This study showed a high incidence of IRS after initiating HAART in advanced stage HIV-infected children. The spectrum of IRS is similar to previous reports. They involve either exacerbation, often with unusual manifestations, of a previously treated opportunistic infections or unmasking of a previously subclinical infection.2–6
Less commonly, IRS can manifest as an occurrence of noninfectious disease, such as Guillain-Barré syndrome.15
There is no generally accepted case definition for IRS. The definition of IRS used in our report covers HIV-infected patients whose antiretroviral treatment has led to an increase in CD4 lymphocyte count and decrease in plasma HIV RNA titer, and who have a disease event caused by microorganisms or conditions that have previously been associated with IRS in major review articles on the subject.2–6
This case definition together with clinical manifestations that are different from manifestations of opportunistic infections in patients not taking HAART, such as localized mycobacterial infections, mild cases of herpes zoster or cases of cryptococcal meningitis with prominent inflammatory response in the CSF, is highly specific for IRS.
Of the 32 episodes of IRS, 14 (43.7%) were caused by Mycobacterium
spp. All patients presented with localized infection in the lymph nodes, subcutaneous or submucosal tissues or lungs. Two patients who had been vaccinated with M. bovis
BCG strain several years before commencing HAART presented with localized infection by that organism. Mycobacterium
spp. are often implicated in IRS, and together they represent about 40% of all reported cases.4
The patients usually present with fever, lymphadenitis, subcutaneous abscesses, pulmonary infiltrates or inflammatory masses, usually during the first 3 months of HAART.16–19
A case of lymphadenitis caused by M. bovis
BCG strain had also been reported.20
There were 7 episodes (21.9%) caused by varicella-zoster virus. In all cases, manifestations were mild and uncomplicated. Studies have shown that the incidence of herpes zoster markedly increase in HIV-infected patients treated with HAART versus those not taking HAART.10,21–23
Herpes zoster represents about 22% of all reported cases of IRS.4
The majority of cases present during the first 4 months of HAART.
Of the 32 episodes of IRS, 6 (18.7%) were manifestations of herpes simplex labialis. One other patient died of encephalitis caused by HSV. Data from 1 observational study suggested that adult patients responding to HAART had a high incidence of mucocutaneous HSV disease.8
The study also showed 1 death from encephalitis caused by HSV after HAART.
Three episodes of IRS in our study were manifestation of cryptococcal meningitis. Cryptococcal IRS is characterized by a more prominent inflammatory response in the CSF than in patients not receiving HAART.24
In our patient, the leukocyte count in the CSF was 147 cells/mL3
. We had reported cases of cryptococcal meningitis in 21 children who were not taking HAART from Chiang Mai University Hospital.25
Mean leukocyte count in the CSF was 17.6 cells/mL3
In our study, 29 (19%) of the 153 children had 32 episodes of IRS within the first year of HAART. Three children died of IRS or its complications. Two more deaths occurred in children without IRS. The baseline CD4 lymphocyte percentage was lower in children who had IRS when compared with those who did not. There have been few reports that studied the incidence of IRS in a cohort of patients started on HAART. French et al8
did a retrospective study on all adult patients commencing HAART at one hospital in Australia. Of 141 patients, ≥1 episodes of IRS developed in 33 (23.4%) during the 30 weeks after commencement of HAART. The most common manifestations were dermatomal zoster, mucocutaneous herpes, cytomegalovirus retinitis and M. avium
complex lymphadenopathy. Logistic regression analysis showed that low baseline CD4 lymphocyte count was a significant risk factor for IRS. In the only published study in children, IRS developed in 7 (11.5%) of the 61 children started on HAART, all of which were dermatomal zoster.10
Average CD4 lymphocyte percentage at initiation of HAART in this study was 21.9% compared with 5.0% in our study. This result could explain the difference in the spectrum of IRS between the 2 studies.
Three studies of the incidence of IRS were reported in specific subsets of patients commencing HAART. In a Thai prospective multicenter study of 60 advanced AIDS patients who had had successful treatment of acute cryptococcal meningitis and were on secondary prophylaxis, 20 episodes of IRS developed in 14 patients (23.3%). The most common causes of IRS were tuberculosis, M. avium
complex, relapsed cryptococcal meningitis and herpes zoster.11
In a retrospective study from India, IRS caused by M. tuberculosis
developed in 11 (7.6%) of the 144 HIV and tuberculosis-coinfected patients.12
Finally Shelburne et al9
conducted a retrospective study of patients who received HAART and were coinfected with M. tuberculosis
, M. avium
complex or C. neoformans
. Of the 180 patients, IRS developed in 57 (31.7%), all from the coinfecting microorganisms.9
Thus, between 7.6% and 32% of patients commencing HAART had IRS develop. The difference in incidence among various studies can be explained by the difference in the case definition of IRS used and the risk factors in the population being studied. In addition, the incidence and spectrum of IRS were likely to be different in pediatric cohorts compared with adult cohorts and in patients from developing countries compared with developed countries. For example, the spectrum of opportunistic infections in Thailand had been shown to be unique.26
During the past few years, progress had been made in providing HAART to patients in developing countries.27
These patients often had multiple opportunistic and concomitant infections,28
and started HAART at a low baseline CD4 lymphocyte count.29
Thus, there were many patients at risk for IRS developing. In 1 report on 743 adult patients starting HAART and followed for 2–7 months, 61 patients (8.2%) died.29
In another report from South Africa, 16 (13%) of 122 children died within the first 6 months of HAART.30
The major causes of death in these patients were likely to be opportunistic infections occurring in patients with residual defects of cell-mediated immunity, IRS and adverse drug events. Educational programs for health care workers and patients concentrating on recognizing and treating these conditions should reduce the rate of early deaths after HAART in these resource-poor countries.