Version May 2024
INTRODUCTION — Cryptococcal meningoencephalitis is a serious opportunistic infection that is seen primarily among patients with untreated AIDS [1]. The initial preferred approach to the patient with cryptococcal meningoencephalitis includes combination antifungal therapy with amphotericin B plus flucytosine (for the induction phase of therapy) followed by fluconazole (for the consolidation and maintenance phases). During therapy, patients should be monitored for recurrence of clinical symptoms that may suggest increased intracranial pressure, relapse of infection (from lack of adherence or drug resistance), adverse events related to antifungal therapy, and immune recovery syndromes secondary to antiretroviral therapy (ART).
This topic is devoted to clinical monitoring of the HIV-infected host with cryptococcal meningoencephalitis. Topic reviews that discuss the epidemiology, clinical manifestations, diagnosis, and treatment of disease are found elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Immune reconstitution inflammatory syndrome" and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
MONITORING ON THERAPY
Monitoring for drug toxicity
Amphotericin B — Infusion-related reactions, particularly nausea, vomiting, chills, and rigors, are common with intravenous (IV) amphotericin B deoxycholate administration and usually occur either during infusion (within 15 minutes to 3 hours following initiation) or immediately following administration of the dose. Patients with infusion-related reactions may be pretreated with acetaminophen, diphenhydramine, or corticosteroids administered approximately 30 minutes before infusion. (See "Pharmacology of amphotericin B", section on 'Infusion-related reactions'.)
Amphotericin B is associated with renal insufficiency, hypokalemia, hypomagnesemia, hypocalcemia, and hypophosphatemia. Thus, patients treated with amphotericin B should have daily monitoring of serum creatinine and electrolytes. Many patients require significant amounts of potassium and/or magnesium supplementation during therapy and hydration with normal saline during amphotericin B infusions. A more detailed discussion of the adverse effects of amphotericin is presented elsewhere. (See "Pharmacology of amphotericin B", section on 'Adverse effects'.)
A lipid-based formulation of amphotericin B has become the preferred polyene in resource-available environments and should be specifically used for patients who develop renal insufficiency (eg, plasma creatinine concentration exceeds 2.5 mg/dL) while receiving amphotericin B deoxycholate or if there are concerns about having to interrupt induction therapy due to toxicity. If this is not possible, the dose of amphotericin B deoxycholate can be reduced by 50 percent or given every other day. It is critical that there is no interruption of the combination regimen during the two-week induction period. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Induction therapy'.)
Flucytosine — The most significant toxicities of flucytosine (5-FC) are hematologic. In particular, leukopenia and thrombocytopenia can limit its use, although dose reduction may ameliorate hematologic toxicities.
In addition, renal dysfunction caused by the concomitant administration of nephrotoxic agents, such as amphotericin B, can lead to flucytosine accumulation and further contribute to dose-related toxicity [2]. Thus, dose reduction is required for patients with renal insufficiency. Dosing recommendations for flucytosine are found elsewhere. (See "Pharmacology of flucytosine (5-FC)", section on 'Dosing'.)
Ideally, serum drug levels of flucytosine should be monitored in patients with renal insufficiency [3] (see "Pharmacology of flucytosine (5-FC)", section on 'Serum concentration monitoring'). However, since flucytosine levels are not readily available in many clinical settings, monitoring for bone marrow toxicity with a thrice weekly complete blood count can act as a surrogate of drug accumulation. For example, dose reduction or discontinuation of flucytosine should be considered when the absolute neutrophil count declines to <500 cells/microL or the platelet count drops below 75,000/microL. (See "Pharmacology of flucytosine (5-FC)", section on 'Renal dysfunction'.)
Approximately 5 percent of patients develop elevations in serum hepatic aminotransferases or alkaline phosphatase. Gastrointestinal complaints such as nausea, vomiting, and diarrhea also occur.
Fluconazole — A minority of patients develop rash while receiving fluconazole. Monitoring of aminotransferases is suggested in patients on long-term therapy. The risk of drug-induced liver injury increases with high doses (eg, >800 mg daily). Alopecia and chapped lips have been reported following long courses of high-dose fluconazole, but they are reversible after drug discontinuation. Drug-drug interactions can indirectly cause toxicity issues with this azole. A more detailed discussion of adverse reactions related to fluconazole is found elsewhere. (See "Pharmacology of azoles", section on 'Adverse effects'.)
Laboratory monitoring for fungal infection
Sterilization of cerebrospinal fluid — We repeat a lumbar puncture (LP) for fungal culture after two weeks of induction antifungal therapy to confirm sterilization of the cerebrospinal fluid (CSF), even among patients who have clinically improved. The opening pressure should also be measured at that time. (See 'Monitoring of intracranial pressure' below.)
However, in resource-limited settings, it may be difficult to obtain a repeat LP. Guideline recommendations from the World Health Organization state that routine LP to monitor the response to induction therapy is not needed in middle- and low-income countries if the patient has evidence of clinical recovery [4].
For those receiving a regimen that uses a shortened duration of amphotericin B, we suggest an LP be done to assess the response sometime between 7 and 14 days after the last dose of polyene therapy. For those who have a positive culture, we would repeat induction therapy with the standard two-week regimen of amphotericin B plus flucytosine (table 1).
The evaluation and management of patients with positive cultures are found below. (See 'Initial approach' below and 'Management of persistent or relapsing infection' below.)
The impact of repeat LP in guiding the transition to consolidation therapy is presented separately. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Consolidation therapy'.)
Monitoring of serum cryptococcal antigen — We do not perform serial monitoring of serum cryptococcal antigen (CrAg) in patients being treated for cryptococcal meningoencephalitis. Changes in CrAg titer do not correlate with clinical improvement during induction or consolidation therapy [5].
However, we monitor serum CrAg in patients who have discontinued maintenance therapy if their CD4 count is <200 cells/microL. Maintenance therapy can be discontinued in patients receiving antiretroviral therapy if they have received at least one year of antifungal therapy and have attained both a CD4 count >100 cells/microL and virologic suppression for at least three months. In the absence of virologic monitoring, maintenance therapy should be continued for one year and until the CD4 count is >200 cells/microL. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Maintenance therapy'.)
The frequency and duration of CrAg monitoring in patients who have discontinued maintenance therapy is unclear. We measure the serum CrAg when maintenance therapy is discontinued and then every three months after that until the CD4 count is >200 cells/microL. We restart maintenance doses of fluconazole (ie, 200 mg daily) in asymptomatic patients who meet the following criteria:
●The CrAg becomes detectable (ie, serum CrAg was negative at end of treatment).
●There is a ≥4-fold rise in the CrAg titer compared with the end-of-treatment level.
Patients who develop symptoms should be reassessed for clinical disease. (See 'Evaluation for treatment failure' below.)
Monitoring of intracranial pressure — Patients with AIDS and cryptococcal meningoencephalitis tend to have a high fungal burden in the CSF, which can lead to increased intracranial pressure (ICP) (defined as >20 cm CSF) [3,6-12]. Most patients have signs and symptoms consistent with increased ICP (eg, headache, clouding of sensorium, visual and hearing loss, ataxia, cranial nerve palsies, and papilledema) [6,8-14]; however, some individuals are asymptomatic and, therefore, difficult to assess clinically.
The mechanism of increased ICP in cryptococcal meningoencephalitis is not completely understood. Potential etiologies include increased vascular permeability secondary to cytokine-induced inflammation and clogging of arachnoid villi with fungal antigen and/or yeasts, leading to impairment of CSF resorptive function [13]. One autopsy study demonstrated infiltration of Cryptococcus, inflammatory infiltrates, and fibrosis within arachnoid cells [15].
When to measure the ICP — The intracranial pressure (ICP) should be measured at the time of the initial LP. Untreated increased ICP can cause significant morbidity, permanent neurologic disability, or mortality [13]. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in patients with HIV", section on 'Diagnosis'.)
●After the initial LP, the ICP is typically measured when repeat fungal cultures are obtained after two weeks of induction therapy. (See 'Sterilization of cerebrospinal fluid' above.)
●A repeat LP and measurement of ICP should be performed sooner in patients who have persistent symptoms during induction therapy, especially if they are severe or worsening. This is particularly important if the baseline ICP was elevated or not measured.
●A repeat LP and measurement of ICP should also be performed in any patient who has recurrent symptoms after initial improvement. (See 'Evaluation for treatment failure' below.)
The management of patients with increased ICP and/or persistent symptoms is discussed below. (See 'Management' below and 'Management of IRIS' below and 'Management of persistent or relapsing infection' below.)
Management — Increased ICP in patients with cryptococcal meningoencephalitis should be managed aggressively to decrease mortality [16,17]. The initial management of patients with increased ICP is presented in a separate topic review. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Management of increased intracranial pressure'.)
A patient who has a continued requirement for serial LPs for management of increased ICP after appropriate antifungal therapy will likely need a permanent ventriculoperitoneal shunt [13,18]. This device should ideally be placed after the patient has completed the induction course of antifungal therapy (ie, while the patient is receiving consolidation or maintenance therapy) [14,16,19].
Increased ICP has been associated with persistently positive cultures and an increased risk of mortality. As an example, in one large trial, 93 percent of deaths that occurred within the first two weeks of therapy were associated with increased ICP [6,18].
EVALUATION FOR TREATMENT FAILURE — During treatment, there may be three different outcomes:
●Successful induction and consolidation antifungal therapy with switch to ongoing maintenance therapy with clinical improvement.
●Successful induction and consolidation antifungal therapy followed by recurrent symptoms during maintenance therapy, consistent with either culture-positive relapse of infection or an immune reconstitution inflammatory syndrome (IRIS).
●Unsuccessful induction or consolidation with antifungal therapy with persistent documentation of viable Cryptococcus in the cerebrospinal fluid (CSF) for four weeks or longer; this outcome should prompt questions regarding adherence, drug resistance, or poor host response. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Consolidation regimen'.)
The evaluation of patients with possible treatment failure will be discussed in this section. The management of patients with persistent or relapsed infection is discussed below. (See 'Management of persistent or relapsing infection' below.)
Initial approach — Treatment failure can be seen in asymptomatic patients who have a positive culture on routine lumbar puncture (LP) performed after induction therapy and in patients with persistent or new symptoms.
●Asymptomatic patients – Asymptomatic patients with a persistent positive CSF culture should be assessed for adherence to the antimicrobial regimen. In addition, drug resistance testing should be performed on the CSF isolate from the repeat LP that demonstrated persistent infection and compared to the original isolate. (See 'Drug resistance testing' below.)
●Patients with persistent or new symptoms – In patients with symptoms (eg, headache) that are persistent or arise after initial clinical improvement, an LP should be performed to rule out the possibility of increased intracranial pressure (ICP) and assess for fungal growth. (See 'When to measure the ICP' above.)
•If the patient has initiated antiretroviral therapy (ART), increased ICP and pleocytosis in the setting of a sterile culture and/or negative polymerase chain reaction (PCR) test are most likely related to paradoxical IRIS. (See 'Immune reconstitution inflammatory syndrome' below.)
•Increased ICP may also be due to persistent or relapsed fungal infection as suggested by a positive culture. Antifungal drug resistance testing should be performed on the isolate from the repeat LP. (See 'Drug resistance testing' below and 'Management of persistent or relapsing infection' below.)
It is important assess and address barriers to adherence (eg, lack of understanding for implications of untreated disease, psychosocial issues, adverse side effects) in all patients with persistent or relapsing infection. Patients who have difficulty taking their medications as prescribed should also have HIV virologic testing to confirm virologic control since they are also at risk for developing resistance to their ART regimen.
Drug resistance testing — To assess for antifungal resistance, an on-treatment cryptococcal isolate should be obtained and evaluated for changes in the minimum inhibitory concentration (MIC) against the antifungal agent that is being administered. It should also be compared to the original (pre-treatment) isolate; specifically, a threefold increase in MIC from the pretreatment isolate to the on-treatment isolate would suggest emerging drug resistance [20]. An absolute MIC of ≥16 mcg/mL for fluconazole or ≥32 mcg/mL for flucytosine for a single isolate may also be suggestive of drug resistance; however, there remains no precise in vitro susceptibility break point for strain resistance in cryptococcosis.
MANAGEMENT OF PERSISTENT OR RELAPSING INFECTION — Management of persistent or relapsing infection depends upon the potential cause (eg, adherence, drug resistance, or poor host response). As examples:
●Relapsing infection with susceptible isolate – If no drug resistance is documented, the patient should undergo repeat induction/consolidation therapy followed by maintenance fluconazole at the usual dose with close follow-up to monitor adherence.
●Relapsing or persistent infection with drug-resistant isolate – When drug resistance is a concern or documented during consolidative therapy, the optimal approach is unclear. The use of alternative therapies may be reasonable, such as voriconazole (200 to 400 mg twice daily), posaconazole tablets (loading dose of 300 mg every 12 hours on the first day, followed by 300 mg daily), or isavuconazole (loading dose of 200 mg every eight hours for six doses, followed by 200 mg daily); however, the use of these agents is based on limited data from case series [3,21-23]. Prior to initiation, the in vitro susceptibility of the recent isolate must be evaluated to all antifungal agents and compared with the initial or pre-treatment isolate.
●Persistent/refractory disease – In patients with a positive culture after two weeks, additional therapy is indicated before transitioning to consolidation therapy. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Consolidation therapy'.)
We typically continue treatment with a preferred combination induction therapy regimen (table 1) and repeat an LP after two more weeks to evaluate for culture sterility. However, if the patient is asymptomatic and never had any issues with elevated intracranial pressures, it is reasonable to treat with a two-week course of high-dose fluconazole (1200 mg a day for those with normal renal function) followed by another LP.
However, some patients have refractory disease (eg, positive cultures and no apparent direct resistance by in vitro testing after four weeks of therapy) despite optimal antifungal management and subsequent initiation of ART. For patients with refractory culture-positive cryptococcal disease on ART for greater than four weeks, adjunctive immunologic therapy using interferon gamma at 100 mcg subcutaneously three times per week in combination with antifungal therapy may be beneficial [24,25]. Interferon gamma has not been used in any large trials for refractory disease, but when used as part of initial induction therapy for cryptococcal meningitis, it has been shown to significantly augment the fungicidal activity of standard therapy [24,25]. The duration of interferon gamma adjunctive therapy has been used for as long as ten weeks, and it has not been shown to adversely affect underlying HIV infection. We would use interferon gamma until the cerebrospinal fluid is sterilized, or for ten weeks, whichever comes first.
Management of increased intracranial pressure is also important in patients with persistent or relapsing infection, as described above. (See 'Management' above.)
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME — Immune recovery with potent antiretroviral medications is key to the management of patients with cryptococcal meningoencephalitis. However, the initiation of antiretroviral therapy (ART) can also lead to complications such as immune reconstitution inflammatory syndrome (IRIS). To reduce this risk, ART should be started between 2 and 10 weeks after antifungal therapy has been initiated. Deciding when to initiate ART within this window depends in part upon the clinical setting and is discussed in detail elsewhere. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'When to initiate antiretroviral therapy'.)
However, even with delayed ART, IRIS can still occur. This section will review the clinical manifestations and management of patients with IRIS.
General background — The term "immune reconstitution inflammatory syndrome" (IRIS) describes a collection of inflammatory disorders associated with paradoxical worsening of a pre-existing treated infectious process following the initiation of potent ART in HIV-infected individuals [26-32]. If immune function improves rapidly following the commencement of ART, systemic or local inflammatory reactions may occur at the site or sites of the pre-existing infection (unmasking). According to one meta-analysis, IRIS occurred in approximately 13 percent of all immunosuppressed patients initiating ART, but occurred with increased frequency among those with cryptococcal disease (ie, 20 percent) [33]. The inflammatory reaction is usually self-limited, especially if the pre-existing infection is effectively treated. However, long-term sequelae and fatal outcomes may occur, particularly when the inflammatory reaction occurs within the central nervous system (CNS). (See "Immune reconstitution inflammatory syndrome".)
Symptoms and signs — Certain patients who have experienced an initial clinical improvement on antifungal therapy will develop symptoms of cryptococcal IRIS after initiating ART, potentially leading to significant morbidity and mortality [33,34]. These symptoms can be localized to the CNS and are related to increased intracranial pressure (ICP):
●Headache
●Nausea and vomiting
●Decreased alertness
Additional non-CNS manifestations can include lymphadenopathy, pneumonitis, or ocular manifestations. Cryptococcosis is a disseminated infection; thus, paradoxical IRIS manifestations can reflect previously silent areas of disseminated infection.
Most cases of cryptococcal IRIS occur within the first three months after ART is initiated; however, late presentations (up to 10 months after ART is started) have also been reported [35-37]. A repeat lumbar puncture (LP) typically demonstrates sterile cerebrospinal fluid (CSF) cultures, reduced CrAg titers and negative polymerase chain reaction (PCR) results, and an inflammatory response that may be greater than baseline [36].
Management of IRIS — Most minor signs of immune reconstitution inflammatory syndrome (IRIS) resolve spontaneously after days to a few weeks.
However, symptomatic patients with CSF pleocytosis and increased ICP are at risk for herniation. Serial LPs are important in managing increased ICP and should be performed until stabilization of symptoms and normalization of ICP occurs; the exact timing of LP is determined on a case-by-case basis. Sometimes a lumbar drain or ventriculoperitoneal shunt is required. (See 'Monitoring of intracranial pressure' above.)
We and other experts also use glucocorticoids to treat patients with symptomatic increased ICP related to IRIS based upon case reports and extrapolation from other disease processes [34,38]. Since there are no controlled trials examining the use of glucocorticoids for IRIS, the dose and duration of treatment are unclear. We typically initiate 0.5 to 1 mg/kg of prednisone daily (or equivalent) and then taper the dose over two to six weeks [3]. A good alternative is to administer a dexamethasone taper, such as the one that is used for the treatment of tuberculous meningitis [38]. (See "Central nervous system tuberculosis: Treatment and prognosis", section on 'Glucocorticoids'.)
Sometimes it is unclear if the patient has IRIS or relapsed infection. In that setting, the approach to treatment must be individualized, and it may be reasonable to administer glucocorticoids and escalate antifungal therapy until the cultures are finalized. Such patients should be managed in conjunction with an infectious diseases specialist.
We do not routinely administer glucocorticoids at the start of cryptococcal meningoencephalitis treatment (which is often done in patients with tuberculous meningitis). Glucocorticoids do not appear to reduce the risk of IRIS, they can have a negative impact on the killing of yeasts in the CSF, and they can produce increased morbidity [39]. (See "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention", section on 'Overview'.)
There are minimal data regarding the successful role for nonsteroidal anti-inflammatory agents or immunosuppressive biologicals such as anti-tumor necrosis factor inhibitors to control inflammation [40]. These therapies are typically used in the management of refractory IRIS.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Cryptococcosis" and "Society guideline links: Opportunistic infections in adults with HIV".)
SUMMARY AND RECOMMENDATIONS
●Treatment – Cryptococcal meningoencephalitis is a serious opportunistic infection that is seen among patients with untreated advanced AIDS. The management of cryptococcal meningoencephalitis involves combination antifungal therapy (table 1), and is discussed in detail separately. (See 'Introduction' above and "Cryptococcus neoformans meningoencephalitis in persons with HIV: Treatment and prevention".)
●Monitoring for drug toxicity – The antifungal drugs used in the treatment of cryptococcal meningoencephalitis can be associated with significant toxicity, particularly amphotericin B and flucytosine. Close laboratory monitoring is needed for renal insufficiency, hematologic abnormalities, and electrolyte disturbances during induction therapy. (See 'Monitoring for drug toxicity' above.)
●Evaluating response to therapy – For most patients, a lumbar puncture (LP) should be performed after two weeks of induction therapy to confirm sterilization of the cerebrospinal fluid (CSF) and to reassess intracranial pressure (ICP). We do not monitor serum cryptococcal antigen during treatment, since changes in this laboratory parameter do not correlate with clinical improvement. (See 'Laboratory monitoring for fungal infection' above and 'Monitoring of intracranial pressure' above.)
●Monitoring ICP – For patients with persistent symptoms, or new symptoms after initial clinical improvement, an LP should be performed to rule out the possibility of increased ICP. Increased ICP may be related to the immune reconstitution inflammatory syndrome (IRIS) among patients who have initiated antiretroviral therapy, or due to persistent or relapsing infection, as suggested by a positive culture. (See 'Monitoring of intracranial pressure' above.)
●Approach to treatment failure – For patients with persistent or relapsing cryptococcal infection, the clinical management depends upon the suspected cause (eg, poor adherence, drug resistance, refractory disease). (See 'Evaluation for treatment failure' above and 'Management of persistent or relapsing infection' above.)
●Management of IRIS – For patients with IRIS, most minor signs resolve spontaneously after days to a few weeks. However, symptomatic patients with CSF pleocytosis and increased ICP are at risk for herniation. For such patients, serial LPs should be performed until stabilization of symptoms and normalization of ICP occurs. In addition, we suggest glucocorticoids (Grade 2C). Although the dose and duration are unclear, we typically initiate 0.5 to 1 mg/kg of prednisone (or equivalent) daily and then taper the dose over two to six weeks. (See 'Management of IRIS' above.)
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