Late-onset CMV disease after prophylaxis in a D+/R– recipient

Transplantmedium

A 48-year-old woman with a history of ESRD status post kidney transplant presents to the emergency department with 2 weeks of intermittent fevers, diarrhea, fatigue, and body aches. She is currently 8 months status post deceased donor kidney transplantation. The kidney allograft functioned immediately. She received anti-thymocyte globulin for induction. Because of positive donor hepatitis C status, the patient was prescribed 12 weeks of glecaprevir/pibrentasvir after transplant and achieved sustained virologic response. Valganciclovir and trimethoprim-sulfamethoxazole were prescribed for 6 months after transplant. Her current immunosuppressive regimen consists of tacrolimus, mycophenolate, and prednisone. Her course has been uncomplicated until the last few weeks, at which time she developed persistent fevers and diarrhea (3-6 loose stools per day). On examination, BP is 108/68 mm Hg, heart rate is 96/min, and temperature is 37.8°C. She is ill-appearing but in no distress. Her allograft is nontender, and the rest of her examination is unremarkable. Pretransplant serologic data (donor; recipient): CMV IgG +; –. EBV IgG +; +. Hepatitis B virus (HBV) surface antigen (HBsAg) –; –. HBV surface antibody (HBsAb) –; +. HBV core antibody (HBcAb) –; –. Hepatitis C virus (HCV) core antibody +; –. HCV nucleic acid test (NAT) +; –. Current laboratory data: WBC count 1.0/µL (reference 4000–11,000); hemoglobin 9.8 g/dL (12–16); serum potassium 3.3 mEq/L (3.5–5.0); total CO₂ 17 mEq/L (23–28); BUN 24 mg/dL (8–20); creatinine 1.1 mg/dL (baseline, 1.0) (0.5–1.1); alanine aminotransferase 76 U/L (10–40); aspartate aminotransferase 82 U/L (10–40); total bilirubin 1.1 mg/dL (0.3–1.0); alkaline phosphatase 128 U/L (30–120). Urinalysis reveals no protein, RBCs, or WBCs. Which ONE of the following is the MOST likely cause of this patient’s symptoms and laboratory abnormalities?

  1. A.Pneumocystis jirovecii
  2. B.Hepatitis C
  3. C.Mycophenolate
  4. D.CytomegalovirusCorrect

Explanation

This patient most likely has primary cytomegalovirus (CMV) infection. This patient exhibits classic signs and symptoms of CMV infection including fever, fatigue, and leukopenia. Additionally, her diarrhea suggests CMV colitis, and the abnormal liver function tests suggest the possibility of CMV hepatitis. Donor-positive/recipient-negative serostatus (pre-transplant CMV IgG) is an important risk factor for CMV infection, in addition to lymphocyte-depleting induction therapy such as anti-thymocyte globulin (ATG). CMV most commonly develops in the first 12 months following transplantation. This patient received standard prophylaxis with valganciclovir for 6 months after transplant. Patients are at increased risk for development of CMV infection in the months following discontinuation of antiviral prophylaxis. The patient received prophylaxis against Pneumocystis jirovecii for 6 months with trimethoprim-sulfamethoxazole, but this was discontinued 2 months before presentation. Pneumocystis infection typically presents with signs and symptoms of pneumonia. This patient has symptoms more consistent with CMV infection rather than the typical pulmonary symptoms expected with Pneumocystis. Mycophenolate is a commonly used medication for maintenance immunosuppression. Its side effects include both gastrointestinal (e.g., diarrhea, nausea) and hematologic (e.g., leukopenia, anemia) manifestations. Although this patient does have diarrhea and cytopenias, mycophenolate is much less likely to cause the fever and liver function abnormalities observed in this patient. Additionally, the timing of symptom onset is more consistent with CMV infection than mycophenolate toxicity. There is an increasing utilization of kidney transplants from donors testing positive for hepatitis C. This patient, who received a kidney from a donor with positive HCV NAT, was appropriately treated with direct-acting antiviral therapy (glecaprevir/pibrentasvir), leading to a sustained virologic response. Although active HCV infection may cause abnormal liver function tests, recurrence of hepatitis C would be very unlikely after treatment and would be less likely to cause the other symptoms reported by this patient.

Why each option

A.
Pneumocystis causes hypoxemic pneumonia, not diarrhea and hepatitis, although risk rises after trimethoprim-sulfamethoxazole prophylaxis stops.
B.
She achieved sustained virologic response after glecaprevir/pibrentasvir; HCV relapse is very unlikely and would not explain fever, leukopenia, and diarrhea.
C.
Mycophenolate causes diarrhea and cytopenias but not fever or transaminitis, and the timing after stopping prophylaxis favors CMV.
D.
Correct. A CMV D+/R– recipient after ATG induction, 2 months off valganciclovir, with fever, leukopenia, diarrhea, and transaminitis has primary CMV disease.

Reference: Kotton CN, Transplantation 2018 (Third International Consensus Guidelines on CMV in solid-organ transplantation); Razonable RR, Clin Transplant 2019 (AST IDCOP CMV guideline)

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