Most HIV-associated cryptococcal infections are caused by Cryptococcus neoformans, but occasionally Cryptococcus gattii is recognized. C. neoformans is found worldwide, whereas C. gattii most often is found in Australia and similar subtropical regions and in the Pacific Northwest. Before the era of effective antiretroviral therapy (ART), approximately 5% to 8% of HIV-infected patients in developed countries were diagnosed with disseminated cryptococcosis.1 Current estimates indicate that every year, nearly 1 million cases of cryptococcal meningitis are diagnosed worldwide and the disease accounts for more than 600,000 deaths.2 In the last decade, incidence has declined substantially in areas with access to effective ART, and most new infections are being recognized in patients recently diagnosed with HIV infection.3 Most cases are observed in patients who have CD4 T-lymphocyte (CD4) cell counts <100 cells/mm3.
In HIV-infected patients, cryptococcosis commonly presents as a subacute meningitis or meningoencephalitis with fever, malaise, and headache.1 Classic meningeal symptoms and signs, such as neck stiffness and photophobia, occur in only one-quarter to one-third of patients. Some patients experience encephalopathic symptoms, such as lethargy, altered mentation, personality changes, and memory loss that are usually a result of increased intracranial pressure, thought to result from impaired cerebrospinal fluid (CSF) absorption, or yeast infection of the brain.
Cryptococcosis usually is disseminated when diagnosed in an HIV-infected patient. Any organ of the body can be involved, and skin lesions may be myriad, including umbilicated skin lesions mimicking molluscum contagiosum. Isolated pulmonary infection is also possible; symptoms and signs include cough and dyspnea in association with an abnormal chest radiograph, which typically demonstrates lobar consolidation, although lobar and nodular infiltrates have been reported. Pulmonary cryptococcosis may present as acute respiratory distress syndrome and mimic Pneumocystis pneumonia.
Analysis of CSF generally demonstrates mildly elevated levels of serum protein, low-to-normal glucose concentrations, and pleocytosis consisting mostly of lymphocytes. Some HIV-infected patients will have very few CSF inflammatory cells, but an India ink or Gram’s stain preparation often will demonstrate numerous yeast forms. The opening pressure in the CSF may be elevated, with pressures ≥25 cm H2O occurring in 60 to 80% of patients.4,5
Cryptococcal disease can be diagnosed through culture of blood or CSF, CSF microscopy with India ink staining, or cryptococcal antigen (CrAg) detection. In patients with HIV-related cryptococcal meningitis, 55% of blood cultures and 95% of CSF cultures are positive and visible colonies can be detected within 7 days. India ink staining of CSF demonstrates encapsulated yeast in 60% to 80% of cases, but many laboratories in the United States no longer perform this test. CSF CrAg is usually positive in patients with meningoencephalitis. Serum CrAg is usually positive in both meningeal and non-meningeal infection and may be present weeks to months before symptom onset.6 A positive serum CrAg should prompt a lumbar puncture to rule out meningeal disease. Three methods exist for antigen detection: latex agglutination, enzyme immunoassays, and lateral flow assay (a newly developed dipstick test). Testing for the antigen is a useful initial screening tool in diagnosing cryptococcosis in HIV-infected patients,7 and it may be particularly useful when lumbar punctures need to be delayed or are refused.
Cryptococcus is ubiquitous in the environment; it is found in soils. HIV-infected patients cannot completely avoid exposure to C. neoformans or C. gattii. Limited epidemiological evidence suggests that exposure to aged bird droppings may increase risk of infection.
Because the incidence of cryptococcal disease is low among HIV-infected patients in the United States, routine testing of asymptomatic persons for serum cryptococcal polysaccharide antigen is not recommended for patients residing there.
Prospective, controlled trials indicate that prophylactic fluconazole or itraconazole can reduce the frequency of primary cryptococcal disease in patients who have CD4 cell counts <100 cells/mm3.8,9 However, in the United States, primary prophylaxis or screening for serum CrAg in asymptomatic patients is not recommended because of the relative infrequency of cryptococcal disease, lack of survival benefit associated with prophylaxis, possibility of drug interactions, potential antifungal drug resistance, and cost (BII).
Treating cryptococcosis consists of three phases: induction, consolidation, and maintenance therapy. The preferred induction treatment for cryptococcal meningitis and other forms of extrapulmonary cryptococcosis is a lipid formulation of amphotericin B in combination with flucytosine (AI). Historically, amphotericin B deoxycholate was the preferred formulation at a dose of 0.7 to 1.0 mg/kg daily (AI). However, based on the growing body of evidence that lipid formulations of amphotericin B are effective for disseminated cryptococcosis and should be used as the preferred formulation (AI), particularly in patients who experience clinically significant renal dysfunction during therapy or who are likely to develop it. The non-comparative CLEAR study demonstrated a 58% response rate in HIV-infected patients treated with amphotericin B lipid complex at mean dose of 4.4 mg/kg daily.10 In a Dutch and Australian study, a 3-week course of liposomal amphotericin B (4 mg/kg daily) resulted in more rapid sterilization of CSF than amphotericin B deoxycholate (0.7 mg/kg daily).11 A recently published comparison of amphotericin B deoxycholate (0.7 mg/kg daily), and liposomal amphotericin B (AmBisome®) (3 mg/kg or 6 mg/kg daily) showed similar efficacy for the three regimens, but nephrotoxicity was lower with 3 mg/kg daily liposomal amphotericin B.12
Therefore, liposomal amphotericin B, in a dose of 3 to 4 mg/kg/daily, is recommended as the preferred amphotericin B formulation for primary induction therapy (AI), based on clinical experience and reduced renal toxicity compared to amphotericin B deoxycholate. Amphotericin B lipid complex in a dose of 5 mg/kg daily is an alternative (BII).
Amphotericin B formulations should be combined with flucytosine at a dose of 100 mg/kg daily in 4 divided doses for ≥2 weeks in patients with normal renal function and is the preferred regimen for primary induction therapy (AI). Renal function should be monitored closely and the flucytosine dose adjusted accordingly for patients with renal impairment. The addition of flucytosine to amphotericin B during acute treatment is associated with more rapid sterilization of CSF.13-16 A recent randomized clinical trial also showed that the combination of amphotericin B deoxycholate in a dose of 1.0 mg/kg/d combined with flucytosine was associated with improved survival compared to the same dose of amphotericin B without flucytosine.17
Amphotericin B deoxycholate in combination with fluconazole 400 mg daily was inferior to amphotericin B in combination with flucytosine for clearing Cryptococcus from CSF.18 However, in two randomized trials, amphotericin B plus fluconazole 800 mg daily compared favorably with amphotericin B alone.17,19 Therefore, amphotericin B deoxycholate or lipid-formulated amphotericin B alone or combined with fluconazole at 800 mg daily may be viable options in some circumstances but are less preferable alternatives than lipid-formulated amphotericin B combined with flucytosine (BI).
Fluconazole (400–800 mg daily) combined with flucytosine is also a potential alternative to amphotericin B regimens (BII).20 Fluconazole alone, based on early fungicidal activity, is inferior to amphotericin B21 for induction therapy and is recommended only for patients who cannot tolerate or do not respond to standard treatment. If it is used for primary induction therapy, the starting daily dose should be 1200 mg (CII).22
After at least 2 weeks of successful induction therapy—defined as substantial clinical improvement and a negative CSF culture after repeat lumbar puncture—amphotericin B and flucytosine can be discontinued and follow-up or consolidation therapy initiated with fluconazole 400 mg daily (AI). This therapy should continue for at least 8 weeks (AI).13,14,23 Subsequently, the fluconazole should be reduced to 200 mg daily and continued as chronic maintenance therapy to complete at least one year of azole therapy (see Preventing Recurrence section below).24 Limited data are available for the newer triazoles, voriconazole and posaconazole, as either primary or maintenance therapy for patients with cryptococcosis. Most of the data on use of these extended-spectrum triazole antifungals have been reported for treatment of refractory cases, with success rates of approximately 50%.25,26 At this time, the role of posaconazole and voriconazole in the management of cryptococcosis is not established. Voriconazole should be used cautiously with HIV protease inhibitors and efavirenz.
Non-central-nervous-system (CNS), extrapulmonary cryptococcosis and diffuse pulmonary disease should be treated similarly to CNS disease (BIII). For mild-to-moderate symptoms and focal pulmonary infiltrates, treatment with fluconazole (400 mg daily for 12 months) combined with effective ART is appropriate (BIII). All patients should have their CSF sampled to rule out CNS disease.
Special Considerations with Regard to Starting ART
Optimal timing for initiation of ART in patients with acute cryptococcal meningitis is controversial. One randomized, controlled trial that included 35 patients with cryptococcal meningitis suggested that ART was safe when started within the first 14 days of diagnosis.27 A subsequent study from Africa demonstrated significantly worse outcomes in 54 patients started on ART within 72 hours of cryptococcal meningitis diagnosis compared with those in which ART was delayed for at least 10 weeks.28 However, in the latter study, cryptococcal meningitis was managed with fluconazole alone, and ART consisted of nevirapine, stavudine, and lamivudine. Neither fluconazole alone nor the latter ART regimen are recommended as preferred initial treatment in the United States. Lastly, another randomized clinical trial conducted in Africa in hospitalized patients with acute cryptococcal meningitis was recently halted by a Data and Safety Monitoring Board due to higher mortality in the early ART arm (defined as ART started during the hospitalization) compared to the arm in which patients waited to start ART until after their discharge from the hospital. In contrast to the other African study, this study used amphotericin B plus fluconazole during the induction phase of antifungal treatment (http://www.niaid.nih.gov/news/newsreleases/2012/Pages/COAT.aspx). Such data must be viewed with caution until fully reported and analyzed.
In patients with severe cryptococcosis (particularly those with elevated increased intracranial pressure [ICP]), it may be prudent to delay initiation of ART until induction (the first 2 weeks) or the total induction/consolidation phase (10 weeks) has been completed. However, for patients with advanced immunosuppression (CD4 count <50 cells/mm3) earlier initiation of ART may be necessary (BIII). If the treating physician elects to begin effective ART earlier, preparations should be made to aggressively address complications of immune reconstitution inflammatory syndrome (IRIS) such as elevated ICP (BIII).
All the triazole antifungals have the potential for complex, and possibly bidirectional, interactions with certain antiretroviral agents. Table 5 lists these interactions and recommendations for dosage adjustments, where feasible.
Monitoring of Response to Therapy and Adverse Events (including IRIS)
ICP can cause clinical deterioration despite a microbiologic response and is more likely if the CSF opening lumbar pressure is ≥25cm H2O4,13 when obtained in the lateral decubitus position with good manometrics assured. In one large clinical trial, increased ICP was associated with 93% of deaths during the first 2 weeks of therapy and 40% of deaths during weeks 3 to 10.4 Although it is uncertain which patients with high opening lumbar pressures will deteriorate, those with symptoms and signs of ICP require immediate clinical intervention.
Lumbar opening pressure should be measured in all patients with cryptococcal meningitis at the time of diagnosis. Measures to decrease ICP should be used for all patients with confusion, blurred vision, papilledema, lower extremity clonus, or other neurologic signs of increased pressure. Lumbar punctures usually are recommended for initial management. One approach is to remove a volume of CSF (typically 20–30 mL) that at least halves the opening pressure29 and repeat daily until symptoms and signs consistently improve. CSF shunting through a lumbar drain or ventriculostomy should be considered for patients who cannot tolerate lumbar puncture or in whom signs and symptoms of cerebral edema persist after multiple lumbar taps (BIII). Corticosteroids and mannitol have been shown to be ineffective in managing ICP and are not recommended (CIII). Acetazolamide is hazardous as therapy for increased ICP management in those without signs IRIS and is not recommended (BII).
After the first 2 weeks of treatment, many experts would advocate a repeat lumbar puncture to ensure that viable organisms have been cleared from the CSF. Even in patients who have clinical improvement, positive CSF cultures after 2 weeks of therapy are predictive of future relapse and less favorable outcome. In such cases, some experts would continue amphotericin B plus flucytosine until the CSF cultures are negative (BIII). Monitoring titers of cryptococcal polysaccharide antigen in serum or CSF is of no value in determining response to therapy and is not recommended. If new symptoms or clinical findings occur later, a repeat lumbar puncture, with measurement of opening lumbar pressure and CSF culture, should be performed.
Patients treated with amphotericin B formulations should be monitored for dose-dependent nephrotoxicity and electrolyte disturbances. Pre-infusion administration of 500 to 1000 mL of normal saline appears to reduce the risk of nephrotoxicity during amphotericin B treatment. Thirty minutes before infusion, acetaminophen (650 mg) and diphenhydramine (25–50 mg) or hydrocortisone (50–100 mg) typically are administered in an attempt to ameliorate infusion-related adverse reactions (BIII), but data supporting these practices are scant. Meperidine (25–50 mg titrated during infusion) is effective for preventing and treating amphotericin B-associated rigors (BII).
In patients receiving flucytosine, dosage should be adjusted based on changes in creatinine clearance and might be guided by flucytosine levels. Peak serum flucytosine levels should be obtained 2 hours after an oral dose and the therapeutic range is between 30 and 80 µg/mL. Alternatively, frequent (i.e., at least bi-weekly) blood counts can be performed to detect development of cytopenia. Patients treated with flucytosine also should be monitored for hepatotoxicity and gastrointestinal toxicities.
An estimated 30% of HIV-infected patients with cryptococcal meningitis experience IRIS after initiation or re-initiation of effective ART.30,31 Patients who have cryptococcal IRIS are more likely to be antiretroviral naive, have higher HIV RNA levels, and have less CSF inflammation on initial presentation.32 Distinguishing IRIS from treatment failure may be difficult. In general, cryptococcal IRIS presents with worsening clinical disease despite microbiological evidence of effective antifungal therapy,32,33 whereas treatment failure is associated with continued positive cultures. Appropriate management of IRIS is to continue both ART and antifungal therapy and reduce elevated ICP, if present (AII). In patients with severe symptoms of IRIS, some specialists recommend a brief course of glucocorticosteroids (CIII), but data based management strategies have not been developed.
Managing Treatment Failure
Treatment failure is defined as lack of clinical improvement after 2 weeks of appropriate therapy, including management of increased ICP, with continued positive cultures; or relapse after an initial clinical response, defined as recurrence of symptoms with a positive CSF culture after ≥4 weeks of treatment. Direct primary fluconazole resistance with C. neoformans has been reported in the United States but is uncommon.34 Therefore, susceptibility testing is not routinely recommended for initial management of cryptococcosis. Isolates collected to evaluate for persistence or relapse should, however, be checked for susceptibility and compared with the original isolate. Strains with fluconazole minimum inhibitory concentrations ≥16 µg/mL are considered fluconazole resistant.35
Optimal therapy for patients with treatment failure has not been established. Patients who fail to respond to induction with fluconazole monotherapy should be switched to amphotericin B, with or without flucytosine, and remain on it until a clinical response occurs. Liposomal amphotericin B (4–6 mg/kg/day) or amphotericin B lipid complex (5 mg/kg/day) is better tolerated and has greater efficacy than deoxycholate formulation in this setting11,12,36 and should be considered when initial treatment with other regimens fails (AII).
Higher doses of fluconazole in combination with flucytosine also may be useful (BIII). Echinocandins have no activity against Cryptococcus spp. and are not recommended for clinical management of cryptococcosis (AII). The newer triazoles—posaconazole and voriconazole—have activity against Cryptococcus spp. in vitro and may have a role in salvage therapy, but probably offer no specific advantages over fluconazole unless in vitro susceptibility testing indicates fluconazole resistance. Most clinical failures are a result of inadequate induction therapy, drug interactions that interfere with treatment, or development of IRIS and are not due to drug resistance.
When to Start Secondary Prophylaxis
Patients who have completed the first 10 weeks of induction and consolidation therapy for acute cryptococcosis should be given chronic maintenance or suppressive therapy with fluconazole 200 mg daily (AI). Itraconazole is inferior to fluconazole for preventing relapse of cryptococcal disease and should not be used (CI).23
When to Stop Secondary Prophylaxis
Only a small number of patients have been evaluated for relapse after successful antifungal therapy for cryptococcosis and discontinuation of secondary prophylaxis while on ART. In a European study, recurrence of cryptococcosis was seen in none of 39 subjects on potent ART whose antifungal therapy was discontinued. In this cohort, when maintenance therapy was stopped, the median CD4 cell count was 297 cells/mm3, the median HIV RNA concentration was <500 copies/mL, and the median time on potent ART was 25 months.37 A prospective, randomized study of 60 patients in Thailand documented no recurrences of cryptococcosis during 48 weeks of follow-up among 22 patients whose antifungal therapy was discontinued after having achieved a CD4 count >100 cells/mm3 with a sustained undetectable HIV RNA level for 3 months on potent ART.38 Given these data and inference from data on discontinuation of secondary prophylaxis for other HIV-associated opportunistic infections, it is reasonable to discontinue chronic antifungal maintenance therapy for cryptococcosis in patients whose CD4 cell counts are ≥100 cells/mm3, who have undetectable viral loads on ART for >3 months, and who have received a minimum of 1 year of azole antifungal chronic maintenance therapy after successful treatment of cryptococcosis (BII).39 Secondary prophylaxis should be reinitiated if the CD4 count decreases again to <100 cells/mm3 (AlII).
Special Considerations During Pregnancy
The diagnosis of cryptococcal infections during pregnancy is similar to that in non-pregnant adults. Treatment should be initiated promptly after a diagnosis is confirmed. It should be emphasized that the postpartum period may be a high-risk period for the development of IRIS.
Lipid formulations of amphotericin B are the preferred initial regimen for the treatment of cryptococcal meningoencephalitis, disseminated disease, or severe pulmonary cryptococcosis in pregnant patients. Extensive clinical experience with amphotericin has not documented teratogenicity. Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.
Flucytosine was teratogenic in animal studies, and human experience is limited to case reports and small series. Therefore, its use should be considered only when the benefits outweigh its risks to the fetus (CIII).
Congenital malformations similar to those observed in animals, including craniofacial and limb abnormalities, have been reported in infants born to mothers who received fluconazole at doses of ≥400 mg/day or more through or beyond the first trimester of pregnancy.40 Although several cohort studies have shown no increased risk of birth defects with early pregnancy exposure, most of these involved low doses and short term exposure to fluconazole.41,42 Based on the reported birth defects, the FDA has changed the pregnancy category for fluconazole from C to D for any use other than a single, low dose for treatment of vaginal candidiasis, (http://www.fda.gov/Drugs/DrugSafety/ucm266030.htm) and use of fluconazole in the first trimester should be considered only if the benefits clearly outweigh risks. For pregnant women, amphotericin should be continued throughout the first trimester with consideration of switching to oral fluconazole, if clinically appropriate, after the first trimester.
Although there are case reports of birth defects in infants exposed to itraconazole, prospective cohort studies of over 300 women with first trimester exposure did not show an increased risk of malformation.43,44 However, in general azole antifungals should be avoided during the first trimester of pregnancy (BIII). Voriconazole and posaconazole are teratogenic and embryotoxic in animal studies, voriconazole at doses lower than recommended human doses; there are no adequate controlled studies in humans. These drugs should be avoided in pregnancy, especially in the first trimester (AIII).
|Treating Cryptococcal Meningitis
Induction Therapy (For At Least 2 Weeks, Followed by Consolidation Therapy)
If the following criteria are fulfilled (BII):