sonneville, R., Kalil, A.C. et al. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med 45, 573–591 (2019).
(2) Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511. doi: 10.1111/ctr.13511. Epub 2019 Mar 22. PMID: 30817023; PMCID: PMC7162209.
(3) Infectiosn in solid organ transplantation recipient- UpToDate.
I appreciate your clinical approach that includes anti-viral drugs, You mention steroids for stress response, that is excellent. However, that is not same as Dexamethasone if patient require respiratory support.
You have NOT mentioned stopping MMF. Your reply is well-referenced.Typing whole sentence in bold or typing in capitals amounts to shouting.
In this young patient with only fever and lethargy with no other symptoms (till that time), mostly viral infection. A detailed history and review of the systems is essential. Followup with serial evaluation (clinical and laboratory) is needed. Because of new high-dose immunosuppression, opportunistic infections should be considered.
Simple URTI of viral etiology usually has a low-grade fever though it can be serious in immunocompromised patients. Influenza usually leads to fever and muscle aches. COVID-19 may cause such a table.
We need to have CBC with differential. Lymphopenia is usually seen in viral infections.
CRP and procalcitonin may help in the differentiation of viral vs bacterial infections.
Management of this patient depends on the aetiology, but in general, we need to hydrate and give symptomatic analgesic and antipyretic. We have to be alert keeping in respect to secondary bacterial infections.
Being generally unwell, I will treat as an inpatient. Monitor for additional symptoms. I have to consider decreasing the immunosuppression in case of definitive CMV/COVİD etc. especially decreasing or stopping antiproliferative therapy.
Your reply is too limited. It does not address all the concerns.
I appreciate your clinical approach that includes stopping MMF.
A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. Urine and blood cultures were negative. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
What is the differential diagnosis?
Differential diagnoses of fever Post transplantation include:
Our Case Received a deceased donor kidney transplant in December 2019 in early period of outbreak of Covid-19, So the Covid 19 infection is the 1st DD.
Other Viral infections, CMV, EBV …. infections.
Bacterial infections, including urinary tract infections.
Fungal Infections, PJP….
This transplant patient is at a high risk of infection due to:
Immunosuppression
Underlying CKD
Hypertension, DM
How would you manage this case?
Detailed history and comprehensive clinical examination
Any history of contact with SARS2-CoV positive patients.
CT thorax without iv contrast (To confirm if there is any chest findings)
CBC, (lymphopenia may be seen)
Kidney function tests.
Urine Analysis, Urine and Blood C/S
CNIs level
C-reactive protein
Nasal and throat swab for COVID-19/PCR.
Sr. Ferritin, IL-6.
CMV viral load.
sputum for PCP
If confirmed to be COVID-19 (mild infection):
Admission in isolation room, under observation
Supportive medical therapy, good hydration (IV fluids and acetaminophen as needed).
Reduction of immunosuppressive medications or even discontinued.
Discontinued MMF or decrease 50% and continue CNIs with close graft monitoring the patient (immunosuppression treatment should be individualized based on the careful assessment of each patient)
Drugs targeting immune response regulation:
Interferons And Dexamethasone.
Dexamethasone in those receiving respiratory support (invasive mechanical ventilation or oxygen alone): resulted in lower 28-day mortality (3)
Drugs that preventing viral replicatation:
Paxlovid, remdesivir, molnupiravir, favipiravir, ribavirin, & Kaletra.
Remdesivir: The Adaptive COVID-19 Treatment Trial proved that remdesivir-treated patients had 31% faster time to recovery when compared to control (1)
Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care (2)
References
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8. PMID: 33291120; PMCID: PMC7801980.
Bitterman R, Kumar D. Respiratory Viruses in Solid Organ Transplant Recipients. Viruses. 2021 Oct 25;13(11):2146. doi: 10.3390/v13112146. PMID: 34834953; PMCID: PMC8622983.
D. K. Brady et al. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection, The FEBS Journal (2022) Federation of European Biochemical Societies. doi: 10.1111/febs.16662
RECOVERY Collaborative Group; Horby P, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
I appreciate your clinical approach that includes anti-viral drugs, Dexamethasone if patient require respiratory support, and stopping MMF. Your reply is well-referenced.Typing whole sentence in bold or typing in capitals amounts to shouting.
-Differential diagnosis
In the current case ,the recipient is 21 y old female hypertensive whom received renal graft from a decreased donor and she presented with fever 3 months post transplant without respiratory symptoms .
Blood ,urine cultures and chest xray are free
Currently on maintenance therapy Tac,MMF ,prednisolone
Differential diagnosis include
Viral infection as
Cytomegalovirus (CMV) ,Herpes simplex (HSV),Varicella zoster virus (VZV),Epstein Barr virus (EBV),Polyomaviruses (BK, JC, SV-40) ,Human herpes virus 6,7,8 (HHV),Human T-lymphotropic virus 1 and 2 (HTLV),Hepatitis B and C viruses (HBV, HCV),Human immunodeficiency virus (HIV),Human papillomavirus (HPV),Adenovirus,Respiratory syncytial virus (RSV),Influenza and parainfluenza viruses,Human metapneumovirus,Rhinovirus,Coronavirus (COVID19)
Bacterial infection as TB ,mycobacterium avium
Fungal infection
Rejection
Malignancy as non-Hodgkin lymphoma, Hodgkin lymphoma, and Kaposi sarcoma, as well as cancers of the liver, stomach, oropharynx, anus, vulva, and penis.
-Management
A careful history need to be taken including the recipient ‘s vaccination history and viral infection history , or any past medical history of importance and travelling history as well as the deceased donor’s available history and virological and medical data available .
Physical examination including lymph node assessment
Initial investigations for fever without localizing findings include Urinalysis ,CMV PCR ,QuantiFERON testing using interferon gamma assays,COVID 19 nasal swab, Antigen detection tests for adenovirus, influenza A, respiratory syncytial virus, and rotavirus; PCR may also be available
Regarding each viral infection specifically
CMV
For treatment of the established disease multiple approaches are needed involving reduction of immunosuppressives , antiviral agents as oral valganciclovir or ganciclovir , and in some cases adjuvant therapy.
HSV,VZV
Diagnosed by direct fluorescence antibody for HSV and VZV from vesicular lesions or PCR from CSF or visceral tissue samples.
Treated with oral acyclovir, valacyclovir, or famciclovir and for disseminated infections IV acyclovir,
EBV
EBV infection causes a mononucleosis-type syndrome and can lead to PTLD treated by R CHOP and adoptive immunotherapy with stimulated T cells .
Polyomaviruses
Urine cytology for monitoring polyomavirus infection after transplantation.
Reduction of immunosuppression is the main therapy meanwhile differentiating between the BKVN and rejection is challenging and crucial as it affects the outcome
HHV-6 , HHV-7 and HHV-8
Diagnosed by qualitative and quantitative molecular assays, by tissue immunohistochemistry or peripheral blood mononuclear cell culture. Treatment includes reducing immunosuppression and antiviral agents.
HHV 8 can be associated with Kaposi sarcoma treated by reducing the immunosuppressive regimen and chemotherapy or foscarnet
HTLV-1
It can progress to HTLVI-associated myelopathy or to adult T cell leukemia/lymphoma.Optimal treatment to be defined
HBV
Diagnosed by HB s Ag , HB c Ab , HB s Ab ,HBV PCR
Treatment involve reduction of immunosuppression and antiviral as entecavir or tenofovir
HCV
Diagnosed by HCV PCR
Treated by DAAT
HIV
Main challenges are the pharmacologic interactions between immunosuppressives agents and some antiretroviral drugs and a higher rate of acute rejection
HPV
Treatment requires decreasing immunosuppression, topical, or surgical treatment.
Respiratory infection viruses
Treatment include supportive care and use of antiviral medications for some cases .
Influenza can be treated with oseltamivir or zanamivir for influenza A and B.
Influenza vaccine should be administered pretransplant and every year after transplant
Ribavirin for treatment of lower respiratory infection with RSV respiratory syncytial virus.
Reference
· Chhabra D . Assessment and Management of the Kidney Transplant Patient.Medscape 2022
· Unal E, Topcu A, Demirpolat MT, Özkan ÖF (2018) Viral Infections after Kidney Transplantation: An Updated Review. Int J Virol AIDS 5:040.
· Jani A A. Infections After Solid Organ Transplantation.Medscape 2022.
· Arasaratnam RJ (2015) Lower-dose valganciclovir for the prevention of cytomegalovirus after solid organ transplantation: An important tradeoff. Transpl Infect Dis 17: 623-624.
· Cowan FM, Copas A, Johnson AM, Ashley R, Corey L, et al. (2002) Herpes simplex type 1 infection: A sexually transmitted infection of adolescence? Sex Transm Infect 78: 346-348.
I appreciate your clinical approach that has been explained really very well. Your reply is well-referenced.
What is the differential diagnosis?The index patient is a hypertensive with recent (3 month back) deceased renal transplant recipient on tacrolimus based triple drug maintenance immunosuppressive drugs, now presenting with fever and lethargy without any respiratory symptoms and having a negative chest x ray and blood and urine cultures.The differential diagnosis of such a scenario having fever in 1-6 months post-transplant include (1,2):
Viral infections: Cytomegalovirus (CMV), Herpes simplex virus (HSV), varicella zoster virus (VZV), BK polyomavirus, relapsed Hepatitis B and C virus, community-acquired viruses (adenovirus, influenza virus, parainfluenza virus, respiratory syncytial virus, metapneumonia virus) and human herpes virus- (HHV-) 6,7,and 8. In view of the timing of the presentation (March 2020), possibility of COVID-19 should also be considered in this scenario.Opportunistic infections: Pneumocystis jirovecii, Listeria, Toxoplasma, Nocardia, Aspergillus, Endemic fungi, Strongyloidiasis, reactivation of tuberculosis.Community acquired infections: Urinary tract infections, pneumonia, C. difficile colitis.Graft rejection, especially in absence of induction therapy, and non-adherence to medications, or subtherapeutic levels of calcineurin inhibitors.Lingering infections from the peri-surgical period, due to empyema, residual pneumonia, infected hematoma, etc.
How would you manage this case?The patient needs to be evaluated in details with respect to presentation of fever and lethargy (3,4).
Detailed history regarding symptoms, including any respiratory symptoms (cough and expectoration, shortness of breath), urinary symptoms (dysuria, oliguria or hematuria), weight loss, night sweats, diarrhea etc. Travel history, and exposure to someone with symptoms suggestive of COVID-19 should also be elicited. History of the deceased donor should also be elicited (to detect any donor-derived infections), and check if other recipients of organs from same donor have developed any infectious complications. History regarding induction therapy, and CMV prophylaxis should also be elicited.Complete physical examination including temperature and SpO2 for hypoxia.Laboratory testing: a) Complete blood count, Renal function test, C reactive protein, Liver function tests, urine routine microscopic examination, blood culture, urine culture, chest x ray, ultrasound abdomen including graft kidney, tacrolimus trough levels, CMV PCR quantitative.
b) Nasopharyngeal swab test for SARS-COV2 virus: Antigen and RT-PCR testing as per availability (in March 2020).
c) Sputum examination (if expectoration present) for AFB, gram stain, and cultures.
d) High resolution computed tomogram (HRCT) chest in presence of hypoxia or respiratory symptoms.
e) If diagnostic uncertainty persists, and there is clinical and radiological evidence of lower respiratory tract involvement, then invasive testing in form of bronchoalveolar lavage may be required (4).
4. Management includes:
1. Supportive: Antipyretics, maintenance of adequate hydration.
2. Specific: depending on etiology. As the timeline in the case is specifically mentioned as March 2020, the most likely diagnosis in this scenario is COVID-19.
a) COVID-19: With respect to the time of presentation, COVID-19 would be at the top of differential diagnosis. As the patient is having no respiratory symptoms at present, only observation and supportive management is required. If the patient worsens (develops respiratory symptoms and hypoxia), then further imaging and hospitalization might be required. Further treatment, depending on the severity of illness (used in March 2020) included reduction in immunosuppression (stopping MMF and reducing dose of tacrolimus), dexamethasone, hydroxycholoroquine, and ivermectin (5,6). Over 2021-2022, many more therapeutic measures for SARS-COV2 infection have been used with variable results, including remdesivir and tocilizumab.
b) CMV: CMV infection is a possibility in this scenario, especially if history of lymphocyte depleting agent use and if CMV prophylaxis not given. Treatment should be started with valganciclovir 900 mg twice a day and continued till negative CMV PCR quantitative, minimum 2 weeks (7).
References:
Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017 Apr;17(4):856-879. doi: 10.1111/ajt.14208. Epub 2017 Mar 10. PMID: 28117944.Agrawal A, Ison MG, Danziger-Isakov L. Long-Term Infectious Complications of Kidney Transplantation. Clin J Am Soc Nephrol. 2022 Feb;17(2):286-295. doi: 10.2215/CJN.15971020. Epub 2021 Apr 20. PMID: 33879502; PMCID: PMC8823942.Timsit JF, Sonneville R, Kalil AC, Bassetti M, Ferrer R, Jaber S, Lanternier F, Luyt CE, Machado F, Mikulska M, Papazian L, Pène F, Poulakou G, Viscoli C, Wolff M, Zafrani L, Van Delden C. Diagnostic and therapeutic approach to infectious diseases in solid organ transplant recipients. Intensive Care Med. 2019 May;45(5):573-591. doi: 10.1007/s00134-019-05597-y. Epub 2019 Mar 25. PMID: 30911807; PMCID: PMC7079836.Manuel O, Estabrook M; American Society of Transplantation Infectious Diseases Community of Practice. RNA respiratory viral infections in solid organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13511. doi: 10.1111/ctr.13511. Epub 2019 Mar 22. PMID: 30817023; PMCID: PMC7162209.RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, Staplin N, Brightling C, Ustianowski A, Elmahi E, Prudon B, Green C, Felton T, Chadwick D, Rege K, Fegan C, Chappell LC, Faust SN, Jaki T, Jeffery K, Montgomery A, Rowan K, Juszczak E, Baillie JK, Haynes R, Landray MJ. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.Brady DK, Gurijala AR, Huang L, Hussain AA, Lingan AL, Pembridge OG, Ratangee BA, Sealy TT, Vallone KT, Clements TP. A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection. FEBS J. 2022 Oct 20:10.1111/febs.16662. doi: 10.1111/febs.16662. Epub ahead of print. PMID: 36266238; PMCID: PMC9874604.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.
References:
I appreciate your clinical approach that has been explained really very well. Your reply is well-referenced.
What is the differential diagnosis?
The index case 4 months post-KT, on triple IS, presented with history of fever without focus and lethargy.
Blood and urine c/s negative, CXR normal.
Fever in early post-transplant period could be resulted from:
-Infection both common and opportunistic infection
– Viral illness:
– Respiratory viruses (infuenza , PIV, RSV, HMNV, adenovirus and COVID-19 ( early during the pandemic),
– CMV, EBV, HSV, VZV
– Bacterial infection: UTI, infected hematoma.
– Fungal infection: candida, aspergillus.
– Protozoal : PCP.
– Malignancy; can present only with fever.
– Rejection also fever can the only presentation ( Noting mentioned about graft function)
Management:
-Detailed history about: contact with any one with COVID, febrile illness, travelling, induction IS, urine output, review prophylaxis therapy and compliance to it. EBV& CMV donor/ recipient status.
– Thorough physical examination: including throat, lymph node, skin rash, graft tenderness.
Work up:
-CBC; lymphopenia or
-Inflammatory markers; CRP, ESR, ferritin
– Coagulation profile
– Cultures: repeat blood culture ( could have culture negative sepsis), urine.
– Respiratory multiples; test wide range of respiratory viruses
– COVID-19 Rapid antigen test, fast result with hour and COVID-19 PCR
– Liver function test: transaminitis.
– Evaluate graft function: kidney function test , urine analysis and culture.
– Abdominal US.
– Viral load PCR: CMV, EBV, BKv and other if history was suggestive.
– Tacrolimus level.
The management will be guided by the result of the tests, may need anti-microbial therapy.
Infectious disease team opinion.
If confirmed to be COVID-19:
-The presentation during the peak of COVID.
-The clinical manifestations of SARS-CoV-2 infection in SOTR are highly variable.
– Normal CXR does not exclude the diagnosis, CT has better sensitivity to detect changes, however; it may be unnecessary if patient has no respiratory symptoms and no hypoxemia.
In mild infection the treatment will be supportive, with home isolation, ensure hospital access is available.
As the patient is febrile, and lethargic better to admit her.
– Isolation precautions.
– IVF for hydration.
– Control fever try to avoid Ibuprofen.
– Discontinue MMF
-Dexamethasone if patient require respiratory support, reduce mortality.
– Remdesivir; the first drug approved by the FDA for COVID-19 treatment,
On 21 January 2022, its use was expanded to include COVID-19 treatment in non-hospitalized patients with positive results of direct viral testing who are at high risk for progression to severe COVID-19
RCT showed 87% reduction in risk of hospitalization or death among high-risk, non-hospitalized patients who received a 3-day course of remdesivir compared to those who received the placebo.
References
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8. PMID: 33291120; PMCID: PMC7801980.
Bitterman R, Kumar D. Respiratory Viruses in Solid Organ Transplant Recipients. Viruses. 2021 Oct 25;13(11):2146. doi: 10.3390/v13112146. PMID: 34834953; PMCID: PMC8622983.
RECOVERY Collaborative Group; Horby P, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
Brady, D.K., Gurijala, A.R., Huang, L., Hussain, A.A., Lingan, A.L., Pembridge, O.G., Ratangee, B.A., Sealy, T.T., Vallone, K.T. and Clements, T.P. (2022), A guide to COVID-19 antiviral therapeutics: a summary and perspective of the antiviral weapons against SARS-CoV-2 infection. FEBS J. https://doi.org/10.1111/febs.16662
I appreciate your clinical approach that includes anti-viral (Remdesivir), Dexamethasone if patient require respiratory support, and stopping MMF. Your reply is well-referenced.
What is the differential diagnosis?
This patient developed febrile illness 4 months after undergoing kidney transplantation with negative blood and urine culture besides unremarkable CXR , the differential diagnosis will be which may be due to viral infections like COVID 19 infection ,herpesviruses (HSV, VZV, CMV, EBV) HBV infection ,Infection with listeria, nocardia, toxoplasma, , leishmania.Pneumocystis Infection
============================
How would you manage this case
Start with proper history (especially contact with febrile or patients with respiratory symptoms )and clinical examination putting in mined that immunosuppressed patients .may have deceiving symptoms and signs
-Full blood counts ,graft function ,,inflammatory markers CRP
-Throat Swab for COVID 19, and herpes viruses .
-CMV IgM and PCR
-HRCT
-Prograf level
Treatment
Start with supportive measures ( oxygen, antipyretics ,IV fluids) as needed .
Reduction of immunosuppressive medications or even discontinuation may be needed . However, there is no consensus on how to adjust immunosuppression & there is the risk of rejection due to reduction of immunosuppression
Antiviral medications:
Patients with mild or moderate symptoms of COVID-19 infection and have risk factors for progression to severe illness have three FDA-approved antiviral treatments which have been shown to reduce the risk of hospitalization and death in this population. They include:
Paxlovid and Lagevrio can be taken at home, by mouth to avoid hospital admtion and risk of nosocomial infections,they must be started within five days of developing symptoms.
Veklury is given intravenously (IV) on three consecutive days , it should be started within seven days of developing symptoms.
Reference :
Treatments for COVID-19 https://www.health.harvard.edu/img/logos/NEW-HHP_logo_stack4.svg,february 28, 2023
I appreciate your clinical approach that is well referenced.
What is the differential diagnosis?
viral pneumonia including covid 19,H1N1 influenzas parainfluenza , adeno and CMV pnemonititis , Mycoplasma pneumonia, PTLD (1-6 months IF EBV +ve D /R-ve )
As she is presenting during the pandemic period of covid 19 on back ground of kidney transplant (4months ) on triple IS including tacrolimus and MMF,High grade fever with normal CXR and no URT still does not rule out the possibility of covid 19 ,as its presentation quite variable and even CXR in the early presentation with lethargy and poor oral intake, ask about history of sick contact with URT symptoms
How would you manage this case?
Assess hydration status ask about diarrhea nausea vomiting with poor oral intake , AKI more common in KTX a nd covid pneumonia ,its multifactorial including pre renal ,renal SARS-CoV-2’s direct attack of tubular cells via ACE2 receptors, other factors that may contribute to kidney injury include hypoxia, CRS, and a hypercoagulable state, drug nephrotoxicity , super added sepsis with bacteria or fungal infection.
Laboratory tests
Covid SAR-PCR, RSV screen, urine for legionella and pneumococcal antigen, CRP, FBC looking for lymphopenia, high CRP, ferritin, LDH, CMV, EBV, Adenoviral screen, RFT, LFT , Urine proteins ,electrolytes , tacrolimus trough level
isolation of the patient, monitor oxygen saturation with IVF and other supportive care with hydration paracetamol, DVT prophylaxes
Immunosuppression medication
stop MMF or reduced by 50% based on the severity of symptoms, continue on same dose tacrolimus and stress dose prednisolone 10 mg , monitor RFT and proteinuria , the use of antiviral like Remdesivir only to hasten the recovery in moderate to severe covid 19 infection and its FDA approved.
predictors for sever covid pneumonia includes high inflammatory markers like high CRP , high ferritin or IL6 , persistent lymphopenia ,thrombocytopenia are indicators of sever inflammatory response and carry high risk of ARDS with high mortality and indicate the need for antiviral course plus dexamethasone 6-10mg for 10 days , assess for the need of o2 therapy , if patient stable normal CXR and no high inflammatory markers , saturation in RA can be advised for self-isolation and treat as op with other supportive care and instruction to come back in case of persistent fever worsening respiratory symptoms , CT no indicate in such case but should be considered in case of worsening respiratory symptoms and desaturation.
Data from a very large cohort of 17 million patients showed that organ transplant recipients had an adjusted 3.55-fold higher risk of death, whereas those GFR < 30 mL/min had a 2.5-fold increased risk (2). And another study also confirm that covid 19 with AKI carry high in hospital mortality by33.7% compared to non AKI group (3).
References
1.Caillard S, Chavarot N, Francois H, Matignon M, Greze C, Kamar N, Gatault P, Thaunat O, Legris T, Frimat L, Westeel PF, Goutaudier V, Jdidou M, Snanoudj R, Colosio C, Sicard A, Bertrand D, Mousson C, Bamoulid J, Masset C, Thierry A, Couzi L, Chemouny JM, Duveau A, Moal V, Blancho G, Grimbert P, Durrbach A, Moulin B, Anglicheau D, Ruch Y, Kaeuffer C, Benotmane I, Solis M, LeMeur Y, Hazzan M, Danion F; French SOT COVID Registry. Is COVID-19 infection more severe in kidney transplant recipients? Am J Transplant. 2021 Mar;21(3):1295-1303.
2. Williamson EJ, Walker AJ, Bhaskanan K. OpenSAFELY: factors associated with COVID-19 death in 17 million patients [published online ahead of print July 8, 2020]. Nature. 10.1038/s41586-020-2521-4
3. Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int. 2020;97(5):829–838.
Yes, stopping MMF is the key step
21 year 3 months post Tx, 2019, fever and being unwell, no resp. symptoms, O/E: unremarkable, ONLY HIGH TEMP, CXR, urine and blood cultures were negative.
What is your differential diagnosis?
This is a case of a typical presentation of a febrile illness in an immunocompromised patient in the early post-transplant period.
1. Viral infection including COVID 19 (the illness occurred during the pan epidemic of COVID 19), CMV, herpes viruses.
2. Other respiratory viruses such as RSV, parainfluenza virus, adenovirus, etc..
3. PJN
4. Bacterial infection, culture is negative, but could be a culture negative infection.
5. Fungal infections
6. PTLD, is a possibility since it can be seen in the first few months post Tx, when the IS therapy is at the highest doses. History of risk factors is important.
7. TB, needs to get history of high risk such as country of origin, travel to an endemic area, latent TB in donor and recipient.
Investigations:
1. NP sample for RT PCR for COVID 19.
2. HRCT chest since CXR is normal
· IF 1 and 2 are positive this would confirm the diagnosis of COVID 19.
· CBC and serum CRP, interleukin-6, CK, troponin I, LDH
· PT, activated PTT
· RFT and LFT, and electrolytes),
· Procalcitonin, fibrinogen.
· d-dimer
· Tacrolimus level
Follow up of new occurrence of symptoms and signs
May need:
For COVID 19
Assess the severity of the disease per national guidelines
· Asymptomatic patients and patients with mild disease (oxygen saturation above 93%, no lung involvement on chest computed tomography) follow up as outpatient (This may be the index case) for recovery or deterioration.
Moderate disease (oxygen saturation above 90%, respiratory rate under 30 breaths/min) may be hospitalized and later on followed up in as outpatient if overcrowding during the panepidemic.
· Severe disease (oxygen saturation under 90%, respiratory rate above 30 breaths/min), cytokine storm (persistent fever, high or increasing CRP, ferritin, and D-dimer, abnormalities in liver function tests, hypofibrinogenemia with cytopenia in the forms of lymphopenia and thrombocytopenia) admit for ICU management.
IS medications
· If mild to moderate we can maintain IS dose (index case) as it appears that temporary withdrawal of IST was not beneficial for survival.
· If severe we can reduce the dose of MMF by 50 % as recommended in severe viral infections by the KDIGO guidelines,
· Needs to adjust Tacrolimus level to the minimum accepted level.
· Follow up of RFT for fear of AR or AKI due to the virus.
Antiviral therapy:
Were considered later on:
· Remdesivir is the only FDA approved antivirus for the treatment of COVID-19
References
1. Erol Demir, COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic, BMC Nephrology (2022) 23:183
2. Maruhum Bonar H, Management of COVID-19 in Kidney Transplant Recipients: A Single-Center Case Series,
3. NIH, COVID -19 treatment guidelines March 6 2023, International Journal of Nephrology, 18 August 2022.
How would Procalcitonin and fibrinogen be helpful in diagnosing the cause of fever?
Non-specific presentation of only fever in such scenario ( require work up such as for pyrexia of unknown origin /despite not fulfilling all criteria !) make the possibility of
so required a more detailed history about the donor especially any history of infectious diseases & revising comprehensive history of recipient and complete physical examination from head to toe and discussion with in an MDT discussion
Laboratory investigations:
imaging:
Treatment:
I appreciate that your list of DD includes acute rejection (though mistyped in your reply) malignancies and autoimmune disease. I am not sure if these explain high grade fever. But a temperature of 39.2 degree centigrade would make me consider possibilities that you mention in the sub-heading of ‘Infections’.
A case of fever in a generally unwell immunocompromised patient with negative blood and urine culture put the following differential diagnosis in consideration
I will perform the following investigations
I will start treatment in the form of
I appreciate that your list of DD includes acute rejection or hyperthyroidism. I am sure these would NOT explain high grade fever. But a temperature of 39.2 degree centigrade would make me consider first 2 among the possibilities that you mention among ‘Infections’.
There are many spelling errors, a I quote, “biobsy to be conidered if her creat is trending up.”
I appreciate that your list of DD includes malignancies and autoimmune disease. I am not sure if these explain high grade fever. But a temperature of 39.2 degree centigrade would make me consider first 2 among the possibilities that you mention in the heading of ‘Infections’.
Four months after receiving a kidney transplant from a deceased donor, this patient is experiencing feverish symptoms.
D/D
1-Infections caused by viruses include those caused by COVID 19, influenza, varicella zoster, herpes simplex, EBV, paramyxovirus, and CMV.
2-Bacterial infections: Immunocompromised transplant recipients are susceptible to any bacterial infections that can infect immunocompetent people.
When there is a fever and negative blood and urine cultures, TB is one of the possible diagnoses.
3-Candida infections, aspergillosis, and cryptococcosis
4-Fever can also be a symptom of malignancy, albeit in this case it is doubtful that the transplant and anti-rejection medicines are to blame.
Management
A more thorough history, including travel and contact information for any patients or kids who may have been ill and more thorough examination that looks for any rashes, redness, swelling, or tenderness in the lymph nodes or the graft.
Investigation;
Blood test
complete blood count, ESR, CRP, LFTs, and lactate dehydrogenase tests.
PCR for CMV, EBV, HSV, influenza, Adenivirus.
Nasal & pharyngeal swap for COVID-10 PCR.
As there is no emergency; and the Patient might receive treatment at home with an emphasis on staying well-hydrated and in regular contact with medical professionals.
Immunosupression need to monitor and dosage should be adjusted according to lab result and patient condition.
Graft function monitoring required
Viral infection in renal transplant recipients
Jovana Cukuranovic Sladjana Ugrenovic, Ivan Jovanovic, Milan Visnjic, Vladisav Stefanovic
Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron.
Comprehensive Clinical Nephrology John Feehally, DM, FRCP
Do you think an immuncompromised patient with high grade fever with the list of investigations you referred to would be managed at home? You probably think of this once you have a confirmed diagnosis!
thnak you prof.
invetigation i wrote are the general investigation in case of high fever but this patient can be manage at home, as he has no respiratory distress and saturation is maintained, but in case thing get worse, admission option can be used.
1. A 21-year-old female − who had a deceased donor kidney transplant in December 2019 presented on March 30 with a fever (39.2°C). She felt lethargic and generally unwell, with no respiratory symptoms. Clinical examination was unremarkable (apart from high temperature), and the chest X-ray was clear. She is hypertensive and maintained on calcium channels and β-blockers. She was on prednisone 5 mg once daily (OD), tacrolimus 2 mg twice a day (BD), and mycophenolate mofetil 250 mg (BD).
===================================================================
History
====================================================================
What is the differential diagnosis?
Other
COVID-19 should be considered a differential diagnosis for many conditions. The differential is very broad and includes many common respiratory, infectious, cardiovascular, oncological, and gastrointestinal diseases.
====================================================================
How would you manage this case?
History
Pulse oximetry
laboratory investigations
IF suspected COVID19
====================================================================
Reference
Thank you for the detailed discussion about potential causes. Is there any risk factor for this young patient to have aspiration pneumonia?
Do you think common cold present with such high grade temperature?
Many thanks for you Prof.Mohesn El Kossi
This patient is presenting 4 months after a kidney transplant from a deceased donor with symptoms of an infection with no clear focus
The differential diagnosis includes:
Viral infection:
Bacterial Infections:
Fungal infections:
Malignancy:
Malignancies can also present with fevers although in this patient it would be unlikely related to the transplant and anti-rejection medications
Management:
As the blood and urine cultures are negative and there is no focus of infection, the patient does not warrant antibiotics
He is hemodynamically stable and not in respiratory distress – he can be managed conservatively with supportive care as the other investigations are awaited
His inflammatory markers and graft function should be monitored closely while awaiting the results
Thank you for the comprehensive review of investigations of pyrexial immuncompromised patient. I take this sentence from your review ‘Malignancies can also present with fevers although in this patient it would be unlikely related to the transplant and anti-rejection medications’
Why malignancy unlikely and what about B symptoms in PTLD including pyrexia?
Thank you Professor Mohsen
The duration of exposure to the CNIs is only 4 months. That’s why, if it was a malignancy, it would be less likely to be directly related to the transplant and anti-rejection medications. However, if it was a missed malignancy prior to transplant, then it can present in a similar way
The B symptoms in PTLD will present in a very similar way
Differential diagnosis:
Because transplantation happened in early period of COVID-19 pandemic, COVID-19 infection should be on the top of differential diagnosis.
Management:
References:
Elhadedy M., Marie Y. and Halawa A. COVI-19 in Renal Transplant Recipient: Case series and a Brief Review of Current Evidence.Nephron,2021;145:192-198.
Well done for considering (in this index case ) home management.
Not urgent hospitalization in an immunocompromised patient can lead to other nosocomial infections.
What is the differential diagnosis?
A case of fever in post transplant patient on immunosuppression 3 months post transplant with negative blood and urine cultures,no respiratory symptoms and chest x ray is clear:Most causes of fever in post transplant patients are infections, Transplant patients are susceptible to both common and opportunistic infections. The risk of a particular infection is related to several factors including the degree of immunosuppression.The incidence of Infections are usually occur between the first and third months following transplant where in immune suppression is at its maximum during this time due to induction therapy.
DD in the current scenario can be (we will need to know regarding graft function):
The presentation of fever in TX patient in March 2019 at the time of era of COVID 19 pandemic. COVID 19 infection initially may be presented with only fever. The other DD still there:
1-CMV,BKV nephropathy.
2-Nocardia asteroides.
3-Listeria monocytogenes
4-Aspergillus fumigatus.
5-Pneumocystis jirovecii pneumonia
6-Hepatitis B and C viruses
7-Herpes simplex virus.
8-Varicella-zoster virus.
9-Epstein-Barr virus and PTLDs
10-Mycobacterium tuberculosis
How would you manage this case?
Early, specific diagnosis and rapid, aggressive treatment are essential to optimal clinical outcomes since Inflammatory responses associated with microbial invasion are impaired by immunosuppressive therapy, which results in diminished symptoms, clinical and radiologic findings. Fever is neither a sensitive nor a specific predictor of infection; up to 40 percent of infections cause no fever (especially fungal infections).
Management:
-Full proper history
-Clinical examination of transplant surgery wound and check for any physical sign that can help to diagnose cause of fever like rashes,skin redness,skin changes,enlarged lymph nodes.
-Investigations including blood tests and imaging:
Serological tests, microbiological cultures, nasal and buccal swabs and even tissue diagnosis as BAL.
-The choice of antimicrobial regimens is complex than in general population due to the urgency of therapy and the frequency of drug toxicities and drug interactions.
References:
Fishman JA. Infection in solid-organ transplant recipients. N Engl J Med 2007; 357:2601.
Sparkes T, Lemonovich TL, AST Infectious Diseases Community of Practice. Interactions between anti-infective agents and immunosuppressants-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant 2019; 33:e13510.
Thankyou what would be your sure test to confirm your diagnosis.?
What is the differential diagnosis?
Differential diagnoses of fever after transplantation include:
1. Infection: viral (responsible for over half of the febrile episodes, especially CMV), bacterial, fungal and parasitic infection
2. Acute rejection (less likely here)
3. Malignancy
How would you manage this case?Detailed history and comprehensive clinical examination
CBC, RFT & electrolytes, ESR, CRP, LFT, RBS, urine analysis, urine and blood C/S
CNI (tacrolimus) level
CMV serology/PCR
Nasal and throat swab for COVID-19/PCR, s.ferritin, IL-6, lymphopenia
This transplant patient is at a high risk of infection due to:
1. Immunosuppression
2. Underlying CKD
3. Hypertension
In 2020, 3 months post transplant presenting with only with fever and lethargy (no respiratory symptoms), normal clinical examination, clear chest x-ray, and negative urine and blood culture, COVID-19 is a high possibility especially with this high risk patient. In COVID-19, fever was reported (two large studies) to be the most common symptom (82–87%) followed by cough (44 to 65.7%)
If confirmed to be COVID-19 (mild infection):
o Admission
o Supportive medical therapy (IV fluids and paracetamol)
o Discontinued MMF with close monitoring the patient (immunosuppression treatment should be individualized based on the careful assessment of each patient)
o Remdesivir: the Adaptive COVID-19 Treatment Trial proved that remdesivir-treated patients had 31% faster time to recovery when compared to control (1)
o Case series and a small RCT suggested better outcomes with interferon and high-dose steroids in conjunction with supportive care (2)
o Dexamethasone in those receiving respiratory support (invasive mechanical ventilation or oxygen alone): resulted in lower 28-day mortality (3)
References
1. Elhadedy MA, Marie Y, Halawa A. COVID-19 in Renal Transplant Recipients: Case Series and a Brief Review of Current Evidence. Nephron. 2021;145(2):192-198. doi: 10.1159/000512329. Epub 2020 Dec 8. PMID: 33291120; PMCID: PMC7801980.
2. Bitterman R, Kumar D. Respiratory Viruses in Solid Organ Transplant Recipients. Viruses. 2021 Oct 25;13(11):2146. doi: 10.3390/v13112146. PMID: 34834953; PMCID: PMC8622983.
3. RECOVERY Collaborative Group; Horby P, et al. Dexamethasone in Hospitalized Patients with Covid-19. N Engl J Med. 2021 Feb 25;384(8):693-704. doi: 10.1056/NEJMoa2021436. Epub 2020 Jul 17. PMID: 32678530; PMCID: PMC7383595.
Thankyou ,well done but in the case series RCT the use of interferon is not without risk of rejection.
thank you prof.
yes
1.What is the differential diagnosis?-She is 3 months posttransplant according to the history
-This bring us to the differential diagnosis of infections 1 to 6 months posttransplant:
A.With PCP & Antiviral prophylaxis(CMV,HBV)
B.Anastomotic complications
C.Without proplyhaxis:
-However, this patient presented at early days of COVID-19 pandemic and therefore has symptoms are likely due to COVID-19 pneumonia. COVID-19 has re-shaped the roadmap of infections in transplant population as it can happen any time without respect to the postulated time lines of infection post transplant.
2.How would you manage this case?
References
How can in this index case HCV present with fever as the first symptom.
What do you mean by anastomotic complications!!
What would be your choice as a gold standard test.?
Thank you prof,
What is the differential diagnosis?
Upper respiratory tract infection possible bacterial infection/ COVID-19 / respiratory syncytial virus/ Influenza virus/ Aspirogliosis
CMV infection
EBV infection
Pnumocystic Jiorvecii
Also possible urinary tract infection which may appear with fever only
How would you manage this case?
History and Examination
Lab test of CBC for lymphopenia / high ESR and CRP/ high ferritin and d. dimmer/ procalcitonin level if there’s hypoxia
ABG
COVID-19 PCR and igG/ igM
CMV PCR/ serology
Urine routine and culture/ blood culture/ sputum culture if available
CT chest
Good hydration
Antipyretic agents
Antibiotic
Antiviral ( remdesivir )
Dexamethazone if there’s decrease oxygen saturation reduce anti metabolites dose to half
How fast would the index case develop ANTIBODIES (except if she had a preTX infection).ANTIGEN PCR will be more informative .
NAT is the best but more expensive.
1-What is the differential diagnosis:
-SARS-COV-2 infection (Most likely COVID-19)
–Viral and bacterial respiratory infections (eg, influenza, respiratory syncytial virus, adenovirus, Haemophilus influenzae pneumonia, Mycoplasma pneumoniae pneumonia)
-CMV infection
-Aspergillosis
2-How would you manage this case?
Evaluation & Hospitalization;
-Patient should be admitted in isolation room,
-Monitoring her vital signs , Po2 Sat. (keep Po2 sat ≥94% ),
-ABG , Prophylaxis for venous thromboembolism
-Supportive medical in the form of IV fluids and antipyretics, and symptomatic treatment with or without ward-based oxygen therapy based on the oxygen saturation ,
-Discontinued MMF and monitoring Graft functions, FK level,
Further investigations;
-CBC (lymphopenia) , CRP , Ferritin,
-Full septic screen (CMV PCR ,Respiratory Multiplex, Pneumonia Multiplex, Sputum c/s , N.P. sample for COVID-19 PCR) ,
-Bronchoalveolar lavage for aspergillosis , PCP ,
-Repeat CXR +/- HRCT scan on chest .
Use of remdesivir;
-Remdesivir (a broad-spectrum antiviral nucleotide prodrug) can be effective against MERS-CoV and SARSCoV infections,
–In the United States, the FDA approved remdesivir for hospitalized children ≥12 years and adults with COVID-19, regardless of disease severity.
-The suggested adult dose is 200 mg intravenously on day 1 followed by 100 mg daily for 5 days total (with extension to 10 days if there is no clinical improvement).
-If a patient is otherwise ready for discharge prior to completion of the course, remdesivir can be discontinued,
-F/U her as Outpatient and advised her to self-isolate at home.
References;
–Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med 2020; 382:1708.
–Day M. Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists. BMJ 2020; 368:m1086.
–Veklury. US FDA approved product information; Foster City, CA: Bristol Gilead Sciences, Inc; October 2020.
Well done.
In this index case would you proceed with a HRCT if the CXR is clear with no cough and probably normal oxygen saturation.
Thanks; our Prof.
If repeated CXR is clear with Po2Sat. >94%
no need to do HRCT.
Differential diagnosismost likely cause of pyrexia would be;
How would you manage this case?Owing to immunosuppressed condition of SOT recipient it would be difficult to ascertain the focus of infection on symptoms, it would rather need to have thorough investigation.
Management;
In case of COVID treatment with
References
UpToDate
Short but comprehensive.
Any suggested antivirals! if of any use!
What is the differential diagnosis?
Infections caused by viruses: infections due to Pneumocystis jirovecii, Nocardia asteroids, Aspergillus spp, Cryptococcus neoformans, cytomegalovirus, varicella-zoster virus, community-acquired respiratory viruses (influenza, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2), or Legionella spp.Infections are caused by bacteria, such as those that affect the urinary tract.
How would you manage this case?Take a look at the complete history of the cadaveric kidney. and physical examination of the recipient.
Conventional radiography shows less infection in these hosts. Consequently, more sensitive imaging methods like computed tomography, magnetic resonance imaging, and positron emission tomography are needed to detect infectious and malignant processes.
Microbiology and histology are the “gold standard” for diagnosis. No radiologic discovery is adequate to replace clinical samples. Multi-infections are prevalent. Thus, transplant patients with infectious disorders must have frequent invasive operations to obtain tissues or fluids for culture and histology. Invasive diagnostics may be needed for non-responders.
Serologic assays, which reveal prior pathogen exposure, are helpful pretransplant to predict disease activation risk with immunosuppression but not after transplantation. Consequently, quantitative tests that directly detect protein products or nucleic acids of organisms should be used, such as enzyme-linked immunosorbent assays, direct immunofluorescence, or quantitative molecular assays (nucleic acid amplification tests).
Acute infection may increase host response by changing immunosuppressive regimen components. Reduced immunosuppression may cause immunological reconstitution syndromes or allograft rejection.
Fishman, Jay A. “Infection in solid-organ transplant recipients.” New England Journal of Medicine 357.25 (2007): 2601-2614.
Thankyou for emphasizing the clinical presentation of the index case ,progression of her clinical course.
The golden quick confirmation in this index case would be NAT or Antigen tests (if you are testing for COVID.
If we consider the index case what do you mean by ( histological diagnosis.)
I mean histopathological (tissue biopsy if suspected malignancy like PTLD). Also, the histology of the body fluid(if the patient has pleural effusion)
What is the differential diagnosis?
How would you manage this case?
Patient with few specific symptoms, only fever and malaise with solid organ transplantation with triple immunosuppression (there is no information on the use of lymphocyte depletion).
The possibilities are:
1. Infection
For the period considering COVID-19, there were no community restrictions or the use of masks.
The period from December to March is winter-spring in the northern hemisphere, we must consider respiratory viral diseases.
CMV is also a possibility and needs to be considered, due to its high frequency in transplant patients.
Fungal infections, mycobacteria, and other viral illnesses need to be evaluated.
It is important to seek information about the donor, including serology and post-mortem diagnosis to consider the possibility that an infectious agent may have been transmitted.
Respiratory viral panel, quantitative viral load for CMV, presence of Epstein Baar, chest CT scan (high risk of respiratory disease with few symptoms and not visible on radiography).
2. Rejection
Inadequate immunosuppression may be related to fever and malaise, so it is important to measure immunosuppressants and assess their serum values. Calcineurin inhibitors present greater drug interaction and greater difficulty for serum levels.
Assessing graft function is important and, if altered, consider graft biopsy.
3. Malignancy
Risk of PTLD (main) and Polyomavirus infections.
In March 2020, all immunosuppressed patients with fever should undergo hospitalization and respiratory isolation for investigation of COVID-19. At the time, we did not have medications for proper treatment.
Arterial blood gas analysis and computed tomography are necessary, if there is a need for oxygen therapy, dexamethasone should be started at a dose of 6mg for ten days or total suppression of symptoms.
Bronchoalveolar lavage was not indicated at the time due to the risk of the team, which is why the respiratory viral panel was so important.
If Influenza, start Osentalmivir;
COVID 19, start dexamethasone;
For other respiratory viruses, evaluate inhaled ribavirin and IVIg;
CMV, start Ganciclovir.
Thanks, Filipe
Any indication from the presentation to think it is a rejection?
I agree that it could be COVID-19 or other viral infections including CMV and PTLD.
Please explain why you put rejection in the differential diagnosis.
Donor deceased less than three months ago with low doses of immunosuppressants without respiratory symptoms.
He would evaluate the renal function, if altered, the investigation would progress.
Measurement of serum levels of immunosuppressants.
There was no description of the use of lymphocyte depletion.
I thought it prudent to initiate an investigation, despite viral diseases being the most prevalent in this case.
· What is the differential diagnosis?
The differential diagnosis of fever in kidney transplant recipient includes (1):
· Infection.
· Acute rejection (less common with modern immune suppression).
· Systemic inflammatory response.
· May occur during treatment with biological agents.
· How would you manage this case?
The data, in this case scenario, is missing a lot of essential points that will affect the decision-making (e.g. the allograft functions at the time of discharge and at the time of presentation, degree of HLA mismatch, presence of signs of rejection like haematuria or oliguria).
My suggested approach:
– I will start by careful history taking, with special conidiation to any recent contact with any patient with a fever, history of travelling, or living in an area with known endemic disease (like TB). I will also ask about a sore throat or change in the bowel habit.
– Due to the COVID-19 pandemic during that time and the negative culture results, I will consider this case to be COVID-positive until appropriate investigations exclude this highly communicable disease (The patient should be isolated, and I will consider the reduction of immune suppression if possible).
– Detailed clinical examination (special attention to chest auscultation and palpation of the allograft for any tenderness).
– Routine laboratory examination (CBC, Full chemistry, Urine analysis, CRP and ESR).
– If she develops any respiratory symptoms, I will proceed directly to CT scan chest.
– General supportive care will be applied (fluid resuscitation and paracetamol) until the underlying cause is accurately defined.
Appropriate treatment will be started after identifying the cause (according to the relevant guidelines).
References:
1) Steddon S, Ashman N, Chesser A, et al. Oxford Handbook of Nephrology and Hypertension. Second edition, Oxford University Press, ISBN 978–0–19–965161–0, 2014.
Thanks, Ahmed
Any indication from the presentation to think it is a rejection?
I agree that it could be COVID-19 or other viral infections including CMV and PTLD.
Please explain why you put rejection in the differential diagnosis.
Dear Dr Ahmed,
The differential diagnosis I mentioned in reply to the first question was a general differential diagnosis for causes of fever in a kidney allograft recipient.
The presented case scenario did not mention any data regarding serum Cr, urine analysis or allograft biopsy. Therefore, there was no data suggestive of allograft rejection in the presented case.
Another rare cause of unexplained fever (with negative culture results) is an undetected haematoma. I have counted a few cases in our centre, which were published as a case series (1). the exact cause of this phenomenon is still unknown to me.
References:
1) Fever in ESRD; Does it Worth a Second Look?. Ahmed Yehia, Omar Ballut and Alaa A Sabry. ARC Journal of Nephrology. 2016; Volume 1, Issue 1, PP 11-15.
The patient had a DBD donor and currently feels lethargic and generally unwell. The patient has no respiratory symptoms. Clinical exam was unremarkable. Urine and blood culture negative. Patient has hypertension and takes calcium channel and beta blockers.
Possible differential diagnosis :
Management
References :
Thanks, Nandita
Any indication from the history to think of TB?
What is the differential diagnosis?
A case of post kidney transplant felt lethargic, feverish and generally unwell, chest X-ray was clear, Urine and blood cultures were negative all these were on COVID 19 pandemic time.
So, on top of my differential diagnosis list is (COVID 19 infection) which should be excluded by RT-PCR. Other causes on my list will be suspected as apart of common infection that occurred between 1- 6 months post KTX such as :
1-Graft rejection
2-CMV infection.
3-Donor derived infection.
4-BK virus infection.
5-TB (reactivation or donor derived).
6-HCV, HIV and /or HBV.
7-PJP infection.
8-Respiratory Virus Infections.
9-Herpesvirus infection(EBV,HSV and VZV).
How would you manage this case?
1-Send COVID-19 RT-PCR.(if came positive send Laboratory investigations included a complete blood count and serum C-reactive protein, interleukin-6, markers of myocardial damage (creatine kinase, troponin I, lactate dehydrogenase), tests of secondary hemostasis profile (prothrombin time, activated partial thromboplastin time), serum biochemical tests (including renal and liver function, and electrolytes), procalcitonin, fibrinogen, d-dimer.
2-Send CMV, BKV, HCV, HBV, and EBV PCR.
3-Respiratory panel .
4-IGRA, Manteaux, and TB culture.
5-KUB/USG for graft. 6-DSA .
6-Graft biopsy to exclude rejection.
=Hospitalization with supportive treatment (indications for hospitalization were severe disease (oxygen saturation under 90%, respiratory rate above 30 breaths/min), cytokine storm (persistent fever, high or increasing CRP, ferritin, and D-dimer, abnormalities in liver function tests, hypofibrinogenemia with cytopenia in the forms of lymphopenia and thrombocytopenia).
=Isolation if COVID 19 came positive and planning for vaccination later on.
=Stop Mycophenolate mofetil and continue CNI and shift steroid to IV, if worsening and our patient being in sever condition , will stop CNI and increase the steroid dose.
=Using anti-viral treatment for COVID 19 and keep in mind drug-drug interaction.
=Treatment according to the cause (for example Valgancyclovir for CMV , anti-tuberculous and so on).
References:
1-Nambiar P, Silibovsky R, Belden KA. Infection in Kidney Transplantation. Contemporary Kidney Transplantation. 2018;307-327. Published 2018 Jun 27. doi:10.1007/978-3-319-19617-6_22.
2-Demir, E., Ucar, Z.A., Dheir, H. et al. COVID-19 in Kidney Transplant Recipients: A Multicenter Experience from the First Two Waves of Pandemic. BMC Nephrol 23, 183 (2022). https://doi.org/10.1186/s12882-022-02784-w.
Thanks, Mohamed
Any indication from the presentation to think it is a rejection?
I agree that it could be COVID-19 or other viral infections including CMV.
Could it be PTLD?
Thanks professor, Halawa.
Our patient has been felt lethargic, feverish and generally unwell.(which is broad and not specific presentation and may be we are stretching our D.D list but this should kept in mind).
So rejection should be one of our differential diagnosis .
What is the differential diagnosis?
============================
How would you manage this case?
Antivirals:(N.B-most of these agents were made available late after the outbreak)
Drugs targeting virus entry into the cell:
Drugs that preventing viral replicatation:
Drugs interfering with protein trafficking & post-translational processing:
Drugs targeting immune response regulation:
References
Excellent as usual
No messing around, well, done.
Thank you, dear Prof. Ahmed
What is the differential diagnosis?
The only positive finding in the index case is fever in 3 months post-kidney transplantation, absence of respiratory symptoms, and no culture growth in blood and urine
How would you manage this case?
Investigations
Treatment
References
I will also want to add SAR- COV -19 as part of my differential diagnosis based on epidemiology and the timing of the illness
Thanks, Isaac
Any indication from the presentation to think it is a rejection?
I agree that it could be COVID-19 or other viral infections including CMV.
Could it be PTLD?
Does BKV infection present in a similar picture?
DD:
1- acute rejection is important cause of fever in transplant recipient, may be alone orr with any infection
2- viral infection is responsible for half cases of fever in renal allograft recipients like community-acquired respiratory viruses (influenza, respiratory syncytial virus, severe acute respiratory syndrome coronavirus 2), or Legionella spp, CMV.
3- bacterial infection
4-fungal infection aspergillus, PCP
5-malignancy like PTLD
management :
1- hospitalization
2-good hydration
3-nasopharyngeal swab for influnza virus and COVID 19
4-induced sputum for PCP
5- CT chest to confirm if there is any chest findings
6-stop MMF or decreased to 50%
7-continue CNI and steroid and manage according to the clinical course
8-monitor graft function, CBC for lymphopenia
Jay A Fishman. Infection in the solid organ transplant recipient. uptodate. 2022
N. Sarabu, C. Michael, D. E. Hricik, J. J. Augustine. Fever of Unknown Origin in a Kidney Transplant Recipient. American Journal of Transplantation.2015; 15: 2006–2008
Thanks, Riham
Any indication from the presentation to think it is a rejection?
I agree that it could be COVID-19 or other viral infections including CMV.
Could it be PTLD?
D.Diagnosis
■ Rejection either chronic abmr or tcmr or chronic allograft nephropathy
■ Cmv being in the 1st 4 months of rtx
■ BK nephropathy
■Obstructive uropathy which one of commonest causes have been underestimated but not ruled out after havine negative urine culture
■ Other differential diagnoses are underrated being i the early period post transplant, and are : PTLD and malignancies
Management :
■ CMV pcr IgM
■ Stool culture
■ Protein creatinine ratio and if there is proteinuria > gram –>Renal biopsy LM / IF and possibly EM
Thanks, Mina
Any indication from the presentation to think it is a rejection?
Does BKV infection present in a similar picture?
Could it be a case of COVID-19 infection?
Thank you our dear & great professor
■ Regarding rejection
I thought of rejection as a differential being having high grade fever above 38 degrees
The pain or tenderness or even heaviness are not mentioned , though they are good positive signs but there absence is unreliable being a denervated graft.
■ Regarding Bk
It present with fever of Bk induced nephropathy that is mostly due to rejection, in addition there are obstructive symptoms in the form of ureteric stenosis as well, yet no evidence in the stem about obstruction.
■ Regarding The Covid
I missed this very important point.
Sure it could be covid infection ,that mist be diagnosed as soon as possible by Covid pcr to adjust the myfortic dose if pOsitive swab result as well monitor Covid effect on the kidney, either by GN or tubular injury.
I meant in the comment if there is a proteinuria > 1 gram > this will mandate renal biospy.