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.[,] Among HIV-infected persons, several cryptococcal serotypes cause disease, but Cryptococcus neoformans is responsible for the vast majority of cases . In recent years, the Pacific Northwest has seen the emergence of Cryptococcus gattii as a significant cause of meningitis in that region, but most cases have not involved HIV-infected persons. 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 meningitiis. 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.
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. 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). 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.[,] 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. 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. 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.[,]
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 25 cm H2O and 27% had an opening pressure greater than 35 cm H2O (Figure 2). In addition, those patients with opening pressure of at least 25 cm H2O had higher CSF cryptococcal antigen titers and higher frequency of positive CSF India ink smears. 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
Key components involved in the therapy of cryptococcal meningitis in AIDS patients consist of (1) antifungal therapy, (2) lowering of elevated intracranial pressure (if present), and (3) management of immune reconstitution syndrome (IRIS) 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. 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.[,] In the acute setting, the management of elevated opening pressure plays a critical role in reducing mortality of AIDS patients with cryptococcal meningitis. Most HIV-infected patients diagnosed with acute cryptococcal meningitis have advanced immunosuppression and will need to start on antiretroviral therapy. Unfortunately, patients with cryptococcal meningitis may develop IRIS after starting antiretroviral therapy. To lessen the chance of developing severe IRIS, initiating antiretroviral therapy is usually deferred for at least 2 weeks after initiating antifungal therapy therapy.[,] The treatment of C. gattii is the same as for C. neoformans.
Induction Therapy for Cryptococcal Meningitis
Based on the 2013 United States Guidelines for the Prevention and Treatment of Opportunistic Infection, the preferred induction therapy regimen consists of liposomal amphotericin B (AmBisome) 3 to 4 mg/kg IV daily plus flucytosine (5-FC, Ancobon) 100 mg/kg PO daily in 4 divided doses, given for at least 14 days (Figure 3). The recommendation to use liposomal amphotericin B over standard amphotericin B is based on several studies that found liposomal amphotericin B at least as effective as standard amphotericin B and less likely to cause nephrotoxicity.[,] The recommendation to include flucytosine in the treatment regimen is based on results from a randomized, controlled trial that showed patients who received amphotericin B plus flucytosine had higher rates of cerebrospinal fluid sterilization and lower rates of relapse than those who received amphotericin B alone. A number of alternative regimens are recommended based on studies showing good efficacy in clinical trials.[,,,] For patients who can not tolerate or do not adequately respond to an amphotericin-based regimen, fluconazole 400 to 800 mg PO or IV daily with flucytosine is considered an alternative.[,,] The echinocandins do not have adequate 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 should undergo close monitoring of renal function and serum chemistries. Patients receiving flucytosine can develop gastrointestinal and bone marrow toxicity; flucytosine levels should be monitored, with peak levels (taken 2 hours after a dose) with a target level of 30 to 80 mcg/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 CSF opening pressure of 25 cm H2O or greater correlates with decreased short-term survival. In a retrospective study, investigators characterized the laboratory and clinical course of HIV-infected patients with cryptococcal meningitis in relation to CSF opening pressure (Figure 4). Some patients underwent serial lumbar punctures in an attempt to reduce CSF pressure. Those patients who had stable CSF pressure (reduced by more than 10 cm or whose CSF pressure did not change) had fewer clinical failures than those who had a CSF pressure increase by more than 10 cm H2O. Patients with opening pressure greater than 25 cm 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 20 cm H2O, or by 50% if it is extremely high and can't be reduced to less than [,,] In addition, patients with increased CSF pressure 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 may 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 20 cm H2O or higher, the investigators terminated the study prematurely because of more serious adverse events in the group receiving acetazolamide. 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.
Consolidation and Maintenance Therapy for Cryptococcal Meningitis
Regardless of the regimen used for induction therapy, all patients require consolidation and maintenance therapy. Prior to switching to consolidation therapy, the patient should have received at least 2 weeks of induction therapy, obtained substantial clinical improvement, and have a negative CSF fungal culture on repeat lumber puncture. The preferred consolidation regimen consists of fluconazole 400 mg PO once daily for at least 8 weeks (Figure 5). 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 once daily. Prior to the use of potent antiretroviral therapy, 37% of patients who did not take maintenance therapy relapsed compared with 3% of those who received fluconazole. Clinical trials of maintenance therapy have shown that fluconazole is superior to itraconazole or amphotericin B.[,]
Cryptococcal Meningitis IRIS
Overall, an estimated 20 to 40% of patients with cryptococcal meningitis will develop IRIS at some point 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.[,] 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 resemble the initial presentation of cryptococcal meningitis. Thus, patients on therapy who develop recurrent meningitis symptoms should undergo repeat lumbar puncture and have CSF studies performed and opening pressure measured. In a study that evaluated patients with IRIS and those with relapsed cryptococcal meningitis, patients 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 versus 4 cells/mm3), and higher CSF opening pressure (45 versus 31 mm H2O). 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. With severe IRIS, some experts recommend using a course of corticosteroids, typically starting with prednisone (or a prednisone equivalent) 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. Patients with elevated CSF pressure may require repeat lumbar punctures (as outlined above for the management of increased intracranial pressure).
Timing for Initiating Antiretroviral Therapy
For patients diagnosed with cryptococcal meningitis who are not on antiretroviral therapy, the timing of when to initiate antiretroviral is a critical question. In the Cryptococcal Optimal Antiretroviral Trial (COAT) trial, patients in Uganda diagnosed with acute cryptococcal meningitis were randomized to receive early antiretroviral therapy (1 to 2 weeks diagnosis) or delayed antiretroviral therapy (5 weeks after diagnosis). Patients in the deferred therapy group had a significantly lower mortality rate than those in the early therapy group (30% versus 45%) and lower incidence of cryptococcal IRIS (13% versus 20%). In addition, patients who had CSF white blood cell count with fewer than 5 leukocytes/mm3 had particularly high mortality rates when they received early antiretroviral therapy. The 2013 opportunistic infections guidelines recommend waiting at least 2 weeks to initiate antiretroviral therapy in patients with severe acute cyptococcal meninigits (elevated intracranial pressure). Based on the findings from the COAT trial, many experts would consider deferring antiretroviral therapy for at least 4 to 5 weeks, if possible.[,]
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. 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. In a 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. Based on the available data and expert experience, the 2013 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 and received at least 1 year of azole maintenance therapy, (2) the patient has no symptoms of cryptococcosis, (3) the patient is taking n antiretroviral therapy and has an undetectable HIV RNA level for at least 3 months, and (4) the patient's CD4 count is 100 cells/mm3 or greater. Patients should restart maintenance therapy if their CD4 count declines again to less than 100 cells/mm3.