Guideline

Guidelines for the diagnosis, prevention, and management of cryptococcal disease in HIV-infected adults, adolescents and children, March 2018: supplement to the 2016 consolidated guidelines of the use of antiretroviral drugs for treating and preventing HIV infection

Year of Publication

2018

Issuing Institution

World Health Organization

Links

WHO IRIS

Recommendations

23 included recommendations

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

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Low

In settings with ready access to and no contraindication for lumbar puncture: i) 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 cerebrospinal fluidcryptococcal antigen assay is the preferred diagnostic approach.

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Low

In settings with ready access to and no contraindication for lumbar puncture: If access to a cryptococcal antigen assay is not available and/or rapid results are not available: Lumbar puncture with cerebrospinal fluid (CSF) India ink test examination is the preferred diagnostic approach.

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Moderate

In settings without immediate access to lumbar puncture or when lumbar puncture is clinically contraindicated: a i) 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.

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Low

In settings without immediate access to lumbar puncture or when lumbar puncture is clinically contraindicated: If a cryptococcal antigen assay is not available and/or rapid access to results is not ensured: Prompt referral for further investigation and treatment as appropriate.

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Low

Screening 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 ART for adults and adolescents living with HIV who have a CD4 cell count <100 cells/mm3

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Moderate

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

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Moderate

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 cerebrospinal fluid (CSF) examination aand cryptococcal antigen assay (or India ink if cryptococcal antigen assay is not available) to exclude active cryptococcal disease

Status

New

Certainty of evidence

Moderate

For adults, adolescents and children, a short-course (one-week) induction regimen with amphotericin B deoxycholate (1.0 mg/kg/day) and flucytosine (100 mg/kg/ day, divided into four doses per day), followed by 1 week of fluconazole (1200 mg/day for adults, 12 mg/kg/day for children and adolescents, up to a maximum dose of 800mg daily), is the preferred option for treating cryptococcal meningitis among people living with HIV

Status

Retired

Recommended in favor

Strong

Certainty of evidence

Moderate

The following induction regimens are recommended as alternative options depending on drug availability: Two weeks of fluconazole (1200 mg daily for adults, 12 mg/kg/day for children and adolescents) + flucytosine (100 mg/kg/day, divided into four doses per day)

Status

Retired

Recommended in favor

Strong

Certainty of evidence

Moderate

The following induction regimens are recommended as alternative options depending on drug availability: Two weeks of amphotericin B deoxycholate (1.0 mg/kg/day) + fluconazole (1200 mg daily for adults, 12 mg/kg/day for children and adolescents up to a maximum of 800 mg daily

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Moderate

Fluconazole (800 mg daily for adults, 6–12 mg/kg/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)

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

Low

Fluconazole (200 mg daily for adults, 6 mg/kg/day for adolescents and children) is recommended for the maintenance phase (or secondary prophilaxys)

Status

Maintained

Recommended in favor

Strong

Certainty of evidence

High

Routine use of adjunctive corticosteroid therapy during the induction phase is not recommended in treating HIV-associated cryptococcal meningitis among adults, adolescents and children

Status

Maintained

Recommended against

Strong

Certainty of evidence

High

Safe administration of amphotericin B should be given priority and may require referral to a centre with access to a minimum package of preventing, monitoring and managing toxicity. A minimum package of preventing, monitoring and managing toxicity should be provided to minimize the serious types of amphotericin B–related toxicity, especially hypokalaemia, nephrotoxicity and anaemia

Status

Maintained

Recommended against

Strong

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 cerebrospinal fluid (CSF) opening pressure to assess for raised intracranial pressure regardless of the presence of symptoms or signs of raised intracranial pressure.

Status

New

Managing raised intracranial pressure • Therapeutic lumbar puncture: relieve pressure by draining a volume sufficient to reduce the cerebrospinal fluid (CSF) pressure to <20 cm H20 or halving the baseline pressure baseline pressure if extremely high.a • The persistence or recurrence of symptoms or signs of raised intracranial pressure 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.

Status

New

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

Status

New

Among people with evidence of a sustained clinical response, routine followup lumbar puncture after completing induction treatment to assess antifungal treatment response cerebrospinal fluid (CSF) fungal culture and CSF cryptococcal antigen) or serum or plasma cryptococcal antigen is not advised in low- and middleincome countries.

Status

New

The following diagnostic approach should be used for people with persistent or recurrent symptoms to establish potential underlying causes: a. 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. b. Perform a lumbar puncture with measurement of the opening pressure to establish the presence or absence of raised intracranial pressure and cerebrospinal fluid (CSF) examination with other relevant investigations to exclude concomitant illnesses.b c. Consider paradoxical cryptococcal immune reconstitution inflammatory syndrome after excluding other causes of recurrent symptoms among people who have started ART. d. Send or resend CSF for prolonged fungal culture (two weeks of incubation).

Status

New

For people who present with cryptococcal meningitis relapse, the following steps are advised: • Start or restart induction treatment according to the recommendations for induction treatment in section 3.3. • Manage raised intracranial pressure with therapeutic lumbar puncture (see section 3.6.1). • Reinforce adherence. • If ART has not already started, initiating ART after 4–6 weeks of optimal antifungal therapy is recommended (see section 3.7 on recommendations on the timing of ART initiation).

Status

New

Screening for cryptococcal antigen followed by pre-emptive antifungal therapy (3 among cryptococcal antigen– positive people to prevent the development of invasive cryptococcal disease may be considered before initiating or reinitiating ART for adults and adolescents living with HIV at a higher CD4 cell count threshold of <200 cells/mm3

Status

Maintained

Recommended in favor

Conditional

Certainty of evidence

Moderate

When cryptococcal antigen screening is not available, fluconazole primary prophylaxis may be considered at a higher CD4 cell count threshold of < 200 cells/mm3

Status

Maintained

Recommended in favor

Conditional

Certainty of evidence

Moderate