Not the Usual Suspect

Résumé fourni par la source

A 64-year-old man was admitted for sepsis 4 days after transurethral resection of the prostate (TURP). Immediately post-operatively he had experienced urinary frequency, dysuria, and hematuria, and subsequently developed fevers, cough, and dyspnea. His medical history included type 2 diabetes mellitus (hemoglobin A1c of 6.6%), hypertension, chronic kidney disease, sarcoidosis (diagnosed >20 years earlier) not requiring therapy, prior unprovoked deep vein thrombosis for which he was on anticoagulation, and prostate cancer managed with active surveillance. On evaluation, he was febrile to 38.3°C, hemodynamically stable, and not hypoxic. He was alert and oriented but had tangential responses to some questions. Pulmonary exam demonstrated right-sided crackles. Initial laboratory workup was notable for a white blood cell (WBC) count of 17.4 × 103 cells/microliter (µL), creatinine 3.1 mg/deciliter (dL) (from a baseline of 1.5 mg/dL), and urinalysis with 47 WBC per high power field (hpf) and >150 red blood cells (RBC)/hpf. The remainder of the physical exam, complete blood count, and comprehensive metabolic panel were within normal limits. A chest radiograph showed diffuse bilateral reticular opacities. Blood and urine cultures were collected, and he was initiated empirically on vancomycin, cefepime, and metronidazole. After 48 hours, his urine culture showed no growth, and both sets of blood cultures were growing yeast. Bloodstream infections are a well-recognized complication following TURP procedures. The temporal association of the patient's infectious symptoms with recent urologic surgery suggests he has developed a post-operative infection, typically a urinary tract infection which can spread to the bloodstream. Respiratory symptoms are not usually associated with urinary tract or bloodstream infections, but the patient meets criteria for sepsis which may account for his dyspnea. Candida species are the most common cause of fungemia and often grow relatively quickly in blood and urine cultures. The absence of yeast in the urine culture is notable but does not rule out candidemia related to the patient's procedure. However, if an infectious pulmonary process accounts for the patient's respiratory symptoms, it is unlikely to be due to Candida. The dimorphic fungus Blastomyces dermatitidis has been associated with prostatitis and can cause pulmonary disease, but it would not be expected to grow in blood cultures within 48 hours. Cryptococcus has also been associated with prostatitis and can be isolated in blood cultures with disseminated disease, although it would typically take longer than 48 hours to grow. Antifungal therapy should be initiated, but the choice is not straightforward. Although echinocandins are the usual initial treatment for patients with candidemia, debate continues about their use for urinary tract infections, due to low drug levels in urine. Amphotericin B (AmB) products provide a broad spectrum of antifungal coverage, but liposomal AmB achieves low levels in the urine and AmB deoxycholate has the greatest risk for renal toxicity. Fluconazole achieves high levels in the urine and covers Cryptococcus but does not cover all Candida species. The clinical laboratory may be able to resolve some of this uncertainty by commenting on the yeast morphology—if the yeast has features that are compelling for Candida, an echinocandin may be the best choice. However, if the morphology is not definitive, I would then recommend AmB empirically considering its broader spectrum of activity. The patient was started on micafungin, and the antibacterial agents were discontinued. Follow-up laboratory testing indicated a rising creatinine (up to 5.2 mg/dL) with muddy brown casts noted on urine microscopy. Non-contrast computed tomography (CT) of the chest showed unchanged bilateral micronodules and fibrotic opacities consistent with the patient's history of sarcoidosis, multiple sub-centimeter and borderline enlarged mediastinal lymph nodes, and new patchy consolidation in the right upper lobe (Figure 1A). Non-contrast abdominal CT showed circumferential wall thickening of the urinary bladder with surrounding fat stranding, but no abdominopelvic abscesses, lymphadenopathy, or evidence of post-operative complications (Figure 1B). A, Computed tomography of the chest. B, Computed tomography of the abdomen/pelvis. Upon discussion with the microbiology lab, the yeast was round and lacked features consistent with Candida species but also did not have a discernable capsule. A serum cryptococcal antigen was requested, and a lateral flow assay returned positive with a titer of 1:80. Based on the round appearance of the yeast isolated from blood cultures and the positive serum cryptococcal antigen test, the patient appears to have cryptococcemia following his TURP. One would speculate that he was harboring Cryptococcus in the prostate prior to the procedure. Given the new findings on chest CT, he may also have had cryptococcal pulmonary infection prior to TURP, although respiratory symptoms were not described in the pre-operative period. Sputum can be obtained for diagnostic studies, including fungal culture, and bronchoscopy can be considered. Cryptococcosis is an opportunistic infection commonly associated with certain hosts—interestingly, the patient has sarcoidosis, which is reported to increase the risk for cryptococcal meningitis even in people who are not receiving immunomodulatory treatment. The patient was noted to answer questions tangentially and to be persistently inattentive. Even in the absence of other neurologic findings, this raises concern for central nervous system (CNS) involvement—furthermore, given the implications of detecting CNS disease for antimicrobial therapy, the threshold for excluding meningitis in a patient with evidence of cryptococcal infection elsewhere should be very low, so head imaging and a lumbar puncture should be performed. Testing for human immunodeficiency virus (HIV) should also be obtained. The patient's antifungal coverage needs to be adjusted, since Cryptococcus is not susceptible to echinocandins. Fluconazole is generally well tolerated but would not be the preferred therapy if the patient has meningitis or disseminated/severe disease; the combination of AmB (usually liposomal AmB) and flucytosine (5-FC) is preferred in such circumstances although this patient is at elevated risk of nephrotoxicity from AmB due to baseline acute kidney injury, as well as myelotoxicity from 5-FC given that this agent is renally excreted. Given the presence of disseminated disease, I would recommend liposomal AmB unless the renal function declines further. Given the worsening renal function and concerns about future renal recovery, high-dose fluconazole (renal dosing equivalent to 800 mg daily) was started, and micafungin was discontinued. Repeat blood cultures on hospital days 3, 5, and 8 remained positive for yeast, which was ultimately identified as Cryptococcus neoformans. CT of the head showed no acute intracranial abnormalities. HIV antigen/antibody testing was negative. The CD4 count was 294 cells/µL (27.7%). A lumbar puncture was performed on hospital day 6—the opening pressure was 16 centimeters of H2O and the cerebrospinal fluid (CSF) profile showed 2 WBC/µL (76% lymphocytes), 7 RBC/µL, protein 31 mg/dL, and glucose 63 mg/dL. The CSF cryptococcal antigen was negative. Further evaluation of the pulmonary infiltrate with bronchoscopy was deferred given his clinical condition. The results of the lumbar puncture suggest the patient does not have cryptococcal meningitis. However, CSF cryptococcal antigen tests are occasionally negative when CSF culture results are positive, and the culture results should be followed until they are finalized. Fluconazole is a fungistatic drug and has been found to clear Cryptococcus more slowly than AmB in studies of cryptococcal meningitis. If the patient's renal dysfunction is due to severe funga

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