Cryptococcal Meningitis Treatment Beyond HIV: Recognizing the need for Individualized Immune-Based Strategies

Abstract The promising results of the Ambition-CM trial in persons with HIV have sparked interest in treating non-HIV-associated cryptococcal meningitis with single 10mg/kg liposomal amphotericin B, combined with oral flucytosine and fluconazole. However, caution is warranted when applying this approach to non-HIV organ transplant recipients, whose immune status may vary due to the effects of immunosuppressive drugs. In these patients, cryptococcal disease, which generally occurs after initial immunosuppressant doses are reduced, may be driven by fungal growth, an immune response to cryptococcal antigens, or both. The latter is particularly relevant as potent antimicrobial therapy can lyse Cryptococcus, releasing antigens that trigger inflammation and cause host-mediated damage. Reducing iatrogenic immunosuppression may enhance host immune responses, which, in the context of neuro-infections, may be fatal. This highlights the importance of understanding the immune status of non-HIV organ transplant recipients within the context of the Damage-Response Framework to guide personalized treatment strategies.