Cryptococcal meningitis

• Cryptococcal meningitis is a subacute infection of the meninges and brain tissue caused by the encapsulated yeast Cryptococcus. Once inside the nervous system it raises the pressure inside the skull, and that raised pressure, rather than the yeast itself, is the commonest immediate threat to life.
• It is the commonest fungal infection of the brain and, in people living with advanced HIV, one of the leading causes of death: in Africa it accounts for about 20 to 25% of AIDS-related deaths.^[4]
• The typical patient has advanced HIV (a CD4 count below 200 cells/mm3) but it also occurs after organ transplantation, with chronic corticosteroid or other immunosuppressant use, and, less often, in apparently healthy people infected with Cryptococcus gattii. ^[1]
• The illness builds over one to three weeks with headache, fever and neck stiffness, often with vomiting, visual change or confusion from raised pressure. It is rarely explosive like bacterial meningitis.
• Diagnosis rests on a lumbar puncture: India ink shows the yeast but misses many cases, while the cryptococcal antigen test on blood or spinal fluid is far more reliable, and the opening pressure must be measured every time.^[3][4]
• Treatment is a stepped programme: a fungicidal induction pairing liposomal amphotericin B with flucytosine, then fluconazole consolidation and maintenance, with repeated lumbar punctures to control pressure and a delay of four to six weeks before starting antiretroviral therapy.

By the end of this page you should be able to:

1. Name the two species that cause cryptococcosis and the host groups in which each dominates.
2. Explain why raised intracranial pressure develops and why it drives so much of the management. ^[1]
3. Choose and interpret the tests that confirm cryptococcal meningitis, including the difference in reliability between India ink and cryptococcal antigen.
4. Plan induction, consolidation and maintenance antifungal therapy, including doses and durations, and adapt it to the drugs actually available.
5. Manage raised intracranial pressure with therapeutic lumbar punctures and know when a shunt is needed.
6. Time antiretroviral therapy safely, screen for and treat cryptococcal antigenaemia, and outline care in a low-resource setting.

Cryptococcosis is the name for disease caused by the yeast anywhere in the body. The lungs are usually the first site of infection after inhaling the spores; in most patients the illness spreads through the bloodstream to the central nervous system. The disease may look localised even when it has spread, so every patient with confirmed cryptococcosis needs a thorough search for central nervous system, lung and other organ involvement.^[1]

Cryptococcus neoformans has been listed by the World Health Organization among its top-priority pathogens.^[1] Cryptococcosis occurs worldwide but the burden is heaviest in low- and middle-income countries, and in sub-Saharan Africa in particular, where advanced HIV disease remains common. In that region cryptococcal meningitis accounts for about 20 to 25% of AIDS-related deaths.^[4]

Ten-week mortality from cryptococcal meningoencephalitis remains high even with modern treatment, reported from 24 to 47% in resource-limited settings.^[1] People who survive report significant long-term morbidity, estimated at 10 to 70%, depending on the syndrome, the underlying illness and the health system that treated them.^[1]

Two species cause almost all human disease:

• Cryptococcus neoformans species complex is the predominant cause of cryptococcosis in people living with HIV. It has a strong preference for the central nervous system.
• Cryptococcus gattii species complex more often causes disease in people who appear immunocompetent. It is more often associated with pulmonary disease and with large cryptococcomas, that is, mass-like fungal lesions inside the brain or lung. Both species can cause the full range of cryptococcal syndromes.^[1]

The classical at-risk groups are people living with HIV, and recipients of solid organ transplants. Individuals receiving immunosuppressive drugs (including chronic corticosteroids) and people with other immunosuppressive conditions are also affected. Occasional cases occur in people without any known immune problem, more often with C. gattii.^[1] In any patient who develops cryptococcosis without a known reason, including HIV serology and a CD4 count, underlying immunodeficiency should be excluded.^[1]

Cryptococcus is acquired by inhaling the yeast from the environment; it often lies dormant for long periods and reactivates when cell-mediated immunity falls.

The story runs from lung to brain. After the first (usually unnoticed) pulmonary infection, the yeast disseminates in the blood. The brain is its preferred target. Several features of the yeast allow this: its polysaccharide capsule, which is strongly anti-phagocytic; melanin, which protects it from oxidative killing by host cells; and enzymes such as phospholipase and urease, which damage tissue. Once in the brain the yeast grows quietly in the perivascular spaces. No dense abscess forms; instead, many small pools of yeast and capsule material accumulate, and the inflammatory response is surprisingly mild. That is why the illness is subacute rather than explosive, and why large volumes of fluid can accumulate before the patient looks very ill.

The capsule material itself partly explains the behaviour of the disease: its high osmotic effect promotes oedema, and the yeast physically obstructs the channels (arachnoid villi) through which cerebrospinal fluid is reabsorbed into the bloodstream. The result is hydrocephalus and markedly raised intracranial pressure. Very high pressures are not unusual. Raised pressure is responsible for headache, vomiting, visual loss (from papilloedema), cranial nerve palsies (especially of the sixth nerve, which produces a lateral rectus palsy) and, ultimately, herniation. Because the pressure can be lethal even after the yeast is dying, controlling it is a central part of treatment.

Cryptococcal meningitis builds over days to a few weeks. The headache is usually diffuse and worse on waking or on straining. Fever is common but may be low-grade. Neck stiffness, photophobia and vomiting are frequent. Confusion, personality change or drowsiness suggest advanced disease or very high pressure. Visual symptoms (blurred or double vision), tinnitus and hearing change, and, less often, seizures, are reported. Memory of the illness is often poor.

Measures of raised intracranial pressure dominate: papilloedema, reduced level of consciousness, and an abducens (sixth cranial nerve) palsy. Meningism (neck stiffness, Kernig and Brudzinski signs) is often present. Focal neurological signs are uncommon unless a cryptococcoma has formed. Skin or mucosal lesions, for example scattered umbilicated papules, may betray disseminated cryptococcosis. In people living with advanced HIV, the presentation can be subtle: a mild headache and low-grade fever in a patient with a very low CD4 count may be the entire picture.

Cryptococcal meningitis must be separated from other causes of subacute lymphocytic meningitis or meningoencephalitis, and from the causes of raised intracranial pressure.

Every suspected case should have a lumbar puncture. The opening pressure must be measured at the start, with the patient relaxed and lying on their side. The fluid is examined for protein, glucose, cell count and differential, Gram stain, microscopy, culture (fungal and bacterial), and cryptococcal antigen. Brain imaging is ideal before lumbar puncture when there are focal signs, seizures, markedly reduced consciousness or other reasons to suspect a mass, but it must not delay treatment.

• India ink. A dark background stain that makes the yeast capsule stand out as a clear halo. It is specific but insensitive: its sensitivity in practice is poor, quoted at 50 to 80%.^[3] A negative India ink never excludes the disease.
• Cryptococcal antigen (CrAg). The most useful test. Detectable in serum, plasma, whole blood and cerebrospinal fluid, it gives a reliable result in minutes with a lateral flow assay. In cerebrospinal fluid the lateral flow assay has a sensitivity of 99.3% and a specificity of 99.1%.^[4]
• Culture. The confirmatory test and the measure of living yeast. Cultures of cerebrospinal fluid and blood should be taken in all patients. Growth may take several days; fungal medium should be requested.
• Microscopy after centrifuging the fluid improves yield. CSF parameters are often surprisingly normal: cell counts may be low, glucose may be near normal and protein only modestly raised. A normal or near-normal cerebrospinal fluid therefore does not exclude cryptococcal meningitis in an immunosuppressed patient.

Brain imaging (preferably magnetic resonance imaging) and chest imaging (preferably computed tomography) are used to define the extent of disease and to look for cryptococcomas. Many patients with meningitis have normal or near-normal brain imaging early in the illness.

There is no formal diagnostic scoring system for cryptococcal meningitis. The diagnosis is made by detecting cryptococcal antigen, by showing the yeast on microscopy, or by growing it in culture, in a patient with a compatible clinical picture. Severity is judged clinically by the level of consciousness, by the opening pressure, by the burden of yeast in the cerebrospinal fluid and by whether disease is limited to the nervous system or disseminated.

The management can be organised as ten principles: screen and risk-stratify; give the best fungicidal induction possible; monitor drug toxicity; control raised intracranial pressure; look for hidden immunosuppression; provide consolidation and maintenance; time antiretroviral therapy precisely; monitor for relapse; investigate microbiological persistence or relapse; and exclude alternative causes before attributing deterioration to immune reconstitution.^[1]

The aim of induction is to kill yeast rapidly in the central nervous system. Two regimens are preferred, chosen by what is available:

• Resource-rich or recommended standard: liposomal amphotericin B 3 to 4 mg/kg intravenously daily plus flucytosine 25 mg/kg by mouth four times daily for two weeks.^[1]
• Single-dose liposomal amphotericin (AMBITION-cm, now preferred by the World Health Organization in low-resource settings): one dose of liposomal amphotericin B 10 mg/kg on the first day, with flucytosine 25 mg/kg four times daily plus fluconazole 1200 mg daily by mouth for 14 days.^[1][2] A phase III trial found 10-week mortality of 24.8% with this regimen versus 28.7% with the previous standard, with similar rates of fungal clearance and significantly less toxicity.^[1]

When the preferred drugs are not available the 2024 global guideline sets out alternatives:

• Lipid amphotericin (ABLC) 5 mg/kg daily plus flucytosine 25 mg/kg four times daily.^[1]
• Amphotericin B deoxycholate 0.7 to 1.0 mg/kg daily plus flucytosine 25 mg/kg four times daily (some centres start at the lower end because of toxicity).^[1]
• If flucytosine is unavailable: liposomal amphotericin B 3 to 4 mg/kg daily plus fluconazole 800 to 1200 mg daily (or amphotericin B deoxycholate plus fluconazole).^[1]
• If amphotericin is unavailable: flucytosine 25 mg/kg four times daily plus fluconazole 800 to 1200 mg daily; if only fluconazole is available, fluconazole 800 to 1200 mg daily.^[1]

Fluconazole alone, up to 1200 mg daily, is associated with ten-week mortality above 50% and one-year mortality above 75%, so monotherapy should be used only when nothing else exists.^[1] In the ACTA trial the best-performing induction arm was one week of amphotericin B deoxycholate 1 mg/kg daily plus flucytosine, followed by fluconazole 1200 mg daily in the second week, with 24% ten-week mortality.^[1]

In solid organ transplant recipients and in non-HIV, non-transplant patients the recommended approach is liposomal amphotericin B 3 to 4 mg/kg daily plus flucytosine 25 mg/kg four times daily for two weeks, with close attention to drug interactions with calcineurin inhibitors and to renal function. In C. gattii central nervous system infection in non-HIV patients, or when a CNS cryptococcoma is present, induction should be extended to four to six weeks.^[1]

This is where many patients are won or lost.

• Measure the opening pressure at every lumbar puncture.^[1]
• If the pressure is 20 cm of cerebrospinal fluid or more and symptoms are present, treat with daily therapeutic lumbar punctures, removing enough fluid (usually 20 to 30 mL) to reduce the pressure to half of the opening pressure and/or to 20 cm or less, recorded as a closing pressure.^[1]
• A scheduled therapeutic lumbar puncture at roughly 48 to 72 hours after the first one, or around day 7, is suggested regardless of the first pressure.^[1]
• If pressure remains high and symptomatic despite repeated taps, decompress surgically: temporary lumbar drainage, ventriculostomy or ventricular or lumbar shunting, according to local expertise. Ventriculoperitoneal shunting (and lumbar peritoneal as an alternative) should ideally be performed after effective antifungal therapy has begun.^[1]
• Raised pressure is managed actively; it should not be treated with mannitol or acetazolamide on the strength of small series.
• Adjunctive dexamethasone is not recommended in routine cryptococcal meningitis: the only randomised trial of high-dose dexamethasone was harmful. A short course may be justified for specific indications such as a space-occupying lesion with surrounding oedema, or cerebral vasculitis.^[1]

• Consolidation (eight weeks): fluconazole 400 to 800 mg daily by mouth, with 800 mg preferred in low-resource settings.^[1]
• Maintenance (12 months, or until immune restoration): fluconazole 200 mg daily.^[1]
• Consider performing a lumbar puncture at the end of induction to check cerebrospinal fluid culture sterility before switching to consolidation, since culture negativity before antiretroviral therapy is associated with fewer relapses and less immune-reconstitution disease; some low-resource guidelines do not require this.^[1]
• At the other extreme, guidelines differ as to whether to look for CSF sterility at all; do not treat sterility as a reason to alter a patient who is clinically improving.
• Maintenance can be stopped after 12 months of therapy in patients who are virologically suppressed on antiretroviral therapy with a CD4 count of more than 100 cells/mm3; it should be restarted if the CD4 count falls under 100.^[1]
• Rarely, fluconazole resistance or intolerance forces substitution with voriconazole (200 mg twice daily with therapeutic drug monitoring) or posaconazole (300 mg daily), although neither has been formally trialled in cryptococcosis.^[1]

Immediate or very early antiretroviral therapy is not recommended in cryptococcal meningitis. In resource-limited settings the standard is to delay for four to six weeks after starting antifungals. In better-resourced settings further individualisation is reasonable, taking into account resolution of symptoms and signs of meningitis and raised pressure (including normalisation of opening pressure), attainment of cerebrospinal fluid sterility, control of co-infections, the patient's readiness, and local experience. The usual range in all settings remains four to six weeks.^[1]

• Immune reconstitution inflammatory syndrome (C-IRIS). Deterioration after starting antiretroviral therapy, caused by restoring immunity against cryptococcal antigen. Exclude recurrent or new infection first. Continue the antifungal drug, manage pressure with therapeutic taps and symptomatic care, and for persistent symptoms unresponsive to taps consider prednisone or prednisolone 0.5 to 1.0 mg/kg daily, or dexamethasone 0.2 to 0.3 mg/kg daily, tapered over four to six weeks. Do not stop antiretroviral therapy.^[1]
• High intracranial pressure and hydrocephalus, requiring taps or shunting (above).
• Relapse or persistence. Think broadly: check adherence, drug interactions (azoles markedly raise calcineurin inhibitor levels), renal function, and request antifungal susceptibility testing if the CSF stays culture-positive. An increase in fluconazole minimum inhibitory concentration of more than two dilutions is concerning.
• Drug toxicity. Ampotericin is nephrotoxic and wastes potassium and magnesium; give pre-hydration and aggressive replacement. Flucytosine can suppress the bone marrow and is renally cleared, so measure levels when renal function is impaired. Monitoring should include a full blood count, renal function and electrolytes at least every other day during induction, with liver function at baseline and weekly.^[1]
• Accepted adjuncts that do NOT help: high-dose dexamethasone, sertraline and tamoxifen have each failed in trials and may cause harm. Interferon-gamma has some supportive evidence in HIV-associated disease but is unresolved.^[1]

Clinical relapse can occur months after apparently successful treatment. Patients should be followed with clinical review, and in HIV care with attention to viral suppression and CD4 recovery. Recurrence after at least one year of therapy on effective antiretroviral therapy with a suppressed virus is uncommon.^[1]

Even where care is good, outcome depends on how early the disease is caught, on the burden of organisms, on whether pressure is controlled, and on whether the underlying immunodeficiency is treated. The single best modifiable factors are early lumbar puncture, measurement and management of pressure, and combination fungicidal induction rather than fluconazole alone. In solid organ transplant recipients outcome is better than in advanced HIV, and mortality has fallen in some cohorts. Cryptococcosis survivors report substantial long-term morbidity, 10 to 70%.^[1]

In adults living with HIV with a CD4 count below 200 cells/mm3, either newly diagnosed or returning to care after a gap, blood should be screened with the cryptococcal antigen lateral flow assay, and the titre determined if positive.^[1] All antigen-positive patients must then be assessed (including lumbar puncture where feasible) to exclude active cryptococcal meningitis and treated accordingly.

• Asymptomatic antigen-positive patients with no cryptococcosis after thorough investigation (including at least a lumbar puncture) are treated with fluconazole 1200 mg daily for two weeks, with antiretroviral therapy started at the same time, then 800 mg daily for eight weeks, then 200 mg daily for about six months.^[1]
• Where the cryptococcal antigen assay is not available, universal primary prophylaxis with fluconazole 100 mg daily is recommended for people with HIV with a CD4 count below 200 cells/mm3.^[1]
• Routine screening, prophylaxis or pre-emptive therapy is not recommended in non-HIV populations.^[1]

Cryptococcosis cannot be prevented by simple behavioural measures; the yeast is environmental. The effective preventions are control of the underlying immunodeficiency (antiretroviral therapy for HIV, careful immunosuppression management after transplantation) and the screening programme above.

• Pregnancy. Azole exposure in pregnancy and the risk of transmission to the infant must be weighed; amphotericin-based induction is preferred for active disease and specialist input is required. Flucytosine has limited pregnancy data; specialist obstetric and infectious-diseases advice is essential.
• Children. Dosing follows weight-based guidance; involvement of paediatric infectious diseases is advised. The WHO recommendations of 2022 cover adolescents and children as well as adults.
• Solid organ transplant recipients. Amphotericin plus flucytosine induction; watch drug levels of tacrolimus, cyclosporine and sirolimus when azoles are added.^[1]
• Apparently immunocompetent patients with C. gattii may need surgical or drainage procedures for large cryptococcomas, longer induction, and imaging follow-up.

Cryptococcal disease kills most of its patients in low-resource settings, and the guidelines are written with this in mind.^[1][2]

• Preferred induction is the single-dose liposomal amphotericin B regimen, with its clear advantages of lower toxicity and less monitoring.^[2]
• If liposomal amphotericin is not available, the 2018/2022 WHO position and supporting trials favour one week of amphotericin B deoxycholate 1 mg/kg daily plus flucytosine, followed by fluconazole.
• If amphotericin is not available at all, use oral flucytosine plus fluconazole.
• Pressure management relies on therapeutic lumbar punctures, which only need a manometer and a syringe; do them daily when needed, and do not wait for computed tomography.
• Screening with the cryptococcal antigen lateral flow assay is cheap (a few US dollars per test) and is the intervention that prevents cases; primary prophylaxis with fluconazole 100 mg daily is the fallback where the assay is unavailable. ^[1]
• In-hospital care for the first one to two weeks is encouraged wherever possible, to manage early complications of therapy.^[1]
• Fluconazole consolidation at the higher 800 mg dose is preferred, because weaker induction regimens leave more residual infection.^[1]

• Cryptococcal meningitis is subacute meningoencephalitis caused by Cryptococcus neoformans or C. gattii, usually in people with advanced HIV, after transplantation or with immunosuppression.
• C. neoformans dominates in advanced HIV and prefers the central nervous system; C. gattii affects people without known immunodeficiency more often and is linked to lung disease and large cryptococcomas.
• The pathophysiology is of quiet fungal growth and obstructed cerebrospinal fluid reabsorption, so raised intracranial pressure is common and dangerous.
• Disease should be suspected from a subacute headache with raised-pressure features, especially in advanced HIV; cerebrospinal fluid can be nearly normal.
• India ink is specific but insensitive (quoted at 50 to 80%); cryptococcal antigen in serum and cerebrospinal fluid is the best test, with lateral flow sensitivity of about 99.3% and specificity of about 99.1%.^[3][4]
• Opening pressure must be measured at every lumbar puncture, and raised pressure is treated with repeated therapeutic taps (removing 20 to 30 mL, down to half the opening pressure and to 20 cm or less), then shunting if needed.
• Preferred induction is either liposomal amphotericin B 3 to 4 mg/kg daily plus flucytosine for two weeks, or (World Health Organization preferred in low-resource settings) a single 10 mg/kg dose of liposomal amphotericin with 14 days of flucytosine plus fluconazole. Alternatives follow drug availability.
• Consolidation is fluconazole 400 to 800 mg daily for eight weeks; maintenance is 200 mg daily for about 12 months or until immune restoration. ^[1]
• Antiretroviral therapy should be delayed four to six weeks; immune reconstitution inflammatory syndrome is treated with pressure control and, if needed, tapered corticosteroids.
• Screen all people with HIV with a CD4 count below 200 cells/mm3 with blood cryptococcal antigen, and treat antigen-positive non-meningitis patients with fluconazole; use fluconazole prophylaxis 100 mg daily only where testing is unavailable.
• Mortality remains high (24 to 47% at ten weeks in resource-limited settings), so early diagnosis and pressure control are the modifiable drivers of outcome.^[1]

• HIV and advanced HIV disease
• Meningitis (bacterial and viral)
• Tuberculous meningitis
• Immunosuppressive drugs and corticosteroids
• Antifungal drugs
• Increased intracranial pressure and hydrocephalus