Immune Reconstitution Cryptococcosis after Initiation of Successful Highly Active Antiretroviral Therapy

Elizabeth R. Jenny-Avital 0 Maria Abadi 0 1 0 Received 26 March 2002; accepted 11 July 2002; electronically published 20 November 2002. Bldg. 5, Rm. 607 , ACS Clinic , 1400 Pelham Pkwy. S, Bronx, NY 10461 (jennyavita @aol.com). Clinical Infectious Diseases 2002; 35:e128-33 2002 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2002/3512-00E2$15.00 1 Pathology, Jacobi Medical Center, Albert Einstein College of Medicine , Bronx , New York Five of 10 patients who commenced successful highly active antiretroviral therapy (HAART) for infection with human immunodeficiency virus type 1 (HIV-1) concurrent with or soon after a diagnosis of cryptococcal infection experienced clinical events characterized by sterile inflammation. Two patients developed aseptic meningitis with elevated intracranial pressure, 1 developed intrathoracic lyphadenopathy with hypercalcemia, 1 developed cavitary pneumonia at the site of a cryptococcal nodule, and 1 developed a supraclavicular abscess. These events occurred 2-11 months after initiation of HAART. For 3 patients, biopsy demonstrated findings atypical for acquired immunodeficiency syndrome-associated cryptococcosis. Results of fungal cultures were negative for all 5 patients, and cryptococcal antigen levels had declined markedly in 4 patients. The timing and clinical features of and biopsy findings for these cases of cryptococcosis suggest the existence of a paradoxical reaction to Cryptococcus infection that occurs in the context of HIV immune restoration. - Immune reconstitution syndromes in patients infected with HIV result from an exaggerated inflammatory response to an opportunistic pathogen during immune restoration. This is analogous to the paradoxical reaction described in patients with tuberculosis in the preAIDS era, a reaction that was characterized by worsening signs and symptoms of tuberculosis but which was associated with negative culture results and was ascribed to improved immune responsiveness. In HIVinfected patients, the immune reconstitution syndromes most commonly described have been responses to tuberculosis [1] or infection with Mycobacterium avium [2] or cytomegalovirus [3]. The occurrence of an exaggerated inflammatory response to Cryptococcus neoformans in patients with AIDS who initiate HAART after a previous diagnosis of cryptococcal infection is less commonly recognized. We observed unusual culture-negative manifestations of cryptococcal infection in 4 patients who responded favorably to antiretroviral therapy that was initiated soon after a diagnosis of cryptococcal infection, which prompted a systematic investigation into the frequency and nature of this occurrence. PATIENTS AND METHODS At Jacobi Medical Center, a city hospital in Bronx, New York, the records of all patients with a positive result of a serological test for cryptococcal antigen between January 1998 and September 2001 were reviewed using the hospitals computerized database. Cryptococcal infection was defined by a positive culture result or by the presence of fever and a clinical syndrome compatible with cryptococcal infection in association with a positive result of a serological test for cryptococcal antigen. Patients with cryptococcal infection who subsequently initiated HAART and who achieved an undetectable HIV-1 load or a 13-log decrease in virus load Before initiation of HAART were identified. Such patients could be considered at risk for immune reconstitution cryptococcosis. The hospitals computerized database and the HIV clinic records were reviewed for the occurrence of clinical events after initiation of HAART. The research was performed in accordance with the ethical standards of the institutional review boards of the Albert Einstein College of Medicine and Jacobi Medical Center. Ten patients were identified who were at risk for immune reconstitution cryptococcosis. Nine patients had culture-positive cryptococcal infection, and 1 patient received a diagnosis of presumed pulmonary cryptococcosis on the basis of the findings of fever and pulmonary nodules and a positive result of a serological test for cryptococcal antigen. Before initiation of HAART, HIV-1 loads ranged from 45,000 to 1750,000 copies/ mL (as determined by RTPCR); post-HAART virus loads were undetectable (!400 or !50 copies/mL) in 9 patients and were reduced by 13 log in 1 patient. Five patients experienced a clinical course compatible with immune reconstitution cryptococcosis while receiving HAART and fluconazole. Three developed focal granulomatous inflammation; in these patients, organisms morphologically compatible with C. neoformans were revealed by histological examination; however, no fungus grew in cultures of biopsy specimens after 28 days of incubation. One patient developed hilar/mediastinal lymphadenopathy 2 months after initiation of HAART, 1 patient developed a supraclavicular mass 11 months after initiation, and 1 patient developed cavitating pneumonia 2 months a (...truncated)