Question | Discussion | References | CME Credit

Case 1: Discussion - Cryptococcal Meningitis

Case Summary

Laboratory studies on the patient in this case subsequently showed a positive serum cryptococcal antigen (1:1028), a positive cerebrospinal fluid (CSF) cryptococcal antigen (1:512), and growth of Cryptococcus neoformans in fungal cultures from the CSF 7 days later. Given the high opening pressure observed on lumbar puncture, therapy for this patient requires effective antifungal therapy and careful management of the elevated intracranial pressure, including serial lumbar punctures. The following discussion will address key issues related to the diagnosis and treatment of cryptococcal meningitis in patients with AIDS.

Background and Epidemiology

Cryptococcal meningitis is the most common life-threatening fungal infection among HIV-infected persons and patients are at risk for this infection when their CD4 count declines to less than 100 cells/mm3[1,2]. Four serotypes of C. neoformans can cause human disease, but serotypes A and D (Cryptococcus neoformans var. neoformans) cause the vast majority of disease in HIV-infected persons. In recent years, the Pacific Northwest has seen the emergence of Cryptococcus neoformans var. gattii as a significant cause of meningitis in that region, but most cases have not involved HIV-infected persons[3]. Cryptococcus neoformans is often found in abundant quantity in soil contaminated with pigeon droppings, but the primary environmental source for transmission to HIV-infected patients remains unclear. Available data suggest that HIV-infected persons acquire infection via inhalation of C. neoformans organisms. Cryptococcal meningitis occurs at a disproportionately higher rate among AIDS patients who are black, male, or injection-drug users, but the reason for these epidemiologic differences remains unknown. Prior to the widespread use of potent antiretroviral therapy, approximately 5 to 8% of HIV-infected patients in the U.S. developed cryptococcal meningitis[4]. Although the incidence of cryptococcal meningitis has markedly declined in HIV-infected patients, the 3-month mortality rate still exceeds 10% among those who develop acute cryptococcal meningitis[5].

Clinical Manifestations of Cryptococcal Meningitis

Clinicians should maintain a high index of clinical suspicion for the diagnosis of cryptococcal meningitis in patients with a CD4 count less than 100 cells/mm3 who develop central nervous system symptoms, particularly if accompanied by systemic symptoms. In HIV-infected individuals, cryptococcal meningitis occurs as a result of disseminated infection and typically manifests with a more indolent presentation than acute bacterial meningitis[4]. Most patients with early cryptococcal meningitis develop non-specific symptoms consisting of fever and headache, and up to 75% have absence of classic signs of meningeal irritation (Figure 1)[2]. As the disease progresses, patients typically develop more neurologic-specific manifestations, including altered mental status, neck stiffness, or cranial nerve abnormalities. Approximately 10% of patients with disseminated cryptococcal disease will have cutaneous manifestations, which may resemble the lesions of molluscum contagiosum. Patients can also develop pulmonary cryptococcal disease, with or without central nervous system involvement.

Diagnosis of Cryptococcal Meningitis

Among patients with cryptococcal meningitis, the serum cryptococcal antigen test is positive in more than 95%, with titers often greater than 1:2048[6,7]. A positive serum cryptococcal antigen, however, is not sufficient to diagnose central nervous system infection and all patients with suspected cryptococcal meningitis should undergo lumbar puncture. Most experts would recommend performing a brain CT in all AIDS patients who will undergo lumbar puncture because of the increased likelihood of patients having a brain mass lesion and the potential for brain herniation triggered by the lumbar puncture. Cerebrospinal fluid analysis should include cryptococcal antigen, fungal culture, glucose, protein, cell count with differential, Gram's stain, and bacterial culture. India ink smears can detect cryptococcal organisms, but this test is less sensitive and specific than the cryptococcal antigen test. More than 50% of patients with cryptococcal meningitis have fewer than 20 leukocytes/mm3 observed on the CSF cell count[2]. Thus, when evaluating patients with advanced AIDS, clinicians should not exclude the diagnosis of cryptococcal meningitis with a low or normal CSF leukocyte count. The CSF glucose and protein levels are abnormal in about 40% of cases, but usually do not contribute significantly in making the diagnosis. More than 50% of patients with cryptococcal meningitis will have positive blood cultures for C. neoformans[4]. The CSF cryptococcal antigen test has a sensitivity of greater than 95%, but false negative tests can occur. Serial measurement of cryptococcal antigen titers to gauge treatment response does not have any proven benefit[8,9].

Evaluation of CSF Opening Pressure

At the time of the lumbar puncture, all patients with suspected cryptococcal meningitis should have CSF opening pressure measured. In one study, among 221 patients who had a pre-treatment CSF opening pressure measured, 54% had an opening pressure greater than 250 mm H2O and 27% had an opening pressure greater than 350 mm H2O (Figure 2)[10]. In addition, those patients with opening pressure of at least 250 mm H2O had higher CSF cryptococcal antigen titers and higher frequency of positive CSF India ink smears[10]. Although clinical signs and symptoms of increased intracranial pressure occurred more frequently in patients with an increased opening pressure, some patients with markedly increased CSF pressure do not manifest obvious neurological signs that would suggest increased intracranial pressure. Thus, increased intracranial pressure can occur in the absence of obvious clinical clues.

General Principles of Therapy for Cryptococcal Meningitis

The components involved in the therapy of cryptococcal meningitis in AIDS patients consist of (1) antifungal therapy, (2) lowering of elevated intracranial pressure (if present), (3) use of antiretroviral therapy to improve immune function, and (4) management of immune reconstitution syndrome if it develops. The prognostic factors that predict death during initial therapy are altered mental status, CSF cryptococcal antigen titer greater than 1:1024, and CSF fluid leukocyte count less than 20 leukocytes/mm3[11]. Prompt and effective antifungal therapy for acute cryptococcal meningitis significantly decreases mortality. The antifungal therapy is divided into three phases: (1) induction therapy given for at least 14 days, (2) consolidation therapy for 8 weeks, and (3) long-term maintenance therapy[4,5]. The general approach to the antifungal management of cryptococcal meningitis is to utilize the most potent and effective regimen for induction therapy and then step down to a less potent, but safer regimen for consolidation and maintenance therapy. In the acute setting, the management of elevated opening pressure plays a critical role in reducing mortality of AIDS patients with cryptococcal meningitis. Since most HIV-infected patients who present with cryptococcal meningitis have advanced immunosuppression and are not taking antiretroviral medications (or have poorly controlled HIV RNA levels because of resistance to the regimen they are taking), initiating antiretroviral therapy (or switching to an effective salvage regimen) to improve the patient's overall immune function is an important goal. Unfortunately, patients with cryptococcal meningitis may develop immune reconstitution inflammatory syndrome (IRIS) after starting antiretroviral therapy. The optimal timing for initiating antiretroviral therapy remains unknown, but most experts recommend deferring antiretroviral therapy for 2 to 10 weeks after initiating antifungal therapy therapy[4,5].

Induction Therapy for Cryptococcal Meningitis

Based on the 2009 United States Guidelines for the Prevention and Treatment of Opportunistic Infection, the preferred induction therapy regimen (Figure 3) consists of amphotericin B (Amphocin, Fungizone) 0.7 mg/kg IV daily plus flucytosine (5-FC, Ancobon) 100 mg/kg PO daily in 4 divided doses, given for at least 14 days[4]. The recommended addition of flucytosine to amphotericin B is based on results from a randomized, controlled trial that showed patients who received amphotericin B plus flucytosine had higher rate of cerebrospinal fluid sterilization and lower rates of relapse than those who received amphotericin B alone[7]. Studies have shown very effective results with lipid formulations of amphotericin B, including liposomal amphotericin B (AmBisome) and amphotericin B lipid complex (Abelcet), and these lipid amphotericin preparations can substitute for conventional amphotericin B[12,13], particularly in patients with renal insufficiency or those likely to develop renal insufficiency[4,10]. Based on available data, the recommended dosing for lipid formulations of amphotericin B is 4 to 6 mg/kg IV daily given with flucytosine[4]. The combination of amphotericin B plus fluconazole is less effective than amphotericin B plus flucytosine, but superior to amphotericin alone[14]. In addition, in a randomized, controlled trial, amphotericin B plus flucytosine was superior to fluconazole (Diflucan)[15]. Fluconazole 400 to 800 mg PO or IV daily with flucytosine is considered an alternative regimen regimen[5,16] for patients who do not tolerate or do not adequately respond to an amphotericin-based regimen. The echinocandins—anidulafungin (Eraxis), caspofungin (Cancidas), and micafungin (Mycamine)—do not have activity against C. neoformans and should not be used to treat cryptococcal meningitis. Patients receiving amphotericin preparations have significant risk of developing nephrotoxicity and electrolyte disturbances and thus should undergo close monitoring of renal function and serum chemistries. Many experts recommend infusing 500 mL of normal saline prior to amphotericin B to reduce the risk of nephrotoxicity[4]. Patients receiving flucytosine can develop gastrointestinal and bone marrow toxicity; flucytosine levels should be monitored, with peak levels (taken 2 hours after a dose) should not exceed 75 ?g/ml. With renal impairment, the flucytosine dose needs adjustment.

Management of Elevated Intracranial Pressure

In addition to appropriate induction antifungal therapy for cryptococcal meningitis, immediate management of elevated intracranial pressure can markedly improve patient outcomes. Several studies have shown that increased CSF opening pressure correlates with decreased short-term survival[10]. In a retrospective study, investigators characterized the laboratory and clinical course of patients with cryptococcal meningitis in relation to CSF opening pressure (Figure 4)[10]. Some patients underwent serial lumbar punctures in an attempt to reduce CSF pressure[10]. Those patients who had their CSF pressure reduced by more than 10 mm or whose CSF pressure did not change had fewer clinical failures than those who had a CSF pressure increase by more than 10 mm. Patients with opening pressure greater than 250 mm H2O should have removal of approximately 20 to 30 ml of CSF with the goal of reducing the opening pressure to a normal pressure of less than 200 mm H2O, or or by 50% if it is extremely high[7,8]. In addition, these patients should have repeat daily lumbar puncture performed with drainage of 20 to 30 ml of CSF until the opening pressure stabilizes in a normal range for 3 or more consecutive days. In some instances, when serial lumbar puncture has failed, patients require placement of a ventriculoperitoneal shunt or lumbar drain to control increased central nervous system pressure. In a double-blind, placebo-controlled trial of oral acetazolamide for 22 patients with cryptococcal meningitis and an opening pressure of 200 mm H2O or higher, the investigators terminated the study prematurely because of more serious adverse events in the group receiving acetazolamide[17]. In addition, there is no evidence that mannitol or corticosteroids provide any clear benefit in the management of increased intracranial pressure in HIV-infected patients with cryptococcal meningitis[5].

Consolidation and Maintenance Therapy for Cryptococcal Meningitis

Regardless of the regimen used for induction therapy, all patients require consolidation therapy. Prior to switching to consolidation therapy, the patient must have substantial clinical improvement and a negative CSF fungal culture on repeat lumber puncture[4]. The preferred consolidation regimen (Figure 5) consists of fluconazole 400 mg PO daily for 8 weeks. Itraconazole (Sporanox) is considered an acceptable alternative to fluconazole, but clearly is less effective. The newer triazoles, voriconazole (Vfend) and posaconazole (Noxafil), have activity against C. neoformans, but are not recommended because of insufficient data. After 8 weeks of consolidation therapy, the patient should step down to maintenance therapy. The preferred maintenance therapy consists of fluconazole 200 mg PO daily. Prior to the era of highly active antiretroviral therapy (HAART), 37% of patients who did not take maintenance therapy relapsed compared to 3% of those who received fluconazole[18]. Clinical trials of maintenance therapy have shown fluconazole superior to itraconazole[19] or amphotericin B[20].

Cryptococcal Meningitis IRIS

Overall, an estimated 20 to 40% of patients with cryptococcal meningitis will develop immune reconstitution inflammatory syndrome after starting antiretroviral therapy. Factors present at the time of the diagnosis of cryptococcal meningitis associated with enhanced risk of developing immune reconstitution include absence of prior antiretroviral therapy, higher baseline HIV RNA levels, CSF cryptococcal antigen titer greater than 1:1024, CSF white blood cell count less than or equal to 25 leukocytes/mm3, and CSF protein less than or equal to 50 mg/dl[21,22]. The onset of cryptococcal meningitis-associated IRIS is highly variable, with a median of about 2 months after initiating meningitis treatment. Clinical manifestations of IRIS resembles the initial presentation of cryptococcal meningitis, including fever, headache, and altered mental status[21]. Thus, patients on therapy who develop recurrent meningitis symptoms need to undergo repeat lumbar puncture and have CSF studies performed (to sort out whether they have IRIS or a relapsed infection), and have measurement of opening pressure. In a study that evaluated patients with IRIS and those with relapsed cryptococcal meningitis, those with IRIS presented earlier after starting therapy (59 versus 165 days), had greater decreases in HIV RNA levels (-2.27 vs. -0.15 log10copies/ml), had greater median CD4 count increases (93 vs. 4 cells/mm3, and had higher CSF opening pressure (45 vs. 31 mm H2O ) on lumbar puncture[21]. In addition, patients with IRIS usually have negative CSF fungal cultures, whereas patients with relapse have positive CSF cryptococcal culture. Further, the finding of a significant lowering of HIV RNA levels and a substantial increases in CD4 cell count serve as a surrogate marker of probable patient adherence with cryptococcal therapy. In general, patients diagnosed with IRIS should continue on antifungal therapy and antiretroviral therapy[4]. With severe IRIS, a course of corticosteroids is warranted; typically starting with prednisone (or a prednisone equivalent) 0.5 to 1.0 mg/kg day and tapering over 2 to 6 weeks, with the pace of the taper based on the patient's clinical course[5]. Patients with elevated CSF pressures, may require repeat lumbar punctures (as outlined above for the management of increased intracranial pressure). The National Institute of Allergy and Infectious Diseases recently announced the discontinuation of patient enrollment in the Cryptococcal Optimal ART Timing (COAT) trial[26], a study performed in Africa that involved subjects with acute cryptocococcal meningitis randomized to receive early antiretroviral therapy (7 to 10 days after starting treatment for cryptococcal meningitis or delayed antiretroviral therapy (at least 4 weeks after starting treatment for cryptococcal meningitis).  The study was stopped due to higher mortality rates among the subjects who received early antietroviral therapy versus those who received deferred therapy.

Discontinuing and Restarting Maintenance Therapy

Prior to the availability of potent antiretroviral therapy, maintenance therapy for cryptococcal meningitis was recommended for life. Investigators in Europe reported no cases of cryptococcal meningitis in 39 patients on effective antiretroviral therapy who discontinued fluconazole maintenance therapy after their CD4 exceeded 200 cells/mm3 for at least 6 months[23]. A similar study from Thailand also showed safe discontinuation of maintenance therapy in 60 patients on antiretroviral therapy, but this study required patients to have an undetectable HIV RNA and a CD4 count greater than 100 cells/mm3 for at least 3 months[24]. In a more recent retrospective trial, 100 patients with a history of cryptococcal meningitis and a CD4 count greater than 100 cells/mm3 discontinued maintenance therapy; after a mean time of 28 months, 4 patients had relapse of cryptococcal disease[25]. Based on the available data and expert experience, the 2009 opportunistic infections guidelines state it is reasonable to discontinue long-term maintenance therapy when the following three conditions are met: (1) the patient has successfully completed a course of initial therapy for cryptococcal meningitis, (2) the patient has no symptoms of cryptococcosis, and (3) the patient's CD4 count is 200 cells/mm3 or higher for at least 6 months in response to effective antiretroviral therapy[4]. In addition, some experts recommend performing a lumbar puncture and documenting negative CSF cultures prior to stopping maintenance therapy. Patients should restart maintenance therapy if their CD4 count declines to less than 200 cells/mm3.

[Back to Case 1 Question | See Case 1 References]

CME Credit | Back to Top

  • The following link will open in a new window.
    Figure 1. Clinical Manifestations of Patients with Cryptococcal Meningitis at the Time of   Diagnosis

    Abbreviations: MS = mental status; CN = cranial nerve

    The graph represents the clinical manifestations of 65 patients from France at the time of diagnosis of cryptococcal meningitis. The mean CD4 count at the time of diagnosis was 46 cells/mm3. Data from Darras-Joly C, Chevret S, Wolff M, et al. Cryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus. Clin Infect Dis. 1996;23:369-76.


    Figure 1
  • The following link will open in a new window.
    Figure 2. Cerebrospinal Fluid Opening Pressure in Patients with Cryptococcal Meningitis at   the Time of Diagnosis

    This graph represents data from 221 patients with cryptococcal meningitis who had CSF opening pressure measured prior to receiving therapy. The investigators defined a normal CSF opening pressure as less 190 mmH2O. Data from Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47-54.


    Figure 2
  • The following link will open in a new window.
    Figure 3. Induction Therapy for Cryptococcal Meningitis

    Abbreviations: IV = intravenous; qd = once daily; bid = twice daily

    Serum flucytosine levels should be drawn 2 hours after dose and optimal levels are between 30-80 ug/ml.

    Source: Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 3
  • The following link will open in a new window.
    Figure 4. Outcome Related to Change in CSF Opening Pressure in Patients with Cryptococcal   Meningitis

    The graph represents outcomes of 161 patients with AIDS and cryptococcal meningitis who had lumbar puncture with opening pressure measured prior to therapy and 2 weeks after treatment. The investigators defined clinical failure as persistent or worsening signs and symptoms of cryptococcal meningitis after 2 weeks of therapy; mycologic failure was defined as positive CSF culture after 2 weeks of therapy. Data from Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis. 2000;30:47-54.


    Figure 4
  • The following link will open in a new window.
    Figure 5. Consolidation and Maintenance Therapy for Cryptococcal Meningitis

    Abbreviations: IV = intravenous; qd = once daily; bid = twice daily

    Serum flucytosine levels should be drawn 2 hours after dose and optimal levels are between 30-80 ug/ml.

    Source: Kaplan JE, Benson C, Holmes KK, et al. Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. MMWR Recomm Rep. 2009;58(RR-4):1-207.


    Figure 5