Journal of Postgraduate Medicine
 Open access journal indexed with Index Medicus & ISI's SCI  
Users online: 1192  
Home | Subscribe | Feedback | Login 
About Latest Articles Back-Issues Article Submission Resources Sections Etcetera Contact
 
  NAVIGATE Here 
  Search
 
  
 RESOURCE Links
 ::  Similar in PUBMED
 ::  Search Pubmed for
 ::  Search in Google Scholar for
 ::  Article in PDF (223 KB)
 ::  Citation Manager
 ::  Access Statistics
 ::  Reader Comments
 ::  Email Alert *
 ::  Add to My List *
* Registration required (free) 

  IN THIS Article
 ::  References

 Article Access Statistics
    Viewed298    
    Printed5    
    Emailed0    
    PDF Downloaded1    
    Comments [Add]    

Recommend this journal


 


 
  Table of Contents     
EDITORIAL
Year : 2017  |  Volume : 63  |  Issue : 4  |  Page : 207-209

Tuberculosis, human immunodeficiency virus, and the immune reconstitution inflammatory syndrome


1 Department of Clinical Medicine, Division of Infectious Diseases, University of Massachusetts Medical School and Reliant Medical Group, Worcester, Massachusetts, USA
2 Department of Pediatrics, Seth G. S. Medical College and K. E. M. Hospital, Mumbai, Maharashtra, India

Date of Web Publication11-Oct-2017

Correspondence Address:
A Rapose
Department of Clinical Medicine, Division of Infectious Diseases, University of Massachusetts Medical School and Reliant Medical Group, Worcester, Massachusetts
USA
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpgm.JPGM_365_17

Rights and Permissions




How to cite this article:
Rapose A, Karande S. Tuberculosis, human immunodeficiency virus, and the immune reconstitution inflammatory syndrome. J Postgrad Med 2017;63:207-9

How to cite this URL:
Rapose A, Karande S. Tuberculosis, human immunodeficiency virus, and the immune reconstitution inflammatory syndrome. J Postgrad Med [serial online] 2017 [cited 2017 Oct 19];63:207-9. Available from: http://www.jpgmonline.com/text.asp?2017/63/4/207/216441




Tuberculosis (TB) continues to remain a major health problem in India in spite of achieving nationwide coverage with directly observed therapy since 2006. The estimated incidence of 2.2 million TB cases and a prevalence of 2.5 million in the year 2015 make India the country with the highest burden of TB in the world.[1] In addition, it is estimated that a substantial part of the healthy population (up to 40%) has latent (inactive) TB.

India had estimated 2.1 million people living with the human immunodeficiency virus (HIV) in the year 2015.[2] HIV infection left untreated is associated with a profound immunosuppression secondary to direct invasion and destruction of CD4 cells by the virus.[3],[4] With the introduction of antiretroviral therapy (ART) targeting HIV infection, individuals with HIV infection are now living longer and healthier lives. While ART is destroying the HIV, the infected individuals' immune system recovers to a state of near normal,[5] thus protecting that individual from previously described HIV-associated opportunistic infections and opportunistic malignancies.[6] The National AIDS Control Program has initiated free ART since 2004 which has contributed to a decline in new cases as well as deaths related to HIV. As of January 2017, there are 10.5 lakh Indians living with HIV who are on ART.[7]

HIV and TB coinfection creates a perfect storm in terms of poor outcomes secondary to the multiple challenges in the management of these two infections.[8],[9],[10] In an HIV patient, TB often presents atypically both clinically as well as radiologically, resulting in delayed diagnosis and hence delayed initiation of therapy.[8] In addition, with the multiple medications used to treat HIV (3 or more agents) and TB (4 or more agents), there is a need for dose modification on account of drug-drug interactions. For example, ritonavir which is used in ART is a cytochrome p450 enzyme inhibitor while rifampicin which is used in the treatment of TB is an inducer of the cytochrome p450 enzyme. The high pill burden involved in treating HIV and TB coinfection (7 or more agents) is also associated with reduced compliance resulting in the development of drug-resistant TB as well as the possibility of drug-resistant HIV.[9],[11]

In patients with HIV and TB coinfection, anti-TB medications are initiated first. ART is then recommended within the next 2–8 weeks.[12],[13],[14] Unfortunately, in some individuals, initiation of ART is associated with clinical deterioration. This is in the form of either worsening of a previously diagnosed TB infection or clinical manifestation of a concomitant undiagnosed TB infection. The term “immune reconstitution inflammatory syndrome (IRIS)” is used to describe this apparent clinical worsening when an HIV-infected patient is initiated on ART. Although Shelburne et al.,[15] were the first to coin this term in 2002, the phenomenon of clinical deterioration following the initiation of ART had been previously reported by others like French et al.,[16],[17] and Fox et al.[18] in the 1990s who described this as “immune restoration disease,” proposing that the phenomenon was actually an indication of an improvement in host immunity rather than a true deterioration.

This phenomenon of apparent worsening manifestations has been described with a wide variety of infectious agents including Mycobacteria (Mycobacterium tuberculosis, Mycobacterium avium, and Mycobacterium leprae),[15],[19],[20],[21],[22]Pneumocystis, Cryptococcus, Candida, parasites, and viruses [15],[18],[23],[24] and noninfectious conditions such as malignancies.[15],[24]

There are currently no official data on the incidence of TB-IRIS in India. The reported incidence of around 7.5% by Kumarasamy et al.[25] and Karmakar et al.[26] may be an underestimation because it is quite possible that many patients suffering from HIV and TB coinfection and receiving free treatment may be developing TB-IRIS which may be going undetected or misdiagnosed. On the other hand, the high incidence (nearly 30%) noted by Kumar et al.[27] in their cohort of patients initiating ART may be biased by the fact that the study was conducted in TB clinics, and the criteria used for predicting IRIS were only 22% specific, indicating a high likelihood of overdiagnosis of IRIS.

Patients with TB-IRIS can present with symptoms that can be divided into two broad categories:

  1. Previously diagnosed TB could appear to be getting worse when the patient is started on ART. For example, an HIV patient diagnosed with pulmonary TB and improving on anti-TB medications can develop worsening respiratory symptoms and appearance of new pulmonary lesions on radiologic imaging when he or she is initiated on ART.[22],[28] In some cases, there could be new manifestations of TB at sites distant from the underlying pulmonary disease, for example, new lesions in the brain, eye, heart, or lymph nodes [29],[30],[31],[32]
  2. There could be new clinical symptoms of a previously undiagnosed TB that manifest after initiation of ART.[8],[28] In these cases, when the HIV-positive individual is initiated on ART, a few weeks later the patient develops new clinical manifestations leading to diagnosis of the apparently new TB infection.


In either of the above two categories, the clinical manifestations can be highly variable. In some patients, the manifestations may be mild with low-grade fever, arthralgia, or lymphadenopathy, while in other patients, TB-IRIS is associated with severe clinical deterioration in the form of neurologic (meningitis or tuberculoma), pulmonary (pleural effusions and empyema), gastrointestinal (obstruction or perforation), or organ (liver or kidney) failure. Increased mortality is seen in patients who develop severe IRIS after initiation of ART.[12],[31]

Researchers have tried to identify subsets of HIV- and TB-coinfected patients who are at increased risk of developing IRIS. Some of these risk factors include very low initial CD4 count, with a rapid rise in CD4 count after initiation of ART,[23],[29],[33] deregulation of T-cell responses,[20],[34],[35] and altered ratios of various cytokines.[22],[36],[37] These studies may be tantalizing to research scientists. Unfortunately, there are very few – if any – easily available laboratory tests to diagnose or predict IRIS in any given individual. Hence, the diagnosis of TB-IRIS is mainly clinical. Laboratory studies that support the diagnosis include evidence of a rapid rise in CD4 count and associated fall in viral load.[23],[26],[29],[33]

Management of TB-IRIS is challenging. There is ongoing research into the best approach. One group of researchers is studying the role of prednisone as a preventive agent in patients with HIV and TB coinfection initiating ART – the PredART trial.[38] Results of the study are awaited. Another research group has evaluated whether there was any benefit of HIV chemokine receptor-5 antagonist – maraviroc – as part of initial ART. Unfortunately, it did not reveal any meaningful protection against IRIS.[39] An older study proposing the beneficial effect of interleukin-2 and granulocyte-macrophage colony-stimulating factor immunotherapy also did not prove to be of clinical benefit.[40]

In most clinical situations, when a patient who is initiated on a new medication develops an unexpected reaction, the most recently introduced medication is implicated as the cause of that reaction, and the reflex action is to discontinue that medication. However, when evaluating a patient with HIV and TB coinfection who develops IRIS after ART is initiated, it is very important to understand that the apparent clinical deterioration is in fact due to an immunologic improvement as seen by improved CD4 count compared to baseline.[6],[15],[33]

The first step in the management of suspected TB-IRIS is to review all the medications (ART and anti-TB medications) in detail, evaluating for potential side effects and drug-drug interactions.[8] Once adverse effect of the medications is ruled out, it is very important that ART and anti-TB medications be continued.[8],[9],[12],[32] Patients with TB-IRIS who present with mild reactions can be treated with nonsteroidal anti-inflammatory medications (ibuprofen, naproxen, and piroxicam).[8],[32] In contrast, TB-IRIS manifesting with severe reactions such as complicated pulmonary, cardiac, or neurologic symptoms are treated with systemic corticosteroids [8],[33],[41] with the caveat that corticosteroids themselves carry a risk of worsening infection and increased mortality in HIV patients.[42]

With the high prevalence of both TB and HIV in India, physicians need to be acutely aware of the possibility of IRIS in a patient with HIV and TB coinfection who develops an apparent deterioration after the initiation of ART. With improving access to ART, treating physicians should be alert to the manifestations of IRIS and take prompt and sound clinical measures to ensure that IRIS is diagnosed early and treatment measures are initiated appropriately. When the diagnosis of TB-IRIS is made, it is very important that ART not be interrupted because it remains the backbone of therapy to improve survival of HIV-infected individuals.



 
 :: References Top

1.
Available from: http://www.tbfacts.org/tb-statistics-india. [Last accessed on 2017 Feb 18].  Back to cited text no. 1
    
2.
Available from: http://www.avert.org/professionals/hiv-around-world/asia-pacific/india. [Last accessed on 2017 Feb 18].  Back to cited text no. 2
    
3.
Lifson JD, Engleman EG. Role of CD4 in normal immunity and HIV infection. Immunol Rev 1989;109:93-117.  Back to cited text no. 3
    
4.
Ruegg CL, Engleman EG. Impaired immunity in AIDS. The mechanisms responsible and their potential reversal by antiviral therapy. Ann N Y Acad Sci 1990;616:307-17.  Back to cited text no. 4
    
5.
Rosenberg ES, Altfeld M, Poon SH, Phillips MN, Wilkes BM, Eldridge RL, et al. Immune control of HIV-1 after early treatment of acute infection. Nature 2000;407:523-6.  Back to cited text no. 5
    
6.
Buchacz K, Baker RK, Moorman AC, Richardson JT, Wood KC, Holmberg SD, et al. Rates of hospitalizations and associated diagnoses in a large multisite cohort of HIV patients in the United States, 1994-2005. AIDS 2008;22:1345-54.  Back to cited text no. 6
    
7.
Available from: http://www.naco.gov.in/sites/default/files/English.pdf. [Last accessed on 2017 Feb 18].  Back to cited text no. 7
    
8.
Gopalan N, Chandrasekaran P, Swaminathan S, Tripathy S. Current trends and intricacies in the management of HIV-associated pulmonary tuberculosis. AIDS Res Ther 2016;13:34.  Back to cited text no. 8
    
9.
Varghese GM, Janardhanan J, Ralph R, Abraham OC. The twin epidemics of tuberculosis and HIV. Curr Infect Dis Rep 2013;15:77-84.  Back to cited text no. 9
    
10.
Munawwar A, Singh S. AIDS associated tuberculosis: A catastrophic collision to evade the host immune system. Tuberculosis (Edinb) 2012;92:384-7.  Back to cited text no. 10
    
11.
O'Donnell MR, Wolf A, Werner L, Horsburgh CR, Padayatchi N. Adherence in the treatment of patients with extensively drug-resistant tuberculosis and HIV in South Africa: A prospective cohort study. J Acquir Immune Defic Syndr 2014;67:22-9.  Back to cited text no. 11
    
12.
Abay SM, Deribe K, Reda AA, Biadgilign S, Datiko D, Assefa T, et al. The effect of early initiation of antiretroviral therapy in TB/HIV-coinfected patients: A Systematic review and meta-analysis. J Int Assoc Provid AIDS Care 2015;14:560-70.  Back to cited text no. 12
    
13.
Available from: https://www.aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. [Last accessed on 2017 Feb 04].  Back to cited text no. 13
    
14.
Uthman OA, Okwundu C, Gbenga K, Volmink J, Dowdy D, Zumla A, et al. Optimal timing of antiretroviral therapy initiation for HIV-infected adults with newly diagnosed pulmonary tuberculosis: A Systematic review and meta-analysis. Ann Intern Med 2015;163:32-9.  Back to cited text no. 14
    
15.
Shelburne SA 3rd, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, et al. Immune reconstitution inflammatory syndrome: Emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002;81:213-27.  Back to cited text no. 15
    
16.
French MA. Antiretroviral therapy. Immune restoration disease in HIV-infected patients on HAART. AIDS Read 1999;9:548-9, 554-5, 559-62.  Back to cited text no. 16
    
17.
French MA, Mallal SA, Dawkins RL. Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients. AIDS 1992;6:1293-7.  Back to cited text no. 17
    
18.
Fox PA, Barton SE, Francis N, Youle M, Henderson DC, Pillay D, et al. Chronic erosive herpes simplex virus infection of the penis, a possible immune reconstitution disease. HIV Med 1999;1:10-8.  Back to cited text no. 18
    
19.
Singh AK, Malhotra HS, Garg RK, Jain A, Kumar N, Kohli N, et al. Paradoxical reaction in tuberculous meningitis: Presentation, predictors and impact on prognosis. BMC Infect Dis 2016;16:306.  Back to cited text no. 19
    
20.
Lawn SD, Wood C, Lockwood DN. Borderline tuberculoid leprosy: An immune reconstitution phenomenon in a human immunodeficiency virus-infected person. Clin Infect Dis 2003;36:e5-6.  Back to cited text no. 20
    
21.
Ali NM, Nayak K, Kumar P. Nerve abscess in Hansen's disease as part of immune reconstitution inflammatory syndrome: A case report. Int J STD AIDS 2017;28:196-8.  Back to cited text no. 21
    
22.
Gopal R, Rapaka RR, Kolls JK. Immune reconstitution inflammatory syndrome associated with pulmonary pathogens. Eur Respir Rev 2017;26. pii: 160042.  Back to cited text no. 22
    
23.
French MA, Lenzo N, John M, Mallal SA, McKinnon EJ, James IR, et al. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000;1:107-15.  Back to cited text no. 23
    
24.
Siegel MO, Ghafouri S, Ajmera R, Simon GL. Immune reconstitution inflammatory syndrome, human herpesvirus 8 viremia, and HIV-associated multicentric castleman disease. Int J Infect Dis 2016;48:49-51.  Back to cited text no. 24
    
25.
Kumarasamy N, Chaguturu S, Mayer KH, Solomon S, Yepthomi HT, Balakrishnan P, et al. Incidence of immune reconstitution syndrome in HIV/tuberculosis-coinfected patients after initiation of generic antiretroviral therapy in India. J Acquir Immune Defic Syndr 2004;37:1574-6.  Back to cited text no. 25
    
26.
Karmakar S, Sharma SK, Vashishtha R, Sharma A, Ranjan S, Gupta D, et al. Clinical characteristics of tuberculosis-associated immune reconstitution inflammatory syndrome in North Indian population of HIV/AIDS patients receiving HAART. Clin Dev Immunol 2011;2011:239021.  Back to cited text no. 26
    
27.
Kumar SR, Gopalan N, Patrawalla P, Menon P, Mayer K, Swaminathan S, et al. Immune reconstitution inflammatory syndrome in HIV-infected patients with and without prior tuberculosis. Int J STD AIDS 2012;23:419-23.  Back to cited text no. 27
    
28.
Link-Gelles R, Moultrie H, Sawry S, Murdoch D, Van Rie A. Tuberculosis immune reconstitution inflammatory syndrome in children initiating antiretroviral therapy for HIV infection: A systematic literature review. Pediatr Infect Dis J 2014;33:499-503.  Back to cited text no. 28
    
29.
Jaganmohan D, Chakkalakkoombil SV, Beena AA, Krishnan N. Neurotuberculosis immune reconstitution inflammatory syndrome in the setting of HIV infection: A case report and review of literature. Indian J Radiol Imaging 2016;26:446-50.  Back to cited text no. 29
[PUBMED]  [Full text]  
30.
Jain S, Bajgai P, Tigari B, Sharma K, Sharma A, Gupta V, et al. Bevacizumab for paradoxical worsening treatment adjunct in HIV patient with choroidal tuberculoma. J Ophthalmic Inflamm Infect 2016;6:42.  Back to cited text no. 30
    
31.
Agarwal U, Kumar A, Behera D, French MA, Price P. Tuberculosis associated immune reconstitution inflammatory syndrome in patients infected with HIV: Meningitis a potentially life threatening manifestation. AIDS Res Ther 2012;9:17.  Back to cited text no. 31
    
32.
Rapose A, Sarvat B, Sarria JC. Immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. Cardiology 2008;110:142-4.  Back to cited text no. 32
    
33.
Dibyendu D, Sarkar RN, Phaujdar S, Bhattacharyya K, Pal HK. Incidence and risk factors of immune reconstitution inflammatory syndrome in HIV-TB coinfected patients. Braz J Infect Dis 2011;15:553-9.  Back to cited text no. 33
    
34.
Shankar EM, Vignesh R, Velu V, Murugavel KG, Sekar R, Balakrishnan P, et al. Does CD4+CD25+foxp3+ cell (Treg) and IL-10 profile determine susceptibility to immune reconstitution inflammatory syndrome (IRIS) in HIV disease? J Inflamm (Lond) 2008;5:2.  Back to cited text no. 34
    
35.
Vignesh R, Kumarasamy N, Lim A, Solomon S, Murugavel KG, Balakrishnan P, et al. TB-IRIS after initiation of antiretroviral therapy is associated with expansion of preexistent th1 responses against Mycobacterium tuberculosis antigens. J Acquir Immune Defic Syndr 2013;64:241-8.  Back to cited text no. 35
    
36.
Tan HY, Yong YK, Andrade BB, Shankar EM, Ponnampalavanar S, Omar SF, et al. Plasma interleukin-18 levels are a biomarker of innate immune responses that predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome. AIDS 2015;29:421-31.  Back to cited text no. 36
    
37.
Andrade BB, Singh A, Narendran G, Schechter ME, Nayak K, Subramanian S, et al. Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome. PLoS Pathog 2014;10:e1004433.  Back to cited text no. 37
    
38.
Stek C, Schutz C, Blumenthal L, Thienemann F, Buyze J, Nöstlinger C, et al. Preventing paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome in high-risk patients: Protocol of a randomized placebo-controlled trial of prednisone (PredART trial). JMIR Res Protoc 2016;5:e173.  Back to cited text no. 38
    
39.
Sierra-Madero JG, Ellenberg SS, Rassool MS, Tierney A, Belaunzarán-Zamudio PF, López-Martínez A, et al. Effect of the CCR5 antagonist maraviroc on the occurrence of immune reconstitution inflammatory syndrome in HIV (CADIRIS): A double-blind, randomised, placebo-controlled trial. Lancet HIV 2014;1:e60-7.  Back to cited text no. 39
    
40.
Pires A, Nelson M, Pozniak AL, Fisher M, Gazzard B, Gotch F, et al. Mycobacterial immune reconstitution inflammatory syndrome in HIV-1 infection after antiretroviral therapy is associated with deregulated specific T-cell responses: Beneficial effect of IL-2 and GM-CSF immunotherapy. J Immune Based Ther Vaccines 2005;3:7.  Back to cited text no. 40
    
41.
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. 41
    
42.
Fernández-Sánchez M, Iglesias MC, Ablanedo-Terrazas Y, Ormsby CE, Alvarado-de la Barrera C, Reyes-Terán G, et al. Steroids are a risk factor for kaposi's sarcoma-immune reconstitution inflammatory syndrome and mortality in HIV infection. AIDS 2016;30:909-14.  Back to cited text no. 42
    




 

Top
Print this article  Email this article
 
Online since 12th February '04
2004 - Journal of Postgraduate Medicine
Official Publication of the Staff Society of the Seth GS Medical College and KEM Hospital, Mumbai, India
Published by Wolters Kluwer - Medknow