Review
Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals

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Summary

Immune reconstitution disease (IRD) in HIV-infected patients is an adverse consequence of the restoration of pathogen-specific immune responses during the initial months of highly active antiretroviral treatment (HAART). Previously subclinical infections are “unmasked” or pre-existing opportunistic infections clinically deteriorate as host immunopathological inflammatory responses are “switched on”. IRD is most frequently associated with mycobacterial infections. Our literature search identified 166 published cases of IRD associated with mycobacterial infections. We review the underlying immunological mechanisms, difficulties surrounding case definition and diagnosis, the wide diversity of clinical manifestations, and treatment. The importance of screening patients for mycobacterial disease before starting HAART and the critical impact of the timing of commencement of HAART in patients receiving treatment for tuberculosis are highlighted. We also discuss the problem of IRD associated with mycobacterial diseases in developing countries where tuberculosis prevalence is high and access to HAART is currently expanding.

Introduction

Mycobacterial opportunistic infections are a major cause of morbidity and mortality among patients living with HIV/AIDS worldwide. Mycobacterium avium complex (MAC) is among the most common opportunistic bacterial infections in those with advanced immunodeficiency living in industrialised countries1 and tuberculosis is the leading cause of morbidity and mortality in those with HIV/AIDS living in low income countries.2 A variety of other non-tuberculous mycobacteria, including Mycobacterium kansasii and Mycobacterium xenopi, are also recognised opportunistic pathogens, principally occurring in late-stage disease. Since the mid 1990s, however, a dramatic decline in HIV-associated morbidity and mortality has been observed in countries where highly active antiretroviral treatment (HAART) has been widely available.3, 4 Prophylaxis or treatment of many opportunistic infections, including disseminated MAC infection, can be discontinued among patients who have responded to HAART.5, 6 Several studies have also shown that the incidence of tuberculosis decreases by approximately 70–90% in treated cohorts living in high and low income countries.7, 8, 9, 10

The major beneficial effects of HAART result from gradual restoration of pathogen-specific immune responses. However, during the initial months of HAART immune reconstitution is complicated by adverse clinical phenomena in which either previously subclinical infections are “unmasked” or pre-existing partly treated opportunistic infections clinically deteriorate. These clinical phenomena are thought to result from immunopathological host inflammatory responses being “switched on”. Such phenomena have been variously termed immune reconstitution syndrome, immune reconstitution inflammatory syndrome, immune restoration disease, immunorestitution disease, and immune reconstitution phenomena. Here, we use the term immune reconstitution disease (IRD).

IRD is not a new phenomenon, nor is it specific to HIV-infected individuals receiving HAART. Indeed, the potential for IRD exists whenever patients who have been severely immunocompromised have rapid restoration of immune function. Thus, for example, similar phenomena are recognised following a dosage reduction or withdrawal of steroids and among patients in whom the absolute neutrophil count in the blood recovers following either cytotoxic chemotherapy or bone marrow transplantation.11, 12 The potential pathogens involved in IRD reflect the spectrum of opportunistic infections associated with the specific form of immunosuppression. For example, fungal and pyogenic infections typically present as IRD following recovery from neutropenia.11

IRD is most frequently reported in patients with HIV infection receiving HAART. In such patients, IRD has been associated with a range of opportunistic infections, including cytomegalovirus, hepatitis B and C viruses, Pneumocystis carenii, Cryptococcus neoformans, herpesviruses, progressive multifocal leucoencephalopathy (caused by JC virus), leishmaniasis, and cerebral toxoplasmosis.13, 14, 15, 16 However, mycobacteria are the infections most frequently implicated in IRD, causing approximately 40% of the cases reported up to 2002.13

Section snippets

Paradoxical reactions to antimycobacterial treatment

Before considering IRD triggered by HAART, it is important to consider the related phenomenon of paradoxical reactions, which occurs in some patients receiving treatment for certain mycobacterial infections, irrespective of HIV status. Paradoxical reactions are observed among 2–23% of HIV-seronegative patients receiving treatment for tuberculosis17, 18, 19, 20 and are generally defined as the clinical or radiological deterioration of pre-existing tuberculous lesions or the development of new

Definition and diagnosis of IRD

A precise definition of antiretroviral-associated IRD in HIV-infected patients is difficult to establish. IRD could be defined as the presentation or clinical deterioration of opportunistic infections in HIV-infected patients as a direct result of the enhancement of immune responses to those pathogens during HAART. However, in clinical practice, it may be difficult to either demonstrate or refute a causal relation between starting HAART and development of such clinical phenomena. Competing

HIV and the host response to Mycobacterium tuberculosis

IRD associated with mycobacteria is best understood in the context of existing knowledge of host responses to these pathogens and how these are affected by HIV. Following failure of innate immune responses to prevent Mycobacterium tuberculosis infection, cell-mediated responses develop. Interleukin 12 and interleukin 2 drive the clonal expansion of CD4 lymphocytes that secrete interferon γ, a potent macrophage activator. Chemokines such as interleukin 8, and proinflammatory cytokines such as

Mechanisms of IRD

The development of HAART using combinations of reverse transcriptase and protease inhibitors in 1995 marked the dawn of a new era in HIV management. For the first time, major reductions in plasma viral load were associated with substantial increases in circulating CD4 lymphocyte numbers and restoration of immune function.38, 39, 40 The extremely rapid reversal in immune function gives rise to IRD by switching on immunopathological host responses.

A reduction in plasma viral load of more than 90%

IRD and Mycobacterium avium complex

MAC typically causes disease in patients with AIDS and end-stage immunodeficiency. Usually, the organism can be cultured from a disseminated infection in the blood or bone marrow; focal organ disease is infrequent. The first reports of IRD associated with HAART were among HIV-infected patients presenting with unusual clinical manifestations of MAC infection, such as localised lymphadenitis or endobronchial mass lesions (table 1). Biopsy samples showed an unusual degree of inflammation and

IRD and M tuberculosis

By contrast with MAC, IRD associated with M tuberculosis was not reported among individuals receiving zidovudine monotherapy. The first reports of M tuberculosis-associated IRD were in 1998 after the advent of HAART (table 2). Because paradoxical reactions to antituberculosis treatment have long been recognised, clinical deterioration attributable to zidovudine-mediated IRD may have simply been ascribed to a “normal” paradoxical reaction. Clinically apparent paradoxical reactions are reported

IRD and other mycobacteria

IRD associated with other non-tuberculous mycobacteria and BCG are infrequent and are described among only 16 patients (table 3), comprising 10% of all cases reviewed. Isolation of M xenopi from sputum is uncommonly associated with disease and the need for routine treatment of this organism in HIV-infected individuals receiving HAART is doubtful.98 However, this organism has been implicated in IRD with pulmonary disease in four patients, including the development of cavitation and a pleural

Prevention and treatment of IRD

From the cases reviewed, it is clear that the vast majority of cases of IRD develop in patients with a nadir CD4 lymphocyte count of less than 100 cells/μL (median <50 cells/μL), a viral load of more than 105 copies/mL, and with a rapid response to combination antiretroviral treatment. This finding is to be expected since advanced immunodeficiency is associated with increased likelihood of subclinical mycobacterial infections, high mycobacterial antigen load, increased likelihood of

IRD in developing countries

HAART is now becoming more widely accessible in developing countries where HIV is associated with a different spectrum of opportunistic infections, often with a very high incidence of tuberculosis.105 Newly established community-based antiretroviral projects in developing countries are being accessed by increasing numbers of adults and children with advanced symptomatic disease and profound CD4 lymphocytopenia. Our experience in Cape Town is that M tuberculosis-associated IRD is emerging as a

Search strategy and selection criteria

Multiple Medline searches of literature published in English were done using the following terms: “immune restoration”, “immune reconstitution”, “immune restitution”, “immunorestitution”, “immune reconstitution inflammatory syndrome”, “IRIS”, “paradox*”, “HIV”, “AIDS”, “mycobacter*”, “tuberculosis”, “leprosy”, “BCG” and “Bacille Calmette-Guerin”. Searches were complete up to the end of February 2005. Many additional references were identified from citations in other published papers.

References (105)

  • EM Race et al.

    Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease

    Lancet

    (1998)
  • GM Behrens et al.

    Immune reconstitution syndromes in human immuno-deficiency virus infection following effective antiretroviral therapy

    Immunobiology

    (2000)
  • H Thaker et al.

    Localized Mycobacterium avium complex infection in a patient on HAART

    Clin Microbiol Infect

    (2000)
  • SJ Buckingham et al.

    Immune reconstitution inflammatory syndrome in HIV-infected patients with mycobacterial infections starting highly active anti-retroviral therapy

    Clin Radiol

    (2004)
  • JW Chien et al.

    Paradoxical reactions in HIV and pulmonary TB

    Chest

    (1998)
  • H Furrer et al.

    Systemic inflammatory reaction after starting highly active antiretroviral therapy in AIDS patients treated for extrapulmonary tuberculosis

    Am J Med

    (1999)
  • KA Wendel et al.

    Paradoxical worsening of tuberculosis in HIV-infected persons

    Chest

    (2001)
  • SD Nightingale et al.

    Incidence of Mycobacterium avium-intracellulare complex bacteremia in human immunodeficiency virus-positive patients

    J Infect Dis

    (1992)
  • EL Corbett et al.

    The growing burden of tuberculosis: global trends and interactions with the HIV epidemic

    Arch Intern Med

    (2003)
  • FJ Palella et al.

    Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection

    N Engl J Med

    (1998)
  • JE Kaplan et al.

    Epidemiology of human immunodeficiency virus-associated opportunistic infections in the United States in the era of highly active antiretroviral therapy

    Clin Infect Dis

    (2000)
  • JS Currier et al.

    Discontinuation of Mycobacterium avium complex prophylaxis in patients with antiretroviral therapy-induced increases in CD4+ cell count. A randomized, double-blind, placebo-controlled trial

    Ann Intern Med

    (2000)
  • B Ledergerber et al.

    AIDS-related opportunistic illnesses occurring after initiation of potent antiretroviral therapy: the Swiss HIV Cohort Study

    JAMA

    (1999)
  • G Santoro-Lopes et al.

    Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy

    Clin Infect Dis

    (2002)
  • E Girardi et al.

    Impact of combination antiretroviral therapy on the risk of tuberculosis among persons with HIV infection

    AIDS

    (2000)
  • VC Cheng et al.

    Immunorestitution diseases in patients not infected with HIV

    Eur J Clin Microbiol Infect Dis

    (2001)
  • VC Cheng et al.

    Immunorestitution disease involving the innate and adaptive response

    Clin Infect Dis

    (2000)
  • SA Shelburne et al.

    Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy

    Medicine (Baltimore)

    (2002)
  • MA French et al.

    Immune restoration disease after antiretroviral therapy

    AIDS

    (2004)
  • JA DeSimone et al.

    Inflammatory reactions in HIV-1-infected persons after initiation of highly active antiretroviral therapy

    Ann Intern Med

    (2000)
  • SA Shelburne et al.

    The immune reconstitution inflammatory syndrome

    AIDS Rev

    (2003)
  • JE Fishman et al.

    Pulmonary tuberculosis in AIDS patients: transient chest radiographic worsening after initiation of antiretroviral therapy

    AJR Am J Roentgenol

    (2000)
  • M Narita et al.

    Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS

    Am J Respir Crit Care Med

    (1998)
  • RA Breen et al.

    Paradoxical reactions during tuberculosis treatment in patients with and without HIV co-infection

    Thorax

    (2004)
  • VC Cheng et al.

    Risk factors for development of paradoxical response during antituberculosis therapy in HIV-negative patients

    Eur J Clin Microbiol Infect Dis

    (2003)
  • VC Cheng et al.

    Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients

    Eur J Clin Microbiol Infect Dis

    (2002)
  • M Markman et al.

    Paradoxical clinical improvement and radiographic deterioration in anergic patients treated for far advanced tuberculosis

    N Engl J Med

    (1981)
  • LG Bekker et al.

    Selective increase in plasma tumor necrosis factor-alpha and concomitant clinical deterioration after initiating therapy in patients with severe tuberculosis

    J Infect Dis

    (1998)
  • SD Lawn et al.

    Elevated serum concentrations of soluble CD14 in HIV- and HIV+ patients with tuberculosis in Africa: prolonged elevation during anti-tuberculosis treatment

    Clin Exp Immunol

    (2000)
  • NA Foudraine et al.

    Immunopathology as a result of highly active antiretroviral therapy in HIV-1-infected patients

    AIDS

    (1999)
  • MA French et al.

    Zidovudine-induced restoration of cell-mediated immunity to mycobacteria in immunodeficient HIV-infected patients

    AIDS

    (1992)
  • MA French et al.

    Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy

    HIV Med

    (2000)
  • JF Morlese et al.

    Plasma IL-6 as a marker of mycobacterial immune restoration disease in HIV-1 infection

    AIDS

    (2003)
  • SD Lawn et al.

    Sustained plasma TNF-alpha and HIV-1 load despite resolution of other parameters of immune activation during treatment of tuberculosis in Africans

    AIDS

    (1999)
  • BM Saunders et al.

    Restraining mycobacteria: role of granulomas in mycobacterial infections

    Immunol Cell Biol

    (2000)
  • HC Lane et al.

    Qualitative analysis of immune function in patients with the acquired immunodeficiency syndrome. Evidence for a selective defect in soluble antigen recognition

    N Engl J Med

    (1985)
  • B Spellberg et al.

    Type 1/type 2 immunity in infectious diseases

    Clin Infect Dis

    (2001)
  • SD Lawn et al.

    Anatomically compartmentalized human immunodeficiency virus replication in HLA-DR+ cells and CD14+ macrophages at the site of pleural tuberculosis coinfection

    J Infect Dis

    (2001)
  • B Autran et al.

    Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease

    Science

    (1997)
  • MM Lederman

    Immune restoration and CD4+ T-cell function with antiretroviral therapies

    AIDS

    (2001)
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