HIV-associated cryptococcal immune reconstitution inflammatory syndrome (CM-IRIS) occurs in two forms: classical or ‘paradoxical’ IRIS in patients diagnosed with cryptococcal disease before starting antiretroviral therapy (ART), who initially improve on antifungal therapy, but then deteriorate or develop new clinical manifestations as a result of ART-mediated immune restoration; and ‘unmasking IRIS’ in patients who present with a first episode of cryptococcal disease after starting ART. Immune restoration in these cases exacerbates the clinical symptoms and signs, triggering presentation of patients with previously subclinical but active cryptococcal infection [1▪▪]. Haddow et al.[1▪▪] have recently published useful consensus definitions for paradoxical and unmasking CM-IRIS (Table 1). This review presents an overview of new developments in the understanding of the pathogenesis, prediction and prevention, and diagnosis and management of HIV-associated cryptococcal IRIS.
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).
1▪▪. Haddow LJ, Colebunders R, Meintjes G, et al. Cryptococcal immune reconstitution inflammatory syndrome in HIV-1-infected individuals: proposed clinical case definitions. Lancet Infect Dis 2010; 10:791–802.
A comprehensive review of cryptococcal IRIS, and consensus case definitions for both paradoxical and unmasking IRIS, written on behalf of the International Network for the Study of HIV-associated IRIS (INSHI).
2. Jarvis JN, Boulle A, Loyse A, et al. High ongoing burden of cryptococcal disease in Africa despite antiretroviral roll out. AIDS 2009; 23:1182–1183.
3. Jarvis JN, Meintjes G, Harrison TS. Outcomes of cryptococcal meningitis in antiretroviral naive and experienced patients in South Africa. J Infect 2010; 60:496–498.
4. Jarvis JN, Meintjes G, Williams Z, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis in South Africa: the role of inadequate secondary prophylaxis. S Afr Med J 2010; 100:378–382.
5. Asselman V, Thienemann F, Pepper DJ, et al. Central nervous system disorders after starting antiretroviral therapy in South Africa. AIDS 2010; 24:2871–2876.
6. Achenbach CJ, Harrington RD, Dhanireddy S, et al. Paradoxical immune reconstitution inflammatory syndrome in HIV-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection. Clin Infect Dis 2012; 54:424–433.
7. Chang C, Dorasamy A, Elliott J, et al.
HIV+ patients with CM who attain CSF sterility precART commencement experience improved outcomes in the first 24 weeks. 19th Conference on Retroviruses and Opportunistic Infections; March 5–8 2012; Seattle. 2012.
8. da Cunha Colombo ER, Mora DJ, Silva-Vergara ML. Immune reconstitution inflammatory syndrome (IRIS) associated with Cryptococcus neoformans infection in AIDS patients. Mycoses 2011; 54:e178–e182.
9. Bicanic T, Jarvis JN, Loyse A, et al.
Determinants of acute outcome and long-term survival in HIV-associated cryptococcal meningitis: results from a combined cohort of 523 patients. 18th Conference on Retroviruses and Opportunistic Infections; Feb 27–Mar 7 2011; Boston. 2011.
10. Boulware DR, Meya DB, Bergemann TL, et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med 2010; 7:e1000384.
11. Grant PM, Komarow L, Andersen J, et al. Risk factor analyses for immune reconstitution inflammatory syndrome in a randomized study of early vs. deferred ART during an opportunistic infection. PLoS One 2010; 5:e11416.
12. Sungkanuparph S, Filler SG, Chetchotisakd P, et al. Cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in AIDS patients with cryptococcal meningitis: a prospective multicenter study. Clin Infect Dis 2009; 49:931–934.
13. Haddow LJ, Sahid F, Moosa MY. Cryptococcal breast abscess in an HIV-positive patient: arguments for reviewing the definition of immune reconstitution inflammatory syndrome. J Infect 2008; 57:82–84.
14. Antinori S, Ridolfo A, Fasan M, et al. AIDS-associated cryptococcosis: a comparison of epidemiology, clinical features and outcome in the pre and post-HAART eras. Experience of a single centre in Italy. HIV Med 2009; 10:6–11.
15. Sungkanuparph S, Jongwutiwes U, Kiertiburanakul S. Timing of cryptococcal immune reconstitution inflammatory syndrome after antiretroviral therapy in patients with AIDS and cryptococcal meningitis. J Acquir Immune Defic Syndr 2007; 45:595–596.
16. Shelburne SA 3rd, Darcourt J, White AC Jr, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis 2005; 40:1049–1052.
17. Lawn SD, Bekker LG, Myer L, et al. Cryptococcocal immune reconstitution disease: a major cause of early mortality in a South African antiretroviral programme. AIDS 2005; 19:2050–2052.
18. Lortholary O, Fontanet A, Memain N, et al. Incidence and risk factors of immune reconstitution inflammatory syndrome complicating HIV-associated cryptococcosis in France. AIDS 2005; 19:1043–1049.
19. Bicanic T, Meintjes G, Wood R, et al. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis 2007; 45:76–80.
20. Bicanic T, Meintjes G, Rebe K, et al. Immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis: a prospective study. J Acquir Immune Defic Syndr 2009; 51:130–134.
21. Jarvis JN, Meintjes G, Rebe K, et al. Adjunctive interferon-gamma immunotherapy for the treatment of HIV-associated cryptococcal meningitis: a randomized controlled trial. AIDS 2012; 26:1105–1113.
22▪▪. Boulware DR, Bonham SC, Meya DB, et al.
Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis 2010; 202:962–970.
A prospective cohort study comparing baseline CSF findings and CSF cytokine profiles in 85 Ugandan patients with cryptococcal meningitis initiating ART, 33 of whom subsequently developed IRIS. At cryptococcal meningitis diagnosis patients subsequently developing IRIS had lower CSF WCC, protein, IFNγ, TNFα, IL-6 and IL-8 compared to those not developing IRIS.
23. Kambugu A, Meya DB, Rhein J, et al. Outcomes of cryptococcal meningitis in Uganda before and after the availability of highly active antiretroviral therapy. Clin Infect Dis 2008; 46:1694–1701.
24. Haddow LJ, Easterbrook PJ, Mosam A, et al. Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. Clin Infect Dis 2009; 49:1424–1432.
25. Bicanic T, Harrison T, Niepieklo A, et al. Symptomatic relapse of HIV-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. Clin Infect Dis 2006; 43:1069–1073.
26. Tweddle A, Davies SJ, Topping W, et al. Nodal cryptococcal immune reconstitution inflammatory syndrome masquerading as tuberculosis in an HIV-infected patient. Int J STD AIDS 2012; 23:216–218.
27. Tsai HC, Lee SS, Wann SR, Chen YS. Cervical lymphadenitis caused by Cryptococcus-related immune reconstitutional inflammatory syndrome. QJM 2010; 103:531–532.
28. Tahir M, Sharma SK, Sinha S, Das CJ. Immune reconstitution inflammatory syndrome in a patient with cryptococcal lymphadenitis as the first presentation of acquired immunodeficiency syndrome. J Postgrad Med 2007; 53:250–252.
29. Calligaro G, Meintjes G, Mendelson M. Pulmonary manifestations of the immune reconstitution inflammatory syndrome. Curr Opin Pulm Med 2011; 17:180–188.
30. Burton R, Gogela N, Rebe K, et al. Cryptococcal immune reconstitution inflammatory syndrome presenting with erosive bone lesions, arthritis and subcutaneous abscesses. AIDS 2009; 23:2371–2373.
31. Gasiorowski J, Knysz B, Szetela B, Gladysz A. Cutaneous cryptococcosis as a rare manifestation of the immune reconstitution syndrome in an HIV-1-infected patient. Postepy Hig Med Dosw (Online) 2008; 62:1–3.
32. Shulman J, de la Cruz EL, Latkany P, et al. Cryptococcal chorioretinitis with immune reconstitution inflammatory syndrome. Ocul Immunol Inflamm 2009; 17:314–315.
33. Khurana RN, Javaheri M, Rao N. Ophthalmic manifestations of immune reconstitution inflammatory syndrome associated with Cryptococcus neoformans. Ocul Immunol Inflamm 2008; 16:185–190.
34. Castelnuovo B, Manabe YC, Kiragga A, et al. Cause-specific mortality and the contribution of immune reconstitution inflammatory syndrome in the first 3 years after antiretroviral therapy initiation in an urban African cohort. Clin Infect Dis 2009; 49:965–972.
35. Bisson GP, Nthobatsong R, Thakur R, et al. The use of HAART is associated with decreased risk of death during initial treatment of cryptococcal meningitis in adults in Botswana. J Acquir Immune Defic Syndr 2008; 49:227–229.
36. Jarvis JN, Lawn SD, Wood R, Harrison TS. Cryptococcal antigen screening for patients initiating antiretroviral therapy: time for action. Clin Infect Dis 2010; 51:1463–1465.
37. Jarvis JN, Lawn SD, Vogt M, et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin Infect Dis 2009; 48:856–862.
38. Jarvis JN, Meintjes G, Bicanic T, et al.
CSF cytokine profiles in patients with HIV-associated cryptococcal meningitis: correlates with clinical outcome. 8th International Conference on Cryptococcus and Cryptococcosis; May 4 2011; Charleston, South Carolina, USA. 2011.
39. French MA. Immune reconstitution inflammatory syndrome: immune restoration disease 20 years on. Med J Aust 2012; 196:318–321.
40▪. Wiesner DL, Boulware DR. Cryptococcus-related immune reconstitution inflammatory syndrome (IRIS): pathogenesis and its clinical implications. Curr Fungal Infect Rep 2011; 5:252–261.
An in-depth review of the current understanding of CM-IRIS pathogenesis.
41. Stone SF, Price P, Keane NM, et al. Levels of IL-6 and soluble IL-6 receptor are increased in HIV patients with a history of immune restoration disease after HAART. HIV Med 2002; 3:21–27.
42. Stone SF, Price P, Brochier J, French MA. Plasma bioavailable interleukin-6 is elevated in human immunodeficiency virus-infected patients who experience herpesvirus-associated immune restoration disease after start of highly active antiretroviral therapy. J Infect Dis 2001; 184:1073–1077.
43. Worsley CM, Suchard MS, Stevens WS, et al. Multianalyte profiling of ten cytokines in South African HIV-infected patients with immune reconstitution inflammatory syndrome (IRIS). AIDS Res Ther 2010; 7:36.
44. Tan DB, Yong YK, Tan HY, et al. Immunological profiles of immune restoration disease presenting as mycobacterial lymphadenitis and cryptococcal meningitis. HIV Med 2008; 9:307–316.
45. Jarvis JN, Meintjes G, Williams A, et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect Dis 2010; 10:67.
46. Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:291–322.
47. Sitapati AM, Kao CL, Cachay ER, et al. Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab. Clin Infect Dis 2010; 50:e7–e10.
48. Brunel AS, Reynes J, Tuaillon E, et al. Thalidomide for steroid-dependent immune reconstitution inflammatory syndromes during AIDS. AIDS 2012; 26:2110–2112.
49. Brunel AS, Makinson A, de Champfleur NM, et al. HIV-related immune reconstitution cryptococcal meningoradiculitis: corticosteroid response. Neurology 2009; 73:1705–1707.
50. Lodha A, Haran M. Is it recurrent cryptococcal meningitis or immune reconstitution inflammatory syndrome? Int J STD AIDS 2009; 20:666–667.
51. Zolopa A, Andersen J, Powderly W, et al. Early antiretroviral therapy reduces AIDS progression/death in individuals with acute opportunistic infections: a multicenter randomized strategy trial. PLoS One 2009; 4:e5575.
52. Makadzange AT, Ndhlovu CE, Takarinda K, et al. Early versus delayed initiation of antiretroviral therapy for concurrent HIV infection and cryptococcal meningitis in sub-saharan Africa. Clin Infect Dis 2010; 50:1532–1538.
54. Southern African HIV Clinicians Society. Guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in HIV-infected patients. S A J HIV Med. 2007; 28:25–35.
56. French N, Gray K, Watera C, et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 2002; 16:1031–1038.
57. Lara-Peredo O, Cuevas LE, French N, et al. Cryptococcal infection in an HIV-positive Ugandan population. J Infect 2000; 41:195.
58. Liechty CA, Solberg P, Were W, et al. Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. Trop Med Int Health 2007; 12:929–935.
59. Worodria W, Massinga-Loembe M, Mazakpwe D, et al. Incidence and predictors of mortality and the effect of tuberculosis immune reconstitution inflammatory syndrome in a cohort of TB/HIV patients commencing antiretroviral therapy. J Acquir Immune Defic Syndr 2011; 58:32–37.
60. Desmet P, Kayembe KD, De Vroey C. The value of cryptococcal serum antigen screening among HIV-positive/AIDS patients in Kinshasa, Zaire. AIDS 1989; 3:77–78.
61. Tassie JM, Pepper L, Fogg C, et al. Systematic screening of cryptococcal antigenemia in HIV-positive adults in Uganda. J Acquir Immune Defic Syndr 2003; 33:411–412.
62. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010; 51:448–455.
63. Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007; 45:555–559.
64. Pongsai P, Atamasirikul K, Sungkanuparph S. The role of serum cryptococcal antigen screening for the early diagnosis of cryptococcosis in HIV-infected patients with different ranges of CD4 cell counts. J Infect 2010; 60:474–477.
66. Jarvis JN, Harrison TS, Lawn SD, et al
. Cost effectiveness of cryptococcal antigen screening as a strategy to prevent HIV-associated cryptococcal meningitis in South Africa. 6th IAS Conference on HIV Pathogenesis, Treatment and Prevention; 17–20 July 2011; Rome, Italy. 2011.
67▪. Jarvis JN, Govender N, Chiller T, et al.
Cryptococcal antigen screening and preemptive therapy in patients initiating antiretroviral therapy in resource-limited settings: a proposed algorithm for clinical implementation. J Int Assoc Physicians AIDS Care (Chic) 2012; 11:374–379.
A review of the evidence to date on CRAG screening in patients initiating ART, and a proposed clinical algorithm for the management of CRAG-positive patients identified by screening programmes.
68. Rajasingham R, Meya DB, Boulware DR. Integrating cryptococcal antigen screening and preemptive treatment into routine HIV care. J Acquir Immune Defic Syndr 2012; 59:e85–e91.
69. Patel S, Shin GY, Wijewardana I, et al.
The prevalence of cryptococcal antigenemia in newly diagnosed HIV patients in a Southwest London cohort. J Infect 2012. [Epub ahead of print]
70. Rajasingham R, Boulware DR. Reconsidering cryptococcal antigen screening in the U.S. among persons with CD4 <100 cells/mcL. Clin Infect Dis 2012; 55:1742–1744.