Cryptococcosis stands as a significant global health challenge, representing a widespread and severe invasive fungal infection. Its deadliest form, cryptococcal meningitis, contributes substantially to worldwide mortality and illness. The diverse clinical presentations of cryptococcosis, the varied populations at risk, and the wide range of resource availability across healthcare settings create a complex set of obstacles for clinicians. This updated guideline, developed by global experts, offers crucial recommendations for healthcare practitioners worldwide, focusing on practical clinical approaches, screening methods, Asm Diagnosis techniques, management strategies, and essential follow-up care for cryptococcosis patients. Synthesizing the latest evidence, this resource aims to improve clinical decision-making in cryptococcosis and address its numerous clinical complexities. Grounded in core management principles, the guideline also acknowledges the real-world challenges of antifungal access and resource limitations faced by many. Endorsed by over 70 international societies, this guideline serves as an essential resource for clinicians navigating the evolving landscape of cryptococcosis care.
Key Insights for Cryptococcosis Management and ASM Diagnosis
Effective management of cryptococcosis hinges on accurate identification of its clinical form. These syndromes are categorized into CNS involvement, disseminated disease, isolated pulmonary infection, or direct skin inoculation, as illustrated in Figure 1. Precise delineation is critical as it directly informs antifungal treatment selection and duration.
For cryptococcal meningitis, disseminated cryptococcosis, and severe isolated pulmonary cryptococcosis, particularly in high-resource settings, the optimal initial treatment involves liposomal amphotericin B at 3–4 mg/kg daily combined with flucytosine at 25 mg/kg four times daily.
In resource-limited settings, especially for HIV-associated cryptococcal meningitis, a recommended induction therapy consists of a single dose of liposomal amphotericin B at 10 mg/kg, followed by 14 days of flucytosine at 25 mg/kg four times daily, and fluconazole at 1200 mg daily. It is important to note that this specific regimen has not been formally evaluated for non-HIV-associated cryptococcal meningitis or cryptococcosis outside the central nervous system.
Achieving the best patient outcomes necessitates delivering the most effective antifungal treatment while diligently preventing, monitoring, and managing potential toxicities. Premature cessation or switching to a less effective treatment regimen should be avoided.
Clinicians must be vigilant for clinical relapse and conduct thorough investigations to determine the underlying cause. Adherence to antifungal therapy and potential drug interactions should be carefully reviewed. During follow-up, it is crucial to understand that persistent blood antigenemia (blood cryptococcal antigen), persistently positive CSF cryptococcal antigen, visible cryptococci in CSF (without culture positivity), or abnormal CSF microscopy or biochemistry are not necessarily indicators of microbiological failure and do not warrant escalation of antifungal therapy.
This ECMM global guideline is intended to be adapted and integrated into local clinical practice. Continuous advocacy for improved antifungal access, critical appraisal of new clinical trial data, and ongoing review of local outcomes data are essential for enhancing patient care.
Introduction: The Global Burden of Cryptococcosis and the Role of ASM Diagnosis
Cryptococcosis poses a substantial global burden of disease and death. The World Health Organization (WHO) recognized Cryptococcus neoformans as a top fungal priority pathogen in 2022, underscoring its global health significance. While cryptococcosis frequently affects the central nervous system (CNS) and lungs, disseminated disease can impact any organ system, sometimes presenting with localized symptoms. Despite advancements in understanding and treating cryptococcosis, informed by numerous clinical trials conducted primarily in resource-limited settings, mortality from cryptococcal meningoencephalitis remains alarmingly high, ranging from 24% to 47% at 10 weeks. The greatest disease burden is concentrated in low- and middle-income countries, particularly in sub-Saharan Africa, where HIV and AIDS are major risk factors. However, an increasing number of cases are also being reported in high-income countries among newly recognized non-HIV immunocompromised groups and individuals without apparent immunodeficiency.
Existing guidelines offer valuable diagnostic and management recommendations for cryptococcosis. This comprehensive global guideline aims to facilitate clinical decision-making while acknowledging the complexities and uncertainties in cryptococcosis management. By incorporating expertise and addressing challenges from diverse global settings, this guideline provides universally relevant recommendations. It offers general principles and treatment guidance, while emphasizing the importance of clinical judgment in tailoring treatment plans to individual patient needs. Detailed supplementary information, including expanded text, tables, and panels, are available in the full guideline. Figure 1 summarizes first-line treatments for various cryptococcosis syndromes.
