Coccidioidal Meningitis after Liver Transplantation in a Nonendemic Region

Coccidioidomycosis is a fairly common diagnosis in immunocompromised individuals in endemic regions but may be underdiagnosed elsewhere. We report a case of coccidioidal meningitis diagnosed after liver transplantation in a nonendemic region (Northeastern United States) based on delayed seroconversion in the cerebrospinal fluid. Diagnosis was initially suggested by travel history and retinal lesions. The patient was treated successfully with fluconazole. This is a rare report of nonfatal coccidioidal meningitis after liver transplantation in a nonendemic region. A 42-year-old white man with a history of cirrhosis related to hepatitis C virus (genotype 2B), hemachromatosis (C282Y heterozygous), and alcoholism as well as diabetes mellitus underwent orthotopic liver transplantation (OLT). Computed tomography (CT) of the chest performed on day 9 after OLT for fevers revealed multiple bilateral small pulmonary nodules; a chest roentgenogram at the time of OLT was normal. Bronchoscopy with bronchoalveolar lavage was performed with negative bacterial, fungal, and viral studies; he was given 8 days of empiric treatment with fluconazole 100 mg po qD, and the fevers resolved. Nine weeks after OLT he returned with headache, nuchal rigidity, altered mental status, and temperature of 100.6°F. At the time of presentation, he was taking cyclosporine A (Neoral), atovaquone, famciclovir, interferon alpha, ribavirin, insulin, esomeprazole, thiamine, and folate. He had been on itraconazole 100 mg daily for 6 weeks after OLT to maintain his serum cyclosporine level; this had been discontinued 3 weeks prior to admission due to an elevated cyclosporine A level (622 ng/ml). Further historical data was not available due to the patient's altered mental status. (Table 1) shows the abnormal cerebrospinal fluid (CSF) results. An MRI scan revealed multiple nonenhancing T2 hyperintense foci within the subcortical and periventricular white matter (Fig. 1A) and nonspecific T2 hyperintense signal within the central pons in triangular configuration. Chest CT showed significant reduction in the size of the pulmonary nodules.TABLE 1: Cerebrospinal fluid profileFIGURE 1.: Brain MRI images. (A) Axial FLAIR images demonstrating scattered areas of increased T2 signal in the subcortical white matter (arrows). (B) Irregular nodular enhancement along the superior surface of the posterior fossa contents (arrow), suggestive of granulomatous disease. (C and D) Multiple whitish chorioretinal spots, compatible with disseminated fungal infection.The patient was treated empirically for bacterial meningitis with ceftriaxone, ampicillin, and vancomycin. The lumbar puncture was repeated 3 days later, which showed an increased white blood cell (WBC) count and lymphocytic predominance (Table 1). On day 8, he had a grand mal seizure. Repeat lumbar puncture showed doubling of the WBC count with a markedly low glucose (<20 mg/dl) and increased total protein; serum was sent for fungal serologic testing (including the coccidioidomycosis complement fixation test and coccidioidomycosis immunodiffusion test) to the Centers for Disease Control and Prevention. With worsening clinical and CSF parameters by day 12, he was begun on fluconazole (800 mg IV, then 400 mg IV per day) and antituberculosis therapy. His cyclosporine dose was reduced; interferon alpha and ribavirin were stopped. Subsequent CSF samples showed a reduction in the WBC count with negative Gram stains, fungal smears, acid fast smears, VDRL test, and PCR assays for herpes simplex virus, Bartonella, Mycobacteria, Varicella, Toxoplasma, and cytomegalovirus. Bacterial, fungal, and mycobacterial cultures as well as cryptococcal antigen assays of the blood and CSF were also negative. On day 13, a brain MRI revealed new irregular nodular enhancement along the superior surface of the posterior fossa contents, as well as nonspecific leptomeningeal enhancement filling the fissures of the superior vermis (Fig. 1B), suggesting granulomatous disease. A retinal exam showed multiple lesions suggestive of fungal disease (Fig. 1C). Antibacterial and antituberculosis treatments were stopped and fluconazole was continued. Subsequent information from his family confirmed that he had resided in Arizona for 16 years and moved to New England a year before undergoing OLT. His serum serology later revealed a coccidioidomycosis complement fixation test that was positive with a titer of 1:16, and a coccidioidomycosis immunodiffusion test that was positive. (Pre-OLT serology was not checked.) CSF from day 8 was negative for Coccidioides by the complement fixation test as well as the immunodiffusion test, but turned positive on day 18 and was repeatedly positive on day 49. He responded well to treatment with fluconazole 400 mg and remains on that medication (19 months). His mental status and liver function are excellent. In the general population, it is estimated that there are more than 150,000 infections with Coccidioides spp. annually in the United States, largely in the endemic southwestern states, but <100 new meningeal infections per year (1). Coccidioidomycosis is a fairly common diagnosis in immunocompromised individuals in endemic regions but may be underdiagnosed elsewhere (2–5). When the diagnosis is made in organ transplant recipients, extrapulmonary (disseminated) infection is common, occurring in ≤75% of transplant patients (6); mortality as high as 72% has been reported, particularly with meningeal involvement (7, 8). Infection generally presents as pneumonia an average of 8 weeks after transplantation (5, 7). The diagnosis of coccidioidal meningitis requires clinical suspicion with serologic testing of blood and CSF, tissue histopathology, or growth in culture. In immunocompromised hosts, serologic responses are often delayed or absent; low serologic titers may be clinically significant and merit repeating. Up to one third of AIDS patients with pulmonary involvement fail to mount an antibody response (9). Transplant recipients with active disease may not develop serologic positivity (7, 10). The coccidioidomycosis complement fixation test detects IgG reactive with a fungal chitinase and is useful for both diagnosis and assessment of prognosis. The coccidioidomycosis immunodiffusion test, as well as ELISA and latex agglutination assays, may enhance diagnostic sensitivity (10). If any test is positive, the patient should undergo careful evaluation for coccidioidal infection. In this patient, initial CSF serologies (day 12) were negative with seroconversion by day 18. Retinal coccidioidomycosis is a very rare finding, hardly ever seen or reported in the literature. In the absence of other diagnostic data at that time, the retinal findings provided an important clinical clue. In transplant recipients, fluconazole is generally considered the drug of choice for coccidioidal meningitis based on efficacy and less toxicity (11–14). Drug interactions with itraconazole may be limiting for patients receiving calcineurin inhibitors. Voriconazole is effective in vitro and in case reports (15, 16). Given reports of relapsed infection after treatment of coccidioidomycosis in organ transplant recipients, lifelong secondary prophylaxis should be instituted (7, 17, 18). This patient represents a rare case of disseminated reactivation coccidioidomycosis in a nonendemic region (19), the Northeastern United States. The presentation may have been delayed by initial treatment with itraconazole to increase the cyclosporine A levels. This low dose therapy may have been adequate to suppress pulmonary infection as suggested by improvement in the chest CT, but inadequate prophylaxis against meningitis. In endemic regions, data suggest that transplant candidates with either a positive history or serologic results reflecting previous coccidioidal infection can be given fluconazole to prevent recurrent infection after transplantation (3). Patients who are pre- or postorgan transplant and have any history of exposure to endemic regions should undergo serologic testing (7, 20). In a series of 37 patients who had undergone liver transplant and moved to an endemic area, the annual incidence of new coccidioidal infection was 2.7% (21). In one recent series, of 290 patients with end-stage liver disease, 6 (2.1%) were found to have active coccidioidal infection (22). In summary, this is a case of an unusual etiology of meningitis in an organ transplant recipient outside the usual regions for this endemic fungus. Diagnostic perseverance may be required to confirm clinical suspicions in such individuals. Camille N. Kotton Vincent C. Marconi Jay A. Fishman Transplant Infectious Disease and Compromised Host Service Infectious Disease Unit Raymond T. Chung Gastrointestinal Unit Nahel Elias Martin Hertl Transplantation Unit Department of Surgery Massachusetts General Hospital and Harvard Medical School Boston, MA ACKNOWLEDGMENTS The authors thank Demetre Daskalakis, M.D., for the review.