Cryptococcal disease is one of the most common opportunistic infections among people living with advanced HIV disease and is a major contributor to illness, disability and mortality (1).
By far the most common presentation is cryptococcal meningitis, which caused an estimated 223 100 incident cases and 181 100 deaths among people living with HIV in 2014 and accounted for 15% of all the people dying from HIV-related deaths globally (2). Cryptococcal disease is uncommon among children with HIV.
A public health approach leading to the prevention, earlier diagnosis and improved treatment of cryptococcal disease and its complications is critical to reducing the incidence and associated high mortality of cryptococcal meningitis in low- and middle-income countries.
These guidelines summarize recommendations that were first released in 2018 on diagnosing, preventing and managing cryptococcal disease. In response to important new evidence that became available in 2021, a new recommendation is provided on the preferred antifungal regimen for the induction phase of treatment.
These guidelines, which replace the 2018 guidelines, were developed in accordance with procedures established by the WHO Guideline Review Committee. All recommendations are based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to reviewing evidence, supported with information about acceptability, values and preferences, information on cost–effectiveness and feasibility. The guideline development process also identified key gaps in knowledge that will help to guide research.
The objective of these guidelines is to provide updated, evidence-informed recommendations for treating adults, adolescents and children living with HIV who have cryptococcal disease. These guidelines are aimed at HIV programme managers, policy-makers, health care professionals and people living with HIV.
Recommendations for diagnosing, preventing and managing cryptococcal disease among adults, adolescents and children living with HIV
Summary of recommendations
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| Diagnosis of cryptococcal meningitis (2018 recommendations) |
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For adults, adolescents and children living with HIV suspected of having a first episode of cryptococcal meningitis, prompt lumbar puncture with measurement of cerebrospinal fluid (CSF) opening pressure and rapid cryptococcal antigen assay is recommended as the preferred diagnostic approach. Strong recommendation; moderate-certainty evidence for adults and adolescents and low-certainty evidence for children
The following diagnostic approaches are recommended, according to the context.Settings with ready access to and no contraindication for lumbar puncture
If both access to a cryptococcal antigen assay (either lateral flow assay or latex agglutination assay) and rapid results (less than 24 hours) are available: lumbar puncture with rapid CSF cryptococcal antigen assay is the preferred diagnostic approach.a Strong recommendation; moderate-certainty evidence for adults and adolescents and low-certainty evidence for children If access to a cryptococcal antigen assay is not available and/or rapid results are not available, lumbar puncture with CSF India ink test examination is the preferred diagnostic approach. Strong recommendation; moderate-certainty evidence for adults and adolescents and low-certainty evidence for children
a For a first episode, CSF cryptococcal culture is also recommended in parallel with cryptococcal antigen testing if this is feasible. |
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Settings without immediate access to lumbar puncture or when lumbar puncture is clinically contraindicatedb
If both access to a cryptococcal antigen assay and rapid results (less than 24 hours) are available, rapid serum, plasma or whole-blood cryptococcal antigen assays are the preferred diagnostic approaches. Strong recommendation: moderate-certainty evidence for adults and adolescents and low-certainty evidence for children If a cryptococcal antigen assay is not available and/or rapid access to results is not ensured, prompt referral for further investigation and treatment is appropriate. Strong recommendation; moderate-certainty evidence for adults and adolescents and low-certainty evidence for children
Note: Other diseases that can present with symptoms and signs similar to cryptococcal meningitis (such as viral, bacterial or tuberculous meningitis) should also be considered.
b Contraindications include significant coagulopathy or suspected space-occupying lesion based on focal nervous system signs (excluding cranial nerve VI palsy) or recurrent seizures and, where possible, confirmed by computed tomography. Raised intracranial pressure does not contraindicate lumbar puncture in (suspected) cryptococcal meningitis. Other contraindications include major spinal deformity and refusal by the patient after fully informed consent was sought.
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| Prevention and screening (2018 recommendations) |
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Overarching principle
Screening for plasma, serum or whole-blood cryptococcal antigen is the optimal approach for guiding resources in a public health approach and is the preferred approach for identifying infection when managing people 10 years and older presenting with advanced HIV disease.
Recommendations
Screeningc for cryptococcal antigen followed by pre-emptive antifungal therapy among cryptococcal antigen–positive people to prevent the development of invasive cryptococcal disease is recommended before initiating or reinitiating antiretroviral therapy (ART) for adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3.
Strong recommendation; moderate-certainty evidence
This may be considered at a higher CD4 cell count threshold of <200 cells/mm3.
Conditional recommendation; moderate-certainty evidence
All people living with HIV with a positive cryptococcal antigen screening should be carefully evaluated for signs and symptoms of meningitis and undergo lumbar puncture, if feasible, with CSF examination and India ink or CSF cryptococcal antigen assay to exclude meningitis. India ink has low sensitivity and a negative result on India ink should be confirmed by CSF cryptococcal antigen testing or CSF culture.
When cryptococcal antigen screening is not available, fluconazole primary prophylaxis should be given to adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3.
Strong recommendation; moderate-certainty evidence
This may be considered at a higher CD4 cell count threshold of <200 cells/mm3.
Conditional recommendation; moderate-certainty evidence
c All people living with HIV with a positive cryptococcal antigen result on screening should be carefully evaluated for signs and symptoms of meningitis and undergo a lumbar puncture if feasible with CSF examination and cryptococcal antigen assay (or India ink if cryptococcal antigen assay is not available) to exclude meningitis.
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| Treating people with cryptococcal meningitis (2022 recommendations) |
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Induction therapy
A single high dose (10 mg/kg) of liposomal amphotericin B with 14 days of flucytosine (100 mg/kg per day divided into four doses per day) and fluconazole (1200 mg/daily for adults; 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily) should be used as the preferred induction regimen for treating people with cryptococcal meningitis.
Strong recommendation; moderate-certainty evidence for adults and low-certainty evidence for children
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Alternative induction regimens
If liposomal amphotericin is not available:
A seven-day course of amphotericin B deoxycholate (1 mg/kg per day) and flucytosine (100 mg/kg per day, divided into four doses per day) followed by seven days of fluconazole (1200 mg daily for adults and 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily).
Strong recommendation; moderate-certainty evidence for adults and low-certainty evidence for children and adolescents
If no amphotericin formulation is available:
14 days of fluconazole (1200 mg daily, 12 mg/kg per day for children and adolescents) and flucytosine (100 mg/kg per day, divided into four doses per day).
Strong recommendation; moderate-certainty evidence
Note: fluconazole and flucytosine is the only recommended oral combination regimen and has been associated with lower mortality compared with amphotericin B deoxycholate and fluconazole (3).
If flucytosine is not available:
14 days of liposomal amphotericin B (3–4 mg/kg per day) and fluconazole (1200 mg daily, 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily).
Strong recommendation; moderate-certainty evidence
If liposomal amphotericin B and flucytosine are not available:
14 days of amphotericin B deoxycholate (1 mg/kg per day) and fluconazole (1200 mg daily, 12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily).
Strong recommendation; moderate-certainty evidence
Note: flucytosine-containing regimens are superior, and steps should be taken to ensure access to this drug.
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Consolidation (2018 recommendation)
Fluconazole (800 mg daily for adults or 6–12 mg/kg per day for children and adolescents up to a maximum of 800 mg daily) is recommended for the consolidation phase (for eight weeks following the induction phase).
Strong recommendation; low-certainty evidence
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Maintenance (2018 recommendation)
Fluconazole (200 mg daily for adults or 6 mg/kg per day for adolescents and children) is recommended for the maintenance phase until immune reconstitution (CD4> 200 mm3) and suppression of viral loads on ART.
Strong recommendation; high-certainty evidence
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| Use of adjunctive systemic corticosteroids in treating people with cryptococcal meningitis (2018 recommendations) |
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Routine use of adjunctive corticosteroid therapy during the induction phase is not recommended in treating adults, adolescents and children who have HIV-associated cryptococcal meningitis.
Strong recommendation; high-certainty evidence for adults and adolescents and moderate-certainty evidence for children
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| Timing of ART (2018 recommendations) |
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Immediate ART initiation is not recommended among adults, adolescents and children living with HIV who have cryptococcal meningitis because of the risk of increased mortality and should be deferred 4–6 weeks from the initiation of antifungal treatment.
Strong recommendation; low-certainty evidence for adults and very-low-certainty evidence for children and adolescents
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Good practice principles
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| Preventing, monitoring and managing amphotericin B toxicity (2022 good practice principles) |
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Infusion-related toxicity and side-effects from amphotericin B therapy are barriers to optimal induction treatment, especially in low- and middle-income countries.
Safe administration of amphotericin B should be given priority and may require referral to a centre with access to the recommended package of preventing, monitoring and managing toxicity. Liposomal amphotericin has fewer risks of drug toxicity than amphotericin B deoxycholate and requires a less intensive package for preventing, monitoring and managing toxicity. The recommended package of preventing, monitoring and managing toxicity should be provided to minimize the serious types of amphotericin B–related toxicity when using amphotericin B deoxycholate–based regimens, especially hypokalaemia, nephrotoxicity and anaemia. A single high dose (10 mg/kg) of liposomal amphotericin B and a seven-day amphotericin B deoxycholate regimen are better tolerated than a 14-day amphotericin B deoxycholate regimen, but these two regimens still require careful monitoring.
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| Monitoring for and managing raised intracranial pressure (2018 good practice principles) |
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Monitoring for raised intracranial pressure
Adults, adolescents and children living with HIV with suspected cryptococcal meningitis should have an initial lumbar puncture and an early repeat lumbar puncture with measurement of CSF opening pressure to assess for raised intracranial pressure regardless of the presence of symptoms or signs of raised intracranial pressure.
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Managing raised intracranial pressure
Therapeutic lumbar puncture: relieve pressure by draining a sufficient volume to reduce the CSF pressure to <20 cm H2O or to halve the baseline pressure if extremely high.a The persistence or recurrence of symptoms or signs of raised intracranial pressure (headache, blurred vision and vigilance disorders) should determine the frequency of repeat therapeutic lumbar puncture. For people with persistent symptoms of raised intracranial pressure, repeat daily therapeutic lumbar puncture (with measurement of CSF opening pressure where available) and CSF drainage, if required, are recommended until the symptoms resolve or the opening pressure is normal for at least two days.
a There are no data on the maximum volume of CSF that can be safely drained at one lumbar puncture. CSF opening pressure can be rechecked after every 10 ml removed. Usually 20–30 ml is enough to reduce the opening pressure sufficiently. |
| Monitoring treatment response (2018 good practice principles) |
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Clinical response (including resolution or recurrence of fever, headache and symptoms or signs of raised intracranial pressure) should be assessed daily during the initial two weeks of induction therapy. Among people with evidence of a sustained clinical response, routine follow-up lumbar puncture after completing induction treatment to assess antifungal treatment response (CSF fungal culture) is not advised in low- and middle-income countries. CSF, serum or plasma cryptococcal antigen testing is not recommended for monitoring response to treatment in any setting.
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| Diagnostic approach to persistent or recurrent symptoms (2018 good practice principles) |
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The following diagnostic approach should be used for people with persistent or recurrent symptoms to establish potential underlying causes.
Review the patient history for evidence suggesting underlying treatment failure from (1) inadequate drug regimen, dose and duration, (2) poor adherence to fluconazole consolidation and maintenance treatment or (3) underlying fluconazole drug resistance among people with previous prolonged fluconazole therapy. Perform a lumbar puncture with measurement of the opening pressure to establish the presence or absence of raised intracranial pressure and CSF examination with other relevant investigations to exclude concomitant illnesses.b Consider paradoxical cryptococcal immune reconstitution inflammatory syndrome after excluding other causes of recurrent symptoms among people who have started ART. Send or resend CSF for prolonged fungal culture (two weeks of incubation).
b Other diseases that can present with symptoms and signs similar to cryptococcal meningitis (such as viral, bacterial or tuberculous meningitis) should also be considered. Where possible, fluconazole susceptibility testing should be performed at a national reference laboratory when clinically suspected (culture-positive relapse despite fluconazole adherence). |
| Managing relapse (2018 good practice principles) |
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For people who present with cryptococcal meningitis relapse, the following steps are advised:
Start or restart induction treatment according to the recommendations for induction therapy. Manage raised intracranial pressure with therapeutic lumbar puncture. Reinforce adherence. If ART has not already started, initiating ART after 4–6 weeks of optimal antifungal therapy is recommended. Consider fluconazole susceptibility testing if available.
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