Infections in the Immunocompromised Host — Clinical Case

DCE Long Case

Patient brief (provided to trainee)

Patient: Mr Samuel Ateya, 45 years old, schoolteacher, originally from South Sudan, resident in Australia for 15 years. [1] />

Presenting complaint: Admitted to hospital with a 10-day history of fever, watery diarrhoea (6 to 8 times daily, occasionally blood-streaked), malaise, and anorexia. [1] />

Transplant history: Received a deceased-donor kidney transplant 4 months ago for end-stage renal failure from hypertensive nephrosclerosis. The donor was cytomegalovirus (CMV) IgG-positive and the recipient was CMV IgG-negative (a D+/R- mismatch). Induction was with basiliximab. Maintenance immunosuppression is tacrolimus (modified-release, trough target 5 to 8 ng/mL), mycophenolate mofetil 1 g twice daily, and prednisolone 5 mg daily. He received valganciclovir prophylaxis 900 mg daily for 3 months post-transplant, which was stopped 1 month ago. Co-trimoxazole for PCP prophylaxis continues. [1] />

Current presentation:

• Fever to 38.6 degrees, heart rate 96, blood pressure 128/78, respiratory rate 18, oxygen saturation 97 per cent on room air.
• Mild abdominal tenderness, no peritonism.
• No cough, no dysuria, no headache.
• Two recent creatinine results: 130 micromol/L 2 weeks ago (baseline post-transplant 120), now 165 micromol/L. [1] />

Investigations on admission:

• Full blood count: haemoglobin 112 g/L, white cell count 2.6 x 10^9 per litre (neutrophils 1.8, lymphocytes 0.6), platelets 140 x 10^9 per litre.
• CRP 62 mg/L.
• Electrolytes normal; creatinine 165 micromol/L, eGFR 42.
• Liver function tests: ALT 38, ALP 110, bilirubin 12 — mild transaminitis.
• CMV quantitative PCR on whole blood: 120,000 IU/mL.
• Stool: negative for C. difficile toxin, culture, and ova/cysts/parasites.
• Flexible sigmoidoscopy with biopsy: scattered subepithelial haemorrhages and ulceration; biopsy shows enlarged cells with intranuclear and intracytoplasmic inclusions positive for CMV on immunohistochemistry.
• BK virus quantitative PCR on plasma: 25,000 copies/mL (raised).
• Urinalysis: trace protein, no haematuria, no leucocyte esterase; urine culture negative. [1] />

Past history: Hypertension (15 years), gout, no diabetes. No history of TB. QuantiFERON-TB Gold negative pre-transplant. HBsAg negative, anti-HBc positive, anti-HBs positive pre-transplant (resolved hepatitis B). HIV negative. [1] />

Current medications: Tacrolimus modified-release 7 mg nocte, mycophenolate mofetil 1 g twice daily, prednisolone 5 mg daily, co-trimoxazole 960 mg daily, valaciclovir 500 mg daily (for HSV/VZV prophylaxis), amlodipine 10 mg daily, allopurinol 100 mg daily. [1] />

Social history: Lives with his wife and three children. Teaches at a secondary school. Non-smoker, does not drink alcohol. Keen to return to work. Has not travelled recently. [1] />

Candidate's structured presentation (model)

SASPOP opening statement: [1]

"Mr Samuel Ateya is a 45-year-old teacher, originally from South Sudan, who is 4 months post a deceased-donor kidney transplant for hypertensive end-stage renal failure, on tacrolimus, mycophenolate, and prednisolone, and who now presents with CMV colitis in the setting of a D+/R- mismatch, complicated by a rising creatinine from BK virus nephropathy and leucopenia. He had valganciclovir prophylaxis for 3 months which was stopped 1 month ago, and his presentation reflects the typical 1 to 6 month post-transplant opportunistic window." [1] />

Structured problem list: [1]

1. CMV colitis (tissue-invasive CMV disease) — D+/R- recipient, prophylaxis stopped 1 month ago, now CMV PCR 120,000 IU/mL, biopsy-proven colitis with viral inclusions.
2. BK virus nephropathy with rising creatinine — BK viraemia 25,000 copies/mL, creatinine risen from 130 to 165, in the differential with acute rejection and calcineurin-inhibitor nephrotoxicity.
3. Leucopenia and thrombocytopenia — CMV-induced marrow suppression, exacerbated by the valganciclovir he will receive for treatment.
4. CMV-induced immunosuppression — CMV disease itself suppresses host immunity, increasing the risk of bacterial sepsis, invasive fungal infection, and EBV-driven post-transplant lymphoproliferative disorder, and of acute rejection when immunosuppression is reduced.
5. Resolved hepatitis B (HBsAg-negative, anti-HBc-positive) — requires ongoing vigilance, though the risk of reactivation is lower than with rituximab; allopurinol is continuing safely.
6. The balance of immunosuppression — reducing it to control CMV and BK against the risk of acute rejection. [1] />

Integrated management plan

1. CMV colitis — antiviral therapy and immunosuppression reduction: [1] />

The treatment of CMV colitis in a solid organ transplant recipient is intravenous ganciclovir 5 mg/kg every 12 hours, dose-adjusted for renal function, for 2 to 3 weeks, with weekly CMV quantitative PCR monitoring until two consecutive negatives, then transition to valganciclovir 900 mg daily for a further 1 to 3 months of secondary prophylaxis. The CDC/IDSA/ASBMT transplant prophylaxis principles underpin the approach [1]. I will reduce the mycophenolate (typically halve it) to allow immune recovery against CMV, while monitoring for acute rejection. I will not stop the tacrolimus abruptly because of the rejection risk and the nephrotoxicity overlap with BK nephropathy — I will adjust it to the lower end of the trough target and recheck. I will monitor the full blood count weekly — ganciclovir worsens the CMV-induced leucopenia, and I may need G-CSF if neutropenia is severe, or dose-reduce the ganciclovir (with caution, balancing marrow suppression against antiviral efficacy). I will not give CMV intravenous immunoglobulin routinely — it has a limited role in CMV pneumonitis (particularly in lung transplant) and in refractory disease, not in routine colitis.

2. BK nephropathy — reduce immunosuppression, monitor: [1] />

The management of BK nephropathy is reduction of immunosuppression — typically the mycophenolate first, then the tacrolimus — with serial monitoring of the BK viral load (every 2 to 4 weeks) and the creatinine, and a low threshold to biopsy the allograft if the creatinine continues to rise (to distinguish BK nephropathy from acute rejection, which require opposite management). The trap is treating presumed rejection with intensified immunosuppression, which worsens the BK. Cidofovir and fluoroquinolones have a limited role; the mainstay is controlled immunosuppression reduction. I will work closely with the transplant team on the balance — reducing it enough to control BK and CMV, not so much as to precipitate rejection. [1] />

3. Leucopenia and thrombocytopenia: [1]

Both are driven by CMV (marrow suppression) and will be worsened by ganciclovir. I will monitor the full blood count twice weekly during induction therapy, use G-CSF if neutrophils fall below 0.5 with infection, and transfuse platelets only for bleeding or counts below 10 (or 20 if febrile). The leucopenia itself increases the risk of bacterial infection, so I will have a low threshold for blood cultures and empiric broad-spectrum antibiotics if he becomes febrile. [1] />

4. CMV-induced immunosuppression and surveillance: [1] />

Because CMV disease increases the risk of secondary bacterial sepsis, invasive fungal infection, and EBV-driven PTLD, I will monitor for these — weekly EBV viral load (quantitative PCR) during and after the CMV treatment, surveillance for bacterial infection, and a low threshold for chest CT and antifungal therapy if he develops persistent fever or pulmonary signs. I will continue the co-trimoxazole for PCP prophylaxis throughout. [1] />

5. The resolved hepatitis B: [1]

The risk of HBV reactivation is lower than with rituximab (the transplant immunosuppression does not deplete B-cells as profoundly), but it is not zero, and any rise in ALT will require HBV DNA testing. I will monitor the LFTs monthly. [1] />

6. Symptom and nutritional support: [1]

He has significant diarrhoea and anorexia from the colitis. I will ensure hydration (oral or intravenous as required), electrolyte correction, and nutritional support (dietitian, oral supplements, or nasogastric feeding if intake is poor). Antidiarrhoeals are avoided in infectious colitis. [1] />

Examiner discussion questions

Q1: "He was a D+/R- mismatch and received 3 months of valganciclovir prophylaxis, stopped a month before this presentation. Why did the prophylaxis fail, and how do you decide between universal prophylaxis and pre-emptive therapy?" [1] />

"This is a classic case of late-onset CMV disease after prophylaxis — the valganciclovir suppressed CMV replication for 3 months, but it did not allow the recipient to develop CMV-specific T-cell immunity (the virus was suppressed, not presented to the immune system), so when the prophylaxis stopped the recipient's naive immune system encountered the donor-derived virus for the first time and could not control it. This is the recognised limitation of universal prophylaxis in D+/R- recipients, and it is why many centres extend prophylaxis to 6 months in the highest-risk groups (D+/R- kidney, lung, heart-lung, alemtuzumab induction). The alternative strategy is pre-emptive therapy — monitoring CMV PCR weekly during the high-risk window and treating only when viraemia rises. Each strategy has trade-offs: universal prophylaxis prevents early CMV disease but risks late-onset disease after cessation and exposes the patient to ganciclovir toxicity (leucopenia) throughout; pre-emptive therapy reduces drug toxicity and may allow some immune priming, but requires reliable, frequent monitoring and risks missing a rapidly progressing case. For Mr Ateya, a D+/R- kidney recipient, many centres now favour either 6 months of universal prophylaxis or a hybrid approach (prophylaxis followed by a period of pre-emptive monitoring after cessation). His case is an argument for extending the prophylaxis window." [1] />

Q2: "His creatinine is rising. How do you distinguish BK nephropathy from acute rejection and from calcineurin-inhibitor nephrotoxicity?" [1] />

"The three causes of a rising creatinine in a transplant recipient on tacrolimus — BK nephropathy, acute rejection, and tacrolimus nephrotoxicity — can coexist and require different management, so the distinction matters. Tacrolimus nephrotoxicity is suggested by a high tacrolimus trough, the absence of viraemia, and a biopsy showing arteriolar hyalinosis and isometric vacuolisation; the management is dose reduction. BK nephropathy is suggested by a rising BK viral load (above 10,000 copies/mL is the usual threshold for probable nephropathy), with a biopsy showing viral inclusions in tubular epithelial cells (SV40 immunohistochemistry positive) and interstitial inflammation that can mimic rejection; the management is immunosuppression reduction. Acute rejection is suggested by a rising creatinine with a low or absent BK load and a biopsy showing tubulitis, interstitial inflammation, and (in antibody-mediated rejection) C4d positivity and donor-specific antibodies; the management is INCREASED immunosuppression (methylprednisolone, antibody therapy) — the opposite of BK. The critical point is that the biopsy is the discriminator, and the trap is empirically treating presumed rejection with intensified immunosuppression in a patient who actually has BK nephropathy — that worsens the virus and can lose the graft. Mr Ateya has a BK load of 25,000 and a creatinine that has risen — I would reduce the immunosuppression, but I would also biopsy the allograft if the creatinine continues to rise, to confirm the diagnosis and exclude coincident rejection." [1] />

Q3: "Why does CMV disease put him at risk of other complications, and what will you do about it?" [1] />

"CMV is itself immunomodulatory. CMV infection suppresses host T-cell function and shifts the immune balance, which increases the risk of secondary bacterial sepsis (particularly with Gram-negative organisms and listeria), invasive fungal infection (Candida, Aspergillus in the more heavily immunosuppressed), and EBV-driven post-transplant lymphoproliferative disorder (PTLD). It also increases the risk of acute rejection when the immunosuppression is reduced to treat it — a vicious cycle, because rejection is then treated with more immunosuppression, which worsens the CMV. So preventing and promptly treating CMV prevents these secondary complications. For Mr Ateya I will monitor the EBV viral load weekly during and after the CMV treatment (a rising EBV load prompts evaluation for PTLD with imaging and, if needed, biopsy), I will continue the co-trimoxazole for PCP, and I will have a low threshold for investigating fever or new symptoms. The single most effective intervention is to clear the CMV with ganciclovir and controlled immunosuppression reduction." [1] />

Q4: "What is his long-term vaccination and prophylaxis plan once he recovers?" [1] />

"The 2013 IDSA vaccination of the immunocompromised host guideline sets the principles [2]. Once he has recovered and is on stable maintenance immunosuppression, his vaccination plan includes: annual inactivated influenza (for him and his household contacts), pneumococcal (PCV13 or 15 followed by PPSV23 at least 8 weeks later, with a PPSV23 booster at 5 years), recombinant zoster (Shingrix) which is inactivated and safe in immunosuppression, hepatitis B series (given his resolved HBV and the importance of maintaining anti-HBs), COVID-19 as per current guidance, and inactivated polio, tetanus, diphtheria, pertussis boosters as age-appropriate. Live vaccines — MMR, varicella, yellow fever, live attenuated influenza (intranasal), oral polio, oral typhoid Ty21a, and BCG — are contraindicated while he is on maintenance immunosuppression. His household contacts should be fully vaccinated with inactivated vaccines and should avoid the live intranasal influenza vaccine. His ongoing prophylaxis is co-trimoxazole for PCP for at least 6 months post-transplant (longer if he remains on higher immunosuppression or has had a rejection episode), CMV surveillance with periodic PCR after the treatment course (a rising load prompts pre-emptive valganciclovir), and valaciclovir for HSV/VZV while he remains on immunosuppression. I will give him written documentation of his vaccination status and prophylaxis plan, and communicate it to his general practitioner."

Q5: "He is originally from South Sudan and his QuantiFERON was negative pre-transplant. Does this change anything?" [1] />

"The QuantiFERON-TB Gold can be falsely negative in the setting of end-stage renal failure and immunosuppression (anergy), so a negative test does not fully exclude latent tuberculosis, particularly in someone born in a high-prevalence country. I would maintain a low threshold for investigating tuberculosis if he develops any compatible symptom (chronic cough, weight loss, fever, lymphadenopathy, unexplained sterile pyuria), with sputum for acid-fast bacilli and mycobacterial culture, imaging, and (if indicated) biopsy. The strongyloides question is also relevant — he is from a tropical area, and any immunosuppressed patient from an endemic area should be screened for strongyloides (serology) and treated with ivermectin before or during immunosuppression, because hyperinfection under immunosuppression is fatal in over half of cases and presents as polymicrobial Gram-negative sepsis from larvae carrying enteric bacteria out of the gut. If his strongyloides serology was not checked pre-transplant, I would check it now and treat if positive." [1] />

Q6: "How will you communicate this complex plan to him and his wife, who is his main support?" [1] />

"I will sit down with both of them, ideally with an interpreter if there is any language barrier (he has been in Australia for 15 years and his English is good, but medical complexity benefits from his first language), and explain clearly. I will tell them that his body's defence system is being deliberately lowered to protect the new kidney, that this has allowed a virus called CMV to take hold, that we are treating it with an antiviral through the drip and reducing some of the immunosuppression tablets to let his own immune system help, and that we are watching his kidney function closely because a second virus (BK) may be affecting it. I will explain the expected timeline — weeks of treatment for the CMV, months of monitoring — and that he will need close follow-up. I will ask about his goals (return to teaching, his family, his values around intensity of treatment), and I will arrange a family meeting with the transplant team, the infectious diseases team, and the renal nurse coordinator. I will give written information, a clear point of contact, and a plan for what to do if things change. The communication is part of the treatment — a patient who understands the plan adheres to it, recognises problems early, and comes back when it matters." [1] />