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Year : 2015  |  Volume : 36  |  Issue : 2  |  Page : 207-210

Abstracts from current global literature: Immune reconstitution inflammatory syndrome

Department of Skin and VD, Medical College Baroda, Vadodara, Gujarat, India

Date of Web Publication12-Oct-2015

Correspondence Address:
Dimpal Patel
Department of Skin and VD, Baroda Medical College, Vadodara, Gujarat
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Source of Support: None, Conflict of Interest: None

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How to cite this article:
Patel D, Jose SK, Marfatia YS. Abstracts from current global literature: Immune reconstitution inflammatory syndrome. Indian J Sex Transm Dis 2015;36:207-10

How to cite this URL:
Patel D, Jose SK, Marfatia YS. Abstracts from current global literature: Immune reconstitution inflammatory syndrome. Indian J Sex Transm Dis [serial online] 2015 [cited 2021 Jul 25];36:207-10. Available from:

Human immunodeficiency virus and immune reconstitution inflammatory syndrome

Sharm SK, Soneja M. Indian J Med Res 2011;134:866-77.

Antiretroviral therapy (ART) initiation in human immunodeficiency virus (HIV)-infected patients lead to the recovery of CD4 + T-cell numbers and restoration of protective immune responses against a wide variety of pathogens, resulting in reduction in the frequency of opportunistic infections and prolonged survival. However, in a subset of patient's dysregulated immune response after initiation of ART leads to the phenomenon of immune reconstitution inflammatory syndrome (IRIS). The hallmark of the syndrome is a paradoxical worsening of an existing infection or disease process or appearance of a new infection/disease process soon after initiation of therapy. The overall incidence of IRIS is unknown but is dependent on the population studied and the burden of underlying opportunistic infections. The immunopathogenesis of the syndrome is unclear and appears to be the result of unbalanced reconstitution of effector and regulatory T-cells, leading to an exuberant inflammatory response in patients receiving ART. Biomarkers, including interferon-γ, tumor necrosis factor-α, C-reactive protein, and interleukin-2, 6, and 7, are subject of intense investigation at present. The most common forms of IRIS are associated with mycobacterial infections, fungi, and herpes viruses. The majority of the patients with IRIS have a self-limiting disease course. ART is usually continued and treatment for the associated condition optimized. The overall mortality associated with IRIS is low; however, the patients with central nervous system involvement with raised intracranial pressures in cryptococcal and tubercular meningitis, and respiratory failure due to acute respiratory distress syndrome have poor prognosis and require an aggressive management including corticosteroids. Paradigm shifts in the management of HIV with earlier initiation of ART is expected to decrease the burden of IRIS in developed countries; however, with enhanced rollout of ART in recent years, and the enormous burden of opportunistic infections in developing countries like India, IRIS is likely to remain an area of major concern.

Immune reconstitution inflammatory syndrome: The trouble with immunity when you had none

Barber BL, Andrade BB, Sereti I, Sher A. Nature Reviews Microbiology 2012;150-6.

Some individuals who are infected with human immunodeficiency virus rapidly deteriorate shortly after starting antiretroviral therapy, despite effective viral suppression. This reaction, referred to as immune reconstitution inflammatory syndrome (IRIS), is characterized by tissue-destructive inflammation and arises as CD4 + T-cells re-emerge. It has been proposed that IRIS is caused by a dysregulation of the expanding population of CD4 + T-cells specific for a co-infecting opportunistic pathogen. Here, we argue that IRIS instead results from hyper-responsiveness of the innate immune system to T-cell help, a mechanism that may be shared by the many manifestations of IRIS that occur following the reversal of other types of immunosuppression in pathogen-infected hosts.

Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for human immunodeficiency virus infection: A systematic review and meta-analysis

Monika Müller M, Simon Wandel S, Colebunders R, Attia S, Furrer H, Egger M. The Lancet Infectious Disease 2010;10:251-61.

In patients with human immunodeficiency virus-1 infection who are starting combination antiretroviral therapy (ART), the incidence of immune reconstitution inflammatory syndrome (IRIS) is not well-defined. We did a meta-analysis to establish the incidence and lethality of the syndrome in patients with a range of previously diagnosed opportunistic infections and examined the relation between the occurrence and the degree of immunodeficiency. A systematic review identified 54 cohort studies of 13,103 patients starting ART, of whom 1699 developed IRIS. We calculated pooled cumulative incidences with 95% credibility intervals (CrI) by Bayesian methods and did a random-effects metaregression to analyze the relation between CD4 cell count and incidence of IRIS. In patients with previously diagnosed AIDS-defining illnesses, IRIS developed in 37.7% (95% CrI 26.6-49.4) of those with cytomegalovirus retinitis, 19.5% (6.7-44.8) of those with cryptococcal meningitis, 15.7% (9.7-24.5) of those with tuberculosis, 16.7% (2.3-50.7) of those with progressive multifocal leukoencephalopathy, and 6.4% (1.2-24.7) of those with Kaposi's sarcoma, and 12.2% (6.8-19.6) of those with herpes zoster. 16.1% (11.1-22.9) of unselected patients starting ART developed any type of IRIS. 4.5% (2.1-8.6) of patients with any type of IRIS died, 3.2% (0.7-9.2) of those with tuberculosis-associated IRIS died, and 20.8% (5.0-52.7) of those with cryptococcal meningitis died. Metaregression analyses showed that the risk of IRIS is associated with CD4 cell count at the start of ART, with a high risk in patients with fewer than 50 cells/μL. The occurrence of IRIS might, therefore, be reduced by the initiation of ART before immunodeficiency becomes advanced.

A rare case of immune reconstitution inflammatory syndrome presenting as secondary syphilis

Khatri A, Skalweit MJ. Int J STD AIDS 2015;26:749-51.

Immune reconstitution syndrome has rarely been reported in the context of syphilis infection. We report a patient with AIDS (CD4 42 cells/mm 3 , viral load 344,000 cp/ml), treated previously for secondary syphilis and started on an integrase inhibitor-based single-tablet antiretroviral treatment regimen. After 4 weeks of antiretroviral treatment, he presented with nontender, nonblanching erythematous nodules on his chest, an elevated rapid plasma reagin (1:1024), and immune reconstitution (CD4 154 cells/mm 3 , human immunodeficiency virus-RNA 130 cp/ml). A detailed workup to exclude the opportunistic infections including secondary and neurosyphilis was performed. The patient was continued on antiretroviral treatment and treated empirically for neurosyphilis given cerebrospinal lymphocytosis and dermatopathology suggesting treponemal antigen-driven B-cell hyperplasia. We favor a diagnosis of immune reconstitution in association with prior syphilis infection attributable to rapid and potent immune restoration afforded by integrase inhibitors.

Recurrent giant molluscum contagiosum immune reconstitution inflammatory syndrome after initiation of antiretroviral therapy in a human immunodeficiency virus-infected man

Drain PK, Mosam A, Gounder L, Gosnell B, Manzini T, Moosa M-Y S. Int J STD AIDS 2014;25:235-8.

We describe a human immunodeficiency virus-infected South African man who experienced two distinct episodes of disseminated giant molluscum contagiosum immune reconstitution inflammatory syndrome (IRIS) over a 6-year period. The first episode of molluscum contagiosum IRIS occurred with rapid virologic suppression following antiretroviral therapy initiation. The second episode occurred during a rapid increase in CD4 cells following stable viral suppression with second-line antiretroviral therapy. His molluscum contagiosum lesions then completely resolved during a reduction in CD4 count, despite maintaining virologic suppression. Nearly, 1-year after the resolution of his giant molluscum contagiosum IRIS lesions, he maintains an undetectable viral load, but his level of immune deficiency has not improved. In the absence of well-controlled therapeutic trials, molluscum contagiosum IRIS presents important management challenges.

Early development of immune reconstitution inflammatory syndrome related to Pneumocystis pneumonia after antiretroviral therapy

Mok HP, Hart E, Venkatesan P. Int J STD AIDS 2014;25:373-7.

Immune reconstitution inflammatory syndrome (IRIS) is a recognized complication after the initiation of combination antiretroviral therapy (cART). We report a patient who developed life-threatening pulmonary IRIS 3 days after initiation of cART. We reviewed published cases of IRIS after Pneumocystis pneumonia (PCP), in particular, the time from initiation of cART to IRIS event. The median duration from the initiation of cART to the onset of IRIS was 15 days in the 33 patients reviewed. This report alerts the clinicians to the rapidity of the development of pulmonary IRIS following PCP after the initiation of cART.

Immune reconstitution inflammatory syndrome associated with Kaposi's sarcoma.

Bower M, Nelson M, Young AM, Thirlwell C, Newsom-Davis T, Mandalia S, Dhillon T, Holmes P, Gazzard BG, Stebbing J. J Clin Oncol 2005;23:5224-8.

Purpose: A proportion of patients with human immunodeficiency virus (HIV) infection who subsequently receive highly active antiretroviral therapy (HAART) exhibits a deterioration in their clinical status, despite the control of virologic and immunologic parameters. This clinical response, known as the immune reconstitution inflammatory syndrome (IRIS), occurs secondary to an immune response against previously diagnosed pathogens. Patients and Methods: From our cohort of 5832 patients treated in the HAART era, we identified 150 therapy-naive patients with a first presentation of Kaposi's sarcoma (KS). Their clinicopathologic features and progress were recorded prospectively. Results: After commencing HAART, 10 patients (6.6%) developed progressive KS, which we identify as IRIS-associated KS. In a comparison of these individuals with those whose KS did not progress, we found that IRIS-KS occurred in patients with higher CD4 counts (P = 0.03), KS-associated edema (P = 0.01), and therapy with both protease inhibitors and nonnucleosides together (P = 0.03). Time to treatment failure was similar for both groups, although the CD4 count declined more rapidly at first, in those patients with IRIS-associated KS. Despite this initial decline, in our clinical experience HAART could be successfully continued in those with IRIS-associated KS. Conclusion: We have identified IRIS-KS in a cohort of HIV patients with KS, who start HAART.

Herpes zoster infection as an immune reconstitution inflammatory syndrome in human immunodeficiency virus-seropositive subjects: A review

Feller L, Wood NH, Lemmer J. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:455-60.

The use of highly active antiretroviral therapy (HAART) in the management of human immunodeficiency virus (HIV) infection has resulted paradoxically in the worsening of clinical symptoms of previously subclinical infections, such as herpes zoster (HZ), herpes simplex, angular cheilitis, warts, tuberculosis, hepatitis B and C, cytomegalovirus retinitis, and others, as a result of substantial reconstitution of the host's immune responses. This phenomenon is referred to as immune reconstitution inflammatory syndrome (IRIS). It may affect up to 32% of HIV-seropositive subjects within a wide range of time after the initiation of HAART but mainly after 8-12 weeks. Mucocutaneous HZ accounts for 7-12% of the diseases associated with HIV infection that become worse again when the subject's immunity improves from the administration of HAART. It usually occurs after 4 weeks from the initiation of HAART, and under these circumstances, the clinical symptoms and natural course of mucocutaneous HZ are similar to those in HIV-seropositive subjects who do not manifest IRIS.

Paradoxical immune reconstitution inflammatory syndrome in human immunodeficiency virus-infected patients treated with combination antiretroviral therapy after AIDS-defining opportunistic infection

Achenbach CJ, Harrington RD, Dhanireddy S, Crane HM, Casper C, Kitahata MM. Clin Infect Dis 2012;54:424-433.

Background: The incidence of immune reconstitution inflammatory syndrome (IRIS) when antiretroviral therapy (ART) is initiated after an AIDS-defining opportunistic infection (OI) is uncertain and understudied for the most common OIs. Methods: We examined patients in the University of Washington human immunodeficiency virus Cohort initiating potent ART subsequent to an AIDS-defining OI. IRIS was determined through retrospective medical record review and adjudication using a standardized data collection process and clinical case definition. We compared demographic and clinical characteristics and immunologic changes in patients with and without IRIS. Results: Among 196 patients with 260 OIs, 21 (11%; 95% confidence interval, 7-16%) developed paradoxical IRIS in the 1 st year of ART. The 3 most common OIs among study patients were Pneumocystis pneumonia (PCP, 28%), Candida esophagitis (23%), and Kaposi sarcoma (KS, 16%). Cumulative 1-year incidence of IRIS was 29% (12/41) for KS, 16% (4/25) for tuberculosis, 14% (1/7) for Cryptococcus, 10% (1/10) for Mycobacterium avium complex, and 4% (3/72) for PCP. Morbidity and mortality were highest in those with visceral KS-IRIS compared with other types of IRIS (100% [6/6] vs. 7% [1/15], P < 0.01). Patients with mucocutaneous KS and tuberculosis-IRIS experienced greater median increase in CD4 + cell count during the first 6 months of ART compared with those without IRIS (+158 vs. +53 cells/μL, P = 0.04, mucocutaneous KS; +261 vs. +113, P = 0.04, tuberculosis). Conclusions: Cumulative incidence and features of IRIS varied depending on the OI. IRIS occurred in >10% of patients with KS, tuberculosis, or Cryptococcus. Visceral KS-IRIS led to considerable morbidity and mortality.

Impact of the immune reconstitution inflammatory syndrome on mortality and morbidity in human immunodeficiency virus-infected patients in Mexico

Hoyo-Ulloa I, Belaunzarαn-Zamudio PF, Crabtree-Ramirez B, Galindo-Fraga A, Pérez-Aguinaga ME, Sierra-Madero JG. Int J Infect Dis 2011;15:E408-14.

Objectives: To estimate the impact of immune reconstitution inflammatory syndrome (IRIS) on morbidity and mortality in patients starting highly active antiretroviral therapy (HAART). Methods: A retrospective cohort study of human immunodeficiency virus-positive patients starting HAART was conducted at a tertiary care referral center in Mexico City. We estimated the incidence of IRIS, hospitalizations, and death rates during the first 2 years of HAART. The relative risk (RR) of death and hospitalization for patients with IRIS were adjusted for relevant covariates using regression methods. Results: During the 2-year follow-up period, 27% of patients developed IRIS (14 IRIS cases per 100 person-years). The RR of death among patients who developed IRIS was 3 times higher (95% confidence interval (CI) 1.19-7.65, P = 0.03). After adjusting for previous opportunistic infections, we still observed a higher death rate among patients with IRIS (RR 2.3, 95% CI 0.9-5.9, P = 0.09). An effect modification of IRIS over mortality was observed by previous opportunistic infection. Conclusions: IRIS-associated mortality is strongly confounded by previous opportunistic infection. Patients with AIDS, who eventually developed IRIS, had the highest risk of death at the 2-year follow-up.


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