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

Abstract

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.

Figure 1:

Management algorithm for cryptococcal meningitis/ cryptococcal meningoencephalitis (CM) in PLHIV

Figure 2:

HIV-CM Induction antifungal treatment recommendations by antifungal drug availability

1. *(L-Amb 3–4 mg/kg/d + 5-FC 25 mg/kg 4x a day for 2 weeks) has not been compared to #(Single dose 10mg/kg L-Amb with 14d of 5-FC 25.kg 4x a day and Fluconazole 1200 mg daily). # has only been trialled in HIV-CM.

2. ^&Polyene includes Amphotericin B formulations such as conventional deoxycholate Amphotericin B (Amb-D), Liposomal Amphotericin (L-Amb), Amphotericin B lipid complex (ABLC).

3. ^{^}Amb-D: 1 mg/kg showed earlier fungicidal activity than 0.7 mg/kg but some institutions use the lower dose due to toxicity concerns.

4. ^@Fluconazole induction doses of up to 1200 mg daily have been trialled but caution is advised. Consider drug-drug interaction and liver toxicity.

5. Grading of recommendation and level of evidence in bolded red letters.

6. Recommendations by shading: green (Strong), yellow (Moderate), pink (marginal)

Figure 3:. Recommended first-line antifungal therapy by cryptococcosis syndrome.

This simplified figure summarises the recommendations for first-line antifungal therapy where optimal antifungal options are available. The grading of recommendation and level of evidence is in red, with the duration of the therapy shaded by strength of recommendation. Isolated pulmonary cryptococcosis may be divided into severe or mild, and with or without pulmonary cryptococcoma. Mild pulmonary cryptococcosis is defined as asymptomatic or mildly symptomatic patients, or those with a solitary small nodule (< 2 cm) while severe pulmonary cryptococcosis includes those with multiple lesions, large lesions (≥2 cm), lobar consolidation, cavitation, multi-lobar involvement, and those with hypoxaemia. In HIV-associated CM/ CNS cryptococcosis we recommend L-Amb 3–4 mg/kg daily and 5-Flucytosine 25 mg/kg four times a day OR single-dose L-Amb 10 mg/kg and 14 days of 5-Flucytosine 25 mg/kg four times a day and Fluconazole 1200 mg daily, for a minimum of 2 weeks. Importantly, the single-dose L-Amb 10 mg/kg and 14 days of 5-Flucytosine 25 mg/kg four times a day and Fluconazole 1200 mg daily has only been trialled in HIV-CM. There is currently no data of its application in non-HIV-CM settings. See Figure 2 for treatment cascade in HIV-CM by antifungal availability. In non-HIV associated CM/ CNS cryptococcosis, disseminated cryptococcosis and severe isolated pulmonary cryptococcosis, we recommend L-Amb 3–4 mg/kg daily and 5-Flucytosine 25 mg/kg four times a day for 2 weeks or more. Extensions in the duration of induction therapy may be considered in SOT recipients, non-HIV-non-SOT patients, and in non-HIV patients with C. gattii infection (4–6 weeks), those with CNS cryptococcomas (4–6 weeks) or severe isolated pulmonary cryptococcosis with lung cryptococcomas (4–6 weeks). All CNS-based induction therapy should be followed by 8 weeks of fluconazole 400–800 mg daily as consolidation therapy, then fluconazole 200 mg daily as maintenance therapy for 12 months or until immune restoration. The consolidation dose for HIV-CM in resource limited settings (RLS) is currently commonly prescribed as fluconazole 800 mg daily, and the 400 mg daily dose is used in other non-RLS settings, and other non-CM cryptococcosis syndromes. In settings where antifungal therapy availability is limited, refer to Figure 2 for alternatives. Patients with mild isolated pulmonary cryptococcosis (regardless of immune state, presence of cryptococcoma or infecting strain) may be treated with fluconazole 400–800 mg daily for 6–12 months (note: a shorter duration of 3 months may be considered in those who are immunocompetent). If the presence of Cryptococcus spp. in respiratory specimens is deemed as airway colonisation after careful evaluation and no treatment is elected, regular follow-up is recommended especially in the setting of future immunosuppression (see Table 6). In the rare case of skin cryptococcosis from direct skin inoculation, fluconazole 400 mg daily for 3–6 months is recommended. See Table 6 for details on pulmonary cryptococcosis and pulmonary cryptococcoma. Footnote: *L-Amb 3–4 mg/kg daily and 5-Flucytosine 25 mg/kg four times a day has not been directly compared against #L-Amb 10 mg/kg single dose and 2 weeks of 5-Flucytosine 25 mg/kg four times a day and Fluconazole 1200 mg daily. *L-Amb 3–4 mg/kg daily and 5-Flucytosine 25 mg/kg four times a day is strongly preferred in CM/ CNS cryptococcosis in SOT and non-HIV non-SOT settings, disseminated cryptococcosis and severe pulmonary cryptococcosis. #L-Amb 10 mg/kg single dose and 2 weeks of 5-Flucytosine 25 mg/kg four times a day and Fluconazole 1200 mg daily. This regimen has only been trialled in HIV-CM. There is no supporting data of its use in SOT, or non-HIV non-SOT patients, and in other cryptococcosis syndromes. $: solid organ transplant (SOT) recipients. *L-Amb 3–4 mg/kg daily and 5-Flucytosine 25 mg/kg four times a day is strongly preferred in SOT patients. ^: Isolated C. neoformans or C. gattii pulmonary cryptococcosis. Mild pulmonary cryptococcosis (with or without cryptococcoma): asymptomatic or mildly symptomatic patients or with a solitary small nodule (< 2 cm). Severe pulmonary cryptococcosis: multiple lesions, large lesions (≥2 cm), lobar consolidation, cavitation, multi-lobar involvement, hypoxaemic. %: May consider a shorter duration (e.g., 3 months) in immunocompetent individuals with mild isolated pulmonary cryptococcosis. &: If the presence of Cryptococcus spp. in respiratory specimens is deemed as airway colonisation after careful evaluation and no treatment is elected, regular follow-up is recommended especially in the setting of future immunosuppression. W: weeks Grading of recommendation and level of evidence in bolded red letters Recommendations by shading: green (strongly recommended), yellow (moderately recommend)