Case Presentation: A 68-year-old man with type 2 diabetes, coronary artery disease, and a liver transplant three months prior for MASLD-related cirrhosis presented with three days of weakness, fatigue, chills, and fevers. Post-transplant medications included tacrolimus, mycophenolate, prednisone, and prophylactic acyclovir. He denied headache, neck stiffness, respiratory or gastrointestinal symptoms, rash, vision changes, recent travel, or animal exposures, though he noted mild confusion.On arrival, his temperature was 102°F with an otherwise normal exam, including an intact neurological examination. Labs showed a normal tacrolimus trough, WBC 5.5 K/µL and creatinine 2.1 mg/dL (baseline 1.5). Liver enzymes, urinalysis, chest radiograph, and non-contrast head CT were unremarkable. With no clear source of infection, he was started empirically on vancomycin and piperacillin-tazobactam.Despite broad-spectrum therapy, fevers persisted. Blood cultures remained negative, and CMV PCR was negative. CT chest and abdomen/pelvis showed scattered pulmonary nodules and expected post-transplant changes. Given ongoing fevers without a source, his infectious workup was broadened to include fungal testing, which was negative for Histoplasma and Coccidioides. Serum cryptococcal antigen returned positive at 1:640, and fungal blood cultures later grew Cryptococcus neoformans.Given his subtle cognitive symptom of self-reported confusion, a lumbar puncture was performed and demonstrated CSF WBC 95 cells/µL (76% lymphocytes), protein 57 mg/dL, and CSF cryptococcal antigen titer of 1:1280, with a mildly elevated opening pressure—consistent with cryptococcal meningitis. Induction therapy with amphotericin and flucytosine was started and later transitioned to fluconazole for consolidation therapy. His cognitive symptoms improved, and his fevers resolved.
Discussion: Cryptococcosis is a life-threatening fungal infection seen in individuals with impaired cell-mediated immunity, including solid-organ transplant recipients. Cryptococcus is the third most common invasive fungal infection among individuals who have received solid organ transplants (1). Unlike the classic presentation in HIV/AIDS, cryptococcal disease in transplant patients is often subacute and may lack classic findings of bacterial meningitis, such as nuchal rigidity or photophobia, contributing to delayed diagnosis. Cryptococcal meningitis in transplant patients results from hematogenous spread following inhalation of Cryptococcus neoformans from the environment. Symptoms may include fatigue, low-grade fevers, confusion, or mild headaches. Diagnosis requires a high index of suspicion, particularly in transplant patients with unexplained fevers or cognitive decline. Serum cryptococcal antigen is highly sensitive; however, evaluation for central nervous system involvement requires lumbar puncture with CSF antigen titers and opening pressure measurement. Early initiation of induction therapy is essential to prevent neurologic deterioration and mortality.
Conclusions: Hospitalists caring for solid-organ transplant recipients should consider cryptococcal disease in cases of persistent fevers, pulmonary nodules, or subtle cognitive changes. Because clinical findings may appear mild, early serum antigen testing and timely lumbar puncture are critical for identifying cryptococcal fungemia and meningitis and initiating lifesaving antifungal therapy.