Pulmonary Perspective Immune Reconstitution and “Unmasking” of Tuberculosis during Antiretroviral Therapy

Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925, Cape Town, South Africa.
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 05/2008; 177(7):680-5. DOI: 10.1164/rccm.200709-1311PP
Source: PubMed


Tuberculosis (TB) is the most common opportunistic disease in HIV-infected patients during the initial months of antiretroviral therapy (ART) and presents a great challenge to ART programs in resource-limited settings. The mechanisms underlying development of TB in this period are complex. Some cases may represent progression of undiagnosed subclinical disease present before starting ART, emphasizing the importance of careful screening strategies for TB. It has been suggested that progression in such cases is due to immune reconstitution disease-a phenomenon in which dysregulated restoration of pathogen-specific immune responses triggers the presentation of subclinical disease. However, whereas some cases have exaggerated or overtly inflammatory manifestations consistent with existing case definitions for IRD, many others do not. Moreover, since ART-induced immune recovery is a time-dependent process, active TB may develop as a consequence of persisting immunodeficiency. All these mechanisms are likely to be important, representing a spectrum of complex interactions between mycobacterial burden and changing host immune response. We propose that the potential range of effects of ART includes (1) shortening of the time for subclinical TB to become symptomatic (a phenomenon often referred to as "unmasking"), (2) increased rapidity of initial onset of TB symptoms, and (3) heightened intensity of clinical manifestations. We suggest that the term "ART-associated TB" be used to refer collectively to all cases of TB presenting during ART and that "immune reconstitution disease" be used to refer to the subset of ART-associated TB cases in which the effect on disease severity results in exaggerated and overtly inflammatory disease.

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    • "The sample size for this analysis was small so there was limited power to investigate effects by duration of ART. Some patients might have had active subclinical disease at the time of ART initiation and presentation of symptomatic disease might have arisen from ART-induced restoration of an immune reaction against M. tuberculosis (unmasking) [21]. There is a suggestion that cavitation was more common later, which would be expected with further improvement in immune function [27]. "
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    ABSTRACT: HIV infection reduces the likelihood that individuals with pulmonary tuberculosis are smear positive and that they have cavitatory disease. Antiretroviral therapy (ART) may shift the pattern of disease to be more similar to that of HIV negative patients. This would aid diagnosis- which often depends on sputum smears - but would also increase infectiousness. We assessed the effect of HIV and ART on smear positivity and cavitatory disease in laboratory-confirmed pulmonary TB patients. Three sputum samples were collected per pulmonary TB suspect and were examined using microscopy and culture. Chest radiographs were available for a subset of patients as part of another study. The effect of HIV and ART status on sputum smear positivity and lung cavitation were evaluated using multivariable logistic regression. Of 1024 laboratory-confirmed pulmonary TB patients who were identified between January 2005 and December 2011, 766 had HIV and ART status available. Positive sputum smears were significantly more common among HIV negative individuals than HIV positive individuals (adjusted OR = 2.91, 95% CI 1.53 - 5.55). Compared to those HIV positive but not on ART , patients on ART were more likely to be smear positive (adjusted OR = 2.33, 95% CI 1.01 - 5.39) if they had been on ART <= 6 months, but only slightly more likely to be smear positive (adjusted OR = 1.43, 95% CI 0.68 - 2.99) if they were on ART > 6 months. HIV negative patients were more likely than HIV positive patients to have cavitatory disease (adjusted OR = 1.97, 95% CI 1.20 - 3.23). Patients on ART > 6 months had a slight increase in cavitatory disease compared to HIV positive patients not on ART (adjusted OR = 1.68, CI 0.78 - 3.63). HIV infection is associated with less smear positivity and cavitation in pulmonary TB patients. Among HIV positive patients, the use of ART shifts the presentation of disease towards that seen in HIV-negative individuals, which facilitates diagnosis but which also could increase infectiousness.
    Full-text · Article · Feb 2014 · BMC Infectious Diseases
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    • "Secondly, immune reconstitution inflammatory syndrome (IRIS) may have been responsible for some of these cases. TB is the most frequently reported IRIS associated infection [21]. Though the available data did not permit making this distinction, it was known that IRIS occurred in the early initiation of HAART [22]. "
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    ABSTRACT: Tuberculosis (TB) is the leading killer of people living with HIV (PLHIV). Many of these deaths occur in developing countries. This study aimed at determining the incidence and predictors of tuberculosis among PLHIV. A five year retrospective follow up study was conducted among adult PLHIV. The Cox proportional hazards model was used to identify predictors. A total of 470 patients were followed and produced 1724.13 Person-Years (PY) of observation, and 136 new TB cases occurred during the follow up period. The overall incidence density of TB was 7.88 per 100 PY. It was high (95.9/100PY) in the first year of enrolment. The cumulative proportion of TB- free survivals was 79% and 67% at the end of the first and fifth years, respectively. Baseline WHO clinical stage III (AHR = 2.88, 95% CI = 1.53-5.43), WHO clinical stage IV (AHR = 3.82, 95% CI = 1.86-7.85), CD4 count <50 cell/ul (AHR = 2.13, 95%CI = 1.28-3.53) and ambulatory or bed ridden functional status (AHR = 1.64, 95%CI = 1.13-2.38) were predictors of time to TB occurrence. TB incidence rate among PLHIV, especially in the first year of enrollment was high. Advanced WHO clinical stage, limited functional status, and low CD4 count (<50 cell cell/ul) were found to be the independent predictors of TB occurrence. Early care seeking and initiation of HAART to improve the CD4 count and functional status are important to reduce the risk of TB infection.
    Full-text · Article · Jun 2013 · BMC Infectious Diseases
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    • "Antiretroviral therapy (ART) reduces the incidence of HIV-associated TB by 67%, but TB rates never reach those of the non-HIV-infected population (Lawn et al. 2005, 2010b). Early after ART initiation reactivation of TB-specific immune responses causes an increase in TB incidence, a phenomenon called 'unmasking' of TB (Lawn et al. 2008b; Manabe et al. 2009). This high incidence of TB early after the start of ART contributes to the early mortality among ART initiators in resource-limited settings (Lawn et al. 2008a; Castelnuovo et al. 2009). "
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    ABSTRACT: Objectives: To investigate whether an unrecognised diagnosis of tuberculosis (TB) at the start of antiretroviral therapy (ART) influences subsequent CD4+ T cell (CD4) count recovery in an urban HIV clinic in Uganda. Methods: In a retrospective cohort study, a multivariable polynomial mixed effects model was used to estimate CD4 recovery in the first 96 weeks of ART in two groups of patients: prevalent TB (started ART while on TB treatment), unrecognised TB (developed TB within 6 months after start ART). Results: Included were 511 patients with a median baseline CD4 count of 57 cells/mm(3) (interquartile range: 22-130), of whom 368 (72%) had prevalent TB and 143 (28%) had unrecognised TB. Compared with prevalent TB, unrecognised TB was associated with lower CD4 count recovery at 96 weeks: -22.3 cells/mm(3) (95% confidence interval -43.2 to -1.5, P = 0.036). These estimates were adjusted for gender, age, baseline CD4 count and the use of zidovudine-based regimen. Conclusions: Unrecognised TB at the time of ART initiation resulted in impaired CD4 recovery compared with TB treated before ART initiation. More vigilant screening with more sensitive and rapid TB diagnostics prior to ART initiation is needed to decrease the risk of ART-associated TB and sub-optimal immune reconstitution.
    Full-text · Article · Nov 2012 · Tropical Medicine & International Health
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