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5. A 68-year-old woman was admitted with diarrhoea and normal kidney function. She had a cadaveric renal transplant 3 months ago for ESRD secondary to APKD. She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation). She received ATG for steroid-resistant CMR 3 weeks after transplantation. A routine infection screen and USS of her kidney were normal. Quantitative CMV PCR reported negative for CMV. Colonoscopy and biopsy are shown below:
- What is your differential diagnosis?
- How do you manage this case?
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Colonscopy show hypermia , biopsy show big cells with inclusion bodies , CMV DR+/R- support diagnosis of CMV colitis
Other DD
Other causes of diarrhea
Bacterial, viral, parasitic, traveller’s diarrhea, IBD, drug related
Management
Reduction of immunosuppression
Good hydration
Care of fluid and electrolyte balance
Iv Ganciclovir followed by oral Valganciclovir
What is your differential diagnosis?CMV colitisTBHow do you manage this case?stool analysis and culture Colonoscopy with tissue biopsyBlood PCR for CMV and TBstop MMFiv fluid
This colonoscopy displays areas of hyperemia without visible ulcers. Colonic biopsy reveals giant cells with viral inclusion bodies. Making the most likely diagnosis tissue invasive CMV.
Other diagnoses include infectious causes of diarrhea as bacterial, viral, parasitic, traveler’s diarrhea, or could be drug related as MMF or inflammatory bowel disease or antibiotic related diarrhea due to pseudomembranous colitis.
Management is by reduction of immunosuppressive therapy (withdrawal of antimetabolite and decreasing CNI dose), fluid and electrolytes resuscitation, stabilization of hemodynamics, the use of antiviral agents as gancyclovir or acyclovir. IVIG can be administered in lack of response to antiviral agents.
Colonoscopy showing mucosal inflammation and ulceration.BIopsy showingGiant cell with inclusion body characteristic of cytomegalovirus colitis.
What is your differential diagnosis?
CMV colitis
Mycophenolate drug side effect
other possible differntial-
Cryptosporidium,
Giardia,
Entamoeba
mycobacteria
Shigella
Campylobacter, and
Strongylodes
Involvement by lymphoma or kaposi sarcoma
How do you manage this case?
IV ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for kidney function .The typical duration of therapy is 21 days but is often longer, particularly for patients with tissue invasive disease
What is your differential diagnosis?
Given data:
Recent cadaveric kidney transplant, over immunosuppressed after being treated with ATG for steroid resistant ACR. His CMV sero-status(D+/R+ status). He has stable graft function but has diarrhea(CNV PCR in blood is negative , but colonoscopy shoe areas of hyperemia without visible ulcers and colonic biopsy show giant cells with viral inclusion bodies. So, the most likely diagnosis is tissue invasive CMV.
Other DD:
– Infectious causes: bacterial, viral , parasitic, traveller diarrhea)
– Drug related
– Inflammatory bowel disease
– Antibiotic related diarrhea causing pseudomembranous colitis
How do you manage this case?
· Management depends on the primary cause, supportive measures including adequate hydration and management of electrolytes) to avoid deterioration of graft functions due to the diarrhea.
· Proper counseling is given to the patient about the need to reduce immunosuppression and the risks of rejection and graft loss with this approach
· MDT approach including ID and the Transplant team
· Management of CMV colitis:
· Immunosuppression modification: Stop anti-metabolites and reduce CNIs by 25-50%(diarrhea may be caused by increased TAC exposure due to impaired metabolism). Titrate steroids upwards(pulse steroids can be given to treat ACR if present) and monitor graft function. Antimetabolites can be reintroduced once infection has cleared at a lower dose but if CMV recurs stop antimetabolites completely)
· Antiviral treatment: IV ganciclovir 5 mg/kg (adjust dose according to Creatinine clearance) for1-2 weeks then change to oral valganciclovir 900mg BID with weekly CMV PCR monitoring, graft function and FBC. Treatment is continued until 2 negative PCR results are obtained coupled with resolution of symptoms, then back to the prophylactic dose of valgancyclovir for another two months to reduce the risk of disease relapse.
· . In case of Ganciclovir resistance (no response after 2 weeks)switch to second line treatment with consideration to their side effects( Foscarnet, Letermovir, Maribavir or Cidofovir). IVIG or CMV IG to be considered.
References:
1. 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.
2. Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13550.
Infectious Causes
• Viral
• CMV
• Rotavirus and norovirus
• Bacterial
• C-Difficile
• Campylobacter
• Protozoal
• Cryptosporidium
• Giardia lamblia
• Fungal
Drug-Related
• Duodenal Villous Atrophy
• IBD-like disease (crypt
distortion)
• Graft Versus Host-like disease
(apoptosis)
treatment generaly with adjustment of immunosuppression medication, IV fluid, close observation of electrolytes, and treatment of underlying cause
Differential diagnosis include:
CMV colitis
TB
malignancy
Management :
supportive treatment of fluids and electrolytes
reduction of immunsuppression
68-year-old woman
Admitted with diarrhoea and normal kidney function.
She had a cadaveric renal transplant 3 months ago
ESRD secondary to APKD.
She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation).
She received ATG for steroid-resistant CMR 3 weeks after transplantation.
A routine infection screen and USS of her kidney were normal.
Quantitative CMV PCR reported negative for CMV.
Colonoscopy and biopsy are shown below:
● What is your differential diagnosis?
Diarrhea in intense Immunocompromised patient
Bacterial infections
Viral infections
Fungal infections
Protozoal infections
Drug related diarrhea
IBD
Colonoscopy shows colitis
Biopsy shows cell inclusions ( Giant cell ) that characters the CMV infection
● How do you manage this case?
Reduction immunosuppression
Antiviral therapy with GCV 5 mg /kg twice daily until improvement of diarrhea then switching to VGCV for 2-3 weeks
In case of resistant CMV-disease foscarnet is alternative treatment.
Reference
UK Guidelines on prevention and Management of cytomegalovirus (CMV) infection and disease following solid organ
transplantation . British Transplantation Society.April 2022.
Diarrhea is common in transplant recipients.
While the majority of cases are mild and transient, some are severe and prolonged, which can threaten graft survival through dehydration.
causes of diarrhea:
might be caused by infections, dietary problems or diarrhea-causing concomitant medications (immunosuppresion mainly MMF) and IBS .
In this case donor and recipient were CMV positive, ACR occurred in the 3 weeks post transplantation, diarrhea in the first 3 months so high possibility of CMV colitis.
Other infection may also occur as salmonella, other viral infection as rota virus
How do you manage this case?
Investigations:
CBC, CRP
KFTs
CNI trough level
Stool analysis and culture.
PCT for CMV.
treatment
– Symptomatic treatment for diarrhea with good hydration and monitor graft function.
-Biopsy shows CMV colitis with characteristic intracellular viral inclusion bodies.
Treatment mainly consist of IV Gangiclovir 5 mg every 12 hours for of 2 weeks followed by oral vanganciclovir for 2 months
-Dose adjustment of ganciclovir according to graft function
-Reduction of immunosuppression as MMF which should be stopped or decreased by 50 %.
Most cases shows good response to antiviral treatment and reduction of MMF.
Am J Transplant. 2007 Sep;7(9):2106-13.
DR Ahmad Halawa lecture
What is your differential diagnosis?
The differential diagnosis is of CMV colitis and CMV nephritis. The diarrhoea is observed after three months of transplantation, the disease is considered due to CMV infection that is considered by the Stool microbiological analysis.
How do you manage this case?
Stool test for atypical microorganisms and parasitic infection. Testing for the CMV virus infection.
Alteration in immunosuppressive drugs by Reduction or stopping of immunosuppressants. IV Ganciclovir 5mg for 4-14 days is given after the confirmation of CMV infection.
Q1: Colonoscopy shows inflamed and ulcerative colitis and her kidney shows a characteristic owl’s eye inclusion body which indicates CMV nephritis. In tissue invasive CMV disease, CMV PCR may be negative.
Other differential diagnosis includes:
-Bacterial (Campylobacter, Shigellosis, E. coli), viral (Rota virus, Norovirus), cryptosporidium, fungal or mycobacterial infections.
– MMF induced diarrhea
– Flaring of the previous IBD
– Malignancies like PTLD or colon cancer
Q2: Management includes:
-Stool exam for ova and parasites, WBC and RBCs, stool culture, C-difficile toxin assay.
– Stop antimetabolites, start IV ganciclovir at least for 5 days or until oral toleration, switch to valganciclovir and continue for at least 21 days. Monitor CBC, renal function, and electrolytes and CNI levels. In ganciclovir resistance cases consider IV foscarnet and genotype for resistant mutations.
· What is your differential diagnosis?
Diarrhea 3 months post-renal transplant, 3 weeks after treatment of rejection with ATG, CMV D+/R+, CMV PCR negative, colonoscopy showed inflamed colonic mucosa, biopsy showed inclusion body which is suggestive of viral infection.
DD includes:
1- CMV colitis: PCR can be negative in tissue invasive disease, in this case the diagnosis will depend on biopsy and histological diagnosis.
2- Viral induce gastro-enteritis like norovirus, adenovirus, covid.
3- Drug induced such as MMF.
4- Bacterial induced such as clostridium difficle.
5- Protozoal infection.
6- Part of IBD or GIT malignancy (no evidence in the index case.)
· How do you manage this case?
General measures including well hydration and correction of electrolyte disturbance.
Stool analysis and culture and sensitivity
If CMV colitis is confirmed: stop anti-metabolites, keep CNI with target trough level 5-9 ng/ml, keep steroids.
CMV antiviral treatment: IV Ganciclovir for 2 weeks at least then switch to oral once he is symptoms free.
Monitor bloods including FBC and U&Es
Treatment according to the cause
Risk factors
Donor serology positive for CMV
ATG
Steroid resistant CMR
3 M after renal transplantation
Differential diagnosis
●CMV colitis
●Viral infection:( Rota virus, Adenovirus and enterovirus)
●Bacterial infection: Clostridum difficile,
Shigella spp., Salmonella spp., Vibrio spp., Aeromonas spp., Escherichia coli, Campylobacter spp
●parasites ( Isospora belli, Cryptosporidia, Microsporidia, Pneumocystis carinii, Balantidium coli)
●fungi (including but not limited to Candida spp., Cryptococcus spp., Aspergillus spp.)
●drugs induced (MMF)
●Other causes
IBD
Cancer
Step 1: The first step was to determine the impact of nonimmunosuppressive diarrhea-inducing drugs.
all medications were recorded and checked if they cause diarrhea (anti-arrhythmics, antibiotics, anti-hypertensives, diuretics, anti-diabetic medication, laxatives, proton-pump inhibitors, protease inhibitors).
Then the drug should be stopped, or replaced, at the discretion of the investigator.
Step 2: a microbiological stool examination was performed.
The stool examination included cultures for pathogenic bacteria, examination for ova and parasites and assays for fungi. An assay for Clostridium difficile toxin was also performed.
Laboratory investigation;CBC- CRP CREA – LFT
Bacterial, If the test was positive, then the patient was given relevant antibiotic therapy at the discretion of the investigator.
Step 3: Screens for viruses
If a positive CMV case was identified or suspected, then a biopsy specimen was taken from the upper and/or lower GI tract for histology and immunoperoxidase staining.
Because PCR CMV is only positive in 50% of patients.
CMV Culture, however it may take long time.
CMV pp65 antigenaemia However false negative results may happen
Regarding of the risk factors mentioned above, we should ask if the patient is under treatment of the routine valganciclovir prophylaxis
if no we should start treatment IV ganciclovir 14 days then po valganciclovir 2-3 w after the improvement of symptoms
-viral gene typing, In case of CMV resistance;
second line therapy may be indicated.
Step 4: If no diagnosis or remission , the patient was subjected to more invasive procedures.
Step 5: stop the immunosuppression drug that may induce diarrhea (MMF)
Step 6: Patients with persistent diarrhea were then investigated via a colonoscopy with mucosal biopsies
Step 7: If patients’ diarrhea had still not resolved, empirical treatment with anti-diarrheal drugs, supplemental bacteria (e.g. Lactobacillus casei Shirota) or diets (including lactose-free diets) was allowed.
Gram positive donor tx to gram positive recipient with tissue biopsy showing Owel eye appearance of intracellular inclusion bodies.
So most probably the diagnosis is CMV tissue invasive disease.
With steroid resistant cellular rejection 3 weeks post-transplant which was treated with injection ATG.
Diarrhoea with CMV negative PCR and no graft dysfunction.
Colonoscopy shows hyperemia and biopsy shows giant cell inclusion bodies suggesting CMV tissue invasive disease.
CMV colitis is most probably the diagnosis to be confirmed by immunohistochemistry
Yet we should exclude other causes of diarrhea including
A. Infection induced diarrhea e.g cryptosporedium, cl difficile
B. Drug induced especially MMF, CNIs
C. IBD
Treatment of CMV invasive disease
Gangiclovir 5 mg iv every 12 hours for minimum of 2 weeks followed by 1 to 2 months of vanganciclovir
Dose adjustment of ganciclovir according to Creatinine clearance
Reduction of immunosuppression esp MMF which should be stopped or decreased by 50 %
Check for possible rejection with reduction in immunosuppression
Differential Diagnosis:
CMV colitis
Clostridium difficile infection
Management:
For CMV:
1. CMV PCR
2. Reduction of immunosuppression: stop MMF/AZA, continue CNI and steroids, and discuss the risk of rejection.
3. CNI levels
4. IV ganciclovir and monitoring of CMV PCR.
CMV colitis is the central differential, but ischemic colitis and other infectious colitis must be considered. MMF may be stopped due to probable effects on diarrhea but the critical treatment is antiviral therapy, usually started with iv ganciclovir, followed by oral valganciclovir. We need to investigate by checking CMV PCR, and check for c.difficile, giardia etc
In colonoscopy there are features of haemorrhagic colitis in the histology there is giant cell inclusion body with inflammatory infiltrate. So my differential diagnosis are:
– CMV colitis
– Tubercular colitis
– Clostridium difficile infection
– IBD
– Malignancy
Investigations:
– CBC, CRP
– Stool microscopy & culture
– Stool for clostridium difficile toxin
– Quantiferin TB gold test
N.B – CMV PCR may be negative in CMV colitis
Treatment:
According to cause
CMV colitis
a) Reduction of immunosuppression
b) Anti CMV therapy (I/V gancyclovir for 14- 21 days due to decrease absorption)
c) Monitoring of graft function.
Differential diagnosis:
My differentials are:
· CMV colitis
· Diarrhoea due to norovirus, giardia and cryptosporidium
· C Difficile colitis
· MMF induced diarrhoea
Management:
Refrences:
Gioco et al-Post transplant colitis after kidney transplantation ;clinical, endoscopic and histological features;2020.dec 22;12(24);24709-24720
3.Razonable et al ; CMV in SOT recipients – Guidelines of American Society of Transplantation Infectious Disease Community Of Practice .Clin Transplant.2019 sep;33(9);e13512
Prof Halawa lecture on CMV post transplant.
The colonoscopy reveal erythema and edema of colonic mucosa, histopathological study shows the characteristics owls eyes gaint cell of CMV disease.
DDx include:
CMV colitis
C.diff colitis
Cryptosporidium
MMF induced colitis
Salmonella,giardiasis
The management plan start with iv gancyclovir 5 mg /kg for 5 days followed by oral Valcyte 900mg for 2-3 weeks.
Hydration
MMF stopped temporary until recovery of infection
CNIs level should be adjusted.
D/D: CMV colitis, MMF associated diarrhoea, Infective cause( C.deficilli, giardiasis, cryptospordium etc), IBD.
Mx: supportive measure, Oral valganciclovir for CMV colitis treatment, consider valganciclovir prophylaxis, stop MMF, continue CNI & steroid.
1- CMV colitis
2- C diff infection
3- Cryptosporidium
4- Drug induced ( Tacrolimus , MMF )
5- IBD
In this case the biopsy showed CMV inclusion body, so treatment of this case is :
Reference :
1) Hand Book of Kidney Transplantation 6th edition
Back ground analysis:
68 years old female patient
3months post Renal transplant from cadaver donor – details of HLA / X match not mentioned; must have received induction (? ATG / Campath) and heavy immunosuppression
Received additional ATG for treatment of ACR
CMV sero-status: D+ / R+
Developed diarrhoea
Admitted to hospital – must be sick, dehydrated, not responding to initial out-patient treatment (antibiotics, Lactobacillus) and common general measures (ORS).
Why Colonoscopy done –
– Initial stool tests probably did not yield any conclusive result
– not responded to IV antibiotics; reduction/stopping MMF
Colonoscopy shows multiple erythematous, inflamed mucosa, ulcerative lesions;
Histology of biopsy from colonic lesion showing CMV inclusion body, which is diagnostic of CMV Colitis.
CMV DNA in blood is negative – can happen in tissue invasive CMV disease.
Diagnosis: CMV colitis (old age, heavy immunosuppression, high dose ATG Treatment, Colonic lesions with typical CMV inclusion body)
Other Differential Diagnosis:
§ MMF induced diarrhoea – common; subsides after stopping MMF
§ Infective Diarrhoea –
o Bacterial Infection: Salmonella, Cl. Difficile – common, responds to appropriate antibiotics
o viral infection – Rota virus, noro virus infection;
o protozoa / amoebic
o EBV infection (PTLD) – rare
§ Inflammatory bowel disease – bloody diarrhoea (red current gel in UC), multiple ulcerations with punched margin
§ Ischemic colitis – generally blood stained, severe abdominal pain, colonic lesions +
Must have been evaluated in detail, before invasive tests like colonoscopy and biopsy
General supportive measures – Stabilization with Intravenous + Oral hydration, Intravenous antibiotics for secondary bacterial infection – (Ciplox + Metrogyl)
Symptomatic treatment:
Anti-diarrhoeal drugs including SPOROLAC
Loperamide, in case intractable diarrhoea
Stabilization with Intravenous + Oral hydration
Tests: Complete blood count, Liver function, LDH, EBV-DNA pcr
stool – RE, ME for ova, cyst; Cl difficile toxin
Specific Medication – Inj Ganciclovir (tissue invasive disease) @ 5mg/kg IV twice daily x 5 days, followed by oral Valgancyclovir 900mg daily x 4 weeks
Weekly monitoring of TLC, Platelet, RFT
Neutropenia – might require GCSF supplement (s/C injection)
Patient usually should respond to treatment by symptom resolution in 4-5days
If diarrhoea continued –
Cl Difficile diarrhoea would respond to oral Vancomycin
Stop MMF – should respond in 3-4days
If still not resolve: Look for Ganciclovir resistance – high chance due to infection by a new strain from donor.
Genotypic analysis of CMV isolated from tissue specimen (Blood CMV DNA is negative) to detect mutation of UL97 kinase.
Gancyclovir-resistant CMV shall need Inj Foscarnet IV / IV Maribavir – with monitoring RFT, electrolytes
Responder shall be put on oral Valganciclovir prophylaxis 900mg once a day for the next 6 months, with reduction of MMF dose
Differential diagnosis:
(i) Tissue invasive CMV colitis – most probable diagnosis
(ii) Inflammatory bowel disease
(iii) C. difficile infection
Management:
– Supportive treatment: replacement of fluid
– Hold MMF temporarily
– Treatment of CMV colitis
The differential diagnosis:
In this case:
There is D+/R+ recipient with biopsy suggestive of “Owl-eye” appearance, thus its a case of CMV colitis (Invasive CMV infection)
Management of the case:
UK Guideline On Prevention And Management Of Cytomegalovirus (Cmv) Infection And Disease Following Solid Organ Transplantation
· What is your differential diagnosis?
This is a fresh deceased transplant three months back with history of strong immunosuppression for CMR. Also she was positive initially for CMV.
Currently presented with diarrhea, the picture shows erythema and infected and inflamed mucosal surfaces.
The differential are,
. CMV colitis,
. Bacterial infection,
. Protozoal infection,
. Inflammatory bowel disease,
. Other inflammatory disease.
· How do you manage this case?
. Good history,
. Examination,
. Anti-inflammatory,
. Antipyretic,
. Fluid management,
. Stool DR, ova and cyst,
. Stool culture,
. Treat according to culture and biopsy result,
. May need to adjust the immunosuppression if CMV colitis
. Anti-viral gencyclovir 5mg /kg BID.
we will send full investigation[CBC,RFT,S.electrolytic,CMV PCR,EBV PCR].
start CMV virus treatment ganciclovir vial 5mg\kg bid according to renal function for 10 to 14 days after that valganciclovir tab 900 mg daily if renal function gooD monitoring renal function and CMV PCR .
good rehydration , IV antibiotics.
Reference:
The given scenario is a post transplant patient who had received a kidney from a deceased donor 3 months ago with normal renal function now…She had received Inj ATG for her steroid resistant cellular rejection 3 weeks after transplant..She also received a kidney from CMV Donor + patient into a CMV positive recipient…
The patient has presented with diarrhea and normal renal function.. CMV DNA PCR was negative…Colonoscopy shows multiple ulcers in the colon with biopsy showing owl eyed nuclei in the lymphocytes suggestive of CMV Colitis
The differential diagnosis of diarrhea 3 months after renal transplant are
In tissue invasive CMV there are symptoms of disease with tissue presence of infection like positive biopsy….there need not be positive viral load detected….
Management includes stool routine, stool ova, cyst, CBC, LDH, Liver function test, CMV DNA PCR, EBV serology…. patient should receive IV hydration and IV antibiotics to cover for secondary bacterial infection….Treatment of choice is IV Ganciclovir as it is a tissue invasive disease which is associated with poor oral absorption…IV Ganciclovir 5mg/kg IV BD for 5 days with monitoring of CBC is needed…after atleast 5 days of IV, oral valganciclovir 900 mg twice a day is indicated for 14 days \….Neutropenia is a common side effect and patient should be supplemented with IV GMCSF as needed…If there is no response to diarrhea patient may have Ganciclovir resistance…Blood test to detect mutation of UL97 kinase can be done…Patient may need to get switched to IV foscarnet with careful monitoring for seizures, electrolyte abnormalities and nephrotoxicity….Patient needs to be put on oral Valganciclovir prophylaxis 900mg once a day for the next 3 months…
Mangement of immunosuppression reduction involves reducing the dose of antimetabolite… Continuation of CNI and steroids are indicated…
👉 The present case is old age, with Extensive immunosupression duty to ATG treatment of resistant TCMR. Presented with diarrhea and colonoscopy shows colitis (erythema and edema of colonoic mucosa).
👉 Differential diagnosis includes:
_ CMV colitis (due to presence of large inclusion bodies suggestive of viral infection).
_ MMF side effect (presented with diarrhea and GIT upset).
_other causes of infectious colitis as clostridium difficile, salmonella or parasitic or protozoal infection.
👉 Management plan:
_start anti viral for CMV infection as IV ganciclovir for 5 days then 14 days at least of oral valganciclovir.
_Stop MMf for 3_5 days until diarrhea improves to decrease GIT upset and diarrhea and to help in controlling infection.
_ Adjust dose of CNI according to the trough level (as diarrhea will increase trough level and diarrhea and dehydration can cause ATN which will be aggrevated by CNI nephrotoxicity ).
_Keep on steroids to compensate for MMF stoppage and CNI reduction.
_Adequate hydration and increase fluid intake to minimize additional risk of ATN.
👉 Basal and follow up of labs as CBC, CRP and stool analysis and culture.
_FU of the graft function.
⭐ FU by PCR will not be logic as initial PCR is negative, but FU patient for clinical improvement and by colonoscopy.
The differential diagnosis of such case would be
CMV colitis
Drug induced colitis
IBD
C diff Colitis
cryptosporidium
Norvo virus
however Histopath is suggestive of CMV colitis
Aggressive treatment with Iv Ganciclovir followed by oral valganciclovir should be started.
The patient mostly developed CMV colitis which resulted in the presenting diarrhea
he was CMV positive before transplantation and received ATG for steriod-resistant CMR early post-transplantation so he may undergo reactivation of the latent virus or may get an infection by another strain from the donor
Differential diagnosis may include other viral infections: Norovirus, Adenovirus, Rotavirus, parasitic: Entameba, Giardia, and bacterial; clostridium D, Salmonella or non-infectious causes; MMF side effects
Work up
CBC, WBCs
Chemistry & Electrolytes
ESR &septic screen
CMV culture of biopsy, immunostaining.
stool culture
clostridium diffiule toxin assay
Breath tests.
CNI level
EBV PCR
pelvi abdominal US
Treatment-
Adequate hydration of the patient
MMF should be reduced until clearance of infection then restarted again with dose up-titration considering holding off if infection recurs
steroids and CNI will be continued with close-level monitoring
For confirmed CMV; IV Ganciclovir 5mg/kg iv for 5 days followed by Valcyet 900 mg bid for 14-21 days and better extended for three months to avoid relapse
Biweekly CMV monitoring,
What is your differential diagnosis?
My differentials will be:
· CMV colitis
· Diarrhoea due to norovirus, giardia and cryptosporidium
· C Difficile colitis
· MMF induced diarrhoea
Management
Gioco et al-Post transplant colitis after kidney transplantation ;clinical, endoscopic and histological features;2020.dec 22;12(24);24709-24720
3.Razonable et al ; CMV in SOT recipients – Guidelines of American Society of Transplantation Infectious Disease Community Of Practice .Clin Transplant.2019 sep;33(9);e13512
Prof Halawa lecture on CMV post transplant.
Well done. Following successful treatment what would be your recommendations?
What is your differential diagnosis?
How do you manage this case?
I will adopt MDT approach and will involve Infectious disease and gastroenterology team.
The investigations will include Full blood count, CRP, Renal and liver functions.
C Difficile Toxin test
CMV PCR
Management will start with rehydration and maintaining an electrolyte balance.
I will start treatment and monitor it. I will start with IV ganciclovir according to renal functions and monitor the treatment.
I will check viral load at 2 week and then weekly.
I will halt the treatment once symptoms have resolved and two negative CMV PCR are achieved.
I will hold MMF for 2-3 weeks and watch graft functions. MMF can be restarted at lower doses but DNA PCR should be monitored.
Reference
Yerushalmy-Feler A, Padlipsky J, Cohen S. Diagnosis and Management of CMV Colitis. Curr Infect Dis Rep. 2019 Feb 15;21(2):5. doi: 10.1007/s11908-019-0664-y. PMID: 30771028.
What is your differential
– Tissue-invasive CMV disease(CMV colitis)
-Drug induced diarrhea (MMF)
-Clostridium difficle infection.
How do you manage this case?
– CBC , and RFT.
-Stool analysis and culture.
-C.difficle toxin assay.
-Rehydration.
– Started IV ganciclovir for a duration of at least 2 weeks and adjust the dose of ganciclovir according creatinine clearance.
-Assess CMV viral load after 2 weeks of treatment and repeat at a minimum interval of 7 days and consider stopping treatment for CMV disease after resolution of symptoms and two consecutive, CMV viral load tests that confirm that CMV is not detected.
Reference:
-UK GUIDELINE ON PREVENTION AND MANAGEMENTOF CYTOMEGALOVIRUS (CMV) INFECTION ANDDISEASE FOLLOWING SOLID ORGANTRANSPLANTATION.
OUR CASE.
68 yr old woman with post transplant diarrhoea
Normal UECS.
2 Months post transplant.
97ESRD from ADPKD.
RISKS;
CMV D+/R+
ATG for steroid resistant CMR 3 WEEKS POST TRANSPALNT.
RESULTS;
CMV PCR – Neg
Biopsy- Inclusion bodies typical of CMV.
DIAGNOSIS ; Severe CMV- Invasive dx with colitis.
DDX;
INFECTIOUS ;
Bacterial ; C .difficile, Salmonella, Bacterial overgrowth.
Virus ; Norovirus, Rotavirus, Sapovirus.
Parasitic ;Giadia, Cryptosporida,Isospora cyclospora, Entaoeba
NON INFECTIOUS;
IS meds- Tac, MMF
Others – PTLD, IBD, Colon CA
MANAGEMENT.
1.MDT approach, Gastro team, ID team and Transplant nephrologist.
2.Admit the pt for hydration and regular monitoring of graft function, CMV mgt and monitoring.
3.We would do ;
a. Baseline tests ; FHG -assess for neutropenia before starting treatment, LFTS, LDH, RBS, Uric acid and PITC
b. Investigate other causes of diahrrea post transplant ; stool MCS, ova and cyst, Mutiplex PCR -Norovirus, C .difficile PCR, Giardia and cryptosporidia EIA, Breath tests for bacterial overgrowth etc.
4.Immunosuppressive meds and Treatment;
a. Stop all antimetabolites, maintain Tacrolimus and Steroids, We treat CMV ,monitor with regular colonoscopy and PCR, at the end of treatment ,if cleared, we consider restarting MMF at a lower dose ,if it recurs, we stop it indefinitely.
b. Start IV ganciclovir mg/kg bd, renal dose it for 5 days then PO Valganciclovir 900 mg BD for 21 days, possibility of treatment to be extended for 3 months to prevent relapse can be assessed depending on how the patient tolerates treatment.
c. PCR can be done weekly to determine viral replication status during treatment and possibly a repeat endoscopy at end of treatment to monitor our treatment. In the event the PCR becomes positive in our case and VL starts creeping up despite treatment, we would test for resistance, UL97 and UL 54 mutations then opt for alternative treatment with renal monitoring ; Cidofovir/Foscarnet/ Maribavir/ Letermovir.
d. Regular monitoring of FHG to look out for neutropenia and if it occurs we explore other causes post transplant including septrin use and opt for GM-CSF administration and reserve decreasing of antiviral dose to last option to avert CMV resistance from exposing patient to sub therapeutic drug level.
REFERENCES;
1.Prof Halawa lecture on CMV post transplant.
2.Gioco et al-Post transplant colitis after kidney transplantation ;clinical, endoscopic and histological features;2020.dec 22;12(24);24709-24720
3.Razonable et al ; CMV in SOT recipients – Guidelines of American Society of Transplantation Infectious Disease Community Of Practice .Clin Transplant.2019 sep;33(9);e13512
1-CBC
2-LFT.RFT.(FULL CHEMISTRY).
3-ESR &CRP
4-STOOL analysis and stool culture.
4-CMV PCR.
5- clostridium diffiule toxin assay.
TREATMENT
I.V. fluid to replace the fluid loss.
I, V ganciclovir 5mg/kg every 12 hours for 5 days and them ganciclovir 900 mg bid for 2 to 3 weeks and continue for more 6 months from the clearance of the virus
hold MMF for days.
decrease CNIA drug level to the lower acceptable level
References
1-PROF AHMED HALWALECTURE OF CMV POSTTRANSPLANT.
.
A 68-year-old woman was admitted with diarrhoea and normal kidney function. She had a cadaveric renal transplant 3 months ago for ESRD secondary to APKD. She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation). She received ATG for steroid-resistant CMR 3 weeks after transplantation. A routine infection screen and USS of her kidney were normal. Quantitative CMV PCR reported negative for CMV. Colonoscopy and biopsy are shown below:
What is your differential diagnosis?
1- CMV Colitis (tissue invasive disease)
2. Inflammatory bowl disease(IBD)
3. Clostridium Difficile(CD)
4. Drug (MMF) induced colitis
5. Other infectious cause of colitis
6. Malignancy : Colon cancer, PTLD
How do you manage this case?
Workup:
– CBC with Diff , CRP , Lytes, Creatinine, Urea, LFTs, CNIs Level
– Stool Workup (Analysis, Ova , Parasites , Culture , C Diff)
– Blood CMV PCR , EBV PCR , Norovirus, Rotavirus, Adenovirus
– US for abdomen/ Pelvis
– The histological work up (CMV infection ), The diagnosis of CMV colitis is by
histopathology with immuno-histochemistry or viral culture of tissue specimens.
TREATMENT:
1- MMF Discontinued For a week or Two .
2- Continue CNIs With Low target Level
3- Continue steroids
4- Treatment as Sever CMV è IV Ganciclovir recommended dose as 5mg/kg iv for 5
days then 900 mg bid for 14-21 days and , recommended colonoscopy after one month
for tissue biopsy again.
5- Continue Valganciclovir prophylaxis for another 6 month from clearance of the virus by
tissue biopsy.
6- Consider resuming MMF after 1-2 weeks for confirmed pathology clearance of the
virus by half the dose and titrate it to usual doe 1000 mg bid from 1-2 month .
Reference :
1. Prof Ahmed Halawa lecturer of CMV post transplant
2. Am J Transplant. 2007 Sep;7(9):2106-13. doi: 10.1111/j.1600
6143.2007.01910.x. Epub 2007 Jul 19
DD:
CMV tissue invasive colitis, infectious colitis. Inflammatory bowel disease ,c difficile infection and MMF induced colitis
Management:
Supportive treatment including IV fluids
MMF discontinuation with close monitoring of renal function
Gancylovir 5mg/kg bid or adjusted for GFR for 21 days then switch to Valgancyclovir and continue for 6months with renal dosing.
Re adminstration of MMF at lower doses and monitor DNA PCR
In case of poor response ,we consider IVIG.
Drug resistance to be considered with use of Foscanet.
I agree that one would discontinue antimetabolites for few days.
Colonoscopy showing CMV Colitis
Giant cell with inclusion body characteristic of CMV Colitis
1-First of all we should exclude the other causes of diarrhea
((infectious causes with stool culture, C.diff toxins, norovirus, giardia and cryptosporidium.))
2-immunosuppression side effect like MMF
Management
Ganciclovir is the treatment of choice for CMV colitis at a dose of 5 mg/kg intravenously every 12 hours for 2 to 3 weeks, but a switch to oral valganciclovir may be an alternative, allowing outpatient-based therapy after 3 to 5 days if early clinical response is seen, for the remainder of the treatment course.
Myelotoxicity is the major adverse effect of ganciclovir with up to 40% of patients demonstrating features of bone marrow sup- pression.
Other side effects include headache, somnolence, psy- chosis, deranged liver function tests, and based on animal data, inhibition of male and female infertility which is typically but not always reversible, and fetal toxicity. Foscarnet is a possible alter- native in the event of resistance or intolerance to ganciclovir but has other side effects including nephrotoxicity, central nervous system abnormalities, and metabolic derangements.
The commencement of antiviral therapy does not necessar- ily mandate interruption of immunosuppressive therapy, given that most CMV reactivation is subclinical or mildly symptomatic. However in cases of severe CMV colitis or other end-organ disease, reduction or cessation of concurrent immunosuppression is warranted
Reference
1-Lauren Beswick, MBBS, BSc Hons, FRACP,*,† Bei Ye, MBBS, BMedSci, FRACP,*,† and Daniel R. van Langenberg, MBBS, PhD, FRACP*, †. Toward an Algorithm for the Diagnosis and Management of CMV in Patients with Colitis.
Inflamm Bowel Dis Volume 22, Number 12, December 2016
2- Lecture of CMV in Kidney Transplantation By Ahmed Halawa Consultant Transplant Surgeon. Associate Professor, University of Liverpool – UK
I like your comprehensive approach
5. A 68-year-old woman was admitted with diarrhoea and normal kidney function. She had a cadaveric renal transplant 3 months ago for ESRD secondary to APKD. She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation). She received ATG for steroid-resistant CMR 3 weeks after transplantation. A routine infection screen and USS of her kidney were normal. Quantitative CMV PCR reported negative for CMV. Colonoscopy and biopsy were done.
What is your differential diagnosis? (1-5)
– most likely she has CMV colitis given the colonoscopy and biopsy findings
Other differential diagnosis would include: –
– Bacterial e.g., E. coli, Klebsiella, Shigella, Citrobacter, C. difficile, M. tuberculosis
– Protozoal e.g., E. histolytica, Giardia, Cryptosporidia, Microsporidia, Cyclospora
– Noninfective causes like post-transplant lymphoproliferative disease (PTLD), Kaposi sarcoma (KS), inflammatory bowel disease (IBD), Ca colon, drug-induced diarrhoea (especially the mycophenolic analogues)
– Diarrhoea in kidney transplant recipients can be infective and noninfective.
– Risk factors: – deceased donor transplantation, induction immunosuppression, antirejection therapy
– GI complications post-kidney transplantation is associated reduced quality of life, decline in graft function, high mortality.
How do you manage this case? (2, 3, 5)
– Detailed history and thorough physical examination i.e., fever, night sweats, weight loss, lymphadenopathy.
– Baseline investigations e.g., FHG, UECs and extended electrolytes, LFTs, blood sugar, urinalysis, stool for ova and cyst, microscopy, culture and sensitivity, Clostridium difficile toxin, stool modified ZN staining for Cryptosporidium, stool modified trichome staining for Microsporidia, HIV status, fecal occult blood
– Imaging i.e., abdominopelvic ultrasound, graft ultrasound
– Multidisciplinary approach i.e., involve gastroenterologist, renal pathologist, infectious disease specialist.
– AKI management i.e., volume repletion to replace any volume losses hence preventing a hastened decline in graft function
– Correct any electrolyte imbalances.
– Antimotility agents as needed.
– Antibacterial and antiprotozoal agents as indicated i.e., if there is a superimposed infection
– Antiviral agents – initiate IV ganciclovir (especially in patients with severe disease or patients who cannot tolerate oral medication) then switch to oral valganciclovir (dose adjusted according to the renal function) while monitoring the CMV viral load. The duration of treatment is usually 3 weeks then followed by 3months of prophylaxis with valganciclovir.
– If resistant to ganciclovir (as evidenced by failure of a log drop in the viral load two weeks into treatment) other agents can be considered e.g., letermovir, maribavir, foscarnet or cidofovir.
– The initial quantitative CMV PCR was negative hence it would be difficult to follow up the patient with CMV viral loads. Hence a follow up colonoscopy would suffice to check the patient’s response to treatment.
– Immunosuppressive therapy – judicious adaptation of immunosuppressive agents to avoid increased risk of acute rejection and formation of de novo DSAs
– We can discontinue the antimetabolite or reduce the dose by 50% (i.e., mycophenolic analogues, azathioprine) especially in the setting of leucopenia but continue with prednisone and CNI
– In case of severe neutropenia, GMCSF injections can be offered.
– Once the CMV infection has cleared the antimetabolite can be introduced at a small dose and thereafter titrated to target dose as guided by patient’s tolerance/ response.
References
1. Shin HS, Chandraker A. Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Current opinion in nephrology and hypertension. 2017 Nov;26(6):484-93. PubMed PMID: 28863048. Epub 2017/09/02. eng.
2. Sonambekar A, Mehta V, Desai D, Abraham P, Almeida A, Joshi A, et al. Diarrhea in kidney transplant recipients: Etiology and outcome. Indian Journal of Gastroenterology. 2020 2020/04/01;39(2):141-6.
3. Jyothindrakumar J, Dhanasekaran R, Natarajan G, Thanigachalam D, Rajendran P. Diarrhea in renal transplant recipients – Retrospective observational study from a center in South India. Indian Journal of Transplantation. 2021 October 1, 2021;15(4):320-4.
4. Hardinger KL, Brennan DC, Lowell J, Schnitzler MA. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transplant international : official journal of the European Society for Organ Transplantation. 2004 Nov;17(10):609-16. PubMed PMID: 15517170. Epub 2004/11/02. eng.
5. Bunnapradist S, Neri L, Wong W, Lentine KL, Burroughs TE, Pinsky BW, et al. Incidence and risk factors for diarrhea following kidney transplantation and association with graft loss and mortality. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2008 Mar;51(3):478-86. PubMed PMID: 18295064. Epub 2008/02/26. eng.
I would discontinue antimetabolites for few days.
Well noted Prof, thank you.
Differential diagnosis;
1.CMV tissue invasive disease(colitis)
2. Inflammatory bowl disease
3.c difficile infection
4. Drug (MMF) induced colitis
Management
Already admitted patient so apart from supportive treatment like IV fluids etc will do,
1. Stop MMF with close monetring of renal function
2. Start gaincylovir 5mg/kg bid or adjusted for GFR for 21days after ward can be switch to valgaincyclovir and continue for upto 6months.
3. Re introduce MMF at lower doses and monitor DNA PCR
4 if poor response, may consider cytoGam (ivig).
5. Consider drug resistance
I like your DD
What is your differential diagnosis?
Considering the following points in the index scenario:
· KTR, with GI symptom(diarrhoea).
· Pre-transplant serostatus for CMV was D+/R+(high risk for CMV infection and disease).
· She received ATG for steroid-resistant CMR.
· Colonoscopy showed hemorrhagic colitis.
· Biopsy finding revealed cellular infiltration and intracellular inclusion(appearance of an “owl’s eye”) suggestive of tissue invasive CMV.
The likely differential diagnoses for this scenario are:
· CMV colitis.
· Colitis after clostridium difficile infection.
· Vascular(hemorrhagic or ischemic colitis).
· Inflammatory bowel disease(IBD).
· Colonic cancer.
How do you manage this case?
1. Hospital admission, supportive measures and hydration.
2. Investigations:
· CBC, LFT, RBG,
· virology screening for HIV,
· High viral DNA levels detected with quantitative NAT in tissue is indicative of CMV, especially when blood sampled at the same time does not contain CMV DNA(1).
3. Valganciclovir for a duration of at least 2 weeks. Most commonly valganciclovir 900mg twice daily has been used as treatment dose, adjusted for level of kidney function(2).
4. I will consider a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine. I will review the dosing of immunosuppression following resolution of CMV infection or disease (2).
5. I will consider CMV prophylaxis for 90-180 days after resolution of CMV infection.
References
1. Kumar D, Caliendo AM, et al The third international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation. Transplantation 2018;102:900–31.
2. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
I like your comprehensive approach but typing in capitals as in the last reference is seen equal to shouting!
The available data presented include:
– History of ATG use, which will result in severe immune suppression.
– The donor and recipients are both CMV virus positive (risk of CMV disease in the setting of significant immune suppression).
– Colonoscopy shows generalized hyperemia suggestive of active inflammation (I could not recognize any ulceration). These findings may occur with many conditions like inflammatory bowel syndrome, infective enteritis (secondary to bacterial, viral or parasitic infection) and pseudomembranous colitis secondary to prolonged antibiotic use.
– Microscopic examination of the biopsy showed giant cell with viral inclusion bodies (suggestive of tissue-invasive CMV disease)
Therefore, the combination of all these pieces together makes tissue-invasive CMV the likely diagnosis (despite the negative CMV- PCR in the blood).
1) The first step will be supportive care:
– Adequate hydration (the oral route is the preferred one. IV fluids can be used in severe cases or if oral replacement is not tolerated).
– Review of serum electrolytes and correction of any electrolyte imbalance.
2) Review serum Tacrolimus levels (diarrhoea may be associated with a rise in serum Tacrolimus levels even with the same daily dose due to the impaired enteric metabolism of tacrolimus).
3) Reduction of the dose of anti-metabolites or even stopping them completely in severe cases.
4) Change valganciclovir doses from prophylactic dose to therapeutic doses (the recipient and donor are CMV-positive serology, and he received ATG. Therefore, she must have been on CMV prophylaxis). Oral valganciclovir can be used in mild to moderate cases who are expected to have good absorption of oral medications. Otherwise, IV ganciclovir can be used at a dose of 5 mg/kg IV every 12 hours for five days, then shift to oral valganciclovir. Dose adjustment will be required in case of renal impairment.
5) Continue therapeutic valganciclovir till the resolution of symptoms (Blood PCR is negative from the start in this case) then we may shift the patient back to the prophylactic dose for another two months to reduce the risk of disease relapse.
6) Follow up CBC with special consideration to the leukocytic count throughout the treatment course.
References:
Santos CAQ, Vella J, Brennan DC. Clinical manifestations, diagnosis, and management of cytomegalovirus disease in kidney transplant recipients. ©2023 UpToDate® (accessed on 10 February 2023).
The dose adjustment of valganciclovir based on the eGFR is illustrated in the attached table.
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.
I like your comprehensive approach
This patient has diarrhoea and is heavily immunosuppressed with ATG and recent post-RTX four months. So this patient’s endoscopy showed features of CMV colitis.
After successful suppression of viral replication, an additional course of suppressive therapy, valganciclovir 900 mg once daily, may be continued for an additional 1 to 3 months.
2- Reducing immunosuppressant medication
refrences
Prof Halawa lecture
I like your comprehensive approach
What is your differential diagnosis?:
· CMV gastritis
· CMV colitis
· Infections like giardia
· Drug side effect
In this case the most common diagnosis is CMV colitis based on symptoms of the patient and colonoscopy and histopathology whished showed giant cell with inclusion body .
How do you manage this case?
Investigations:
· Full blood count
· Liver function test
· Stool general and culture ,test for occult blood
· Drug level
· US for abdomen
· Serum CMV can be negative in patient with CMV colitis
· “CMV PCR q PCR had an 85% sensitivity and 95% specificity to diagnosed CMV GIT .Sensitivity was highest in D+/R- patients (100%) and lowest in D+/R+patient (72.7%).senstivity was higher for liver transplant recipient (100%)”
Treatment :
1-intravenous gancyclovir for 10- 14 days
· Patients with high CMV viral loads (e.g., >5 × 105 IU/mL) or severe tissue-invasive disease, and those who fail to achieve a reduction in viral load after 7 or more days of oral valganciclovir treatment should be treated with intravenous ganciclovir (5 mg/kg every 12 hours).
· Patients with CMV disease should receive at least weekly monitoring of blood viral load, and antiviral therapy should be continued until there is suppression of viremia, typically 14 to 21 days.
· After successful suppression of viral replication, an additional course of suppressive therapy, valganciclovir 900 mg once daily, may be continued for an additional 1 to 3 months.
2- Reducing immunosuppressant medication
References :
1-Prof Ahmed Halawa lecture
2-Hand book of kidney transplant
CMV gastritis??
-MY DIFFERNTIAL DIAGNISIS IS
,But most probably form the pathology which showed incluision bodiewes with punched ulcer in the clonoscopy sugeesting CMV cloitis (tissue invasive ).
-my plane to admitt the patient with good hydration and to,
I like scientific contents of your reply, but typing in capitals is seen equal to shouting!
Differtial diagnosis:
1. CMV colitis as a casue of her diarrhea should be the first differential diagnosis as this patient is at risk of CMV disease:
2. Others: bacterial especially colostridium difficle , and other viruses especially norovirus. Other infections are less common.
3.GIT Tuberculosis should be considered in this context. History of fever and night sweats should be explored. If clonoscopy done biopsy specimen can be examined for granuloma or sent for ZN Stain and tuberculosis PCR.
4. Post transplant lymphoma, clonoscopy is helpful
5. Colonic cancer, colonscopy is helpful
6. Possible is inflammatory diarrhoea such as CD and UC, conscopy is helpful
7. IS medications such as MMF and tacrolimus. This is usually a diagnosis of exclusion.
Management,:
I like your comprehensive approach
1- Based on the provided clinical data and the finding on the colonoscopy and histopathology:
The diagnosis is CMV colitis
other causes should be excluded by stool culture
DD:
a- Bacteria colitis: Clostridium difficilea, Salmonella spp., brucellosis, Escherichia coli.
b-Viruses: CMV, Rotavirus, adenovirus
c-Parasitic: entamoeba, Giardia
d- Inflammatory disese: Ulcerative colitis and Crhons disease
.
e-MMF induced colitis
f- Malignancy: Colon cancer, PTLD
2- Management:
IV ganciclovir 5 mg/kg twice daily for 2-3 weeks till resolution of synptoms
then start oral valganciclovir prophylaxis for 3 months
I like scientific contents of your reply. But we may discontinue MMF for few days rather than just reducing the dose.
The causes of diarrhea in post kidney transplant patients could be infectious or noninfectious causes .
In the index of this case both patient and donor are CMV positive before kidney transplantation in addition to development of ACR in the 3rd week post kidney transplant puts our patient at high risk of CMV infection and disease . Although CMV PCR is negative it is not excluding CMV colitis which is the most likely diagnosis.
Other differential:
– Infectious causes
Bacterial causes are: e coli ,salmonella species ,shigella ,clostridium difficile and campylobacter species.
parasitic causes : entameba histolítica ,giardiasis ,cryptosporidium.
viral causes https://s.w.org/images/core/emoji/14.0.0/svg/1f44d.svg; In addition to CMV ,rotavirus and adenovirus.
Non infectious causes :
-Inflammatory bowel disease.
-Drugs like MMF and CNI .
-Malignancy PTLD.
Symptomatic treatment antipyretic and hydration, take blood sample for CBC ,graft function ,stool analysis gram stain and culture ,CMV serology and PCR.
-Stop offending drugs( esp MMF) and adjust the CNI level .
-This is tissue invasive CMV colitis evident by intracellular viral inclusions needs aggressive management by iv ganciclovir 5 mg/kg /day for 5 days then continued with valgancyclovir 900 mg bid for total of 3 weeks with the dose adjustment according to GFR.
-Follow the patient clinical response
Referrense :
1.Am J Transplant. 2007 Sep;7(9):2106-13. doi: 10.1111/j.1600-6143.2007.01910.x. Epub 2007 Jul 19
2.DIDACT study
2.Prof Ahmrd Halawa lecturer of CMV post transplant
I like scientific contents of your reply.
Your count of references is: 1,2, 2 rather than 1,2,3!
The risk for CMV infection is high as;
1-She received a kidney from CMV positive donor (she was also CMV-positive at the time of transplantation).
2- She received ATG for steroid-resistant CMR 3 weeks after transplantation.
The macroscopic emge showed ulceration and erosion and the microscopic showed presence of viral inclusions(picure of CMV colitis ) .
What is your differential diagnosis?
——————————————————
1-Infeciuos colitis ;
a- Bacteria;
Clostridium difficilea
Campylobacter spp.
Salmonella spp.
Bacterial overgrowtha
Aeromonous spp.
Escherichia coli.
b-Viruses
CMV
Norovirus
Sapobavirus
Rotavirus
Adenovirus
c-Parasitic
Giardia
Cryptosporidium
Isosopora Cyclospora
Microsporidium
Entameoba
2-Inflammatory ;
Ulcerative colitis
Crhons disease
.
3- Drugs ;
Mycophenolate mofetyl induced colitis
4- Malignancy ;
Colon cancer
PTLD
How do you manage this case?
————————————————————-
The diagnosis ;
1-Microbial work up ;
a-Stool culture for pathogenic bacteria
b-Stool examination for parasite and fungi
c-C-defficile toxin assay
d-Quick tests for rotavirus ,adenovirus and norvirus
e-CMV Q-PCR in case of fever ,cytopenia and raised liver enzymes.
2-The histological work up (CMV infection ) ;
The diagnosis of CMV colitis is usually by histopathology with immunohistochemistry or viral culture of tissue specimens; molecular assays such as quantitative PCR also often have a role . Since CMV typically produces latent infection residing in leukocytes, concern has been raised that positive PCR might therefore not necessarily reflect active disease in the colon but only latent infection.
2-The treatment ;
1-antiviral ;
2. IV ganciclovir 5mg/kg bd* for 5 days followed by oral valganciclovir 900mg od. The dose showed be adjusted according to creatinine clearance . IV ganciclovir is indicated where enteric absorption is likely to be compromised (proven GI involvement, diarrhoea or vomiting). The duration of antiviral therapy should be guided by resolution of clinical symptoms (for 14-21 days).
2-Immunosuppression dose reduction ;
a-The guidelines suggest a dose reduction of either calcineurin inhibitor or mycophenolate mofetil / azathioprine [1C] .
b-In the setting of leucopenia , the guidelines suggest reducing or stopping MMF or azathioprine 2C .
3-Supportive treatment
Ensure well hydration .
Monitor the immunosuppressant levels
Reference ;
1- Angarone M, Ison MG. Diarrhea in solid organ transplant recipients. Current Opinion ,Infect Dis 2015; 28:308–316.
1-Lemonovich TL, Watkins RR. Update on cytomegalovirus infections of the gastrointestinal system in solid organ transplant recipients. Current Infectious Disease Reports. 2012;14(1):33-40.
2- UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
I like scientific contents of your reply, but typing in capitals as in the last reference is seen equal to shouting!
Your count of references is: 1,1, 2 rather than 1,2,3!
The recipient criteria:
Differential Diagnosis:
Management:
Challengeable case:
According to the DIDACT study:
References:
Am J Transplant. 2007 Sep;7(9):2106-13. Epub 2007 Jul 19. Oral valganciclovir is noninferior to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid organ transplant recipients. Asberg A1, Humar A, Rollag H, Jardine AG, Mouas H, Pescovitz MD, Sgarabotto D, Tuncer
Thank you for your reply, agree. Well done Dr Kamal
What is your differential diagnosis?
Differential diagnosis includes infectious and noninfectious causes.
Infectious causes are most common and include:
-CMV Colitis
– Norovirus
– Giardia
– Cryptosporidium
– Clostridiodes Difficile infection
Non-infectious causes include:
– Immunosuppression side effects in particular MMF
– IBD
– Malignancies including PTLD
Histopathological finding of giant cell with intranuclear inclusion is in favor of CMV colitis
How do you manage?
Initial treatment should aim to maintain euvolemia for the patient having fever and diarrhae. Comprehensive laboratory studies should follow, to evaluate organs function tests and cultures including CBC, Renal profile, Liver function test, LDH, ESR, Stool analysis and culture and Clostridiodes difficile toxin/GDH)
Involvement of multidisciplinary Team onboard, Gastro-enterologist and ID consultant.
As histological findings are suggestive of CMV colitis, we should initiate treatment by reducing immunosuppression, specifically the antimetabolite (MMF) dose by 50%, while continuing CNI and steroids.
Commence antiviral treatment with gancyclovir or valganciclovir.
Administer intravenous Gancyclovir at a dose of 5mg/kg daily for a minimum of 14 days and continue treatment for two weeks until symptoms resolve and two PCR tests for CMV DNA are negative. Do viral load testing every two weeks, then weekly. In the indexed case, however, the preceding PCR was negative, hence subsequent PCR are not useful for monitoring illness response.
Alternatively, 900 mg twice daily of oral valgancyclovir is administered for at least 21 days if the patient is symptom-free and CMV PCR is negative. In the event that the initial PCR is negative, a second coloscopy with biopsy may indicate when to discontinue anti-viral therapy.
-Avoid oral valganciclovir for the time being if the patient has persistent diarrhea due to absorption issues.
-During treatment with either ganciclovir or valganciclovir, the renal profile and complete blood count (CBC) are monitored at regular intervals to check for potential renal dosage modification and potential hematological adverse effects.
Thank you for your reply
But I will treat it as severe CMV and give IV Gancyclovir for 5 days followed by oral valganciclovir for 2 weeks.
The colon was the most commonly involved organ,The most common symptoms reported by patients with colon-predominant disease (n = 60) were hematochezia (55 percent), abdominal pain (22 percent), and diarrhea (20 percent).
CMV colitis can be confused with ischemic colitis when an older adult patient presents with bloody diarrhea and abdominal pain CMV has also been implicated as a cause of esophagitis , gastritis , Ménétrier’s disease (protein-losing hypertrophic gastropathy) , ileitis , appendicitis , colonic obstruction , and proctocolitis with perforation in patients without underlying immunosuppression.
1-Differential diagnosis
2-How do you manage this case?
the gold standard method for diagnosing CMV colitis is Immunohistochemistry for CMV
ivf -fluid replacement
GOOD HYDRATION
DAILY RFT
-FLUID CHART
septic screen (cbc -CRP-BLOOD -URINE -STOOL CULTURE-URINE ANALYASIS -STOOL ANALYASIS)
GASTRO CONSULTATION
IF PATIENT CONFIRMED DIAGNOSIS OF CMV COLITITS AS OUR CASE
We reduce immunosuppression in all kidney transplant recipients with CMV disease
. We typically stop the antimetabolite immunosuppressant (ie, mycophenolate or azathioprine).
gastrointestinal disease (with either diarrhea or nausea and vomiting that impair absorption), we suggest IV ganciclovir rather than oral valganciclovir. We administer ganciclovir 5 mg/kg IV every 12 hours, with dose adjustment for kidney function
. We monitor the blood for CMV replication with PCR at weekly intervals for four weeks to ensure that CMV does not reactivate at the lower antimetabolite dose. If CMV recurs, we discontinue the antimetabolite indefinitely and restart treatment with antiviral therapy. If CMV reactivation does not occur, we continue the antimetabolite at the reduced dose
.
Antiviral therapy — Ganciclovir or its oral derivative, valganciclovir, is the preferred agent for most patients with CMV viremia or CMV disease.
Oral maribavir, intravenous (IV) foscarnet, and IV cidofovir are alternatives and are primarily used for patients with known or suspected infection with resistant or refractory CMV
The index case is PCR negative.
How will you follow up during the 4 weeks?
You have only : clinical progress
follow up colonoscopy.
·What is your differential diagnosis?
=============================
·How do you manage this case?
References
Thankyou
Differential diagnosis
Management
References
Fine but clostrid. difficile is not a virus it is a gm+ bacteria.
Treated by antibiotics as oral Vancomycin.
The index case is
a) A recent (3 month) cadaveric renal transplant recipient
b) CMV D+/R+ status
c) She developed steroid resistant cellular rejection 3 weeks post-transplant which was treated with injection ATG.
Now she developed diarrhea with negative routine infection screen and CMV PCR and without any graft dysfunction.
This patient was investigated by colonoscopy which shows severe hyperemia
Colon biopsy shows giant cell with inclusion body suggestive of CMV colitis.
In the light of the clinical features and the histopathology, this patient is having tissue-invasive CMV disease: CMV colitis (1). CMV antigen detection by immunohistochemistry of the biopsy specimen can help in diagnosis.
Nevertheless, other causes of diarrhea should be ruled out in such a scenario (2):
1) Infections: Giardia, cryptosporidium, C. difficle, norovirus etc.
2) Drug induced (MMF, CNIs, proton pump inhibitors, metformin)
3) Inflammatory bowel disease, PTLD
For these, a stool examination for ova and cyst, cryptosporidium, stool culture, stool for C difficle toxin, rotavirus antigen, breath test for bacterial overgrowth needs to be done in a stepwise manner (2).
This case of tissue-invasive CMV is managed by:
1) Supportive therapy: Oral rehydration solution (ORS) and intravenous fluid to maintain adequate hydration.
2) Review of medications to stop medications causing diarrhea (like metformin).
3) Treatment with intravenous ganciclovir (5mg/kg IV 12 hourly, to be adjusted according to creatinine clearance). It should be continued for minimum 2 weeks (can be changed to oral valganciclovir, if symptoms improves earlier), and until resolution of clinical symptoms and radiological findings with clearance of CMV in blood, if present (3).
4) Complete blood count and serum creatinine should be monitored weekly during the treatment. If no response in 2 weeks, assessment for ganciclovir resistance and shift to Foscarnet and additional CMV immunoglobulin or intravenous immunoglobulin (IVIG) should be considered (3).
5) Secondary prophylaxis with oral valganciclovir post-treatment can be given for 1-2 months in patients with high-risk of relapse.
6) Immunosuppression reduction: Antimetabolites should be stopped/ reduced by 50% and the CNI levels should be checked.
7) Patient should be watched for and counselled regarding the risk of rejection in such a scenario when the dose of immunosuppression is being reduced.
References:
1) Gioco R, Puzzo L, Patanè M, Corona D, Trama G, Veroux P, Veroux M. Post-transplant colitis after kidney transplantation: clinical, endoscopic and histological features. Aging (Albany NY). 2020 Dec 22;12(24):24709-24720. doi: 10.18632/aging.202345. Epub 2020 Dec 22. PMID: 33353887; PMCID: PMC7803550.
2) Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13550. doi: 10.1111/ctr.13550. Epub 2019 Apr 10. PMID: 30913334.
3) 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.
Well done.
What is your differential diagnosis?
Differential diagnosis includes identifying infectious and noninfectious causes.
Infectious causes are most common and include:
-CMV Colitis
– Norovirus
– Giardia
– Cryptosporidium
– Clostridiodes Difficile infection
Non-infectious causes include:
– Immunosuppression side effects in particular MMF
– IBD
– Malignancies including PTLD
Histopathological finding of giant cell with intranuclear inclusion is in favor of CMV colitis
How do you manage?
Initial treatment should aim to maintain euvolemia for the patient with fever and diarrhea. Comprehensive laboratory studies should follow, to evaluate organs function tests and cultures including CBC, Renal profile, Liver function test, LDH, ESR, Stool analysis and culture and Clostridiodes difficile toxin/GDH)
involvement of a multidisciplinary team onboard, a gastroenterologist, and an ID consultant.
As histological findings are suggestive of CMV colitis, we should initiate treatment by reducing immunosuppression, specifically the antimetabolite (MMF) dose, by 50% while continuing CNI and steroids.
Commence antiviral treatment with gancyclovir or valganciclovir.
Administer intravenous Gancyclovir at a dose of 5 mg/kg daily for a minimum of 14 days and continue treatment for two weeks until symptoms resolve and two PCR tests for CMV DNA are negative. Do viral load testing every two weeks, then weekly. In the indexed case, however, the preceding PCR was negative, hence subsequent PCR are not useful for monitoring illness response.
Alternatively, 900 mg twice daily of oral valganciclovir is administered for at least 21 days if the patient is symptom-free and the CMV PCR is negative. In the event that the initial PCR is negative, a second coloscopy with biopsy may indicate when to discontinue anti-viral therapy.
-Avoid oral valganciclovir for the time being if the patient has persistent diarrhea due to absorption issues.
During treatment with either ganciclovir or valganciclovir, the renal profile and complete blood count (CBC) are monitored at regular intervals to check for potential renal dosage modification and potential hematological adverse effects.
Well done.
What is your differential diagnosis?
CMV colitis is the most probable diagnosis
Due to history of CMV infection D+/R+ and ATG use for steroid-resistant CMR presenting with diarrhea ,also as confirmed with the biopsy showing giant cells with inclusion body characterstic of CMV colitis
Other DD
Bacterial Gastroenteritis
Campylobacter Infections
Clostridium Difficile Colitis
Colon Cancer
Inflammatory bowel Disease
Cryptosporidiosis
Mycobacterium Avium Complex
Viral Gastroenteritis
Drug induced diarrhea
How do you manage this case?
Detailed history
Full lab tests
-Direct specific immunofluorescent antibody detects viral antigens or viral DNA.
– Shell viral assay cultures
-antibody tests, qualitative or quantitative PCR (came negative)are less diagnostic
-stool analysis and culture
– co-infecting pathogens must be excluded as Clostrium difficle toxin assay
-The graft function needs evaluation by KFT , eGFR ,urine analysis , renal US is normal
– basic lab ;CBC ,LFT, Inflammatory markers, blood and urine cultures
-Immunosuppressive levels
-Colonoscopy showing CMV colitis and biopsy for histologic examination revealing giant cell with inclusion body, antigen detection, and viral cultures.
Treatment
MDT team must be involved with patient counselling including a gastroenterologist and virology specialist
-Antiviral therapy IV Ganciclovir at least 14 days for invasive CMV ,till symptoms resolve
– immunosuppressive agents can be reduced or stopped particularly MMF due to diarrhea, m TOR can be used due to it’s lower risk of association with CMV .
-graft function must be closely monitored as well as CMV viral load tracing
Reference
· Heuman DM etal CMV colitis treatment and management , Medscape 2021
· Professor Halawa lecture.
Well done.
– Diarrhea 3 months post KT.
– Both D&R are CMV positive; risk for of superinfection with donor virus or reactivation of recipient virus, CMV prophylaxis after treatment for ACR is recommended in this condition.
– Received heavy IS ATG for steroid resistance CMR
– CMV PCR is negative.
– Colonoscopy showed inflamed mucosa with diffuse erythema. Biopsy showed giant cell with characteristic inclusion body of CMV colitis.
What is your differential diagnosis?
-Invasive CMV disease; CMV colitis is the likely diagnosis, supported by colonoscopy, and histopathological finding, and the presence of risk factor.
-Negative CMV PCR does not exclude the diagnosis. PCR had 85% sensitivity and 95% specificity to diagnose CMV GI disease; sensitivity was highest in the D+/R− patients (100%) and lowest in the D+/R+ patients (72.7%).
Other differential for diarrhea in immunocompromised individuals should be considered:
Among transplant recipients, the prevalence of diarrhea is between 20% and 50%.
The most commonly identified etiology of diarrhea:
Infectious;
– Viruses; CMV, Norovirus, Rotavirus, Adenovirus, Enterovirus
– Bacterial; Clostridioides difficile, Campylobacter spp, Salmonella spp. Bacterial overgrowth
– Parasitic; Giardia, Cryptosporidium, Cystoisosopora, Cyclospora, Microsporidium, Entameoba
Noninfectious causes;
How do you manage this case?
-Coordinate the management with GIT, infectious disease team.
Work up:
– CBC, CRP,LFT, blood culture.
– RF and drug level Tacrolimus.
– Viral load PCR CMV, EBV.
– Stool for : analysis and culture, multiplex PCR rotavirus Ag, enterovirus , ova and parasites, Clostridium difficile toxin assays, giardia and cryptosporidium , and norovirus,
General consideration:
– Detailed clinical history and medication history.
-Fluid replacement is the mainstay for management.
Management of CMV colitis:
This patient should be treated as tissue invasive CMV disease, irrespective of viral load.
IS management :
– Stop/reduce (by 50%) azathioprine/MMF/myofortic
– Do not discontinue CNI unless there is evidence of life-threatening infection, keep level of Tacrolimus 5.
– Corticosteroids are generally continued
– Monitor graft function as the risk of rejection will increase.
Antiviral therapy:
– IV GCV for minimum of 14 days followed by oral vGCV for 2-3 weeks after resolution of symptoms. ( as viral load is negative)
-The doses should be adjusted to renal function
-Monitor RF, CBC, LFT is required
-In vGCV/GCV resistance; viral gene typing, second line therapy with help of ID team.
– After completing the treatment, continue VGCV prophylaxis for 3 months.
– CMV Ig and IVIG as adjunctive therapies
References;
-Ison MG. Diagnosis of gastrointestinal cytomegalovirus infections: an imperfect science. Clin Infect Dis. 2013 Dec;57(11):1560-1. doi: 10.1093/cid/cit524. Epub 2013 Aug 15. PMID: 23956171.
-Prof. Halawa lecture CMV in Kidney transplantation.
– Angarone M, Snydman DR; AST ID Community of Practice. Diagnosis and management of diarrhea in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13550. doi: 10.1111/ctr.13550. Epub 2019 Apr 10. PMID: 30913334.
– Aulagnon F, Scemla A, DeWolf S, Legendre C, Zuber J. Diarrhea after kidney transplantation: a new look at a frequent symptom. Transplantation. 2014 Oct 27;98(8):806-16. doi: 10.1097/TP.0000000000000335. PMID: 25073040.
Well done.
Oedematous, Inflamed mucosa with inclusion bodies on biopsy suggestive of CMV colitis.blood CMV PCR can be negative in tissue invasive disease.
Differential diagnosis of diarrhoea in immunosuppressed transplant recipient
Bacterial, viral, parasitic, fungal and mycobacterial infections
Drug induced: MMF associated diarrhoea
Flare of pre-existing inflammatory bowel disease
Malignancy; including lymphoma and Kaposi sarcoma
Management
Stool for culture, including ova, parasites and c -diff to rule out other causes of diarrhoea.
Start IV Ganciclovir, as oral absorption won’t be adequate, continue at least 3 weeks, switch to oral when patient can tolerate and absorb oral medication.
Reduction of immunosuppression; withhold antimetabolite.
Ensure adequate hydration, monitor renal function and electrolyte.
Monitor CNI level as diarrhoea can both increase and decrease CNI levels.
Council patient about risk of rejection with reduction of IS.
Monitor FBC while on Ganciclovir, (neutropenia is a common side effect).
Consider repeat colonoscopy and biopsy to ensure resolution.
If persistent or worsening symptoms despite adequate valganciclovir dose for at least 2 weeks, consider ganciclovir resistance, assess for mutation and consider switching to IV Foscarnet. Monitor renal function and ensure adequate hydration during treatment with Foscarnet.
Review immunosuppression once disease resolves.
Welldone.
Thankyou .
what if there is Gancyclovir resistance.
Thank you prof Dawlat for your question
Ganciclovir resistance is more in seropositive D to seronegative R-v, due to more prolonged use of ganciclovir prophylaxis also the higher incidence of ganciclovir resistance found in recipients of lung and pancreas TX, which may be due to more intense IS and prolonged CMV prophylaxis, in KTX reported in 1%.
Ganciclovir resistance mutations in UL97 were found in 9.5% of patients
Valganciclovir is more potent compared to oral ganciclovir and has less risk of CMV resistance infection. valganciclovir was shown to be superior to oral ganciclovir for the prevention of resistant CMV infection, so preferred to use oral valganciclovir 900mg BID for 3 weeks as it associated with less CMV resistance but more neutropenia as side effects.
Foscarnet The primary alternative to ganciclovir for the treatment of CMV viremia and disease is foscarnet.
Foscarnet was approved by the FDA in 1991. Mutation in the DNA polymerase gene UL54 does confer foscarnet resistance and can sometimes
be selected for prolonged ganciclovir therapy. Foscarnet is associated with renal toxicity, electrolyte abnormalities, and seizures, and its use is restricted due to the intolerance with more side effects
combination of both foscarnet and ganciclovir with CMV immunoglobulin
cidofovir and its use is limited its adverse effects.
leflunomide immunomodulating agent does not appear to be nephrotoxic but can cause transaminase elevation. The long-term effectiveness,
tolerability, and ideal settings for the use of leflunomide remain to be defined by ongoing and future studies.
References
History
===================================================================
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What is your differential diagnosis?
====================================================================
How do you manage this case?
Discuss the case with a consultant gastroenterologist and neessery virologist to agree best treatment regime and discuss resistance testing.
Plan Mangement
1- Reduction in immunosuppression 50% (MMF,MPA,AZA.)
2- Continue CNI unless there is evidence of life-threatening infection.
3- Corticosteroids are generally continued
4- In patients with CMV disease weekly monitoring of CMV DNA is required
5-Treatment should continue until CMV DNA is no longer detectable in plasma
6- Dose reductions for renal impairment are commonly needed with valganciclovir and ganciclovir therapy.
====================================================================
Reference
How long after PCR 9which was negative!
Decision taking is the main issue here.
What are the criteria of improvement and when is there gancyclovir resistance.
Thanks for you very much Prof.Dawlat
How long after PCR 9which was negative!
Edematous mucosa with multiple erosions, ulceration, easy bleeding with inclusion
bodies suggestive of CMV colitis.
Mycophenolic acid/related colitis.
Inflammatory bowel disease.
Post-transplant colitis.
Graft-vs–host colitis.
Ischemic colitis.
Clostridium difficile.
T.B.
Treatment:
Valganciclovir for CMV colitis with reduction of immunosuppression.
Reduction of MPA for MPA colitis..
Mesalazine and cortico-steroids are the mainstays of treatment of de novo IBD
we need more information for the scenario!
Causes of diarrhea after transplantation encompass:
Infectious: (bacterial, parasitic, and viral pathogens)
Noninfectious: etiologies (PTLD, IBD, Malabsorption ,Drugs).
Common viral:
Norovirus, adenovirus, rotavirus, and cytomegalovirus (CMV).
Cytomegalovirus:
CMV is the most common opportunistic infection afflicting SOT recipients, with
enter colitis being the most frequent form of end-organ diseases.
The risk of CMV is highest when a seronegative (CMV IgG negative) individual
receives an organ from an individual who is CMV seropositive (D+/R−).
In absence of prophylaxis, CMV reactivations typically occur within the first 3–6
months post-transplantation.
Diagnosis of CMV gastrointestinal:
Is based on the presence of upper and/or lower GI symptoms with CMV
identified in biopsied tissue via histopathology, immunohistochemistry, or DNA
hybridization from macroscopic mucosal lesions visualized during endoscopy.
Cases are classified as probable when upper and/or lower GI symptoms are
present with CMV identified in tissue specimens, but macroscopic mucosal
lesions are not seen.
Treatment:
Careful reduction in immunosuppression plays an important role in the control of
CMV disease, particularly in cases of drug resistance or intolerance.
Parenteral ganciclovir is the first-line treatment for CMV GI tissue-invasive
disease, followed by a transition to oral Valganciclovir upon improvement in
symptoms and once a patient is reliably absorbing medications .
CMV should be treated for a minimum of 2 to 3 weeks, through the resolution of
clinical symptoms, and until the virologic clearance is achieved
. Viral loads should be monitored while on therapy, generally weekly; if the viral
load does not decline by 1 log10 after two weeks of treatment, genotypic
resistance testing targeting UL97 and UL54 genes should be performed.
Summary:
In this case scenario; diarrhoea after 3 months post transplantation with normal graft function, CMV positive donor to CMV positive recipient at the time of transplantation, received ATG due to steroid resistant CMR. The routine infection screen and USS was normal, quantitative CMV-PCR negative and colonoscopy showed ulceration with well-defined punched out appearance and inflammation secondary to cytomegalovirus colitis and H&E stained tissue sections relies on the presence of giant cell with inclusion body characteristic of CMV.
The differential diagnosis:
Infection
*Viral: CMV colitis
Other viral infection (Norovirus, Sapobavirus, Rota virus, Adenovirus)
*Bacterial: Clostridum difficile, Campylobacter, Salmonell, Aeromonous and E coli.
*Parasitic: Giardia, Cryptosporidium, Entameoba and Microsporidium
Drugs induced, IS medication (MMF, Tac, Sirolimus) and other drugs (antibiotics, Antiarrhythmic).
Inflammatory bowel disease
Colonic cancer
Management:
* MDT including the gastroenterologist and hematologist should be involved.
*History and physical examination.
In CMV colitis, the patient presented with diarrhea, abdominal pain, fever, and the stool may be grossly or occult bloody
*Routine investigation (CBC, RFT, LFT, UG,CRP, stool analysis and culture, look for clostridium difficile toxine and other parasites, ELISA and PCR for other virus, USS.)
*Serological testing:
CMV IgG, screening test but not for diagnosis of the disease and indicates past infection.
CMV IgM for acute infection.
*DNA PCR can be qualitative or quantitative
Real time PCR CMV DNA quantification but it is only positive in 50% of patients with biopsy proven colitis/ enteritis.
*Endoscopic Evaluation and H&E stain
* IHC is considered as gold standard for identification of CMV more sensitive and specific compared to plain histological microscopy, false negative result can occur due to focal distribution of the virus
CMV Culture, high sensitive and specific for CMV colitis but take long time to obtain the result.
CMV pp65 antigenaemia by fluorescent assay, semi- quantitative method, and false negative results may occur.
****Imp (GI-CMV: Is common presentation of tissue invasive CMV, the virus may not detected in the patient serum or it can be detectable without pathological evidence, so they need OGD or colonoscopy with biopsies or culture and PCR for diagnosis.
Treatment:
*Stop or reduce the IS by 50% Azathioprine, MMF, Myofortic. *Do not stop CNI unless there is evidence of life threatening infection.
* Steroid should continue.
*Evaluate patient with CMV disease weekly for CMV DNA, and the treatment should continue until CMV DNA is no longer detected in the plasma.
*All treatment must be continuing until disappearance of the symptoms, for at least 2 weeks.
*Patients with serious tissue invasive disease should be treated with I/V GCV.
*All IS therapies must be reduced or stopped in life threatening CMV disease and CMV disease that persists in spite of treatment until the disease is resolved.
*Evaluation of the graft function and considering the risk of rejection is important
*Patients with CMV disease but not serious can be treated with I/V GCV or oral vGCV.
*Treatment of GCV resistance is indicated when:
A) CMV PCR level not drops by ≥ 1 log copies/ ml after 2 weeks of treatment.
B) There is no clinical benefit from treatment.
So, we should exclude other causes, more reduction of IS, immunooglobulins and shift to second line Foscarnet, Cidovir, Letermovir, Maribavir. Ask for genotypic resistance.
*Adoptive immunotherapy for resistant or recurrent CMV.
*Treat neutropenia if present after exclusion of other causes.
Lecture of Ahmed Halawa , Consultant Transplant Surgeon, Associate professor, University of Liverpool- UK, 2023
Thankyou well done
Thankyou alot prof Belal
Differential diagnosis
CMV colitis- despite the negative PCR this case is still suspicious for CMV colitis due to her high immunological risk D+/R+ and recently treated for rejection. A negative PCR doesn’t rule out CMV colitis.
The colonoscopy should inflamed colon and the histology should increased macrophages. However this is a H&E stain which has low sensitivity Immunohistochemistry would have high sensitivity.
Other differential would be infective causes of diarrhoea:
viruses- norovirus, adenovirus,rotavirus
bacterial – salmonella, campylobacter, clostridium, Ecoli, shigella, TB
parasites- Giardia, entamoeba histolytica
Another differential to consider is side effects of drugs-MMF
Management
Stool for microscopy and culture to rule out other causes of diarrhoea.
C.diff toxin assay and rapid viral tests to rule out viral causes
CBC, renal and liver function tests, tacrolimus trough levels
Reduce the immunosuppression- preferentially the antimetabolites.
Close monitoring of the renal function due to the risk of rejection with reduced antimetabolite.
Patient has GIT symptoms absorption may be compromised hence can initiate with IV Ganciclovir 5mg/kg bd renal dose for 5 days then switch to PO valganciclovir 900mg od for 2 weeks.
Since the patient has a negative PCR when to stop treatment will be guided by resolution of symptoms and repeat colonoscopy.
Exellent plan but please note there is an inclusion body ( owl eye) in the right sided slide.
Okay thank you
The colonoscopy picture shows inflamed, reddish edematous colon.
The biopsy showed inflammation of the colon with giant cell, with typical Owl’s eye appearance, characteristic of CMV infection.
So, the most probable diagnosis is CMV colitis. This because of the high risk patient,:
1-CMV positive recipient from CMV positive donor.
2- History of lymphocyte depleting agents.
3-3months post transplant ( time of stopping prophylaxis, if given).
4-Typical presentation ( diarrhea).
Having negative CMV PCR does not exclude tissue-invasive disease. As this can be negative in 30-50% of cases.
Other possibilities:
1- Drug-induced colitis.
2- Bacterial colitis
3- Inflammatory bowel disease.
4- C .difficile colitis
1-General management:
Routine investigations, CBC, RFT, electrolytes, CRP, LFT.
Good hydration and electrolytes replacement as needed.
CNI level, as they are affected by diarrhoea and drug interaction.
2-Immunosuppressio:
Reduction of immunosuppressive medications is needed to give chance to get rid of the infection.
Starting with reducing antimetabolites by 50% or stopping them altogether in case of severe infection or no improvement and continuous diarrhoea.
CNI dose to be adjusted according to local protocols level. Usually 6-8 at this stage post transplant, unless severe, life threatening disease we need to stop them altogether.
Steroid is usually continued same dose, however in shock status we need to consider stress dose.
Immunosuppression to be resumed back after resolution of infection.
3-Anti viral treatment:
In such case of CMV colitis we will start with iv gancicolovir 5mg/kg 12 hourly( adjusted for renal impairment) for 1-2 weeks, till symptoms improvement. Then we can shift to oral valganciclovir 900mg bid , adjusted for renal impairment. Induction dose is continued for 3-4 weeks, then maintenance dose 450mg bid for 2-3 months.
In case of ganciclovir resistance, we will consider foscarnet.
Reflection on local practice: recently, I’ve patient 60 years old, 10 years post-transplant presented with significant unintentional weight loss, 20kg over 6 months with dyspepsia and intermittent diarrhoea. Initially, we were considering malignancy more than infectious process. PAN CT did not show any suspicious lesions, except thickened wall colon. Tumour markers were negative. Upper GIT endoscopy showed severe ulceration of esophagus with raised borders, biopsy showed CMV esophagitis. CMV PCR was strongly positive with 36000 copies per ml. Colonoscopy was not completed due to poor preparation. He is still being treated, initially with IV ganciclovir then shifted to oral valganciclovir. He showed significant symptoms improvement, his appetite is better, started to gain weight and he was discharged to be seen in the clinic in next few weeks.
References:
1-UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION.
Thankyou for sharing your case this should be encouraged for everyone.
But what was the reason of 6 months .
thanks prof Dawlat
Our impression is that his symptoms were insidious initially, then became more severe recently. Also because OPD visit for him is every 3-4months, it was not noticed till recently. still we need to be opened mind for other causes if he does not show resolution of symptoms after curing his CMV disease.
1-What is your differential diagnosis?
-CMV Colitis (most likely)
(Bx Giant cell inclusion body & Colonoscopy)
-Infectious causes;
(Norovirus, Giardia , Cryptosporidium , Mycobacterium avium Complex , and Mycobacterium avium-Intracellulare)
-Clostridium Difficile infection
-Immunosuppression side effects (CNI / MMF)
-Inflammatory bowel disease
-Malignancies including PTLD
2-How do you manage this case?
-Unfortunately, serum CMV can be negative in patients with CMV colitis.
-CMV PCR is neither sufficiently sensitive nor specific
-qPCR had an 85% sensitivity and 95% specificity to diagnose CMV GI disease.
-Sensitivity was highest in the D+/R− patients (100%) and lowest in the D+/R+ patients (72.7%). Sensitivity was higher for liver transplant recipients (100%) than for kidney transplant recipients (72.7%).
-Full history and physical examination, evaluating volume status of the patient.
-Monitor input and output, IV Hydration and Electrolytes Replacement for correction.
-Further Investigations;( CBC, RFTs, LFTs , LDH, ESR, Hco3, Stool analysis and culture & CDF pcr , CNI trough)
-Multidisciplinary Teams (Nephrology / GIT / ID)
If the case proved to be CMV colitis (by histopathological diagnosis)
-Reduction of immunosuppression; will reduce the dose of antimetabolite by 50% & Keep CNI at lower trough (5-7 ng/ml), Continue on steroids.
-Resume lower dose of antimetabolite only in high risk patients for rejection like the current patient after PCR is negative for 2 successive samples 1 weeks apart.
-Close follow up of PCR weekly for 1 month after starting low dose antimetabolite.
-Review immune-suppression after resolution of CMV.
-Start antiviral therapy in the form of gancyclovir In a dose of 5mg/kg/12 hours for the first 5 days then after improvement we can shift to oral valgancyclovir In a dose of 900 mg twice daily for at least 21 days provided the patient is symptom free -Since CMV PCR is negative, a repeat coloscopy & biopsy may determine when to stop the anti-viral therapy
-Avoid oral valganciclovir at the moment because of absorption problems ( pt has diarrhea)
-After treatment of CMV; prophylaxis should be initiated using valgancyclovir in a dose of 900 mg daily for 1-3 months.
-IV ganciclovir can be transitioned to oral valganciclovir once the patient has demonstrated clear clinical improvement, viral loads are down-trending, and the patient can tolerate/absorb oral medications.
-While treating with either ganciclovir or valganciclovir, we monitor the serum creatinine at regular intervals in case dose adjustment is needed.
-Monitoring on therapy; Renal function / Blood cell counts.
-Gancyclovir ( intolerant or resistant);
-Resistance to ganciclovir should be considered in recipients who fail to improve clinically and/or virologically after two weeks of adequate doses of antiviral therapy or who have recurrent relapses following treatment.
–Resistance testing ;Genotypic resistance testing should be performed in patients with suspected ganciclovir resistance (UL97 mutation & UL54 mutations)
-Switching the immunosuppressive regimen to one that includes an mTOR inhibitor (eg, sirolimus, everolimus)
–Foscarnet 60 mg/kg IV every 8 hours (or 90 mg/kg IV every 12 hours), with adjustment for renal dysfunction.
-It is important to note that nephrotoxicity is common when foscarnet is given in combination with cyclosporine or tacrolimus. Electrolyte disturbances are also common with foscarnet.
-An alternative to foscarnet is cidofovir, but there is less clinical experience with this agent for treating resistant CMV infection, and its use is limited by the potential for severe nephrotoxicity.
-References;
1- UK Guidlines on prevention and management of cytomegalo virus (CMV) infection and disease following solid organ transplantation.
2-Klauber Scand J Infect Dis.1998;30 (6):559.
3-Ison, Clinical Infectious Diseases Advance Access,September,2013.
4-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.
Well done. Exellent.
This is a patient who has presented with gastroenteritis 3 months after kidney transplant. She has received ATG for ACR putting her at high risk for opportunistic infections.
The colonoscopy shows hemorrhagic colitis and the histology shows inclusion bodies with PMN leucocytes and lymphocytes suggestive of CMV colitis. The CMV PCR is negative which can be negative in CMV colitis with a sensitivity of 72% in D+/R+.
The differential diagnosis includes:
Management
The patient requires admission and should be started on IV fluids
We should rule out other causes of diarrhea: Stool for microscopy, cultures, C.difficile Ag, modified ZN stain for cryptosporidium
The patient should be started on IV ganciclovir at 5 mg/Kg and monitored for bone marrow suppression
Once the acute phase subsides, the patient can be converted to valganciclovir
The treatment duration should be for 2-3 weeks.
Its difficult to monitor treatment efficacy in this case as the quantitative PCR was negative
Well done.
Thank you Prof
starting by general measures such as maintenance of hydration and workup for the causes such as stool culture
depending on the causes …antivial for viral infections such as CMV (patient at moderate to high risk /induction with ATG )
alteration of immunosuppressants
TOO short!
Details of your plan!
What is your differential diagnosis?
Our case is post kidney transplant with diarrhea who received heavy dose of immunosuppression with ATG for steroid resistant CMR.
With CMV status (R +ve =èD+ ve).
CMV PCR came negative and unfortunately, serum CMV can be negative in patients with CMV colitis as qPCR had an 85% sensitivity and 95% specificity to diagnose CMV GI disease and lowest in the D+/R+ patients (72.7%), colonoscopy done showed hyperemic lesion on the mucosal surface with ulcers, and detection of intranuclear inclusions in the biopsy which is considered the hallmark of CMV infection.
It is considered a case of CMV colitis which accounts about 30-50% of patient with CMV disease.
But we should exclude all cause of infection that cause diarrhea such as
1-Infectious causes with stool culture.
2-C.diff toxins.
3-Norovirus.
4- Giardia.
5-Cryptosporidium.
6-Drug induced such as MMF and Tacrolimus .(non-infectious which accounts 50% of causes of diarrhea post kidney transplant).
7- PTLD, small intestinal bacterial overgrowth and others.
How do you manage this case?
1-Supportive treatment and Gastroenterologist referral.
2-Reduce /Stop MMF/AZA.
3-Decrease tacrolimus level and continue steroid dose.
4-Start VGC oral or IV according to clinical condition.
5-Treatment should be continued till CMV PCR came negative for 2weeks follow up.
6- Weekly CMV PCR.
7-F/U RFT and CBC ( to avoid further attacks of rejection and to avoid VGC side effects).
References:
1- Aulagnon, Florence1,2; Scemla, Anne1,2; DeWolf, Susan3; Legendre, Christophe1,2,4,5,6; Zuber, Julien1,2,3,4,6,7. Diarrhea After Kidney Transplantation: A New Look at a Frequent Symptom. Transplantation 98(8):p 806-816, October 27, 2014. | DOI: 10.1097/TP.0000000000000335.
2- Aulagnon F, Scemla A, DeWolf S, Legendre C, Zuber J. Diarrhea after kidney transplantation: a new look at a frequent symptom. Transplantation. 2014;98(8):806-816. doi:10.1097/TP.0000000000000335.
3- Sonambekar A, Mehta V, Desai D, et al. Diarrhea in kidney transplant recipients: Etiology and outcome. Indian J Gastroenterol. 2020;39(2):141-146. doi:10.1007/s12664-020-01022-1.
4- CMV in Kidney Transplantation Lecture By: professor Ahmed Halawa.
What if PCR is negative to start with.?
If CMV PCR came negative , we will check it in tissue sample .
Will start GCV till complete clinical improvement .
Patient with intensive immunosuppression history presented with posttransplant diarrhea colonoscopy presented showed extensive hyperemia and the specimen showed infiltration with macrophages
DDx
Viral
CMV 5-20% of posttransplant diarrhea colitis occure in 30- 50 % of CMV infection
Norovirus 17-26% of posttransplant diarrhea
Rota virus 1-15% of posttransplant diarrhea
Adnovirus 0.7% of posttransplant diarrhea
Bacterial
Cholestridum difficil 3.5-15% of posttransplant diarrhea
Chambelbacter: 5-28% of posttransplant diarrhea
Enteropathogenic E.coli 20-30% of posttransplant diarrhea
Salmonella species” 2.7% of posttransplant diarrhea
Listeria monocytogens
bacterial overgrowth,
Parasites
Giardia
Cryptosporidium
1. Immunosuppression
2. Mycophenolate Mofetil and Enteric-Coated Mycophenolate Sodium
3. Tacrolimus
4. Mammalian Target of Rapammycin inhibitors
PTLD
Diagnosis
The prospective Diarrhea Diagnosis Aid and Clinical Treatment study evaluated a stepwise prospective diagnostic and therapeutic flow chart that aimed to eliminate nonimmunosuppressive drug toxicity causative factors and treat infectious causes before adjusting the immunosuppressive regimen (2)
The first line microbiologic stool investigations consist of standard stool cultures for pathogenic bacteria,
examinations for parasites and fungi,
C. difficile toxin assay, and quick tests for Rotavirus, Adenovirus, and norovirus.
If the first-line investigations fail to isolate an enteric pathogen
multiplex PCR assays may be useful to identify the following agents:
Campylobacter species, enteropathogenic and enterotoxigenic E. coli, Shigella species, Salmonella species, Yersinia, Clostridium difficile, Cryptosporidium, Enterocytozoon bieneusi, Enteric viruses (rotavirus, adenovirus, norovirus, and enterovirus).
In case of fever, CMV D+/R− serologic status, cytopenia, liver enzymes studies, and plasma CMV Q-PCR should be performed.
If Ptld or CMV suspected upper git endoscopy with biopsies or capsule biopsies for other GIT parts affection
Treatment
For febrile diarrhea or bacteria or parasite detection : antimicrobial accordingly
For CMV gancyclover IV 5 mg/kg adjusted to eGFR according to cockroft gault equation
If diarrhea persistent more than 1 month
Adaptation of immunosuppression
Change MMF to EC-MPs
Or change tp AZA if the dose of ECMPS reduced >50%
Reduction of TAC ( trough level 5-8ng/ml) or switch to cyclosporin
Changing CNI to mTOR vice versa
Source
Diarrhea After Kidney Transplantation: A New Look at a Frequent Symptom
Transplantation98(8):806-816, October 27, 2014.
Aulagnon, Florence1,2; Scemla, Anne1,2; DeWolf, Susan3; Legendre, Christophe1,2,4,5,6; Zuber, Julien1,2,3,4,6,7. Diarrhea After Kidney Transplantation: A New Look at a Frequent Symptom. Transplantation 98(8):p 806-816, October 27, 2014.
Well done but are you going to wait for one month to decide to reduce the IS?
If diarrhea persisted (more than one month as you stated )despite gancyclovir then this will be a non responding case to the drug.
By colonscopic figure – unhealthy inflamed mucosa, by histopathology i can only identify macropahges.
no evidnece of CMV by
histopathology!
However, negative serology doesn’t preclude a diagnosis of CMV, if biopsy approved it.
The scenario raises the diagnosis of CMV especially the donor is CMV+ve.
What is your differential diagnosis?
How do you manage this case?
Refernces:
(1) CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023.
(2) Razonable RR, Humar A. Cytomegalovirus in solid organ transplant recipients-Guidelines of the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019 Sep;33(9):e13512. doi: 10.1111/ctr.13512. Epub 2019 Mar 28. PMID: 30817026.
(3) CMV in Kidney Transplantation By Ahmed Halawa, consultant Transplant Surgeon Associate Professor, University of Liverpool –UK.
Slide on the right shows one cell with a large nuclear inclusion suggestive of viral infection.
Otherwise fine.
Thank you Prof. Dawlat
This patient has just had her transplant for three months and has been given a lot of immunosuppressant medication to address rejection. Even in the context of negative CMV PCR results, the clinical presentation suggests CMV colitis since this test does not rule it out.
-CMV colitis
-Clostridium difficile is the most common cause of nosocomial diarrhea and accounts for most infectious diarrhea within the first months after transplantation
– Norovirus
-Campylobacter species infections
-Microsporidia
-Drug induced(Tacrolimus or MMF)
-PTLD
Definite Gastrointestinal CMV disease needs:
The presence of upper and/or lower GI symptoms plus macroscopic mucosal lesions plus CMV is documented in tissue by histopathology, virus isolation, rapid culture, immunohistochemistry, or DNA hybridization techniques.
Universal prophylaxis has reduced GI tract cytomegalovirus (CMV) infections. Biopsies show CMV-specific immunostaining. Plasma quantitative PCR has low CMV GI tract disease detection sensitivity.
Plasma quantitative PCR has low CMV GI tract disease detection sensitivity. Recent research showed that plasma quantitative PCR is a very sensitive test for GI tract illness caused by CMV in kidney and liver transplant recipients, especially in the D+/Rj group (100%).
Oral valganciclovir (900 mg bid) has been shown to treat CMV gastroenteritis and colitis (26.6% of patients in the study.
Intravenous ganciclovir is still the gold standard for tissue-invasive CMV illness(5mg/kg BID per day ).
Immunosuppression reduction may avoid relapses. In our case, the patient is at high risk for rejection. I will avoid reducing immunosuppressive treatment at the beginning. If the infection is refractory or life-threatening infection, I will reduce the immunosuppressive )
References:
Aulagnon, Florence1,2; Scemla, Anne1,2; DeWolf, Susan3; Legendre, Christophe1,2,4,5,6; Zuber, Julien1,2,3,4,6,7. Diarrhea After Kidney Transplantation: A New Look at a Frequent Symptom. Transplantation 98(8):p 806-816, October 27, 2014. | DOI: 10.1097/TP.0000000000000335
Your quantitative PCR in GI CMV are contradicting so you have to mention references.
Plan for IS reduction.???
This patient is high risk for CMV colitis as she is R+D+ ,recently transplanted since 3 month and received heavy IS to treat rejection . clinical presentation suggest CMV colitis even in presence of negative CMV PCR as it doesn’t exclude CMV .
Differential diagnosis
1- Viral colitis specially CMV colitis
2- Bacterial colitis : Closteridium diffecile colitis
3- Parasitic infection as giardia and entameba
4- AIDs associated colitis
5- Drug induced as MMF
6- Celiac disease
Treatment :
1- CBC : presence of leucopenia or thrombocytopenia increase possibility of CMV infection
2- Stool analysis and C&S to diagnose bacterial causes as closteriduum difficile
-decrease the dose of IS drugs and stop antiproliferative drugs as MMF and AZA
– Monitoring of graft function for detection of early graft rejection .
– IV fluid with maintaining adequate fluid balance .Monitor and correct electrolytes disturbance .
– GIT consultation , soft diet , try gluten free diet for suspected celiac disease
– repteat CMV PCR and colonoscopy to detect CMV infection
For CMV colitis : start treatment with IV gancyclovir 5 mg /kg bdIV for14-21 days followed by oral valgancyclovir with monitoring of CMV PCR . Treatment should continue for at least 2 weeks after obtaining 2 negative CMV PCR results.
For Cl. Difficile : vancomycin 125 mg oral /6h.
For celiac disease : gluten free diet.
Well done but remember to judge improvement :PCR could be negative in such tissue invasion.
HISTOLOGY with viral inclusion could be focal.
In this case clinical and endoscopic follow up is what is left.
What is your differential diagnosis?
How do you manage this case?
Fine but please remember tissue invasive CMV as the index case are usually PCR negative.
HISTOLOGY is conclusive but bbut remember lesion could be FOCAL.
So give the FULL coarse and judge by the clinical improvement.
-What is your differential diagnosis?
The differential diagnosis for this patient with history of steroid-resistant rejection and diarrhea 4 months after transplantation are:
-How do you manage this case?
Management is MDT and the principle are;
Source, Prof Halawa lecture, Sheffield protocol, Medscape, Oxford hand book of nephrology & hypertension 2th edition
Excellent Ben
How would you exclude other infections as a cause of the diarrhoea?
Thank you prof;
What is your differential diagnosis?
1. Diarrhea 3 months after transplantation
2. Received depleting antibody treatment
3. Colonoscopy showed a diffuse area of inflamed, ulcerated,haemorrhagic, and friable mucosa (severe inflammation)
4. And biopsy showed giant cell with inclusion body (characteristic of CMV Colitis)
Although QCMV PCR is negative (sensitivity for D+/R+ is 72.7%), the most likely diagnosis is CMV colitis
Other differential diagnoses of diarrhea include:
1. Immunosuppressive medications
2. Other infections (norovirus, giardia and cryptosporidium, cryptosporidiosis, mycobacterium avium Complex, and mycobacterium avium-Intracellulare)
3. Clostridium difficile infection
4. Viral and bacterial gastroenteritis
5. colon malignancy
6. Inflammatory bowel disease
How do you manage this case?
*MD approach and a gastroenterologist involvement
*Full history and examinations
*Lab Lab: CBC, RFT and electrolytes, LFT, RBS, urine analysis, ESR, CRP, blood culture, and ABG. Stool analysis, stool culture, and Clostridium difficile toxin assays
*CMV viral load (a negative plasma or whole-blood does not exclude tissue-invasive disease)
Treatment:
Correction of fluid and electrolytes
Immunosuppressions:
*Reduce (by 50%) or stop azathioprine/MMF/myofortic (discontinue CNI only if there is evidence of life-threatening infection). Continue steroids
*Monitor graft function closely and discuss the risk of acute rejection with the patient
* Review the dosing of immunosuppression following resolution of CMV disease
Antiviral:
* Treatment is mandatory regardless to viral load if confirmed to be CMV-tissue invasive
* Give intravenous GCV (5mg/kg bd) for a minimum of of 14 days and for 2 weeks and continue until resolution of symptoms and two tests of CMV DNA by PCR are negative. Do viral load first after 2 weeks and then weekly. Reduce the dose in renal impairment
* Do CBC twice weekly (neutropenia)
* Be aware of ganciclovir resistance if there is no clinical improvement despite treatment or CMV PCR count has not fallen by ≥ 1 log copies/ml after two weeks. If confirmed, stop ganciclovir and give Intravenous Foscarnet for at least 3 weeks after virology advice (newer agents Letermovir and Maribavir may be an alternative)
* Valganciclovir prophylaxis (200 days after ATG)
GI CMV disease
· Is the most common manifestation of tissue-invasive CMV
· Can affect any part of the GI tract, including the esophagus, stomach, and small and large intestines (colon stomach are the most common sites)
· Diarrhoea, abdominal pain, fever are the commonest presenting symptoms. Among patients reporting diarrhoea, stool was described as grossly bloody in 53% and positive for occult blood in 20%
· Generally requires an esophagogastroduodenoscopy or colonoscopy coupled with biopsies for histology or, less frequently, culture to make a definitive diagnosis
· Biopsies are routinely stained for CMV with immunohistochemical stains
· Immunosuppressive medications are the most common cause of diarrhea in SOT recipients.
· The general approach to evaluate diarrhea in SOT recipients is to screen for common infectious causes with stool culture, Clostridium difficile toxin assays, giardia and cryptosporidium enzyme immunoassays, and norovirus polymerase chain reaction (PCR) of the stool and CMV testing of the serum
· If the tests are negative and diarrhea persists, immunosuppression is frequently reduced
· If reduction of immunosuppression fails to improve the diarrhea, the patient will often undergo colonoscopy to identify the cause of infection and rule out CMV colitis
· Unfortunately, serum CMV can be negative in patients with CMV colitis
· CMV PCR is neither sufficiently sensitive nor specific
· qPCR had an 85% sensitivity and 95% specificity to diagnose CMV GI disease; sensitivity was highest in the D+/R− patients (100%) and lowest in the D+/R+ patients (72.7%). Sensitivity was higher for liver transplant recipients (100%) than for kidney transplant recipients (72.7%)
References
1. UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION. BTS, 2022.
2. Ison MG. Diagnosis of gastrointestinal cytomegalovirus infections: an imperfect science. Clin Infect Dis. 2013 Dec;57(11):1560-1. doi: 10.1093/cid/cit524. Epub 2013 Aug 15. PMID: 23956171.
3. CMV in Kidney Transplantation By Ahmed Halawa (lecture), consultant Transplant Surgeon Associate Professor, University of Liverpool –UK, 2023
4. 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.
Excellent answer Mohamed
it is CMV colitis proved by owl eye/inclusion body appearance by biopsy.
management:
1- hospital admission
2-fluid challenge
3-PPI
4-treatment of CMV by iv ganciclovir after doing PCR qualitative for CMV
5-monitor by CBC, graft function and PCR for CMV
6-stop or reduce azathioprin and MMF by 50%
7-continue steroid
8-CNI should be stopped in the life threating conditions
Not good enough Riham
Please focus on the case
renal transplant recipient with resistant CMR treated by ATG make this patient more exposed to CMV infection or any other infection
CMV DNA quantitative is negative
biopsy showed inclusion body or owl eye appearance matched with diagnosis of CMV even with negative PCR
DD:
1- CMV colitis
2-fungal colitis
3-bacterial colitis
4-IBD
5-PTLD
management of CMV colitis:
1- hospital admission
2- iv fluids
3-do qualitative PCR for CMV
4-give iv ganciclovir provided renal dose adjustment
5-reduce MMF by 50%
6-continue steroid
7-stop CNI in life threating condition
8-follow up clinically, CBC, graft function
9-follow up colonoscopy
CMV colitis
Bacterial gastroenteritis
Drug induced colitis (MMF)
Inflammatory bowel disease
Stool culture
CMV PCR
Colonoscopy and biopsy is confirmatory
Reduce immunosuppressive therapy to half and continue same steroid dose
Stop MMF
Start ganciclovir 5mg/kg/day twice a day for 2weeks
Not good enough Sahar
Colonoscopy showcased inflamed mucosa.
Differential diagnosis:
1] Bacterial Infective diarrhea: particularly Clostridium difficile associated colitis and E. Coli colitis. Salmonella, shigella, Campylobacter, vibrio
2] Viral infection, such as Norovirus and CMV, although PCR was negative for CMV. Adeno virus, Rota virus
3]Parasitic E. hystolytica. cryptosporidium,
4] non-infective inflammatory diarrhea, attributed to inflammatory bowel disease IBD.
management:
Testing for C.Difficile toxins, PCR for other viruses and pathogens.
This histopathology picture reveled a swollen epithelial cell with enlarged nucleus consistent with CMV infection.
In certain patients’ percent CMV infection is associated with negative PCR result.
Treatment consist of Ganciclovir 5 mg/kg /day for 2 weeks.
modification of immunosuppressants with avoiding MMF and continuing with prednisolon and CNi. Prophylactic anti-CMV post treatment is indicated with Valgancyclovir.
Reference :
1] Ho Sik Shin , Anil Chandraker,Causes and management of postrenal transplant diarrhea: an underappreciated cause of transplant-associated morbidity. Curr Opin Nephrol Hypertens. 2017 Nov;26(6):484-493
hanks, Batool
Agree with your treatment plan.
How would exclude pseudomembranous colitis?
C.difficile endotoxin A and B testing
The above case deals with diarrhea in immune-compromised patient. Possible differentials which can be considered: Cytomegalovirus (CMV), Microsporidia, and Cryptosporidia along with other causes which are responsible for causing diarrhea in immunocompetent patient like bacteria (Campylobacter, Escherichia coli, Clostridium difficile), parasites (Giardia intestinalis), and viruses (Norovirus and Rotavirus) .Drug induced diarrhea can also be considered.In the above 68-year-old woman with cadaveric renal transplant and CMV D+/R +status and receiving ATG(T -cell depleting agent) for CMR places the patient high risk for CMV disease despite negative Quantitative CMV PCR.This patient’s colonoscopy revealed intranuclear inclusion(Owl’s eye appearance) which are hallmark of CMV colitis .
How do you manage this case?
The first strategy will be to reduce the antimetabolite (AZA, MMF) by half and if no improvement then completely stopped. While steroids and CNIs(lower trough level) to be continued. Antiviral in the form of I.V Ganciclovir at a dose of 5mg/kg 12 hours initially and once the patient can tolerate orally then switch to oral valganciclovir 900mg twice a day for at least 21 days or till the patient is asymptomatic. Close monitoring of blood counts and allograft function needed as antivirals causes bone marrow suppression. Weekly PCR for CMV DNA also needed to monitor the response or to check for resistance.After treatment, patient has to be placed on valganciclovir in a prophylactic dose for at least 03 months. In resistant cases, other drugs which can be used include Marabavir, Foscarnet, and cidofovir.
REFERENCES:
1- UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION-2022
2- Professor Ahmed Halawa Lecture.
Thanks, Batool
Agree with your treatment plan.
You mentioned monitoring VIRAL LOAD with PCR, BUT THE INITIAL PCR WAS NEGATIVE. Will still do PCR?
How would exclude pseudomembranous colitis?
What is your differential diagnosis?
From the clinical and histopathological findings, in addition to the macroscopic finding, it is highly suggestive of CMV colitis.
The chance of serum PCR positivity for CMV is low in this context, and the test is not suitable for diagnosis and follow-up.
Pseudomembranous colitis due to Clostridioidis, viral infections (rotavirus, adenovirus), opportunistic infections (Isospora, Microsporidiosis), use of medication (MMF) are some possible causes in this context, but would not have the findings described in the case above.
How do you manage this case?
Start treatment with Ganciclovir 5mg/kg/dose twice a day (correct according to creatinine clearance) for 14 to 21 days.
Decrease immunosuppression (if possible suspend mycophenolate and/or azathioprine).
Monitor renal function aggressively.
Laboratory tests to monitor the possibility of systemic disease triggered by CMV
Thanks, Filipe
Agree with your treatment plan.
Reference your answer, please
How would exclude pseudomembranous colitis?
Thank you, Professor
Clostridium toxin dosage or specific collection of PCR in feces.
What is your differential diagnosis?
1- CMV colitis (most probable diagnosis) since the recipient is CMV positive and the patient received ATG and heavy immunosuppression
2- Other causes of diarrhea includes drug effect (MMF).
3- Bacterial gastroenteritis.
How do you manage this case?
If the case proved to be CMV colitis (by histopathological diagnosis)
Thanks, Sherif
Agree with your treatment plan.
Reference your answer, please
REFERANCES
1- UK GUIDELINE ON PREVENTION AND MANAGEMENT OF CYTOMEGALOVIRUS (CMV) INFECTION AND DISEASE FOLLOWING SOLID ORGAN TRANSPLANTATION
2- PROF AHMAD HALAWA LECTURE
Differential diagnosis
CMV Colitis – based on tissue histology appearance of an Owl’s intranuclear inclusion which is the histological hall of the diagnosis
Note: CMV colitis can still occur even with negative CMV viraemia/antigenaemia
Risk factors
Management
Investigation others
Treatments
References
Thanks, Isaac
Agree with your treatment plan.
Reference your answer, please
Thanks, prof Halawa for the response.
Reference
Protocol for prophylaxis, surveillance, and treatment of CMV after renal transplantation. Sheffield Teaching Hospitals. NHS Foundation Trust.
She high risk to developed CMV colitis:
My differential diagnosis are:
Management
Thank you, Maisara
CMV PCR is negative. Will you still repeat it again?
Reference your answer, please
step wise approach to diarrhea in renal transplant
Step 1
Drugs like anti – arrhythmics, antibiotics, anti hypertensives, diuretics, anti diabetic medication, laxatives, proton pump inhibitors, protease inhibitors cause diarrhea. So offending drug iF any to be identified and stopped if possible.
Step 2
Microbiological stool examination For
Bacteria – Shigella Salmonella Vibrio Eromonas Ecoli Campylobacter
Mycobacterium complex
Ova and parasites – Isospora belli, Cryptosporindia, Micro sporindia, Balantidium coli, Pneumocystis carinii.
Fungus – Candida, cryptococcus, aspergillus
Assay for clostridium difficile toxin
Step 3
Screen For virus like adenovirus, rotavirus, enterovirus, cytomegalovirus. if CMV suspected then upper or lower gi biopsy.
Reevaluate within 1 week
Step 4
If still no diagnosis on remission then exclude microbial overgrowth and plan more invasive procedures.
Watch For 1-2 weeks
Step 5
Adjust immunosuppressive agent by stopping MMF, replacing with Azathioprine if still no relief. Watch For the next 1-2 weeks.
Step 6
if still diarrhea persistent then do Colonoscopy and send biopsy samples for histopathology. if lesion found, treat
Step 7
if diarrhea still not resolved
anti- diarrheal drugs, supplemental bacteria, lactose free diets. Reevaluate patient after 1-2 weeks.
Severe Diarrhea in Renal Transplant Patients: Results of the DIDACT Study
in the index case
Colonoscopy shows a diffuse area of inflamed, ulcerated, exudative and friable mucosa and punched-out ulcers . number of inclusion bodies on histology are seen.
so tissue sample is suggestive of CMV colitis although CMV PCR is negative.repeat CMV PCR and treat with Iv ganciclovir.
B. Maes
Thank you Sir for your reply.
In this setting, the initial PCR was negative. However, I will still repeat it at different intervals as part of the monitoring.