Unmasked Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Disease: A Disease Spectrum after Initiation of Antiretroviral Therapy

Manabe, Yukari C.; Breen, Ronan; Perti, Tara; Girardi, Enrico

doi:10.1086/595985

Cited by 78 publications

(54 citation statements)

References 48 publications

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“…21 However, TB unmasking often occurs in patients starting ART, suggesting that early reactivation or subclinical disease exists at the time of ART initiation. 22,23 In highly immunosuppressed patients, TB may be disseminated, smear-negative, and therefore difficult to diagnose with traditional clinical screening, including (sputum) smears. 24 In this trial in SSA, the primary objective was to assess the effect of presumptive anti-TB treatment on severely immunosuppressed, underweight, HIV-infected patients starting ART on 6-month mortality and to evaluate anti-TB medicationrelated toxicity.…”

Section: Introductionmentioning

confidence: 99%

Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial

Manabe

Worodria

Leth

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Abstract. Early mortality after initiation of antiretroviral therapy (ART) occurs in 9-39% of patients in sub-Saharan Africa. A significant proportion of deaths are attributable to tuberculosis (TB). Low baseline CD4 T-cell count and low body mass index (BMI) are strongly associated with early mortality. We hypothesized that initiation of ART concurrent with presumptive anti-TB chemotherapy in high-risk patients would reduce mortality within the first 6 months by treating unrecognized TB. From October 2011 to December 2012, ART-naive, smear-negative participants with a CD4 T-cell count < 50 cells/μL and BMI < 18 kg/m 2 were randomly assigned to undergo either empiric four-drug anti-TB treatment followed 2 weeks later by efavirenz-based ART (N = 23) (ART + TB) or ART only (N = 20). This open-label, 1:1 randomized, controlled trial took place in Uganda, Mozambique, and Gabon and was stopped prematurely by the sponsor for slow recruitment. Overall, the 43 participants had a median CD4 of 22 (interquartile range [IQR]: 9-35) cells/μL and a median BMI of 17.5 (IQR: 16.6-18.0) kg/m 2 . The mortality was 14% (95% confidence interval [CI]: 5.3-27.9); two (10.0%) participants (ART-only group), and four (17.4%; ART + TB group). The associated hazard ratio (HR) for all-cause mortality was 1.6 (95% CI: 0.30-8.90). Despite limited enrollment, the study did not suggest that empiric TB treatment in severely immunosuppressed patients with low BMI decreased mortality and, had an HR in the opposite direction than expected. Notably, two participants in the ART + TB group died with autopsy-confirmed drug-induced hepatotoxicity. Improved TB diagnostics sensitive in immunosuppressed patients presenting late to care are urgently needed for more targeted interventions.

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Section: Introductionmentioning

confidence: 99%

Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial

Manabe

Worodria

Leth

et al. 2016

The American Society of Tropical Medicine and Hygiene

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“…Two forms of TB-IRIS have been described, namely paradoxical and unmasking. Whereas the paradoxical form manifests as new or recurrent TB disease in subjects with treated TB during early cART, the unmasking form mainly results from an exaggerated, nonclassical inflammatory presentation of TB during early cART (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Tan

Yong

Shankar

et al. 2016

The Journal of Immunology

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Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) complicates combination antiretroviral therapy (cART) in up to 25% of patients with HIV/TB coinfection. Monocytes and IL-18, a signature cytokine of inflammasome activation, are implicated in TB-IRIS pathogenesis. In this study, we investigated inflammasome activation both pre- and post-cART in TB-IRIS patients. HIV/TB patients exhibited higher proportions of monocytes expressing activated caspase-1 (casp1) pre-cART, compared with HIV patients without TB, and patients who developed TB-IRIS exhibited the greatest increase in casp1 expression. CD64+ monocytes were a marker of increased casp1 expression. Furthermore, IL-1β, another marker of inflammasome activation, was also elevated during TB-IRIS. TB-IRIS patients also exhibited greater upregulation of NLRP3 and AIM2 inflammasome mRNA, compared with controls. Analysis of plasma mitochondrial DNA levels showed that TB-IRIS patients experienced greater cell death, especially pre-cART. Plasma NO levels were lower both pre- and post-cART in TB-IRIS patients, providing evidence of inadequate inflammasome regulation. Plasma IL-18 levels pre-cART correlated inversely with NO levels but positively with monocyte casp1 expression and mitochondrial DNA levels, and expression of IL-18Rα on CD4+ T cells and NK cells was higher in TB-IRIS patients, providing evidence that IL-18 is a marker of inflammasome activation. We propose that inflammasome activation in monocytes/macrophages of HIV/TB patients increases with ineffective T cell–dependent activation of monocytes/macrophages, priming them for an excessive inflammatory response after cART is commenced, which is greatest in patients with TB-IRIS.

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“…In a recent review, MANABE et al [7] proposed a new way of classifying the different forms of TB occurring during cART. According to the authors, ''primary TB'' is only temporally associated with cART and is not associated with a rapid recall of TB antigen-specific memory immune response.…”

Section: Methodsmentioning

confidence: 99%

Unmasking tuberculosis in the era of antiretroviral treatment

Lapadula¹,

Soria²,

Bandera³

et al. 2011

Eur Respir J

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Tuberculosis (TB) can develop soon after antiretroviral treatment initiation, as the result of restoration of the anti-TB specific immune response. This form of the disease is often defined as ''unmasked TB'', and it represents a major challenge for severely immune-suppressed HIV-infected subjects initiating treatment. Emergence of previously unrecognised TB disease occurs frequently in countries where TB/HIV co-infection is common, and where antiretroviral treatment has become increasingly accessible. The challenges posed by unmasked TB, such as its high incidence, the lack of reliable diagnostic tools and the uncertainties on its optimal management, may hamper our ability to face the TB/HIV epidemic. Therefore, unmasked TB appears a major threat to global health and poses additional barriers to successful HIV/AIDS care and treatment programmes.This review focuses on the epidemiology, immunopathogenesis and clinical manifestations of unmasked TB, and provides evidence-based recommendations for management and care of the disease.

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Unmasked Tuberculosis and Tuberculosis Immune Reconstitution Inflammatory Disease: A Disease Spectrum after Initiation of Antiretroviral Therapy

Cited by 78 publications

References 48 publications

Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial

Prevention of Early Mortality by Presumptive Tuberculosis Therapy Study: An Open Label, Randomized Controlled Trial

Aberrant Inflammasome Activation Characterizes Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome

Unmasking tuberculosis in the era of antiretroviral treatment

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