EPIDEMIOLOGY AND CLINICAL PRESENTATION
Despite increasing access to ART, the mortality and morbidity related to cryptococcal disease remains very high in many resource-limited centres [2,3], and CM-IRIS remains a significant contributor to this cryptococcal disease burden [4,5].
Paradoxical cryptococcal immune reconstitution inflammatory syndrome
Paradoxical CM-IRIS occurs in between 6% and 45% of patients with HIV-associated cryptococcal meningitis who survive to start ART [6–18]. Most cases occur 1–2 months post-ART initiation [4,6,8,10–12,16,19–21,22▪▪], although cases have been reported after 8 or 9 months of ART, and occasionally even later [15,23] (Table 2). The variation in reported incidence and timing reflects in part differences in disease severity and organism burden at presentation and timing of ART initiation, but also the lack of standardized definitions of CM-IRIS, and the difficulties of making what is often a diagnosis of exclusion. Alternative diagnoses may be hard to substantiate where investigations, especially microbiological tests, are very limited, and the real danger is that CM-IRIS cases are overestimated based simply on this failure to recognize common alternative diagnoses when they occur.
In the largest prospectively followed cohort, including 170 South African patients with cryptococcal meningitis, all treated with amphotericin B induction therapy and ART initiated a median of 31 days after antifungal therapy, IRIS developed in 13% a median of 29 days after starting ART . A recent study from Thailand reported similar results, with 13 of 101(13%) cryptococcal meningitis patients initially treated with amphotericin B developing IRIS a median of 63 days post-ART initiation . Higher rates of IRIS were seen in a cohort of 101 cryptococcal meningitis patients in Uganda, again initially treated with amphotericin B, in which 30% developed CM-IRIS with central nervous system (CNS) manifestations, and an additional 15% developed non-CNS IRIS manifestations, a median of 8.8 weeks after ART initiation .
Paradoxical CM-IRIS usually presents as an aseptic meningitis [1▪▪,10,12,22▪▪]. Raised opening pressure is common [12,15] and a number of studies have shown a more inflammatory cerebrospinal fluid (CSF) in CM-IRIS compared with initial cryptococcal meningitis episodes, with raised white cell counts (WCC), raised CSF protein [22▪▪] and reduced CSF glucose levels . Other CNS manifestations including cryptococcomas have been reported [1▪▪,10], along with a wide range of non-CNS manifestations, such as lymphadenitis [1▪▪,8,10,22▪▪,26–28], pneumonitis [1▪▪,10,29], soft tissue, skin, bone and joint lesions [1▪▪,13,30,31], and choreoretinitis [32,33].
Mortality due to CM-IRIS ranges from 0 to 36% [3,6,8–12,14–16,18] (Table 2). It is likely that appropriate management, including aggressive treatment of raised intracranial pressure, can improve outcomes, and emerging evidence suggests that mortality due to CM-IRIS is low if recognized and managed early [8,11,21]. Although CM-IRIS was found to be an independent predictor of mortality in the Ugandan cohort described above (hazard rate for death 2.3) , the recent prospective cohort studies in both South Africa and Thailand found no differences in mortality between patients who did and did not develop IRIS [9,12], and overall the contribution of IRIS to mortality in patients initiating ART is negligible .
Unmasking cryptococcal immune reconstitution inflammatory syndrome
In sub-Saharan Africa, between 20% and 33% of all cryptococcal cases now present for the first time after initiation of ART [3,19,35]. The contribution of IRIS to these presentations is difficult to ascertain. While many of these cases may have developed regardless of ART initiation in patients who are profoundly immunosuppressed, some cases may be precipitated or exacerbated by ART-related immune restoration. Given the difficulty of differentiating IRIS from progression of untreated subclinical infection, recent consensus definitions suggest referring to both as ‘ART-associated’ cryptococcal meningitis [1▪▪]. The majority of these ART-associated cryptococcal meningitis cases develop within the first 2 months of ART [1▪▪,3,36,37], and clinical presentations are similar to cryptococcal meningitis developing prior to ART [1▪▪,3]. Bisson et al.  in Botswana, in an adjusted analysis, reported a lower in-hospital mortality in these post-ART cases compared with ART-naïve cryptococcal meningitis patients; however, in two series from Cape Town, the clinical manifestations of cryptococcal meningitis presenting before or after ART initiation were similar [3,19]. Despite the fungal load (based on % CSF India Ink positive, and CSF CFU counts) being lower in patients presenting on ART, the acute mortality was the same in the two groups . The longer term, 1-year, survival of those on ART at presentation was, however, considerably higher .
Three factors have consistently been found to be associated with the development of CM-IRIS: poor baseline inflammatory response, rapid immune reconstitution from this low baseline, and a high organism or antigen burden. In keeping with other forms of IRIS, initial studies reported an association between profound immune suppression at baseline, as evidenced by low CD4 cell counts, and subsequent development of CM-IRIS. Later work has confirmed and better characterized this association, demonstrating that poor inflammatory responses at the site of infection in the CNS at baseline are predictive of subsequent IRIS. Low CSF WCC and protein levels during the initial cryptococcal meningitis episode are associated with later IRIS [21,22▪▪,38]; and patients who go on to develop IRIS have lower levels of CSF interferon (IFN)γ, tumour necrosis factor (TNF)α, interleukin (IL)-2, IL-6, IL-8 and IL-17 at baseline compared with cryptococcal meningitis patients who do not develop IRIS [21,22▪▪,38]. A similar picture of low TNFα production at baseline has been observed in serum , although in contrast to the CSF findings, baseline levels of serum IL-4 and IL-17 are elevated in patients who subsequently develop IRIS .
Closely related to this paucity of inflammation, high organism burden at baseline has been shown to be a strong risk factor for the subsequent development of IRIS. Fungaemia, high cryptococcal antigen (CRAG) titres in both serum and CSF, and high CSF quantitiative culture counts are all significantly associated with the development of IRIS [10,16,21,37,38], as is the rate of clearance of infection during initial antifungal therapy . The resultant fungal burden following antifungal induction therapy and prior to ART initiation is of key importance, with increasing evidence to show that the risk of developing cryptococcal IRIS is far greater if the CSF is not sterile following 2 weeks of treatment, or at ART initiation [7,9,21,22▪▪].
Thus ART timing is probably important in relation to organism/antigen load: early studies suggested that earlier ART initiation (within 1–2 months) increased the risk of CM-IRIS [16,18]. Although no association between earlier ART initiation and subsequent IRIS was seen subsequently in cohorts in Thailand , South Africa  or Uganda [10,23], this may relate to relatively uniform approaches to the timing of ART within these cohorts. Randomized studies of ART timing are discussed below (see Prevention section).
The rate of immune restoration is also of importance, with several studies demonstrating more rapid CD4 count increases and viral load reductions on ART in patients who develop IRIS compared with those who do not .
The pathogenesis of CM-IRIS is still not well understood. A recovery of pathogen specific T-cell responses is thought to be the primary driver of the inflammatory reaction , but only a minority of patients who experience ART-mediated immune restoration develop IRIS. Pathophysiological changes happen long before the IRIS event becomes clinically apparent, with poor baseline immune responses and defective antigen clearance during the initial cryptococcal meningitis episode, followed by the development of an aberrant inflammatory reaction to persisting antigen. It has been hypothesized that a persistently elevated cryptococcal antigen level following initiation of ART leads to increased pro-inflammatory signalling from antigen-presenting cells, with a lack of effective antigen clearance due to the absence of adequate T-cell help, and secondary activation of the coagulation cascade [40▪]. Raised IL-6, probably from macrophages [10,40▪,41,42], and C-reactive protein levels have been demonstrated in cryptococcal meningitis patients after starting ART, and are a strong risk factor for development of IRIS . Once a sufficient T-cell response develops, an excessive inflammatory response evolves, described as a ‘cytokine storm’ [40▪] characterized by the production of Th1-type cytokines, such as IFNγ and TNFα [38,40▪,43,44]. The host and pathogen factors leading to the initial paucity of inflammatory response to cryptococcus that appears critical for the development of IRIS are not known. Earlier suggestions that cryptococcal IRIS pathogenesis is due to an imbalance of homeostatic mechanisms between effector and regulatory T cells during immune recovery have not be borne out by later studies, with no evidence of decreased regulatory cell numbers in IRIS versus non-IRIS patients .
The pathophysiology of ‘unmasking’ IRIS is even less well understood. No differences in levels of CSF inflammation have been convincingly demonstrated in populations of patients developing cryptococcal meningitis on and off ART [3,35], probably reflecting the heterogeneity of the patients with ART-associated cryptococcal meningitis, in whom the contributions of IRIS is highly variable.
DIAGNOSIS AND MANAGEMENT
There are no controlled clinical trials addressing the management of paradoxical CM-IRIS, and current advice is necessarily based on expert opinion and case reports. A pragmatic approach is outlined below, based largely on our experience of prospectively studying 523 patients enrolled in phase II trials . In cryptococcal meningitis patients representing with symptomatic relapse after initiation of ART, it is imperative to exclude alternative explanations and diagnoses: firstly, noncompliance with, or failure to prescribe, maintenance fluconazole . Patients with significant headache should have a lumbar puncture to measure CSF opening pressure, check CSF fungal culture status, and look for alternative diagnoses, notably rare cases of concomitant cryptococcal and tuberculosis (TB) meningitis . For patients with systemic manifestations, alternative microbiological diagnoses should be sought. While awaiting results in-patients may be re-induced with amphotericin B-based therapy, if available, and otherwise high-dose fluconazole. ART is continued. If the CSF is sterile, then antifungal maintenance therapy should be continued or resumed. Raised CSF pressure should be managed aggressively with careful daily therapeutic lumbar punctures. We routinely drain up to 30 ml of CSF, measuring the CSF pressure after every 10 ml removed.
For patients who are deteriorating clinically, with no alternative diagnosis, and especially if the CSF is sterile, corticosteroids should be considered: 0.5–1.0 mg/kg per day of prednisolone, or dexamethasone at higher dose for severe CNS signs and symptoms . The length and the dose of the corticosteroids, and the rate at which they are tapered should be chosen on a case-by-case basis, but a 2–6-week course is a reasonable starting point . Although cases have been reported of successful use of agents such as the anti-TNFα monoclonal adalimumab  and thalidomide , most experience, including our own, is with steroids [18,20,49,50].
If the CM-IRIS is not severe, usually disease outside the CNS, then an expectant approach is reasonable while alternative diagnoses are sought. If the diagnosis is CM-IRIS, symptoms will usually resolve spontaneously within days to weeks. In patients presenting with cryptococcal meningitis for the first time after the initiation of ART, who include those with unmasking CM-IRIS, there are as yet no data to support a different approach from that for ART-naïve patients .
There is accumulating evidence to suggest that many cases of unmasking CM-IRIS could be prevented by screening patients for sub-clinical cryptococcal infection at ART-programme entry, and that the risk of paradoxical CM-IRIS could be minimized by using rapidly fungicidal induction treatment and carefully timed ART initiation.
Prevention of paradoxical cryptococcal immune reconstitution inflammatory syndrome
The prevention of paradoxical CM-IRIS has been considered in two sections: first, ART timing and second, individualized therapy.
Antiretroviral therapy timing
Cryptococcal meningitis is a disease of the profoundly immunosuppressed, affecting patients with a median CD4 cell count of around 25 . These patients are at high risk from other opportunistic infections and HIV-associated malignancies. In a Ugandan cohort, 40% of patients died prior to starting ART and 25% of those deaths were as outpatients during workup for ART [22▪▪,23]. In our combined cohort, most deaths after the first 2 weeks were thought related to other HIV-related complications, not the cryptococcal infection . Thus, the decision as to when to start ART is a difficult balance between starting early to prevent further AIDS-defining illnesses but not so early that this benefit is outweighed by increased overall mortality secondary to increased frequency and severity of CM-IRIS.
Emerging data are helping to narrow the recommended time window for ART initiation. However, optimal timing of ART is still unclear, and timing may be individualized depending on the severity of initial cryptococcal disease, strength (fungicidal activity) of induction therapy, and setting. In AIDS Clinical Trials group study A5164, 282 patients presentating with opportunistic infection (177 pneumocystis pneumonia, 37 cryptococcal meningitis, TB was excluded) were randomized to early (median 12 days) or late ART (median 45 days). The early ART arm had fewer AIDS progression/deaths (OR = 0.51) , and there was no increase in IRIS, overall or in those who had had cryptococcal meningitis . In contrast, in Zimbabwe, in the context of weak initial antifungal therapy with fluconazole monotherapy 800 mg per day, overall mortality was much higher in patients started on ART within 3 days, compared with those in whom ART was delayed until 10 weeks .
On this background, the Cryptococcal Optimal ART Timing (COAT) study, in South Africa and Uganda, using 2 weeks of amphotericin B induction for all patients, compared ART started as an inpatient (during second week, median 8 days) versus ‘standard’ outpatient initiation at 4–5 weeks. The trial was ended early after less than 200 of the intended 500 patients had been enrolled due to a ‘substantially higher’ mortality rate amongst the patients who started ART earlier. Based on preliminary data released on the National Institute of Allergy and Infectious Diseases website, the absolute difference in the 6-month survival is approximately 15% between the two arms .
We have recently analysed our experience from a series of phase II studies in South Africa in which induction treatment was with amphotericin B. One hundred and seventy cryptococcal meningitis patients started ART a median of 31 days after initiation of antifungal therapy. IRIS developed in 13% of these patients, of whom 18% died. IRIS was associated with day 14 CSF fungal burden but not with time to ART . Interestingly, although survival was not significantly different between those who started ART before or after the median interval of 31 days, the shape of the survival curves differed suggesting that earlier ART in this combined series, from 23 days of antifungal therapy, did prevent some of the later non-cryptococcal meningitis, HIV-related deaths (Fig. 1).
Based on these incomplete data and expert opinion, guidelines have varied in recommended time windows for ART initiation: 2–4 weeks ; 2–10 weeks ; and most recently, 2–4 weeks in the context of induction with amphotericin B combination therapy, and 4–6 weeks in the context of fluconazole induction . Based on our experience and the recent COAT data, we would recommend starting ART after around 3 weeks in the setting of amphotericin B-based therapy, and 4 weeks with fluconazole induction.
As discussed above, there is consistent evidence regarding the importance of higher antigen and organism load at the time of ART initiation as a predictor of IRIS. The data reinforce the importance of rapidly fungicidal induction regimens, but also raise the possibility of customising induction treatment of cryptococcal meningitis. Plausibly, the risk of IRIS in high-risk patients (high initial organism load) could be reduced through prolongation of induction, or modest delays in ART initiation. Such a strategy may be best based on an initial determination of organism or antigen load and knowledge of the fungicidal activity of induction therapy used, rather than on determination of CSF culture conversion on follow-up lumbar puncture. Although a 2-week lumbar puncture and prolonged therapy for those whose CSF is still culture positive have been proposed , this is as yet an untried strategy, and implies prolonging induction, with the related side effects, for all patients pending culture results. This is likely to be feasible only in well resourced settings, in which facilities for CSF culture and toxicity monitoring are readily available and the incidence of opportunistic infections and mortality while delaying ART is low.
Prevention of unmasking cryptococcal immune reconstitution inflammatory syndrome
ART-associated cryptococcal meningitis usually occurs soon after ART initiation (a median of 5–6 weeks [3,19,37]), and there is evidence suggesting that screening patients for subclinical cryptococcal infection at the time of entry into ART programmes using CRAG tests is highly effective at identifying patients at risk of developing cryptococcal meningitis [36,37]. Cryptococcal antigenaemia in the blood is known to be detectable prior to disease onset [37,56,57], and a large South African study found that a negative screen for CRAG in plasma samples obtained 2 weeks prior to ART initiation is associated with a 100% negative predictive value for the development of cryptococcal meningitis in the first year of ART . In contrast, a positive CRAG screen was associated with development of cryptococcal meningitis in more than one quarter of patients and with adjusted hazards of death of 3.2 (95% confidence interval, 1.5–6.6). Other recent studies have also demonstrated that cryptococcal antigenaemia at ART initiation is a strong risk factor for early mortality in ART programmes [34,58,59].
The prevalence of asymptomatic cryptococcal antigenaemia in patients with CD4 cell counts of 100 cells/μl or less at ART programme entry in Africa and south east Asia ranges from 6 to 13% [37,58,60–64], and several prospective studies are examining the use of CRAG screening and targeted ‘preemptive’ therapy to prevent the development of severe disease in patients initiating ART. Although trial data to inform the optimal ‘preemptive’ treatment strategy in CRAG positive patients identified by screening is still lacking, both the WHO  and the South African Department of Health  have recommended that CRAG screening programmes be considered in areas of high cryptococcal disease incidence, owing to the high burden of mortality due to cryptococcal meningitis in patients initiating ART and data showing that such screening programmes would be cost-effective [62,66]. Interim guidance has been published outlining how CRAG positive patients may be treated based on current evidence, and how screening programmes could be incorporated into ART programmes [67▪,68]. Recent data suggests that CRAG screening programmes may also be beneficial and cost-effective in developed world settings [69,70], particularly in patients originating from areas with high burdens of cryptococcal meningitis, such as African-born individuals .
Although the precise immune mechanisms of CM-IRIS remain poorly understood, risk factors for the development of CM-IRIS are largely consistent across studies. These point to the need for rapidly fungicidal induction therapy, with initiation of ART when the organism and antigen load is low. Optimal timing of ART so as to minimize overall mortality and paradoxical IRIS is still not defined but recent data have narrowed the recommended time windows (2–4 weeks in the context of amphotericin B induction). Recent cohorts suggest early recognition and appropriate management can significantly reduce the impact of paradoxical CM-IRIS. Unmasking CM-IRIS is preventable through a cost-effective strategy of screening for cryptococcal antigen prior to ART and preemptive antifungal treatment for those testing positive.
Funding source: Wellcome Trust, UK.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 100).
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Keywords:Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.
AIDS; cryptococcal meningitis; cryptococcosis; HIV; immune reconstitution inflammatory syndrome; immune restoration disease; IRIS