We read with interest the recent paper by Lortholary et al.  describing cryptococcocal immune reconstitution disease (IRD) in France. This is an increasingly recognized complication of the initial weeks of antiretroviral treatment (ART) [1–5]. However, to our knowledge, the frequency of cryptococcocal IRD in low-income countries has not previously been reported.
We run a community-based ART programme in Gugulethu, Cape Town, South Africa . Between September 2002 and November 2004, 434 treatment-naive patients started triple-drug ART according to WHO 2002 treatment guidelines . The patients’ mean age was 34 years, their median blood CD4 cell count was 86 cells/μl [interquartile range (IQR) 46–146 cells/μl], and the median plasma HIV load was 76 337 copies/ml (IQR 32 723–192 772 copies/ml). A total of 137 patients (32%) had WHO stage 4 disease, and among these cryptococcal meningitis was the AIDS-defining illness in 18 (13%). These diagnoses were made a median of 7 months (range 2–24 months) before the initiation of ART. According to national guidelines, cryptococcal meningitis was treated with fluconazole 400 mg/day for 8 weeks followed by 200 mg/day as secondary prophylaxis.
At data censorship in February 2005, the median follow-up was 46 weeks. During a total of 460 person-years of observation (PYO), nine patients developed either recurrent (n = 6) or new (n = 3) symptomatic cryptococcal disease of the central nervous system (Table 1). The median duration of ART at the onset of symptoms was 4 weeks. In the first, second and third months of ART, disease incidence based upon the time of symptom onset was 18.2 cases/100 PYO [95% confidence interval (CI) 8.2–40.6], 6.2 cases/100 PYO (95% CI 1.6–25.1) and 0 cases/100 PYO, respectively. Only one case of cryptococcal disease occurred after 12 weeks’ ART. Six of the nine patients (66%) died and cryptococcal disease accounted for six out of 22 total deaths (27%) during the first 3 months of ART.
IRD results from the rapid restoration of immune function, leading to an exacerbation of partly treated opportunistic infections or unmasking of previously undiagnosed subclinical infections . Several factors have suggested that IRD was the likely mechanism underlying the presentation of most or all of these cases of cryptococcosis: the very high incidence density rate within the initial weeks of ART, the sudden onset, the typically rapid evolution and fulminant clinical course. Of those with a previous history of cryptococcosis, one-third developed probable IRD. Although this proportion is comparable with other series [2,5], the mortality rate in our series is higher and represents a substantial problem that needs to be addressed to reduce the early mortality during ART among patients in resource-limited settings.
Live organisms, dead organisms or their shed antigens may trigger IRD . Among cases from whom viable organisms are cultured, symptoms may either be caused by IRD or simply represent new opportunistic disease. IRD case definitions that exclude clinically suspected cases with positive cultures increase the specificity of IRD diagnoses but may limit sensitivity. Of the nine patients described, seven had sterile cultures; although cultures from the remaining two cases were positive, a review of their clinical presentation suggested that IRD was potentially the underlying mechanism.
Cryptococcocal IRD is likely to be increasingly frequently encountered in ART programmes in sub-Saharan Africa for several reasons. First, ART programmes in the region are currently inundated with large numbers of patients with very advanced immunodeficiency; such patients are at the greatest risk of developing IRD. Second, HIV-associated cryptococcal disease is common in the region. Third, the local standard of care for cryptococcal meningitis is treatment with oral fluconazole, which is supplied free of charge by the manufacturer. Fluconazole is a fungistatic drug, which is broadly effective as secondary prophylaxis, but has far less efficacy than amphotericin in clearing the organism during the initial treatment phase . We suggest that the use of this agent for primary treatment may increase the risk of cryptococcal antigen persistence within the cerebrospinal fluid (CSF), possibly increasing the risk of IRD during ART.
Among those with a previous history of cryptococcosis, an analysis of CSF before the initiation of ART might be used to identify those with a persistent antigen burden who might then be retreated to reduce the fungal burden before starting ART. However, this strategy may be impractical in view of the huge logistic challenges facing many ART programmes in low-income countries. However, the optimum interval between the treatment of cryptococcal meningitis and the initiation of ART needs to be defined, and clinicians should be made aware of cryptococcal IRD to promote early diagnosis and prompt treatment. Optimal management strategies for cryptococcal IRD need to be defined by future studies, including the choice of antifungal agents, the use of corticosteroids, and the role of the discontinuation of ART.
Sponsorship: S.D.L. is funded by the Wellcome Trust, London.
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