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Year : 2012  |  Volume : 6  |  Issue : 1  |  Page : 1-3

Tuberculosis-associated immune reconstitution inflammatory syndrome: Management challenges in resource-limited settings

Department of Medicine, Ahmadu Bello University Teaching Hospital, Shika, Zaria, Kaduna State, Nigeria

Date of Web Publication28-Aug-2012

Correspondence Address:
Mukhtar A Adeiza
Department of Medicine, Ahmadu Bello University Teaching Hospital, PMB 06, Shika, Zaria, Kaduna State
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0331-3131.100196

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How to cite this article:
Adeiza MA. Tuberculosis-associated immune reconstitution inflammatory syndrome: Management challenges in resource-limited settings. Ann Nigerian Med 2012;6:1-3

How to cite this URL:
Adeiza MA. Tuberculosis-associated immune reconstitution inflammatory syndrome: Management challenges in resource-limited settings. Ann Nigerian Med [serial online] 2012 [cited 2020 Oct 30];6:1-3. Available from: https://www.anmjournal.com/text.asp?2012/6/1/1/100196

The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of highly active antiretroviral therapy (HAART) in resource-limited settings, especially in patients with tuberculosis (TB). [1] The immune recovery associated with HAART results in dramatic clinical benefits, but this restoration of immunity may result in immunopathological reactions and clinical deterioration when HAART is introduced in patients with TB. [2] The condition results from rapid restoration of pathogen-specific immune responses to opportunistic infections, causing either the deterioration of a treated infection or the new manifestation of a previously subclinical infection, which may complicate the clinical course. In TB-associated IRIS, there is transient worsening of symptoms and signs of TB after the initiation of antiretroviral treatment, despite a reduction in human immunodeficiency virus (HIV) viral load (1 log10 copies/mL) and immunological recovery of CD4+ T-lymphocytes. [3]

Currently, the lack of controlled clinical trials and specific confirmatory diagnostic tests, as well as the broad clinical spectrum of TB-IRIS, make this syndrome a real challenge for clinicians. [4] The incidence of TB-IRIS is expected to increase in low resource, high TB. and HIV burden countries like sub-Saharan Africa as more patients are started on HAART and the fact that the majority of HIV-infected patients present late with profound immunosuppresssion and increased risk for TB-IRIS. Moreover, 29% of HIV infected patients with active TB may be missed [5] as subclinical infection (no symptoms or chest radiograph finding) because of heavy reliance on sputum acid fast bacilli (AFB), which is inferior to sputum AFB culture in developing countries.

The incidence of paradoxical TB-associated IRIS ranges from 8% to 43%. [1] In South Africa, Abdoolkareem

et al., in the SAPiT study, a large randomized clinical trial in patients with TB and HIV that compared early integrated antiretroviral therapy (antiretroviral therapy initiated within 4 weeks of TB treatment initiation), late integrated antiretroviral therapy (antiretroviral therapy initiated within the first 4 weeks of the continuation phase of TB treatment), and sequential therapy (antiretroviral therapy initiated after completion of TB treatment), showed that TB-associated IRIS occurred at a rate of 12.4% when antiretroviral therapy was initiated during TB therapy compared with 3.8% in those who received sequential treatment for TB and HIV (P < 0.05). [6] Though the incidence of IRIS was higher in the early integrated therapy group, there was a 56% reduction in the outcome of death. In Uganda, incidence of unmasking within 6 months of TB treatment was 5.9% while paradoxical worsening was 22%. [7] Median time from initiation of HAART to event was 39 and 22 days in an Indian study respectively. [8]

Since the first description of TB-associated IRIS, arriving at a consensus case definition had remained controversial but currently, two types of presentation are recognized: unmasking of undiagnosed TB and a worsening or paradoxical deterioration of existing TB lesions, that is, appearance of new lesions after initial improvement. [1] Clinical manifestations include fever, lymph node enlargement [Figure 1], worsening respiratory symptoms and signs with pleural effusion, cold abscesses (psoas abscess), central nervous system lesions ; tuberculoma and/or meningitis, and radiological deterioration. [9] Risk factors include lower CD4+ T-cell count, higher viral load at start of treatment, rapidity of viral load decline, bacillary and antigen load (disseminated TB) at initiation, starting HAART closer to starting TB treatment, and genetic predisposition (HLA B-44). Although the pathophysiology of TB-associated IRIS is incompletely understood, it is associated with an exuberant production of cytokines. [3] In developing and developed countries, incidence of active TB occurs most often during the first 3 months after HAART initiation [10] and this has been attributed to high bacillary burden and disseminated disease.
Figure 1: Cervical lymphadenopathy in a patient with paradoxical TB associated-IRIS

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In resource-constrained settings where laboratory diagnostic capacity is limited, a diagnosis of TB-IRIS is suggested based on a case definition as recommended by the International Network for the Study of HIV-associated IRIS (INSHI) in 2008 [Table 1]. The different types of TB presentation in HIV are broadly divided into paradoxical TB-associated IRIS and antiretroviral therapy (ART)-associated TB, a subset of which could have unmasking TB-associated IRIS. [1] In all categories, TB is diagnosed based on the World Health Organization (WHO) recommendations for improving diagnosis in HIV prevalent and resource constrained settings [11] and clinical worsening due to drug resistance, drug reactions/toxicity, and new opportunistic infections/malignancies must be excluded where possible. Incidence of TB-associated IRIS can be reduced by aggressive screening for active TB (tuberculin skin test, chest X-ray, and sputum AFB smears and culture) and can be managed using antiinflammatory drugs and steroids which have been found to reduce the need for hospitalization, therapeutic procedures and hastens improvements in symptoms, performance, and quality of life. [12] Aspiration of abscesses and effusions may be required and timing of HAART should also be carefully considered but should not be delayed where clinically indicated.
Table 1: International Network for the Study of HIV-associated IRIS Case Definitions for use in resource-limited settings (INSHI 2008)

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Though the INSHI standardized case definitions have been used successfully in identifying paradoxical TB-associated IRIS in resource-limited settings, [8],[13] there is a need for further research into the immunological events underlying TB-associated IRIS to define the incidence, risk factors, clinical characteristics, and effect of the different TB-associated IRIS subsets to aid in prevention and management. This will provide clinicians with an appropriate clinical tool in the management of this challenging condition.

   References Top

1.Meintjes G, Lawn SD, Scano F, Maartens G, French MA, Worodria W, et al. Tuberculosis-associated immune reconstitution inflammatory syndrome: Case definitions for use in resource-limited settings. Lancet Infect Dis 2008;8:516-23.  Back to cited text no. 1
2.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.  Back to cited text no. 2
3.Leone S, Nicastri E, Giglio S, Narciso P, Ippolito G, Acone N. Immune reconstitution inflammatory syndrome associated with Mycobacterium tuberculosis infection: A systematic review. Int J Infect Dis 2010;14:e283-91.   Back to cited text no. 3
4.Reyes-Corcho A, Bouza-Jiménez Y. Redefinition of tuberculosis-associated immune reconstitution syndromes in HIV-infected individuals: A need for new clinical tools. J Infect Dis 2010;201:793-4.  Back to cited text no. 4
5.Mtei L, Matee M, Herfort O, Bakari M, Horsburgh CR, Waddell R, et al. High rates of clinical and subclinical tuberculosis among HIV-infected ambulatory subjects in Tanzania. Clin Infect Dis 2005;40:1500-7.  Back to cited text no. 5
6.Abdool Kareem SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray A, et al. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med 2010;362:697-706.  Back to cited text no. 6
7.Baalwa J, Mayanja-Kizza H, Kamya MR, John L, Kambugu A, Colebunders R. Worsening and unmasking of tuberculosis in HIV-1 infected patients after initiating highly active anti-retroviral therapy in Uganda. Afr Health Sci 2008;8:190-5.  Back to cited text no. 7
8.Sharma SK, Dhooria S, Barwad P, Kadhiravan T, Ranjan S, Miglani S, et al. A study of TB-associated immune reconstitution inflammatory syndrome using the consensus case-definition. Indian J Med Res 2010;131:804-8.  Back to cited text no. 8
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9.Cohen K, Meintjes G. Management of individuals requiring ART and TB treatment. Curr Opin HIV AIDS 2010;5:61-9.  Back to cited text no. 9
10.Manabe YC, Breen R, Perti T, Girardi E, Sterling TR. Unmasked tuberculosis and tuberculosis immune reconstitution inflammatory disease: A disease spectrum after initiation of antiretroviral therapy. J Infect Dis 2009;199:437-44.  Back to cited text no. 10
11.WHO. Improving the diagnosis and treatment of smear-negative pulmonary and extrapulmonary tuberculosis among adults and adolescents: Recommendations for HIV-prevalent and resource-constrained settings. Geneva: World Health Organization, 2007. Available from: http://www.WHO/HTM/TB/2007.379. [Last accessed on 2012 Jun 7].  Back to cited text no. 11
12.Meintjes G, Wilkinson RJ, Morroni C, Pepper DJ, Rebe K, Rangaka MX, et al. Randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2010;24:2381-90.  Back to cited text no. 12
13.Eshun-Wilson I, Havers F, Nachega JB, Prozesky HW, Taljaard JJ, Zeier MD, 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 2010;9:104-8.  Back to cited text no. 13


  [Figure 1]

  [Table 1]


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