Introduction and Overview of TB-IRIS
Immune Reconstitution Inflammatory Syndrome (IRIS) refers to a phenomenon experienced by people living with HIV who have recently initiated antiretroviral therapy. The partial reconstitution of the immune system following initiation of antiretroviral therapy in these patients can result in an exaggerated inflammatory response against any concurrent opportunistic infection. Sometimes the opportunistic infection pathogen against which the inflammatory response is directed remains clinically 'silent' prior to initiation of antiretroviral therapy, such that antiretroviral therapy 'unmasks' a previously undiagnosed disease. Tuberculosis-Immune Reconstitution Inflammatory Syndrome (TB-IRIS) refers specifically to IRIS that occurs in the context of a patient with active Mycobacterium tuberculosis infection, and is a relatively common complication for HIV-infected persons who initiate antiretroviral therapy in resource-limited settings, particularly in regions that have a high TB prevalence. Management of TB-IRIS is complicated by the difficulty in establishing the diagnosis and the absence of randomized controlled trials that clearly define optimal treatment strategies.
Tuberculosis IRIS is estimated to occur in 11% to 45% of patients co-infected with TB and HIV following initiation of antiretroviral therapy. Difficulties associated with the diagnosis of TB-IRIS, and the lack (until recently) of a clear case definition for TB-IRIS, have resulted in the wide range of disease estimates. Rates of TB-IRIS within a particular geographic area primarily depend on the prevalence of TB in the region and typical CD4 counts when patients commence antiretroviral therapy. Although TB-IRIS often causes significant clinical symptoms, it is rarely fatal: a recent meta-analysis involving more than 13,000 patients with TB-IRIS reported a case-fatality rate of 3.2%. A case series from South Africa reported a significantly higher mortality rate associated with TB-IRIS among patients in whom TB-IRIS involved the central nervous system.
Pathophysiology, Risk Factors, and Clinical Presentation, for TB-IRIS
The exact pathophysiology of TB-IRIS remains unclear, but it appears to result from an invigorated inflammatory reaction against Mycobacterium tuberculosis antigens driven by antiretroviral therapy-induced reconstitution of the immune system[4,5]. Specific risk factors identified for TB-IRIS include multiple prior opportunistic infections, low CD4 count at initiation of antiretroviral therapy, rapid rise in CD4 cell count following initiation of antiretroviral therapy, and a rapid drop in HIV RNA levels following initiation of antiretroviral therapy[4,6,7,8,9]. In addition, persons with more advanced HIV disease at the time of initiation of antiretroviral therapy appear to have increased risk of developing IRIS . Patients with pulmonary TB-IRIS typically present with fever, lymphadenopathy, and respiratory complaints. Given that disseminated disease frequently develops in HIV-infected persons with active TB, especially in those with advanced HIV infection, TB-IRIS can present in diverse ways. The range of manifestations include abdominal lymphadenopathy, cervical lymphadenitis (Figure 1), abscesses, pulmonary effusions and/or pulmonary infiltrates (Figure 2), pericardial effusions (Figure 3), meningitis, brain tuberculomas, and skeletal lesions (usually vertebral) . In most cases, TB-IRIS typically manifests within 2 months of initiation of antiretroviral therapy , though late presentations of TB-IRIS have been reported .
Diagnosis and Case Definition of TB-IRIS
The diagnosis of TB-IRIS is rarely straightforward, as no single laboratory test can establish or rule out TB-IRIS. To establish a provisional diagnosis of TB-IRIS, clinicians must rely upon a combination of clinical signs and symptoms, laboratory findings, the likelihood of other conditions, and clinical judgment. In 2008, a panel of expert clinicians convened in Kampala, Uganda to formulate a case definition of TB-IRIS that could be practically applied in resource-limited settings . The International Network for the Study of HIV-associated IRIS panel distinguished between “paradoxical TB-IRIS” (worsening of previously diagnosed TB disease in a person with HIV infection who initiates antiretroviral therapy) and "unmasking TB-IRIS" (clinical manifestations of previously undiagnosed TB in a person with HIV infection who initiates antiretroviral therapy). This panel also agreed by consensus on a case definition and a provisional case definition for paradoxical TB-IRIS (Figure 4) and unmasking TB-IRIS (Figure 5). The case definitions deliberately exclude the use of laboratory tests, such as CD4 and viral load testing, recognizing that clinicians managing HIV-infected persons in resource-limited settings do not routinely have access to such tests. Investigators subsequently validated these case definitions in cohort studies in Thailand  and South Africa [16,17], and these definitions remain the most useful case definitions for application in resource-limited settings.
Timing of Antiretroviral Therapy with Known TB
Recently released data from three randomized trials suggest that although delaying the initiation of antiretroviral therapy in patients with HIV and TB coinfection reduces the risk of TB-IRIS, this approach correlates with higher mortality rates when compared with earlier initiation of antiretroviral therapy, especially in patients with low CD4 counts[18,19,20]. The WHO Guidelines therefore recommend starting antiretroviral therapy as soon as tuberculosis therapy is tolerated —specifically, as soon as possible (and within 8 weeks) of initiation of anti-TB therapy [21,22].
Use of Corticosteroids in TB-IRIS
Numerous anecdotal reports and small case series have suggested corticosteroids help reduce inflammation in the setting of TB-IRIS. Specific formulations and doses used in reports have included intravenous methylprednisolone 40 mg every 12 hours and prednisone 20 to 70 mg per day. The length of steroid administration and the use of a steroid taper have also varied considerably . In the only randomized controlled trial that has evaluated the safety and efficacy of corticosteroids for TB-IRIS, investigators randomized 110 South African HIV-infected persons with evidence of paradoxical TB-IRIS to receive either placebo or a 4-week course of prednisone (1.5 mg/kg/day, for 2 weeks, followed by oral prednisone dosed at 0.75 mg/kg/day for 2 weeks) . The study excluded patients with life-threatening manifestations of TB-IRIS. The primary combined endpoint (days hospitalized plus therapeutic outpatient procedures) was significantly lower in patients randomized to the corticosteroid arm. At weeks two and four of the study, patients who received corticosteroids had higher Karnofsky scores, higher quality of life scores, more frequent improvement in chest radiograph findings, and fewer symptoms, when compared with patients who received placebo (Figure 6 series Study Title and SourceStudy DesignWeek 2 Symptom ScoreWeek 4 Symptom ScoreWeek 2 Chest Radiograph ScoreWeek 4 Chest Radiograph ScoreSource & Permission). Severe infections occurred with equal frequency in the two groups. Corticosteroid therapy was re-initiated in 10 patients after 4 weeks, suggesting that some patients may require an extended course of corticosteroids.
Risk of Drug-Resistant TB in Patients with Suspected TB-IRIS
In a recent cohort study of South African patients, 10% of the patients with suspected TB-IRIS were found to have previously undiagnosed rifampicin-resistant TB. Hence, drug resistance should ideally be ruled out in patients with active TB and a presentation consistent with TB-IRIS, especially if administration of corticosteroids is being considered.
Recommendations for the Management of TB-IRIS
Evidence-based guidelines for the management of suspected or confirmed TB-IRIS in resource-limited setting do not yet exist, owing to the scarcity of randomized controlled trials evaluating management approaches. Nevertheless, we recommend the following general principles of treatment based on existing reports, trials, and expert opinion.
1 Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynen L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis. 2006; 10:946-53.PubMed Abstract
2 Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M; IeDEA Southern and Central Africa. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010:10:251-61.PubMed Abstract
3 Pepper DJ, Marais S, Maartens G, Rebe K, Morroni C, Rangaka MX, Oni T, Wilkinson RJ, Meintjes G. Neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. Clin Infect Dis. 2009;48:e96-107.PubMed Abstract
4 Breton G, Duval X, Estellat C, et al. Determinants of immune reconstitution inflammatory syndrome in HIV type 1-infected patients with tuberculosis after initiation of antiretroviral therapy. Clin Infect Dis. 2004; 39:1709–12.PubMed Abstract
5 Bourgarit A, Carcelain G, Martinez V, et al. Explosion of tuberculin-specific Th1-responses induces immune restoration syndrome in tuberculosis and HIV co-infected patients. AIDS. 2006; 20:F1–7.PubMed Abstract
6 Breen RA, Smith CJ, Bettinson H, Dart S, Bannister B, Johnson MA, Lipman MC. Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection. Thorax. 2004; 59:704–7.PubMed Abstract
7 Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis. 2005; 5:361–73.PubMed Abstract
8 Manabe YC, Campbell JD, Sydnor E, Moore RD. Immune reconstitution inflammatory syndrome: risk factors and treatment implications. J Acquir Immune Defic Syndr. 2007; 46: 456-62.PubMed Abstract
9 Valin N, Pacanowski J, Denoeud L, et al. Risk factors for 'unmasking immune reconstitution inflammatory syndrome' presentation of tuberculosis following combination antiretroviral therapy initiation in HIV-infected patients. AIDS. 2010;24:1519–25.PubMed Abstract
10 Robertson J, Meier M, Wall J, Ying J, Fichtenbaum CJ. Immune reconstitution syndrome in HIV: validating a case definition and identifying clinical predictors in persons initiating antiretroviral therapy. Clin Infect Dis. 2006; 42:1639–46.PubMed Abstract
11 Bhrushundi M, Mishra P. Study of immune reconstitution inflammatory syndrome (IRIS) in resource limited settings. XVI International AIDS Conference; Toronto, ON, Canada; Aug 13–18, 2006. Abstract MOAB0305.
12 Murdoch DM, Venter WD, Van Rie A, Feldman C. Immune reconstitution inflammatory syndrome (IRIS): review of common infectious manifestations and treatment options. AIDS Res Ther. 2007;4:9.PubMed Abstract
13 Huyst V, Lynen L, Bottieau E, Zolfo M, Kestens L, Colebunders R. Immune reconstitution inflammatory syndrome in an HIV/TB co-infected patient four years after starting antiretroviral therapy. Acta Clin Belg. 2007;62:126-9.PubMed Abstract
14 Meintjes G, Lawn SD, Scano F, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–23.PubMed Abstract
15 Manosuthi W, Van Tieu H, Mankatitham W, et al. Clinical case definition and manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2009; 23:2467-71.PubMed Abstract
16 Haddow LJ, Moosa MY, Easterbrook PJ. Validation of a published case definition for tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010;24:103–8.PubMed Abstract
17 Eshun-Wilson I, Havers F, Nachega JB, et al. Evaluation of Paradoxical TB-Associated IRIS With the Use of Standardized Case Definitions For Resource-Limited Settings. J Int Assoc Physicians AIDS Care (Chic). 2010;9:104-8. PubMed Abstract
18 Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492-1501.PubMed Abstract
19 Blanc F-X, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471-81.PubMed Abstract
20 Havlir DV, Kendall MA, Ive P, et al. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482-91.PubMed Abstract
21 World Health Organization. Treatment of Tuberculosis: Guidelines – 4th edition. Geneva: WHO, 2010.WHO Publications
22 World Health Organization. Antiretroviral therapy for HIV infection in adults and adolescents: recommendations for a public health approach – 2010 revision. Geneva: WHO, 2010.WHO Publications
23 Meintjes G, Wilkinson RJ, Morroni C, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS. 2010;24:2381–90.PubMed Abstract
24 Meintjes G, Rangaka MX, Maartens G, et al. Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. Clin Infect Dis. 2009;48:667–76.PubMed Abstract
Copyright © 2004-2011 University of Washington