Hypercalcemia Due to Disseminated Histoplasmosis in a Kidney Transplant Recipient with Negative Histoplasma Antigen Testing

Introduction: Histoplasmosis is a fungal infection that can lead to disseminated disease in immunosuppressed patients. Hypercalcemia can occasionally result, as it is a granulomatous disease. We present an interesting case of disseminated histoplasmosis complicated by hypercalcemia but negative histoplasma antigen testing. Case Description: A 68-year-old male with kidney transplanted in 2002 on sirolimus, mycophenolate mofetil, and prednisone presented to clinic complaining of fevers, night sweats, 35-lb weight loss, fatigue, and intermittent diarrhea. He was found to have enteropathogenic E coli on stool enteric panel and esophagitis on upper endoscopy. With ongoing treatment, his serum calcium rose from normal to 11.0 mg/dL. Initial work-up showed PTH was mildly low, 25-hydroxyvitamin D was normal, but 1,25-dihydroxyvitamin D was elevated. CT imaging showed innumerable miliary lung nodules with multiple cavitary nodules and calcified splenic lesions, consistent with granulomatous infection. An extensive infectious work-up was performed, including bronchoalveolar lavage, and was unremarkable. His hypercalcemia and symptoms improved, and he was discharged home, only to return months later with similar symptoms and a calcium of 13.1 mg/dL. Infectious testing was again unrevealing; therefore, he underwent video-assisted thoracoscopic surgery with pleural fluid sampling and lung wedge resection biopsy. Pleural fluid studies and cultures were unremarkable, but lung biopsy both showed necrotizing granulomas with silver-stained yeast forms and grew Histoplasma capsulatum on culture. He was started on itraconazole. A follow-up CT scan eight months later showed contraction of cavitary lesions to smaller nodules and resolution of his symptoms and hypercalcemia. Discussion: Histoplasmosis is a concern for immunosuppressed patients in certain geographic areas. While hypercalcemia can occur with disseminated granulomatous disease, it is relatively uncommon. The usual testing performed when histoplasmosis is suspected is checking blood and/or urine for the histoplasma antigen, which is usually positive in disseminated disease. Interestingly, in this case, both blood and urine antigen were negative at two different time points prior to diagnosis, despite dissemination. Persistent testing including tissue biopsy may be needed in such cases to make a diagnosis.