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A study of TB-associated immune reconstitution inflammatory syndrome using the consensus case-definition.

Tuberculosis (TB) is the most common opportunistic infection among human immunodeficiency virus (HIV) infected patients in developing countries (1). Patients with HIV-associated TB have advanced HIV disease and are at increased risk of death and new opportunistic infections (2-8). Highly active antiretroviral therapy (HAART) markedly decreases HIV-related morbidity and mortality in these patients (8). While the immune restoration following HAART reduces the risk of disease progression, it may also result in exacerbation of certain clinical manifestations known as immune reconstitution inflammatory syndrome (IRIS) (9,10).

IRIS results from rapid restoration of pathogen-specific immune responses. It manifests as either a deterioration of previously diagnosed infection (paradoxical reaction) or an appearance of previously undiagnosed sub-clinical infection (unmasking reaction). A considerable proportion of patients with HIV-associated TB but on HAART develop IRIS reactions (11-13). Nonetheless, the diagnosis of TB-IRIS in resource-limited settings remains difficult to establish. Recently, a consensus case-definition for TB-associated IRIS has been proposed. This includes paradoxical TB-associated IRIS and antiretroviral treatment (ART) associated TB with provisional case-definition of unmasking TB-associated IRIS14. However, the performance of these case-definitions has not been formally evaluated. In the present study, we describe the frequency and risk factors of TB-associated IRIS diagnosed using the consensus case-definition.

Material & Methods

We retrospectively evaluated all antiretroviral-naive adults initiated on HAART at the ART clinic of the All India Institute of Medical Sciences hospital, New Delhi, India, from June 2006 to September 2008. Ethical approval for the study was not required since this was a retrospective review of case records. A diagnosis of TB was made as per the World Health Organization (WHO) criteria for smear-positive pulmonary TB, smear-negative pulmonary TB, or extrapulmonary TB (15). The data were collected from the case records of both out- and in-patients treated during this period. CD4+ cell counts were performed by flow cytometry at baseline and every six months thereafter in accordance with the National AIDS Control Organisation (NACO) guidelines (16). All patients were receiving HAART free of cost as a part of the National AIDS Control Programme. HAART, consisting of two nucleoside reverse transcriptase inhibitors (zidovudine or stavudine plus lamivudine) and one non-nucleoside reverse transcriptase inhibitor (efavirenz or nevirapine), was started according to the national guidelines (16). Plasma HIV viral load monitoring is not done in the national programme. Drug susceptibility testing (DST) for tuberculosis was not performed due the lack of facility for the same. We reviewed the case records for potential IRIS events and applied the consensus case-definitions retrospectively (14). Paradoxical TB-associated IRIS was diagnosed in an individual diagnosed to have TB before initiation of HAART who typically responded to anti-TB treatment but developed paradoxical worsening of symptoms within three months of initiation of HAART. ART-associated TB was defined as development of active TB within three months of starting HAART in an individual who did not have TB at the initiation of HAART (14).

Statistical analysis: Continuous data are presented as mean [+ or -] standard deviation (SD) or median and interquartile range (IQR). Categorical data are presented as numbers with proportions, n (%). The categorical data were compared between groups by the Fisher's exact test and continuous variables by the Wilcoxon rank-sum test. All tests were two-sided, and P < 0.05 was considered statistically significant. All analyses were done using a statistical software package (Intercooled Stata 8.0 for Windows, Stata Corporation, College Station, TX, USA).

Results

In total, 627 patients were started on HAART during the study period and had completed at least three months of follow up at the time of data collection. Of them, 237 (38%) patients were diagnosed to have TB prior to starting HAART. The median age of the patients was 35 (IQR, 30-40) years. At the time of diagnosis of TB, 159 (67%) patients had disseminated or extrapulmonary TB. The median CD4+ cell count of the study cohort (n = 627) at the initiation of HAART was 107 (IQR, 58-163) cells/[micro]l.

In total, 18 (7.5%) of 237 patients with TB at baseline started on HAART had paradoxical TB-associated IRIS, while 12 (3%) of 390 patients without TB at baseline developed ART-associated TB after starting HAART. The baseline characteristics of patients are presented in Table I. None of the patients with ART-associated TB had an inflammatory clinical presentation suggestive of unmasking TB-associated IRIS.

Ten (56%) of the 18 IRIS episodes and 5 (42%) of 12 ART-associated TB occurred in the first 30 days of starting HAART. Notably, in two of 18 patients with paradoxical TB-associated IRIS, who would otherwise satisfy the case-definitions of TB-associated IRIS, the symptoms began after 90 days of starting HAART as opposed to the time cut-off of less than three months stipulated by the case-definition.

Most common clinical manifestation in patients with paradoxical worsening was new-onset fever followed by the appearance or worsening of cervical lymphadenopathy (Table II). Paradoxical TB-associated IRIS occurred at a median interval of 22 (18-47) days after initiation of HAART. All episodes of paradoxical TB-associated IRIS were of mild to moderate severity not requiring any interruption of HAART. All but three patients responded to antipyretics (paracetamol) and analgesics (non-steroidal anti-inflammatory drugs) for the treatment of paradoxical TB-associated IRIS. Two patients required addition of steroids for six weeks each--one of them had TB meningitis and the other had TB pericardial effusion; one patient required surgical drainage of anterior chest wall cold abscess. Hospitalization was required in 5 of 18 patients for the management of paradoxical TB-associated IRIS. In 12 patients with ART-associated TB, the median interval between HAART and the diagnosis of TB was 46 (23-71) days. Three of the 12 patients required hospitalization. All 12 patients received anti-TB treatment; one patient required steroids in addition for TB meningitis. None of the patients with TB-associated IRIS died during follow up period.

On univariate analyses, age, gender, and presence of extrapulmonary/disseminated TB were not significantly associated with the development of paradoxical TB-associated IRIS or ART-associated TB. In patients who developed paradoxical TB-associated IRIS, the median interval between the initiation of anti-TB treatment and HAART was significantly shorter as compared to those that did not develop paradoxical TB-associated IRIS [33 (24-41) vs. 48 (35-61); P < 0.001; Table I]. Patients who developed paradoxical TB-associated IRIS also had a significantly lower CD4+ cell count at baseline and a greater rise in CD4+ cell count at six months following HAART (Table I). When the baseline CD4+ cell count of patients developing ART-associated TB was compared with those who did not develop TB, no significant difference was noted [93 (20-157) vs. 120 (65-170); P = 0.153].

Discussion

In the present study, we found that 7.5 per cent of patients with HIV-associated TB developed paradoxical TB-associated IRIS after starting HAART, and about 3 per cent of patients with no overt evidence of TB at initiation of HAART developed ART-associated TB. Ours is probably the first study from India to apply the consensus case-definitions for describing the incidence and risk factors of TB-associated IRIS. Earlier studies from developed nations had reported a high incidence of TB-associated IRIS (17-43%) as compared to studies from developing nations (8-13%) (17-25). Kumarasamy et al (19) from southern India found the incidence of TB-associated IRIS to be 8 per cent. However, the lack of uniform case-definitions for TB-associated IRIS makes direct comparison of these results difficult.

We also found that a low CD4+ cell count, greater change in CD4+ cell count at six months with treatment, and early initiation of HARRT after anti-TB treatment were associated with paradoxical TB-associated IRIS. These findings are in consonance with previous studies describing the risk factors of TB-associated IRIS (20-23). Extrapulmonary and disseminated TB have been reported to be associated with the occurrence of TB-associated IRIS in previous studies. However, we did not find such an association with paradoxical TB-associated IRIS. This discrepancy could possibly be due to the small number of IRIS events in the present study. Notably, patients with ART-associated TB had no identifiable risk factors that could be useful clinically. This observation highlights the need for a close clinical follow up of all patients started on HAART, especially during the initial few months, for the development of ART-associated TB.

Overall, it seems that the consensus case-definitions could be easily applied in a resource-limited setting like ours to diagnose both paradoxical TB-associated IRIS and ART-associated TB. However, the consensus case-definitions would have missed the who patients who developed paradoxical TB-associated IRIS after 90 days of HAART. While it remains a theoretical possibility that ART-associated TB occurring after 90 days could represent new infections, from a practical point of view, this ambiguity is unlikely to be sorted out. However, this observation underscores the possibility that some genuine instances of TB-associated IRIS may be missed by the arbitrary time cut-off of three months stipulated by the consensus case-definitions.

Our study has certain limitations. Due to the retrospective nature of the present study, we would have missed clinical events that were not recorded. Thus, the true incidence of TB-associated IRIS might be higher than what is reported here. Similarly, clinical features that may have been risk factors for ART-associated TB may not have been recorded in the clinical notes. Due to lack of resources, we could not devise a criterion standard, which typically incorporates plasma HIV viral load measurements, against which the consensus case-definition could be compared. On the other hand, it is worthwhile noting that the case-definition is meant for use primarily in resource-limited settings like ours where there is no access to plasma HIV viral load measurements. As rifampin-resistant TB could be an important differential diagnosis in this situation and DST was not performed in our patients, we consider it to be a major limitation of our study. However, the consensus case-definition needs to be prospectively and independently validated in different geographical settings.

In conclusion, TB-associated IRIS reactions complicate the course of illness in a considerable proportion of HIV-infected patients started on HAART. Most instances of TB-associated IRIS are easily manageable. The consensus case-definition seems to be a useful tool in the diagnosis of TB-associated IRIS. Its diagnostic performance needs to be prospectively validated.

Received June 9, 2009

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Reprint requests: Dr S.K. Sharma, Chief, Division of Pulmonary, Critical Care & Sleep Medicine, Head, Department of Medicine All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India e-mail: sksharma@aiims.ac.in, surensk@gmail.com

Surendra K. Sharma, Sahajal Dhooria, Parag Barwad, Tamilarasu Kadhiravan, Sanjay Ranjan Sunita Miglani & Deepak Gupta

Department of Medicine, All India Institute of Medical Sciences, New Delhi, India
Table I. Characteristics of patients with HIV-associated TB and factors
associated with paradoxical TB-associated IRIS and ART-associated TB

 Patients with TB at baseline
Characteristic before HAART

 No paradoxical Paradoxical TB-
 TB-associated IRIS associated IRIS
 (n=219) (n=18)

Age (yr) 35 (30-40) 37 (30-42)
Male Sex [n (%)] 186 (85) 17 (94)
Body mass index 17 [+ or -] 2.9 17 [+ or -] 2.6
 (kg/[m.sup.2])
Extrapulmonary or 146 (67) 15 (83)
 disseminated TB [n (%)]
Interval between anti- TB 48 (35-61) * 33 (24-41) *
 treatment and HAART (days)
Interval between HAART and NA 22 (18-47)
 first manifestation of
 IRIS (days)
Baseline CD4+ cell count 95 (52-150) 64 (28-89)
 (cells/[micro]l) ([dagger]) ([dagger])
CD4+ cell count at six 268 (168-364) 220 (162-337)
 months of HAART
 (cells/[micro]l)
Per cent-change in CD4+ 1.7 (0.7-3.2) (+) 2.3 (1.5-7.9) (+)
 cell count at six months.

 ART-associated
Characteristic TB (n=12)

Age (yr) 41 (31-46)
Male Sex [n (%)] 9 (75)
Body mass index 20 [+ or -] 5
 (kg/[m.sup.2])
Extrapulmonary or 9 (83)
 disseminated TB [n (%)]
Interval between anti- TB NA
 treatment and HAART (days)
Interval between HAART and 39 (22-74)
 first manifestation of
 IRIS (days)
Baseline CD4+ cell count 93 (20-157) ([double dagger])
 (cells/[micro]l)
CD4+ cell count at six 246 (141-354)
 months of HAART
 (cells/[micro]l)
Per cent-change in CD4+ 2.2 (1.1-2.6)
 cell count at six months.

Data presented as mean [+ or -] SD or median (IQR) unless specified;
* P<0.001; ([dagger]) P=0.009; P=0.153 as compared to those who did
not develop ART-associated TB; (+) P=0.043; ART, antiretroviral
treatment; HAART, highly active antiretroviral therapy; IRIS,
immune reconstitution inflammatory syndrome; NA, not applicable;
TB, tuberculosis; IQR, interquartile range

Table II. Manifestations in 18 patients with paradoxical
TB-associated IRIS.

 No. of
Manifestation * patients (%)

Clinical:
New-onset fever 12 (67)
New-onset cough 3 (17)
New-onset cervical adenopathy 4 (22)
Worsening cervical adenopathy 2 (11)
New-onset subcutaneous cold abscess 1 (6)

Radiological:
New-onset intra-abdominal lymphadenopathy 5 (28)
New-onset pulmonary infiltrate 1 (6)
Worsening pulmonary infiltrate 2 (11)
New-onset pleural effusion 1 (6)
Worsening meningitis 2 (11)

* Individual manifestations not mutually exclusive, total will exceed
18; IRIS, immune reconstitution inflammatory syndrome; TB, tuberculosis
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Author:Sharma, Surendra K.; Dhooria, Sahajal; Barwad, Parag; Kadhiravan, Tamilarasu; Ranjan, Sanjay; Miglan
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:Jun 1, 2010
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