Global guideline for the diagnosis and management of cryptococcosis: an initiative of the ECMM and ISHAM in cooperation with the ASM

Summary

Cryptococcosis is a major worldwide disseminated invasive fungal infection. Cryptococcosis, particularly in its most lethal manifestation of cryptococcal meningitis, accounts for substantial mortality and morbidity. The breadth of the clinical cryptococcosis syndromes, the different patient types at-risk and affected, and the vastly disparate resource settings where clinicians practice pose a complex array of challenges. Expert contributors from diverse regions of the world have collated data, reviewed the evidence, and provided insightful guideline recommendations for health practitioners across the globe. This guideline offers updated practical guidance and implementable recommendations on the clinical approaches, screening, diagnosis, management, and follow-up care of a patient with cryptococcosis and serves as a comprehensive synthesis of current evidence on cryptococcosis. This Review seeks to facilitate optimal clinical decision making on cryptococcosis and addresses the myriad of clinical complications by incorporating data from historical and contemporary clinical trials. This guideline is grounded on a set of core management principles, while acknowledging the practical challenges of antifungal access and resource limitations faced by many clinicians and patients. More than 70 societies internationally have endorsed the content, structure, evidence, recommendation, and pragmatic wisdom of this global cryptococcosis guideline to inform clinicians about the past, present, and future of care for a patient with cryptococcosis.

Introduction

Cryptococcosis accounts for substantial morbidity and mortality globally. In 2022, WHO listed Cryptococcus neoformans as a top fungal priority pathogen.¹ Cryptococcosis often involves the CNS or the lungs, but disseminated disease can affect any organ, yet appear localised. Despite the knowledge gained and improvements in clinical outcomes generated by multiple interventional trials2, 3, 4, 5, 6, 7 done primarily in low-income settings with insufficient resources, mortality from cryptococcal meningoencephalitis is high, ranging from 24 to 47% at 10 weeks.2, 4, 7, 8 The highest burden of disease is in low-income and middle-income countries, especially in sub-Saharan Africa,⁹ where HIV and AIDS are the dominant risk factor, although new non-HIV immunocompromised risk groups and putatively immunocompetent individuals are increasingly reported in high-income settings with sufficient resources.

Complementary diagnostic and management guidelines for cryptococcosis exist.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 This comprehensive management guideline serves primarily to facilitate clinical decision making while also providing an overview of the uncertainties in cryptococcosis management. With contributors across the globe, this guideline gives voice to expertise and challenges from diverse settings in a globally relevant Review. General principles and treatment recommendations are provided, and clinicians are urged to use careful clinical judgement when formulating treatment plans for the individual patient. See the appendix for more detailed text, tables, and panels relevant to each section. A summary of the first-line treatment for the different cryptococcosis syndromes is in figure 1.³ An explanation of the evidence grading system used for the recommendations throughout is in panel 1.

Key points

• •Accurate delineation of the cryptococcosis clinical syndrome is important as it guides antifungal treatment choice and duration; cryptococcosis syndromes are divided into CNS, disseminated disease, isolated pulmonary disease, or direct skin inoculation (figure 1)
• •Liposomal amphotericin B 3–4 mg/kg daily and flucytosine 25 mg/kg four times a day is the most optimal induction therapy option for cryptococcal meningitis, disseminated cryptococcosis, and severe isolated pulmonary cryptococcosis in high-income settings
• •In low-income settings, patients with HIV-associated cryptococcal meningitis are best treated with liposomal amphotericin B 10 mg/kg as a single-dose, with 14 days of flucytosine 25 mg/kg four times a day and fluconazole 1200 mg daily as induction therapy; this induction therapy has not been trialled in non-HIV-associated cryptococcal meningitis or other non-CNS cryptococcosis syndromes
• •Optimise outcomes by providing the most effective antifungal therapy while preventing, monitoring, and managing potential toxicity; do not stop or switch to an inferior regimen too early or unnecessarily
• •Expect and monitor for clinical relapse and investigate thoroughly for causality; review adherence to antifungal therapy and consider drug–drug interactions; during treatment follow-up, do not escalate antifungal therapy for persistent blood antigenemia (blood cryptococcal antigen), persistently positive CSF cryptococcal antigen, visible cryptococci in CSF (without culture positivity), or abnormal CSF microscopy or biochemistry, as they are not necessarily indicators of microbiological failure
• •Adapt and adopt these ECMM global guidelines to suit local practices, while constantly advocating for better antifungal access, scrutinising new trial data, and reviewing local data to improve patient outcomes