HIV-associated cryptococcal meningitis

Introduction While the incidence of cryptococccal meningitis in the developed world has declined with widespread, early antiretroviral therapy (ART), cryptococcal disease remains a major opportunistic infection and leading cause of mortality in patients infected with HIV in much of the developing world. Most HIV-related cases are caused by Cryptococcus neoformans var. grubii (serotype A), while var. neoformans (serotype D) is responsible for a proportion, especially in Europe, and there are a small number of Cryptococcus gatti infections (formerly C. neoformans serotypes B and C) [1,2]. The last includes a small number of cases in HIV-infected individuals forming part of an unprecedented outbreak of C. gattii infections, predominantly in apparently immunocompetent patients, on Vancouver Island, Canada [3,4]. C. neoformans is distributed worldwide. An ubiquitous environmental saphrophyte, it is found in soil contaminated with pigeon droppings and has also been isolated from the heartwood of several tree species in South America [5] and India [6], and from the homes of African HIV-seropositive patients [7,8]. Exposure may be common [9], although the exact circumstances are usually unclear. Inhalation of small, thinly encapsulated yeasts, or basidiospores [10], may lead to an initial pulmonary infection, which, depending on host immune response and the number and virulence of the organisms, is cleared, contained within granulomata as a latent infection or disseminates. The minority in whom disease disseminates typically have defects in T cell function, through malignancy, immunosuppressive medication, autoimmune disease or sarcoidosis [11,12] or HIV infection, indicating the role of T cell-mediated immunity in host defence. In HIV-seropositive patients, most episodes of cryptococcal meningitis probably represent reactivation of latent infection, which may have been acquired many years earlier. There is compelling evidence for latent infection in a rat model [13] and humans [14]. Dromer and colleagues [15] typed C. neoformans isolates from HIV-seropositive patients diagnosed with cryptococcosis in France, some of whom were from Africa but had lived in France for a median of over 9 years. There was a significant clustering of isolates from African compared with European patients, suggesting that the patients had acquired their isolates long before the development of clinical disease. A proportion of HIV-related cases, however, may result from dissemination of new or primary infection [16], as has been observed in the recent outbreak of C. gattii infection in British Columbia [17]. HIV-associated cryptococcal meningitis usually presents as a subacute meningo-encephalitis in profoundly immunosuppressed patients (CD4 cell counts < 100 cells/μl), with malaise, headache, fever and, later, visual disturbance and altered mental status. Signs, if present, may include meningism, papilloedema, cranial nerve palsies [particularly sixth nerve palsies reflective of raised pressure in cerebrospinal fluid (CSF)] and reduced conscious level. The diagnosis is usually straightforward. The high organism load in this setting means the sensitivity of India ink staining of CSF is high. Those who have a negative result with India ink can be diagnosed by highly sensitive and specific cryptococcal antigen testing of CSF, or serum if CSF cannot be obtained [18]. Lumbar puncture often reveals markedly elevated opening pressures, an important complicating factor, with only modestly elevated or normal white cell counts (usually lymphocytes), elevated protein and low or normal glucose. High organism burden at baseline (indicated by quantitative CSF culture or CSF antigen titre) and abnormal mental status are the most important predictors of death [19,20], while high opening pressures and a poor inflammatory response in the CSF have also been associated with poor outcome [19,21,22]. Autopsy series reveal the lack of a protective granulomatous response in HIV-seropositive patients with cryptococcal meningitis. There is extensive involvement of brain parenchyma in addition to meningitis and higher organism burdens (which are predominantly extracellular) compared with the infection in HIV-seronegative individuals [23–25]. The remainder of this review will focus on the current epidemiology and management of HIV-associated cryptococcal meningitis, with some emphasis on the developing world where the burden of disease is highest. In addition to antifungal therapy, the important complications of elevated CSF pressure and immune reconstitution inflammatory syndrome (IRIS) and future approaches to prevention and therapy are discussed. Epidemiology Increasing numbers of cases of cryptococcal meningitis were reported in young adults in the former Zaire throughout the 1960s, possibly representing the first signs of the evolving HIV epidemic [26,27]. The late 1970s and early 1980s saw a sharp increase in the numbers of cases both in Kinshasa [28,29] and in Zairian immigrants to Europe [30–32], many of whom had, in retrospect, features suggestive of AIDS [33]. As the HIV epidemic expanded in the 1980s, C. neoformans emerged as an important opportunistic infection in the United States, Europe and Australia, occurring in 5–10% of all AIDS patients [34–38]. Rates of infection declined through the 1990s, initially with the widespread and frequent use of azoles to treat candidiasis [38,39], and subsequently with the introduction of HAART [40,41]. The annual incidence in AIDS patients in Atlanta fell from 66 per 1000 in 1992 to 7 per 1000 in 2000 [41]. HIV-related cryptococcal meningitis is now a problem in the West in patients who present with late-stage HIV infection, typically those with limited access to healthcare [40,41]. However, it remains a major opportunistic infection in the developing world in areas of high HIV seroprevalence [42,43]. C. neoformans is the leading cause of meningitis in central and southern Africa, accounting for 26.5% of cases in a series from Malawi [44], 31% in a series from the Central African Republic [45] and 45% from Zimbabwe [46]. In these areas, it is one of the main causes of mortality in cohorts of HIV-infected individuals, responsible for 13–44% of all deaths [47–49]. For comparison, 5–13% of deaths were attributed to tuberculosis in these studies. In Thailand, cryptococcosis accounts for up to 20% of AIDS-defining illnesses [43,50] and it is reported as a major opportunistic infection in India [51] and Brazil [52]. There are interesting geographical variations in incidence that presumably relate to differential rates of exposure. For example, cryptococcal disease appears to be more common in southern and east Africa than in west Africa [53], and in north and northeast Thailand compared with southern Thailand [43]. Even with current optimal treatment, the 10-week mortality of HIV-associated cryptococcal meningitis is high, ranging from 10 to 25% in developed countries, with no evidence of any decrease in recent years [54]. Of note, mortality is higher in less selected series [55] compared with clinical trails in which very sick patients are excluded [21]. In unselected series from resource-poor settings, acute mortality is up to 43% even with amphotericin B therapy [56]. In Zambia, median survival with low-dose fluconazole monotherapy was 19 days [57], barely better than that in the absence of antifungal therapy [57–59]. In South Africa, in a recent unselected prospective series [60], overall 10-week mortality was 37% despite initial treatment with amphotericin B for most patients and access to ART (Fig. 1).Fig. 1: Prospective observational study of survival of 54 patients with HIV-associated cryptococcal meningitis treated according local protocol (49 with amphotericin B 1 mg/kg daily, 5 with fluconazole) in Cape Town South Africa. Patients not already taking antiretroviral therapy at the time of presentation were started on therapy from 4 weeks after antifungal therapy. (From data in Bicanic et al. [60].)However, this last study also confirmed that, once over the acute cryptococcal infection and established on ART, the long-term outlook is good, as in the developed country setting, with a levelling of the survival curve. Therefore, in the setting of expanding access to ART across the developing world, the urgent challenge is to improve acute management and thereby increase the proportion of patients surviving the critical initial months. Antifungal therapy Current antifungal treatment guidelines (Table 1; [61,62]) are based in large part on the results of a large, randomized trial published a decade ago [21]. Initial therapy was with amphotericin B (0.7 mg/kg daily) with or without flucytosine (100 mg/kg daily) for 2 weeks, followed by an 8-week consolidation phase with either fluconazole (400 mg daily) or itraconazole (400 mg daily). The rationale was to gain control of infection with initial more rapidly active amphotericin B-based therapy but switch to well-tolerated azoles for consolidation treatment to minimize the dose-dependent toxicity of amphotericin B. The mortality was the lowest of any published trial, at 9.4% in the first 10 weeks. The addition of flucytosine was associated with a trend towards a higher proportion of patients with sterile CSF at 2 weeks and reduced relapse. Fluconazole was superior to itraconazole for consolidation treatment [21]. That the combination of amphotericin B plus flucytosine is more rapidly fungicidal than amphotericin B alone has been demonstrated in a subsequent study in Thailand using serial quantitative cultures to assess the rate of clearance of cryptococcal colony-forming units from the CSF or early fungicidal activity. The clearance of cryptococci from CSF was significantly faster with amphotericin B plus flucytosine than with amphotericin B alone, amphotericin B plus fluconazole (at 400 mg daily ) or a combination of all three (Fig. 2[20]).Table 1: Antifungal treatment recommendations for HIV-associated cryptococcal meningitisa.Fig. 2: Fall in Cryptococcus neoformans colony-forming units (CFU) in cerebrospinal fluid (CSF) over time by treatment group. The decrease in log CFU/ml CSF per day was calculated for each patient using the slope of the linear regression of log CFU against time. For each treatment group, early fungicidal activity (EFA) is shown as the mean (±SD) rate of fall in log CFU. EFA was significantly greater for amphotericin B (AmB) plus flucytosine compared with AmB alone (P < 0.001), AmB plus fluconazole (P = 0.02), or triple therapy with AmB, flucytosine and fluconazole (P = 0.02). (Adapted from Brouwer et al. [20], with permission).Both these studies also demonstrated that, with appropriate monitoring, conventional amphotericin B is reasonably well tolerated, with drug discontinuations in 3% of patients in the first 2 weeks in the Mycoses Study Group trial [21]. Saline and fluid loading equivalent to 1 litre normal saline daily should be given unless contraindicated, to minimize nephrotoxicity [63], and electrolytes replaced as required. Anaemia, secondary to suppression of erythropoietin transcription [64], is also a predictable side effect of amphotericin B [65–67]. This may be more clinically significant in populations with lower baseline haemoglobin levels, and where transfusion, when occasionally needed, is difficult. Flucytosine, at the historically low daily dose of 100 mg/kg, was also well tolerated without real-time drug level monitoring in either trial. A substudy of the Thai trial comparing oral and intravenous flucytosine at the same daily dosage of 100 mg/kg has provided some insight into this observation. In contrast to earlier studies in other patient populations, oral bioavailability of flucytosine in these patients at a late stage of HIV infection was only around 50%, resulting in relatively low serum concentration, of an order not usually associated with toxicity. Nevertheless, despite the lower serum levels, patients on oral formulation had the same rate of clearance of infection as those on intravenous formulation [68], consistent with evidence for the dose-independent activity of flucytosine [69–71]. The data suggest that even 100 mg/kg daily, if given intravenously, may be in excess of that required for maximal additional fungicidal activity. If renal impairment does develop, liposomal amphotericin B, at 3 mg/kg daily, provides a less nephrotoxic and equally effective alternative. A small study suggested liposomal amphotericin B, at 4 mg/kg daily, was more active than conventional amphotericin B [72], but a larger study found no difference in the proportion of patients with sterile CSF at 2 weeks in patients receiving daily liposomal amphotericn B at 3 or 6 mg/kg compared with conventional amphotericin B at 0.7 mg/kg daily [73]. Unfortunately, in many resource-poor settings, amphotericin B is not available or cannot be used safely because of lack of monitoring, and fluconazole, widely available, through a free access programme or in generic form, is the only treatment option. Outcomes with initial fluconazole monotherapy at 200–400 mg daily have not been good, either in early US-based studies [19,74], including a small randomized study in which 400 mg daily was clinically inferior to amphotericin B plus flucytosine [74], or in more recent series from Africa [57,75,76]. Although the earlier randomized study comparing amphotericin B with fluconazole found no significant difference in clinical outcomes, time to sterilization was very long for fluconazole (median 64 days), and outcomes for both drugs were poor [19]. Furthermore, the dosages used for both drugs were lower than currently recommended, making interpretation difficult. The 10-week mortality of approximately 50% with initial fluconazole monotherapy reported by Schaars and colleagues [75] in South Africa represents a minimum estimate in this setting given the retrospective nature of the study with incomplete out-patient follow up. Recent work from Cape Town has demonstrated that 400 mg fluconazole daily is essentially fungistatic over the first 2 weeks of treatment [60]. The resulting prolonged period with a high viable organism load may predispose to the development of fluconazole resistance. Such resistance is a significant problem when initial therapy is with fluconazole [77]. A further concern is that prolonged active infection could also increase the risk of immune reconstitution reactions (see below) following introduction of ART, although data on this point are studies suggest a with fluconazole There is a linear with fluconazole at up to 2 daily and up to mg daily have in small numbers of patients In addition there is a of a in of the time to sterilization of with a median time to CSF sterilization of 64 days with 200–400 mg daily a mean time of days with 400 mg daily [74], and and days with mg this and given the results of treatment at lower a study of fluconazole therapy is currently in In the in where amphotericin B cannot be used safely and fluconazole is the only the suggest a dose of at mg daily (Table The combination of fluconazole plus flucytosine is or in although not in a study in A clinical study in suggested with addition of flucytosine to fluconazole, although the dose of fluconazole was low mg daily) and in a small series from the United States, the combination of flucytosine and fluconazole at 400 mg daily in a relatively median time to sterilization of CSF of although side with the combination frequent to the fungicidal activity and toxicity of this combination with higher of fluconazole are in where intravenous amphotericin B-based therapy is not While not as at conventional as amphotericin B for initial therapy, fluconazole is highly effective and as therapy Increasing evidence of this secondary is if there has been a significant and immune reconstitution with ART (CD4 cell for 6 cerebrospinal fluid opening pressure raised pressure is a major problem in cryptococcal meningitis, with over of patients pressures and a pressures in an of the last Study Group CSF pressure was associated with more cranial nerve and raised CSF pressure usually as headache, papilloedema, and of impairment and level of The leading to pressure are Although a inflammatory response is not a of HIV-associated cryptococcal meningitis, it is a role in some factor, a of has been in the CSF of patients with cryptococcal disease although no of this and CSF opening pressure has been the primary is to be of CSF at the because of the of and [23–25]. This be consistent with the of raised pressure with higher CSF antigen and higher rates of India ink and it usually remains as there is no pressure the and the CSF over the of the In of have been recommendations are based on small series and Current guidelines suggest daily for all patients with elevated baseline opening pressures with the of CSF to pressures by 50%, pressure has been normal for several days The of CSF that is to at a puncture is but is probably If or of the should be to initial puncture or if raised CSF pressure on therapy in order to cases of and In the cases in which a should be to control pressure and the is CSF can be with a less is long the in CSF but it may be that a significant proportion of patients will to relatively with a the of high of fluid daily) to a pressure are relatively to and have a low risk of complications with monitoring and and who are with their use The use of and for raised CSF pressure is not by available evidence A randomized trial of was early and were associated with higher mortality in patients with elevated CSF pressures in a large, although study meningitis immune reconstitution syndrome As has been with other opportunistic infections of ART can lead to of immune to viable or or in can lead to a clinical with the of cryptococcal disease or of treated has been reported in of patients with cryptococcal meningitis following of ART and may be In the the median time to of after ART was days however, cases have been reported after many include and with the of meningitis of have been by a higher CSF white cell and also higher opening pressures for cryptococcal include higher cryptococcal antigen at or widely disease and ART within 1 of antifungal therapy The diagnosis of cryptococcal is one of the following this ART and clinical presentation evidence of immune in cell of or resistance to fluconazole, a clinical features new or CSF white cell or consistent with an cell-mediated immune response negative cryptococcal cultures The role of is less in when cryptococcal cultures are but it is that immune reconstitution also to the presentation and of some patients who are culture [77]. The of cryptococcal has for the of The increase in the risk of cryptococcal with earlier of ART has to be against the risk of other HIV-related complications if of ART is of ART may be earlier in developing where rates of death to of ART are high currently most ART from 4 weeks into antifungal therapy, although it is earlier ART may be if a rapidly fungicidal is used for initial antifungal therapy. of cryptococcal is further If clinical despite appropriate antifungal therapy and management of any raised CSF which have been used in can be and The for primary antifungal is as access to ART the immune reconstitution with in the absence of ART, or in those who to to treatment, a for primary with fluconazole in those with cell counts < 100 in areas with a high incidence of cryptococcal disease Such a was in Thailand to widespread of ART and is in east Africa. In areas of high in of the significant proportion of patients now after ART [60], a can also be for with serum antigen to ART in order to and treat infection before it is by immune However, studies are needed, and a is not and is not used in areas of lower incidence for the high mortality of HIV-related cryptococcal disease include the of current antifungal therapy, access to some drugs in many areas the problem of raised CSF pressure and the lack of data on optimal of As are to some of these access to antifungal fluconazole is widely available through a free access programme and in generic In although generic amphotericin B is also available, the is and may be significant in very In has been an in some areas, including the United to the reduced for amphotericin B for other infections in the developed world. is a and that is not widely available either in Africa or where the burden of cryptococcal disease is high. one the drug to In where are not flucytosine can be obtained on a patient from If currently comparing fluconazole with flucytosine as a drug to with amphotericin B that flucytosine remains the drug of is to access to The rate of clearance of infection, or early fungicidal from serial quantitative cultures of CSF provides a means by which the activity of new drugs or for antifungal therapy can be in small numbers of this for testing in phase to be selected on a more Such clearance studies are to 1 mg/kg amphotericin B daily is associated with a significant increase in fungicidal activity compared with 0.7 mg/kg daily, and to flucytosine and fluconazole as a drug to with amphotericin B. studies are also with new azoles with activity against C. as although with and antiretroviral are a model data and into the central for and are shown in Of note, have limited activity because which are not important in the cryptococcal cell 2: on activity of and in the of current antifungal and over further drug there is in A against the of neoformans has phase studies and a against protein and reported to be when given with amphotericin B in candidiasis also has activity against C. in cryptococcal meningitis are An is use of There is evidence that is important for clearance of cryptococcal infection in HIV-infected patients A trial that therapy was and well tolerated, with no on HIV load or cell There was also a trend towards outcomes, with of negative cultures at 2 weeks compared with or of those receiving The trend in of was already after 2 weeks of treatment, and studies have shown that in the CSF at day 3 and is by day suggesting that of which be more to may be studies to cryptococcal for development and to the in the of as those with HIV infection

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