Severe Central Nervous System Histoplasmosis in an Immunocompetent Child

To the Editors: Histoplasmosis is an endemic fungal infection caused by Histoplasma capsulatum, with worldwide distribution and hyperendemic areas in the Americas.1 Central nervous system (CNS) involvement occurs in 5%–10% of disseminated cases.1 Diagnosing CNS histoplasmosis is challenging due to nonspecific symptoms, often leading to delayed treatment and poor prognosis. We report the case of a previously healthy 13-year-old male from São Paulo who was hospitalized with a 5-month history of progressive headache and vomiting. He had no significant medical history except for remote exposure to bats at age 3. After an initial CNS magnetic resonance imaging showing obstructive hydrocephalus and multiple heterogeneous lesions affecting the central brain region and structures of the posterior fossa, he was submitted to an endoscopic third ventriculostomy. Thoracic and abdominal computed tomography scans were normal and cerebrospinal fluid (CSF) showed pleocytosis (119 cells/mm³), with lymphocytes predominance, elevated protein (range: 171 mg/dL) and low glucose (range: 5 mg/dL). Extensive tests, including CSF cultures, multiplex polymerase chain reaction meningitis/encephalitis panels and polymerase chain reaction for mycobacteria and fungi, were all negative. A complete immunological investigation was normal. Despite the absence of evidence, it was decided to initiate empirical treatment for tuberculosis. During the following months, his condition deteriorated with decreased consciousness, seizures and left hemiparesis, requiring invasive ventilatory support. During this period, several lumbar punctures were performed, consistently showing lymphocytic pleocytosis. Repeated CNS magnetic resonance imaging showed multiple new lesions with hypersignal on T2/FLAIR, causing a swelling effect at cervical levels and exuberant thickening and diffuse leptomeningeal enhancement (Fig. 1). At this moment, the family decided to transfer the patient to our hospital, when CNS histoplasmosis was then suspected and confirmed by a positive Histoplasma antigen test (HAT) in the CSF (13 ng/mL).FIGURE 1.: CNS and spine magnetic resonance imaging shows multiple heterogeneous lesions affecting the central brain region and structures of the posterior fossas, spinal cord at the cervical and thoracic levels. Exuberant thickening and diffuse leptomeningeal enhancement in the vertebral canal.Treatment was started with liposomal amphotericin B (5 mg/kg/d) for 4 months, without any clinical improvement and persisting, although lower levels of HAT (4.8 ng/mL). Treatment was switched to voriconazole, due to itraconazole intolerance and after 21 months HAT levels decreased to 0.91 ng/mL, but the patient remained neurologically impaired and dependent on mechanical ventilation support. This case highlights the difficulty in diagnosing primary CNS histoplasmosis in an immunocompetent adolescent without significant risk factors, preventing the possibility of a timely and adequate treatment. To our knowledge, there are only 2 reported cases of CNS histoplasmosis in immunocompetent children, both from Latin America.2,3 While culture remains the gold standard for diagnosing histoplasmosis, newer Histoplasma antigen detection assays in urine and CSF have improved diagnostic accuracy.4,5 Amphotericin B administered for 4–6 weeks remains the treatment of choice for CNS histoplasmosis, followed by oral itraconazole for at least 12 months and until resolution of CSF alterations, including Histoplasma antigen levels, ideally monitoring blood levels of itraconazole.4,5 Despite treatment, the prognosis is generally poor, particularly in cases with delayed diagnosis, such as the case here presented. Clinicians should always consider the diagnosis of neurohistoplasmosis in cases of chronic lymphocytic meningitis from patients living in endemic areas.