<i>Cryptococcus neoformans</i>: Brain Preference, Gender Bias, and Interactions with <i>Mycobacterium tuberculosis</i> and <i>Toxoplasma gondii</i> in HIV-Positive Patients

<i>Cryptococcus neoformans</i>, a high-priority pathogen (WHO, 2022) and ubiquitous fungus, is responsible for hundreds of thousands of meningoencephalitis cases annually, with a high fatality rate. Its distribution is uneven: it primarily affects immunocompromised individuals (especially HIV-positive patients). Our study aims to explore the <i>Cryptococcus</i>’ brain tropism in immunosuppressed patients, its gender preference and the possible interactions with other opportunistic neurotropic microorganisms, such as <i>Mycobacterium tuberculosis</i> (MTB) and the brain microbiota, with a particular focus on <i>Toxoplasma gondii</i> (<i>T. gondii</i>). Methods: We conducted a retrospective descriptive analysis of all cases diagnosed with central nervous system cryptococcosis (Crypto-CNS) in HIV-positive patients admitted over 10 years (2010–2019) in a tertiary Romanian hospital. We examined their demographic, clinical, immunobiological, and imaging data, as well as their medical history, comorbidities, and coinfections. Results: Forty-two cases were admitted, with a male predominance (3.6:1) and a mean age of 33.3 years; 24% were diagnosed concomitantly with HIV infection and Crypto-CNS. All patients were severely immunosuppressed, with CD4 counts <200 cells/mm³ (median = 20.5 [1–163], mean = 31.6). Recent/concomitant tuberculosis was found in 10 (27.7%). <i>T. gondii</i>-seropositive patients developed Crypto-CNS at a lower immunological state than seronegative ones (27.1 CD4 cells/mm³ vs. 46.7 cells/mm³, means). Of 25 cases with available brain imagery, 28% had high intracranial pressure. Twelve patients (28.5%) died during the hospitalization within 26.3 days (mean, SD = 21.4); 1-year mortality increased to 50%. In-hospital mortality was associated with lower CD4 counts, increased intracranial pressure, and <i>T. gondii</i>-seropositivity. Conclusions: Crypto-CNS in HIV-positive patients mainly affects men and may be promoted by concomitant or recent tuberculosis. <i>T. gondii</i> may confer some protection even at low immune levels but increases mortality when immunity is critically low.