Cryptococcosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

The choice of treatment depends on the sites of involvement, the patient's immune status, and disease severity. Determination of disease severity is based on clinical judgement.

Treatment of cryptococcal meningitis and other forms of extrapulmonary cryptococcosis is usually initiated with an amphotericin-B formulation in combination with oral flucytosine.[20] Lipid or liposomal formulations of amphotericin-B are preferred to amphotericin-B deoxycholate, where available, because they are effective for cryptococcosis and have lower toxicity.[20][62] Amphotericin-B deoxycholate is associated with renal impairment, renal tubular acidosis, hypokalaemia, hypomagnesaemia, and anaemia.[63] The addition of flucytosine to amphotericin-B during acute treatment may lead to more rapid clearing of cerebrospinal fluid (CSF) cryptococcosis.[63]

Fluconazole is used for maintenance and consolidation therapy in patients with HIV and cryptococcal meningoencephalitis and may also be used as monotherapy for patients with milder forms of infection not involving the central nervous system (CNS).[20][64][65]

Azole antifungals and flucytosine should be avoided during the first trimester of pregnancy because of the risk of teratogenicity, and should be used during pregnancy only if the benefits outweigh the risks.[20][66] Consideration of flucytosine use should be limited to the third trimester.[20] Breastfeeding should not be undertaken if azole antifungals are used for treatment in the postnatal period. Most reported cases of cryptococcosis during pregnancy have been treated by amphotericin-B, with good outcomes for both the mother and infant.[20][28]

People without HIV: mild-moderate focal pulmonary disease

There are no randomised studies for treatment of pulmonary cryptococcosis.[35] Treatment options are based on US and global guidelines.[35][60][67]

Oral fluconazole is the first-choice antifungal treatment for mild-moderate focal pulmonary disease due to Cryptococcus neoformans and single, small cryptococcomas caused by Cryptococcus var. gattii.[35][60][67] The duration of therapy is normally 6-12 months and is guided by symptom resolution.[35][60][67] Follow-up for 1 year is recommended because pulmonary cryptococcosis may disseminate.[60] Fluconazole is recommended in both non-transplant recipients and transplant recipients.[67]
If fluconazole is not an option, oral itraconazole, voriconazole, or posaconazole can be given for 6-12 months.[60][67]
If azole antifungal therapy is contraindicated (e.g., pregnancy), discuss treatment options with an infectious diseases specialist. In pregnant women with no evidence of CNS disease or disseminated infection, and no significant symptoms, careful monitoring and deferral of antifungal therapy until after pregnancy may be considered.[67]
Fluconazole is usually well tolerated. The most common adverse effects are nausea, abdominal pain, and skin rash. Although fluconazole resistance has been reported with C neoformans, it is rare in some countries, such as the US, and susceptibility testing is not routinely recommended unless there is relapse or treatment failure.[64][67][68]
Immunosuppressed patients with pulmonary cryptococcosis should have a lumbar puncture to exclude asymptomatic CNS disease. Lumbar puncture should be considered for immunocompetent patients.[67]
Consider surgery if symptoms do not respond to antifungal therapy. Surgery may aid diagnosis of persistent radiographical abnormalities.[67]

People without HIV: solid-organ transplant recipient with CNS disease or severe pulmonary disease or disseminated disease

Induction treatment is with liposomal amphotericin-B or amphotericin-B lipid complex plus flucytosine for at least 2 weeks.[67] Amphotericin-B deoxycholate is not recommended as first-line therapy due to the increased frequency of renal impairment in transplant recipients and the associated risk of nephrotoxicity. Antifungal doses should be carefully monitored and drug-drug interactions with immunosuppressants considered.[67]

Induction therapy is followed by consolidation therapy with fluconazole for 8 weeks, then fluconazole maintenance therapy for at least 6-12 months.[67]

Patients with a positive initial CSF culture should have a repeat lumbar puncture after 2 weeks, or sooner if there are concerns about treatment failure or raised intracranial pressure.[67] The median time to negative CSF culture after starting treatment is 10 days.[69]

Review the patient's immunosuppressive drugs. Immunosuppressants should be reduced step-wise or sequentially; consider reducing the corticosteroid dose first.[67] Abrupt withdrawal may precipitate immune reconstitution inflammatory syndrome (IRIS) or organ rejection.[67]

People without HIV: non-organ transplant recipient with CNS disease or severe pulmonary disease or high serum CrAg titre

CrAg titre of ≥1:512 indicates a high fungal burden and warrants intensive treatment.[67] Patients with cryptococcal meningitis without HIV or a history of solid organ transplantation are a heterogeneous population, including healthy immunocompetent people as well as people with other immune compromise (e.g., cancer, cirrhosis, connective tissue disease, and long-term corticosteroid use).[35][67] Treatment regimens and duration are tailored to individual needs.[35][67]

Antifungal induction therapy

US guidelines recommend induction therapy with amphotericin-B deoxycholate plus flucytosine.[67] Induction therapy is usually given for at least 4 weeks. The induction period may be shortened to 2 weeks in patients who were diagnosed early, have an excellent response to induction therapy, and have no uncontrolled comorbid disease or immune compromise.[67] A total of 6 weeks of induction therapy may be given to patients with neurological complications.[67] Lumbar puncture is performed after 2 weeks of treatment; patients with persistently positive CSF may require a longer induction period.[67]
Lipid or liposomal formulations of amphotericin-B are used if the patient cannot tolerate amphotericin-B deoxycholate.[67] Lipid or liposomal amphotericin-B formulations may be used for the second 2 weeks of the induction period if toxicity occurs with amphotericin-B deoxycholate.[67]
Flucytosine has been shown to be a strong independent predictor of CSF sterilisation at 2 weeks in people with CNS disease.[64] However, reduced platelet or neutrophil counts preclude the use of flucytosine.[60] If induction therapy does not include flucytosine, consider monotherapy with liposomal amphotericin-B, amphotericin-B lipid complex, or amphotericin-B deoxycholate for at least 4-6 weeks.[67]
Adverse effects associated with amphotericin-B include elevation of serum creatinine, hypokalaemia, hypomagnesaemia, renal tubular acidosis, haematological sequelae, nausea, vomiting, chills, fever, and rigors.[1][67] Renal function should be monitored frequently in patients receiving prolonged (>2 weeks) courses of amphotericin-B and flucytosine therapy, and appropriate dose adjustment (preferably through monitoring serum flucytosine levels measured 2 hours post-dose after 3-5 doses have been administered with optimal levels of 25-100 mg/L) should be undertaken to prevent bone marrow suppression and gastrointestinal toxicity. If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect cytopenia.[20]

Antifungal consolidation therapy

Consolidation therapy is with oral fluconazole.[35][67] The rationale for this approach is rapid control of infection with the most fungicidal regimen, followed by less toxic oral therapy for continued treatment and prevention of relapse, also minimising the dose-dependent toxicity of amphotericin-B.[23]
The recommended consolidation phase of treatment is an 8-week course of fluconazole.[67] After 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[67]

Antifungal maintenance therapy

Following successful induction and consolidation therapy (i.e., clinical improvement and negative CSF culture), antifungal maintenance therapy with oral fluconazole should be continued for at least 6-12 months.[67]

Induction, consolidation, and maintenance regimens for Cryptococcus var. gattii disease are the same as for C neoformans.[67] Surgery may be considered for very large or multiple pulmonary cryptococcomas.[67]

People with HIV: isolated asymptomatic antigenaemia with low serum CrAg titres

Low serum CrAg titres are <1:640 by lateral flow assay (LFA) and <1:160 by enzyme immunoassay (EIA) or latex agglutination.[20]

All people with HIV, including those who are asymptomatic, require pre-emptive antifungal therapy due to the high risk of disseminated or CNS infection.[67][70]

Whether to sample CSF in fully asymptomatic patients with isolated cryptococcal antigenaemia is guided by CrAg titre and the risk of cryptococcal disease (e.g., patients with advanced immunosuppression not taking antiretroviral therapy [ART] would be at higher risk). Patients at lower risk with a serum CrAg titre ≤1:80 by LFA (or <1:20 with EIA or latex agglutination) who are asymptomatic may be treated without lumbar puncture. All symptomatic patients should have CSF sampling to exclude CNS disease.[20]

Patients with normal CSF, no symptoms, and low serum CrAg titres are treated with fluconazole for 6 months. Higher doses are used for the first 12 weeks of treatment.[20]

People with HIV: non-CNS focal pulmonary infiltrates with mild symptoms and negative serum CrAg

For patients with mild symptoms and focal pulmonary infiltrates, treatment with an antifungal plus ART is appropriate.[20] All patients should have their CSF sampled to rule out CNS disease.[20]

Antifungal therapy

Oral fluconazole is generally the first-choice antifungal treatment in these patients. US guidelines recommend oral fluconazole treatment at the same dose for 6-12 months, with duration guided by symptom resolution.[20] Other guidelines may differ. For example, World Health Organization (WHO) guidelines recommend oral fluconazole treatment for 2 weeks at a higher dose, then 8 weeks at a lower dose, followed by maintenance therapy.[23]
Fluconazole may be discontinued depending on the response to ART (i.e., CD4 cell counts ≥100 cells/microlitre, undetectable viral loads on ART, minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis).[20]

ART

The optimum time to begin ART in patients with non-CNS disease is not clear. US guidelines suggest delaying initiation of ART for 2 weeks after starting antifungal therapy.[20] See HIV in adults.

People with HIV: CNS and/or disseminated disease; non-CNS extrapulmonary disease, diffuse pulmonary disease, or non-CNS symptoms with normal CSF and high serum CrAg titres

Asymptomatic patients with high serum CrAg titres (i.e., ≥1:160 by lateral flow assay) should receive the same treatment as patients with CNS disease, due to increased risk for mortality and CNS involvement.[20]

Antifungal induction therapy

According to US guidelines, the first-choice induction regimen is 2 weeks of intravenous liposomal amphotericin-B plus oral flucytosine.[20] Amphotericin-B deoxycholate can be used as an alternative formulation if risk of renal dysfunction is low or if cost is prohibitive.[20][62]
For patients in resource-limited settings, the WHO recommends an induction regimen that consists of a single high dose of liposomal amphotericin-B combined with 14 days of flucytosine and fluconazole.[23] An alternative regimen recommended by the WHO (where liposomal amphotericin-B is not available) is 1 week of amphotericin-B deoxycholate and flucytosine, followed by 1 week of fluconazole.[23][71] [ ] [ ]
Alternative induction regimens recommended by US guidelines are 2 weeks of intravenous amphotericin-B lipid complex plus oral flucytosine, or 1 week of amphotericin-B deoxycholate plus oral flucytosine followed by 1 week of oral fluconazole.[20] Fluconazole monotherapy is markedly inferior to amphotericin-B in HIV-related cryptococcal meningitis and is associated with 30% higher 10-week mortality.[72]
WHO guidelines note that flucytosine-containing regimens are superior and should be used where possible.[23] Flucytosine has been shown to be a strong independent predictor of CSF sterilisation at 2 weeks in both people with HIV and total patient populations.[12][64] However, reduced platelet or neutrophil counts preclude the use of flucytosine.[60]
Adverse effects associated with amphotericin-B include elevation of serum creatinine, hypokalaemia, hypomagnesaemia, renal tubular acidosis, haematological sequelae, nausea, vomiting, chills, fever, and rigors.[1][67] Renal function should be monitored frequently in patients receiving prolonged (>2 weeks) courses of amphotericin-B and flucytosine therapy, and appropriate dose adjustment (preferably through monitoring serum flucytosine levels measured 2 hours post-dose after 3-5 doses have been administered with optimal levels of 25-100 mg/L) should be undertaken to prevent bone marrow suppression and gastrointestinal toxicity.[20][67] If flucytosine levels are not available, frequent (i.e., at least twice weekly) blood counts can be performed to detect cytopenia.[20]
Lumbar puncture is typically performed on days 0, 3, 7, and 14, depending on opening pressure. Patients with positive CSF cultures after 2 weeks of therapy and no clinical improvement should be continued on amphotericin-B until CSF cultures are negative.[20][67] Patients with positive cultures but signs of clinical improvement should go on to receive consolidation therapy.[20]

Antifungal consolidation therapy

Consolidation therapy is with oral fluconazole.[20][23] The rationale for this approach is rapid control of infection with the most fungicidal regimen, followed by less toxic oral therapy for continued treatment and prevention of relapse, also minimising the dose-dependent toxicity of amphotericin-B.[20][23]
Itraconazole is an alternative option for patients who cannot tolerate fluconazole, or if fluconazole is unavailable.[20]
The recommended consolidation phase of treatment is at least an 8-week course of fluconazole.[20][23] After at least 8 weeks, the patient should be switched to low-dose fluconazole for long-term maintenance therapy.[20][23]
Patients with positive CSF cultures but who have improved clinically after 2 weeks of induction therapy should receive a higher dose (1200 mg/day) of fluconazole for consolidation therapy, and have repeat lumbar puncture in another 2 weeks.[20] Alternatively, non-hospitalised patients can receive flucytosine plus fluconazole for an additional 2 weeks before starting single-drug consolidation therapy.[20] The duration of consolidation therapy should be at least 8 weeks from the point at which CSF cultures are negative.[20][23]

ART

For patients with cryptococcal meningitis, immediate initiation of ART is not recommended as there is an increased risk of mortality, thought to be caused by IRIS.[73][74]
WHO and US guidelines recommend that ART should be started 4-6 weeks after initiation of antifungal treatment.[20][23]
For non-CNS cryptococcosis, ART may be delayed for 2 weeks after starting antifungal treatment.[20] See HIV in adults.

Antifungal maintenance therapy

Following successful induction and consolidation therapy (i.e., clinical improvement and negative CSF culture after repeat lumbar puncture), antifungal maintenance therapy with oral fluconazole should be continued for at least 1 year.[20][23]
Itraconazole is an alternative option for patients who cannot tolerate fluconazole, or if fluconazole is unavailable.[20]
Antifungal maintenance therapy can be discontinued if CD4 cell count is ≥100 cells/microlitre, with undetectable viral loads on ART, with the patient having received a minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis. Maintenance therapy should be re-initiated if the CD4 count falls to <100 cells/microlitre.[20]

Management of elevated intracranial pressure (ICP)

Elevated ICP, defined as an opening pressure of >20 cm H₂O, measured with the patient in the lateral decubitus position, occurs in up to 80% of patients with HIV-associated cryptococcal meningitis and when uncontrolled is associated with a poorer clinical response.[23][51][52][53] Managing raised ICP is critical, involving therapeutic lumbar punctures to normalise pressures and, where necessary, surgical interventions for persistent elevation.[35][63] Therapeutic lumbar puncture can be used to reduce elevated ICP and has been associated with 69% relative improvement in survival, regardless of initial ICP.[75] Data for management of raised ICP in people without HIV who have cryptococcal meningitis are lacking; management recommendations are extrapolated from treatment of people with HIV.[67]

Normal baseline opening pressure (≤20 cm H₂O)

The WHO recommends that all patients with HIV-associated cryptococcal meningitis should have an initial diagnostic lumbar puncture, and an early repeat lumbar puncture with measurement of CSF opening pressure to assess for raised ICP regardless of the presence of symptoms or signs of raised ICP. More than one repeat lumbar puncture may be considered, such as a third lumbar puncture on day 3.[23]
Monitoring serum or CSF CrAg is not recommended. If new symptoms or clinical findings occur, a repeat lumbar puncture with measurement of opening lumbar pressure and CSF culture is recommended.[20]

Elevated baseline opening pressure (>20 cm H₂O)

Elevated ICP should be reduced in all patients with confusion, blurred vision, papilloedema, lower-extremity clonus, or other neurological signs of increased ICP.[20]
The principal intervention for the reduction of elevated ICP is percutaneous lumbar drainage.[23] Focal neurological deficits are uncommon in cryptococcosis and should prompt radiographical imaging of the brain to rule out the presence of a space-occupying lesion. Lumbar drainage sufficient to achieve a closing pressure of <20 cm H₂O or 50% of the initial opening pressure should be undertaken.[20] Patients should initially undergo daily lumbar punctures to maintain stable opening pressures within the normal range, and to improve symptoms and signs.[35]
If elevated ICP or signs and symptoms of cerebral oedema persist after repeated lumbar puncture, a lumbar drain or ventriculoperitoneal shunt should be considered.[20][35][67]
Repeated lumbar punctures are recommended for patients with persistently elevated ICP (≥25 cm H₂O) or with symptoms of increased ICP (e.g., headache, altered mental status, or vision changes). These should be done daily or as needed until the opening pressure normalises or symptoms improve.[20]
Corticosteroids are not recommended for managing elevated ICP in people with HIV.[20] In patients without HIV, as evidence of benefit has not yet been established, corticosteroids should also not be used. Acetazolamide, diuretic therapy, and mannitol have not been shown to provide any benefit and are not recommended.[20][60]

Diagnostic lumbar puncture in adults: animated demonstration

How to perform a diagnostic lumbar puncture in adults. Includes a discussion of patient positioning, choice of needle, and measurement of opening and closing pressure.

Treatment failure and persistent lesions

Treatment failure is defined as the lack of clinical improvement after 2 weeks of therapy (including management of increased ICP, with continued positive cultures) or relapse after initial clinical response (i.e., recurrence of symptoms with a positive CSF culture after ≥4 weeks of treatment).[20] Most clinical failures are a result of inadequate induction therapy, drug interactions, or development of IRIS.[20] Fluconazole resistance with Cryptococcus neoformans is rare; therefore, susceptibility testing is not routinely recommended for initial management.[20][68] However, fluconazole resistance is common among relapse cases.[76] Cryptococcal isolates that are checked for persistence or relapse should also be checked for susceptibility. Strains with minimum inhibitory concentrations against fluconazole ≥16 micrograms/mL may be considered resistant.[20]

Treatment-failure patients who are initially treated with fluconazole should have their therapy changed to amphotericin-B, with or without flucytosine, until clinical response is achieved.[20] Patients initially treated with an amphotericin-B formulation should continue this treatment until there is a clinical response.[20] Lipid formulations of amphotericin-B are better tolerated and more efficacious than the deoxycholate formulation, and should be considered when initial treatment with other regimens fails.[20] Higher doses of fluconazole with flucytosine may also be useful.[20] Echinocandins are not recommended as they have no activity against Cryptococcus.[20]

Surgery should be considered for patients with persistent or refractory pulmonary, bone, or CNS lesions.[60][67]

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