Cryptococcosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Cryptococcus is an encapsulated environmental yeast acquired mainly by inhalation. Initial pulmonary infection may be silent, form nodules or cause pneumonia. Failure of cell-mediated immunity permits survival within macrophages and haematogenous spread, with a marked tropism for the central nervous system. The polysaccharide capsule impairs phagocytosis and contributes to high fungal burden with limited early inflammation.

Risk assessment includes HIV testing and CD4 count, solid-organ or stem-cell transplantation, haematological malignancy, corticosteroids, calcineurin inhibitors, sarcoidosis, idiopathic CD4 lymphopenia and other immune defects. C. gattii is more likely than C. neoformans to produce pulmonary masses and cerebral cryptococcomas in hosts without an obvious immune diagnosis.

Management has three phases: fungicidal induction, consolidation and maintenance. It also has an equally important mechanical component because intracranial hypertension drives mortality and neurological injury. Fungal culture clearance, pressure control, host immune strategy and site-specific complications all affect duration.

Key points

Cryptococcus neoformans commonly affects people with advanced HIV, transplantation, haematological disease or corticosteroid exposure; C. gattii can cause severe disease in apparently immunocompetent hosts.
Meningitis is often subacute, with headache, fever, malaise, personality change, visual disturbance or confusion and surprisingly little meningism.
First-line diagnosis uses serum and CSF cryptococcal antigen plus CSF microscopy and culture; measure opening pressure at every diagnostic lumbar puncture.
Neuroimaging before lumbar puncture is reserved for standard contraindication features such as focal deficit, papilloedema, new seizure or markedly impaired consciousness; routine imaging must not create avoidable delay.
High-income-setting first-line induction for CNS, disseminated or severe pulmonary disease is liposomal amphotericin B 3 to 4 mg/kg intravenously daily plus flucytosine 25 mg/kg orally four times daily for two weeks.
After successful induction, consolidate with fluconazole 400 to 800 mg daily for eight weeks, then use fluconazole 200 mg daily as maintenance in HIV until sustained immune recovery.
Treat raised intracranial pressure by repeated lumbar drainage to a closing pressure at or below 20 cm CSF or about half the opening value; mannitol, acetazolamide and routine corticosteroid are ineffective or harmful.
In HIV-associated meningitis, defer antiretroviral therapy for approximately four to six weeks and involve the HIV team; treat other immune causes without abrupt unsafe withdrawal.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Cryptococcus neoformans

This environmental encapsulated yeast causes most disease and particularly exploits advanced HIV, transplantation and corticosteroid-associated cellular immune defects.

Cryptococcus gattii

C. gattii more often affects apparently immunocompetent hosts and has a greater tendency toward pulmonary masses and cerebral cryptococcomas.

Inhalational acquisition

Desiccated yeast or basidiospores are inhaled from environmental reservoirs, establishing pulmonary infection before possible latency or dissemination.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Capsular immune evasion
The polysaccharide capsule inhibits phagocytosis and modulates inflammation, allowing high organism burden despite muted meningeal signs.
2
Intracellular survival
Yeast survives and replicates within macrophages, using them as a vehicle for bloodstream spread from lung to distant organs.
3
Central nervous tropism
Organisms cross the blood-brain barrier and proliferate in CSF and perivascular spaces, producing meningitis, gelatinous pseudocysts or cryptococcomas.
4
Impaired CSF outflow
Capsular polysaccharide and organisms obstruct normal arachnoid-villus resorption, causing severe intracranial hypertension without necessarily producing hydrocephalus.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Subacute meningitisRed flag

Headache, fever, nausea, lethargy, cognitive change and visual symptoms evolve over days to weeks, often without neck stiffness or photophobia.

Raised intracranial pressureRed flag

Severe headache, vomiting, visual obscurations, diplopia, papilloedema or reduced consciousness suggests impaired CSF resorption and needs prompt drainage.

Pulmonary disease

Cough, pleuritic pain, dyspnoea or constitutional symptoms accompany solitary nodules, multiple masses, cavitation or diffuse infiltrates, while some lesions are incidental.

Disseminated diseaseRed flag

Fungaemia, skin papules resembling molluscum, bone pain, prostate involvement, hepatitis or multiorgan illness may coexist with clinically silent CNS infection.

CryptococcomaRed flag

Focal seizures, neurological deficit or mass lesions occur particularly with C. gattii and require prolonged therapy plus careful pressure and inflammatory management.

Red flags requiring action

Reduced consciousness, seizure, focal neurology, papilloedema or rapidly worsening headache requires urgent CNS imaging, specialist review and intracranial-pressure management.
Opening pressure above 20 cm CSF with symptoms, or persistently raised pressure, requires repeated therapeutic lumbar puncture rather than antifungal therapy alone.
New visual loss, diplopia or cranial-nerve palsy can reflect pressure-related optic injury or cryptococcoma and needs urgent ophthalmic and neurological input.
Positive blood culture or serum cryptococcal antigen with systemic symptoms should trigger assessment for CNS and disseminated disease even without headache.
Starting antiretroviral therapy too early in cryptococcal meningitis increases dangerous immune-reconstitution inflammation; HIV and infection teams should coordinate timing.
Renal injury, hypokalaemia, hypomagnesaemia or cytopenia during induction can become life threatening and demands active replacement, drug-level and dose review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
First-line serum cryptococcal antigenFirst stepFirst line
Why
Rapidly detect capsular antigen in suspected disseminated, CNS or pulmonary cryptococcosis.
Interpretation and limitations
A positive result in a high-risk patient is clinically important and generally prompts lumbar puncture unless contraindicated. Antigen titre supports burden but should not be trended as the sole response marker.
02
Lumbar puncture with opening pressure
Why
Diagnose meningitis, quantify intracranial pressure and obtain material for fungal-burden and clearance assessment.
Interpretation and limitations
Measure pressure in the lateral decubitus position before removing CSF; send cell count, protein, glucose, cryptococcal antigen, microscopy and quantitative or standard fungal culture.
03
CSF fungal microscopy and culture
Why
Demonstrate yeast, recover the organism and establish microbiological response after induction.
Interpretation and limitations
India ink is less sensitive at low burden. Culture is the reference for viable organism and species identification; persistent positivity at two weeks can extend or intensify induction.
04
Brain imaging
Why
Identify hydrocephalus, cryptococcoma, infarction or another contraindication to immediate lumbar puncture.
Interpretation and limitations
Use contrast MRI when available for focal disease. Normal imaging does not exclude meningitis or raised pressure and cannot replace lumbar-puncture manometry.
05
Dissemination and host assessment
Why
Define pulmonary and extrapulmonary burden and uncover the cause of immune failure.
Interpretation and limitations
Obtain blood fungal cultures, chest CT and targeted organ imaging, HIV testing, CD4 count, immunoglobulins and treatment history according to presentation.
06
Baseline toxicity panel
Why
Prepare for amphotericin and flucytosine toxicity and identify dose-adjustment needs.
Interpretation and limitations
Check FBC, creatinine, estimated filtration, potassium, magnesium and liver tests; flucytosine concentrations are required, especially with renal impairment.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Tuberculous meningitis

Subacute headache, low CSF glucose and advanced HIV overlap; mycobacterial molecular testing, culture and imaging are essential and co-infection occurs.

Bacterial meningitis

More abrupt fever and neutrophilic CSF are typical, but immunosuppression blunts patterns and empirical bacterial treatment may be required.

CNS toxoplasmosis

Multiple ring-enhancing brain lesions and focal deficits in advanced HIV suggest toxoplasmosis, whereas cryptococcal meningitis may have normal imaging.

Primary CNS lymphoma

Focal lesions, EBV association and immune suppression overlap cryptococcoma; CSF studies, advanced imaging and sometimes biopsy distinguish them.

Viral meningoencephalitis

HSV, VZV and other viruses cause headache, seizures and altered behaviour, requiring prompt molecular testing and empirical aciclovir when indicated.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01DIAGNOSE NOWInvestigate suspected CNS diseaseFirst stepA vulnerable patient has subacute headache, cognitive change, visual symptoms, seizure or positive serum antigen.

1Assess consciousness, focal neurology, papilloedema and seizure; obtain urgent imaging first only when these or another standard contraindication make immediate lumbar puncture unsafe.
2Perform lumbar puncture promptly, record opening pressure accurately and send sufficient CSF for antigen, cell count, chemistry, microscopy and fungal culture.
3Take serum antigen, blood fungal cultures, HIV testing and baseline renal, electrolyte, liver and blood-count measurements.
4Start induction immediately after specimens when possible; do not wait for fungal culture in a compatible antigen-positive illness.

02INDUCTIONDeliver fungicidal combination therapyCNS, disseminated or severe pulmonary cryptococcosis is confirmed or strongly suspected in a high-income care setting.

1Give liposomal amphotericin B 3 to 4 mg/kg intravenously every 24 hours plus flucytosine 25 mg/kg orally every six hours for at least 14 days.
2Use hydration and proactive potassium and magnesium replacement, monitor renal function and FBC closely, and measure flucytosine levels with renal-guided dosing.
3Repeat CSF culture near the end of induction when feasible; persistent viable yeast, cryptococcoma or non-HIV host factors may require a longer induction.
4Avoid substituting the WHO single-dose amphotericin programme automatically in NHS high-income practice; regimen choice belongs with infection, HIV or transplant and pharmacy specialists.

03PRESSUREControl intracranial hypertensionOpening pressure exceeds 20 cm CSF with symptoms, remains persistently high, or pressure-related neurological signs continue.

1Perform therapeutic lumbar puncture and remove sufficient CSF to reduce the closing pressure to 20 cm CSF or below, or by about 50% when the opening value is extremely high.
2Repeat drainage daily while symptoms and raised pressure persist; a scheduled repeat lumbar puncture within the first week can detect recurrence even after initial improvement.
3Seek neurosurgical CSF diversion with a lumbar drain, ventriculostomy or shunt when repeated punctures are insufficient, impractical or complicated by hydrocephalus.
4Do not use mannitol, acetazolamide or routine corticosteroids to control cryptococcal pressure because they do not correct the impaired CSF outflow and may cause harm.

04CONSOLIDATEComplete consolidation and maintenanceThe patient has clinically stabilised after adequate induction and CSF is sterile or improving under specialist review.

1Give fluconazole 400 to 800 mg orally once daily for eight weeks, selecting dose from syndrome, organism, susceptibility, interactions and host.
2In HIV-associated CNS disease, continue maintenance fluconazole 200 mg once daily for at least 12 months and until sustained immune recovery on effective antiretroviral therapy.
3For transplant or non-HIV disease, individualise consolidation, total duration and immune-treatment modification; abrupt reduction of immunosuppression can provoke inflammatory deterioration.
4Reinvestigate recurrent headache with opening pressure and CSF culture rather than assuming microbiological relapse or immune reconstitution from symptoms alone.

05IMMUNE CARERestore immunity without inflammatory harmCryptococcosis occurs with untreated HIV, transplantation, corticosteroids or another modifiable immune deficit.

1For HIV-associated meningitis, plan antiretroviral initiation at about four to six weeks after antifungal treatment begins, rather than immediately.
2Screen antigen-positive people with advanced HIV for CNS disease before pre-emptive fluconazole; headache or high titre strengthens the need for lumbar puncture.
3In transplant recipients, coordinate gradual immunosuppression adjustment with the transplant team to avoid rejection and cryptococcal immune-reconstitution syndrome.
4Investigate an apparently immunocompetent host for subtle immune deficits while recognising that C. gattii can occur without an identified disorder.

Key medicines and prescribing safety4 treatments · regimens, roles and cautions

Preferred fungicidal induction backbone in high-income settings.

Liposomal amphotericin B

Give 3 to 4 mg/kg intravenously every 24 hours with flucytosine for at least 14 days in CNS, disseminated or severe pulmonary disease.

Monitor creatinine, potassium, magnesium, FBC and infusion reactions; provide protocolised hydration and replacement, and never interchange doses with amphotericin B deoxycholate.

Essential induction partner that improves fungal clearance and survival when combined with amphotericin.

Flucytosine

Give 25 mg/kg orally every six hours, equivalent to 100 mg/kg/day, with renal adjustment and therapeutic drug monitoring.

Accumulation causes severe marrow and hepatic toxicity; check FBC and liver tests frequently, monitor post-dose concentrations and adjust promptly in renal dysfunction.

Consolidates CNS or disseminated cure after fungicidal induction and treats selected non-severe pulmonary disease.

Fluconazole consolidation

Give 400 to 800 mg orally once daily for eight weeks after successful induction, selecting the exact dose with the infection team.

Adjust for renal impairment and review QT, liver tests, pregnancy, warfarin, calcineurin inhibitors and other CYP interactions.

Prevents relapse while antiretroviral therapy restores cellular immunity.

Fluconazole maintenance

Give 200 mg orally once daily after consolidation in HIV-associated CNS disease, usually for at least 12 months and until sustained immune recovery.

Do not stop from elapsed time alone; confirm viral suppression, CD4 recovery, adherence and absence of active disease with the HIV team.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Intracranial hypertension

Obstructed CSF resorption causes headache, visual loss, cranial neuropathy, reduced consciousness, herniation and death without repeated drainage.

Cerebral infarction

Inflammation and organisms around small cerebral vessels can produce ischaemic stroke, persistent focal neurological disability and seizures.

Cryptococcoma

Mass-forming granulomatous lesions create focal deficits, epilepsy and prolonged radiological disease requiring extended induction and specialist inflammatory management.

Immune-reconstitution syndrome

Recovering immunity can produce recurrent meningitis symptoms, lymphadenitis or enlarging lesions despite sterile cultures and adequate antifungal therapy.

Antifungal toxicity

Amphotericin causes renal and electrolyte injury, while flucytosine accumulation causes cytopenia and hepatitis, threatening completion of induction.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Check neurological state, headache, vision and opening pressure repeatedly; clinical pressure recurrence can precede any change in serum antigen.
During induction, monitor creatinine, potassium and magnesium daily or more often when unstable, with frequent FBC and liver testing for flucytosine toxicity.
Obtain flucytosine concentrations after steady exposure and after renal change, and review every interacting or nephrotoxic medicine.
Use clinical recovery and CSF culture rather than serial antigen titre alone to determine fungal clearance; antigen can remain positive long after viable yeast disappears.
Watch for immune-reconstitution inflammatory syndrome after antiretroviral initiation or immunosuppression reduction and distinguish it from culture-positive relapse.
Follow hearing, vision, cognition and functional recovery and provide rehabilitation because survivors may have persistent neurological impairment.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Meningism may be absent

Profound immune suppression can produce high organism burden with little CSF inflammation, so a supple neck does not make meningitis unlikely.

Pressure is independently treatable

Antifungals kill yeast but do not rapidly restore CSF absorption; serial lumbar drainage is a separate mortality-reducing intervention.

Antigen can outlive disease

Serum and CSF antigen may decline slowly and should not drive prolonged therapy without culture, clinical or radiological evidence.

Host changes phenotype

HIV often produces diffuse high-burden meningitis, while C. gattii and non-HIV disease more often create cryptococcomas and prolonged inflammatory complications.

Pulmonary disease can disseminate

An apparently isolated lung nodule in an immunocompromised patient still warrants serum antigen and a deliberate assessment for occult CNS involvement.

11Common pitfallsFrequent interpretation and management errors.

01
Do not delay lumbar puncture for routine imaging when there is no clinical contraindication, and never omit opening-pressure measurement.
02
Do not manage raised intracranial pressure with mannitol, acetazolamide or corticosteroid instead of therapeutic CSF drainage.
03
Do not use amphotericin B alone when flucytosine is safely available for CNS induction.
04
Do not start antiretroviral therapy immediately during cryptococcal meningitis; coordinate the four- to six-week delay with HIV specialists.
05
Do not interpret a persistently positive cryptococcal antigen as proof of viable relapse without CSF culture and clinical reassessment.
06
Do not overlook CNS disease in antigen-positive fungaemia or pulmonary infection merely because the patient denies headache.