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Discussion

Epidemiology of Cryptococcal Meningitis

Cryptococcus neoformans, an encapsulated yeast, is the dominant causative agent of cryptococcosis and cryptococcal meningitis. Cryptococcal infection is acquired through the inhalation of C. neoformans spores, which in healthy adults leads to either a sub-clinical response or mild pneumonia. Among HIV-infected adults, acute infection can lead to a severe pneumonia, whereas subacute or chronic infection more often results in cryptococcal meningitis. The risk of developing cryptococcal meningitis is greatest among HIV-infected persons with a CD4 count less than 100 cell/mm3 [1,2]. Globally, cryptococcal meningitis causes more than 500,000 deaths among HIV-infected persons each year[3]. In highly endemic areas, mainly sub-Saharan Africa and Southeast Asia, approximately 5 to 10% of HIV-infected adults develop cryptococcal infection[2,4,5]. In addition, in sub-Saharan Africa, cryptococcal meningitis is the most common cause of meningitis and accounts for 15 to 25% of all AIDS-related deaths[6,7]. The case fatality rate is approximately 20% among patients who receive an amphotericin B-containing regimen, but approaches 100% among patients who present with severe cryptococcal meningitis or do not receive appropriate antifungal therapy[8,9,10].

Clinical Presentation of Cryptococcal Meningitis

The most common symptoms of cryptococcal meningitis are headache, fever, blurry or double vision, difficulty hearing, neck stiffness, and confusion. Some patients present with a new-onset seizure, hence a new seizure in an HIV-infected adult should prompt suspicion for cryptococcal meningitis. Many patients will present initially with mild symptoms of meningitis and/or pulmonary symptoms, such as fever, cough, and dyspnea[11]. Any HIV-infected patient with advanced immunosuppression who presents with signs or symptoms of meningitis should undergo evaluation for cryptococcal disease.

Diagnostic Testing of Patients with Suspected Cryptococcal Meningitis

Cryptococcal Antigen: Diagnostic testing for cryptococcal infection has improved dramatically with the recent World Health Organization (WHO) approval of a rapid, point-of-care, lateral flow assay (LFA) test for the detection of cryptococcal antigens[12]. The LFA test detects the F12D2 and 339 antigens of the cryptococcal polysaccharide capsule glucuronyxylomannan, and can be performed on urine, plasma, serum, or CSF samples [13].

Lumbar Puncture: A lumbar puncture should be performed immediately on any patient suspected of having cryptococcal meningitis based on clinical evaluation or a positive serum cryptococcal antigen (CrAg) test, provided no contraindications exist for performing the lumbar puncture[14,15]. Ideally, a head computed tomography (CT) scan is performed prior to the lumbar puncture to rule out the presence of an intracranial mass lesion. However, a head CT should only be considered if it can be performed immediately; otherwise, the lumbar puncture should not be delayed in the absence of contraindications. The lumbar puncture should include measurement of the cerebrospinal fluid (CSF) opening pressure and either a latex agglutination CrAg or rapid LFA CrAg. More than 90% of patients who have a positive CSF CrAg also have a positive serum latex CrAg[13]. If CrAg testing is not available, an India Ink smear can be substituted, although this test has a much lower sensitivity than CrAg[16]. Contraindications to performing a lumbar puncture include significant coagulopathy, major spinal deformity, confirmed space-occupying lesion on CT scan, or a suspected space-occupying lesion based on focal neurological signs or recurrent seizures[14]. Suspected elevated intracranial pressure is not a contraindication to performing a lumbar puncture in this setting[14]. If a lumbar puncture cannot be safely performed, then a rapid serum CrAg test should be obtained. If the serum CrAg test is positive, then patients should be presumed to have cryptococcal meningitis and treated accordingly.

Initial Management of Cryptococcal Meningitis

According to the WHO guidelines, the management of cryptococcal meningitis (as well as disseminated non-meningeal cryptococcal disease in HIV-infected individuals) consists of an initial 2-week induction phase, followed by an 8-week consolidation phase, and then a long-term maintenance phase (Figure 1) [14]. If present, increased intracranial pressure must also be carefully managed.

Treatment of Cryptococcal Meningitis: Raised Intracranial Pressure

Elevated intracranial pressure (defined as opening pressure greater than 200mm H20) in the setting of cryptococcal meningitis is common and is associated with significant morbidity and mortality. Although no data exist from randomized controlled trials regarding the optimal management of elevated intracranial pressure, worse clinical outcomes have been documented among patients whose intracranial pressure increased during the first two weeks of therapy [17]. Current treatment guidelines therefore recommend aggressive management of elevated intracranial pressure in patients with cryptococcal disease[14,18]:

  • Patients with an opening pressure of greater than 250mm H20 on initial lumbar puncture should have sufficient CSF removed to achieve a closing pressure that is either less than 200mm H20 or less than 50% of the initial opening pressure.
  • Lumbar punctures should be repeated daily, with removal of 20 to 30cc of cerebrospinal fluid with each procedure, until the opening pressure remains below 200 cm H20 for three consecutive days.
  • If the elevated pressure persists after several daily lumbar punctures, insertion of a lumbar drain may be considered.
  • Other approaches for reducing intracranial pressure, such as systemic acetazolamide, mannitol, or corticosteroids are not recommended[15,18,19].

Treatment of Cryptococcal Meningitis: Induction Therapy

The optimal induction therapy for cryptococcal meningitis is two weeks of intravenous amphotericin B (0.7-1.0 mg/kg/day) plus oral flucytosine (100 mg/kg/day divided in four doses). Oral fluconazole 800 mg/day should be substituted for flucytosine if flucytosine is not available[20]. If the patient is unable to receive amphotericin, then the recommended therapy is high-dose fluconazole (1200 mg/day) plus flucytosine (100 mg/kg/day divided in four doses). In settings where neither amphotericin B nor flucytosine is available, high-dose oral fluconazole (1200 mg/day) is recommended.

Treatment of Cryptococcal Meningitis: Consolidation & Maintenance Phases

After the initial 2-week induction phase, the optimal consolidation phase of treatment is an 8-week course of oral fluconazole (400 to 800 mg/day for adults; 6 to 12 mg/kg/day for children). After 8 weeks, patients should be switched to low-dose fluconazole (200 mg/day for adults; 6 mg/kg/day for children) to begin the long-term maintenance phase.

Treatment of Cryptococcal infection without Evidence of Cryptococcal Meningitis

The optimal anti-fungal regimen in patients with isolated serum CrAg positivity (where active cryptococcal meningitis has been excluded) remains to be determined. In this situation, the WHO guidelines recommend treating with fluconazole 800 mg/day for 2 weeks followed by 400 mg/day for 8 weeks [14].

Antiretroviral Therapy in Patients with Cryptococcal Meningitis

Immediate initiation of antiretroviral therapy in the context of acute cryptococcal meningitis has been associated with a higher risk of life-threatening immune reconstitution inflammatory syndrome (IRIS). On the basis of limited clinical trials data [21,22], WHO guidelines recommend deferring initiation of antiretroviral therapy until there is evidence of sustained clinical response to antifungal therapy, and after a minimum of 2 to 4 weeks following initiation of cryptococcal therapy with an amphotericin B containing regimen (Figure 2). If the patient is receiving high-dose fluconazole monotherapy, antiretroviral therapy should be deferred until at least 4 to 6 weeks of treatment have been completed [14]. This recommendation is supported by data from the Cryptococcal Optimal ART Timing (COAT) trial, which randomized patients with HIV infection and cryptococcal meningitis to initiate antiretroviral therapy either simultaneously with anti-cryptococcal therapy or approximately 5 weeks after initiation of anti-cryptococcal therapy. The trial was halted early in May 2012 by the study's Data Safety and Monitoring Board after interim results revealed excess mortality in those patients randomized to start antiretroviral therapy at the same time as anti-cryptococcal therapy (COAT Trial Bulletin).

Monitoring Cryptococcal Meningitis Treatment

For patients receiving amphotericin B containing regimens, the WHO recommends a minimal package of toxicity prevention, monitoring, and treatment in order to minimize the potentially serious hypokalemia and nephrotoxicity associated with Amphotericin B (Figure 3)[14].

Discontinuation of Maintenance Treatment

According to the new WHO guidelines, discontinuation of maintenance treatment for cryptococcal meningitis is recommended if the patient is clinically stable, adherent to both antiretroviral therapy and antifungal maintenance treatment for at least 1 year, and there is evidence of immune reconstitution[14]. If HIV RNA (viral load) testing is not available, then immune reconstitution in this context is defined as a CD4 count 200 cells/mm3 or greater on 2 measurement 6 months apart. If HIV RNA testing is available, immune reconstitution can be defined as a CD4 count 100 cells/mm3 or greater on two measurements 6 months apart AND an undetectable HIV RNA level (Figure 4). The WHO recommends that maintenance treatment should not be discontinued in children less than 2 years of age. Furthermore, maintenance therapy should be restarted if the CD4 count drops to less than 100 cells/mm3 in adults, or less than 25% (or 750 cells/mm3) for children, or if a WHO stage 4 clinical event occurs regardless of patient age or CD4 count.

Prevention of Cryptococcal Disease

Multiple placebo-controlled randomized trials of prophylactic therapy against cryptococcal meningitis have been performed in patients with advanced AIDS[23,24,25,26,27]. A meta-analysis of these studies reported decreased incidence of cryptococcal disease in patients who received prophylactic therapy, but no statistically significant difference in mortality [28]. A randomized controlled trial of HIV-infected patients in Uganda with negative cryptococcal antigen tests (most of whom were on antiretroviral therapy) similarly found that fluconazole prophylaxis was associated with a decreased incidence of cryptococcal meningitis, but no mortality benefit[29]. On the basis of these findings, the 2011 WHO guidelines do not recommend the routine use of primary prophylaxis against cryptococcal meningitis in antiretroviral therapy-naïve HIV-infected individuals with a CD4 less than 100 cells/mm3 and either a negative or unknown CrAg test, unless prolonged delay or no access to antiretroviral therapy is likely. However, in settings with a prevalence of cryptococcal antigenemia greater than 3%, which includes most sub-Saharan African and Southeast Asian countries, the WHO recommends routine screening with a serum or plasma CrAg test for HIV-infected adults (not children) with an absolute CD4 count less than 100 cells/mm3, and, for those individuals who test positive for CrAg, evaluation for cryptococcal disease and possible initiation of anti-fungal therapy[14].

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    Figure 1. WHO Recommendations on the Treatment of Cryptococcal Disease in HIV-infected persons.

    Source: This figure is adapted from World Health Organization. Rapid Advice: Diagnosis, prevention and management of Cryptococcal disease in HIV-infected adults, adolescents and children. Geneva; World Health Organization. December 2011.


    Figure 1
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    Figure 2. WHO Recommendations on the timing of ART initiation for Cryptococcal and HIV co-infected persons.

    Source: This figure is adapted from World Health Organization. Rapid Advice: Diagnosis, prevention and management of Cryptococcal disease in HIV-infected adults, adolescents and children. Geneva; World Health Organization. December 2011.


    Figure 2
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    Figure 3. WHO recommendations for amphotericin B toxicity prevention, monitoring, and management.

    Source: This figure is adapted from World Health Organization. Rapid Advice: Diagnosis, prevention and management of Cryptococcal disease in HIV-infected adults, adolescents and children. Geneva; World Health Organization. December 2011.


    Figure 3
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    Figure 4. WHO Recommendations for the Discontinuation of Treatment Maintenance for Cryptococcal Disease.

    Source: This figure is adapted from World Health Organization. Rapid Advice: Diagnosis, prevention and management of Cryptococcal disease in HIV-infected adults, adolescents and children. Geneva; World Health Organization. December 2011.


    Figure 4