TB-associated Immune Reconstitution Inflammatory Syndrome
TB-associated Immune Reconstitution Inflammatory Syndrome
Objective: To identify inflammatory biomarker profiles during paradoxical and unmasking tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS), and determine whether differences in biomarkers prior to antiretroviral therapy (ART) predict subsequent development of TB-IRIS.
Design: Case–control study within a cohort of patients initiating ART in South Africa (n = 498).
Methods: Participants were followed up for 24 weeks for development of TB-IRIS. Plasma samples were collected at baseline and presentation with symptoms. Groups of cases and controls were as follows: pre-ART TB and developed paradoxical TB-IRIS (n = 9); pre-ART TB but no IRIS (n = 12); no pre-ART TB but developed unmasking TB-IRIS (n = 13); no pre-ART TB and no TB or IRIS during treatment (n = 12). Concentrations of 18 cytokines and chemokines, and C-reactive protein (CRP), were measured and compared.
Results: Event samples were drawn a median of 28 days after ART initiation [interquartile range (IQR) 14–56 days]. During paradoxical TB-IRIS events, there were lower median concentrations of interleukin-10 [IL-10; 22.1 (IQR 15.3–34.9) vs. 82.2 (29.4–128.4) pg/ml, P = 0.047] and monocyte chemotactic protein-1 [MCP-1; 27.6 (20.0–29.7) vs. 71.4 (40.6–77.8) pg/ml, P = 0.005], and higher CRP: IL-10 ratio [2.2 × 10 (1.8–3.4) vs. 0.3 × 10 (0.2–0.5), P = 0.003] than in controls. Patients who developed unmasking TB-IRIS had higher median pre-ART levels of CRP [25 (8–47) vs. 6 (lower limit of detection, LLD–12) mg/l, P = 0.046] and interferon gamma (IFN-γ) [9.1 (4.4–24.7) vs. 0.9 (LLD–8.7) pg/ml, P = 0.032] than controls.
Conclusion: Patients with unmasking TB-IRIS had higher pre-ART levels of plasma IFN-γ and CRP, consistent with preexisting subclinical TB. Paradoxical TB-IRIS was associated with lower levels of biomarkers of monocyte and regulatory T-cell activity, and higher CRP.
Ten to 25% of HIV-infected patients initiating antiretroviral therapy (ART) experience immune reconstitution inflammatory syndrome (IRIS), a clinical deterioration resulting from alterations in immune responses to preexisting antigens or pathogens. Tuberculosis (TB) is the second most common IRIS-associated disease in unselected studies of patients starting ART, accounting for 20% of reported IRIS cases overall, and is the commonest in resource-limited settings. TB-associated IRIS may present in two ways: 'paradoxical' worsening of symptoms of known disease, either at a new body site or at the original body site, with an incidence of 8–43% of TB-co-infected individuals starting ART; or 'unmasking' of occult Mycobacterium tuberculosis infection, in which infection was not clinically apparent prior to ART but presents floridly during ART, affecting around 5% among those starting ART without known TB infection in South Africa. The immunopathogenesis remains poorly understood, but clinical and pathological observations suggest that the mechanisms of IRIS vary according to the target antigen. Mycobacterial IRIS is characterized by suppuration, granuloma formation and delayed-type hypersensitivity responses.
Analysis of systemic cytokine levels can provide insight into immune pathways involved in IRIS. Circulating cytokines in IRIS may reflect 'spill over' of locally released molecules from the site of disease, or they may be part of an immunoregulatory milieu that influences tissue-specific activity. Several studies have assayed concentrations of effector cytokines in the plasma of individuals with IRIS. These studies were limited by small numbers of participants, restricted numbers of cytokines measured and delayed collection of samples, often some time after the occurrence of IRIS. Between-study comparisons are difficult due to the heterogeneity of opportunistic infections studied (including TB, Kaposi's sarcoma, human herpes virus infections,Mycobacterium avium complex and cryptococcosis) and variations in the time of specimen collection of up to 2 years after ART initiation. The main findings regarding paradoxical mycobacterial IRIS were elevations in interleukin (IL)-4, IL-6, IL-7, interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) during clinical events, and no change in circulating IL-2 or IL-12.
Our aim was to compare plasma cytokine and chemokine levels and C-reactive protein (CRP) concentrations pre-ART and during clinical events between individuals who developed IRIS associated with tuberculosis (TB-IRIS) and ART-treated patients with non-IRIS clinical events. TB-IRIS was chosen as the focus of this substudy because one would expect to see changes in circulating biomarkers (in contrast to immune reconstitution folliculitis, for example), TB accounts for up to two-thirds of IRIS in developing countries and TB-IRIS is probably the best studied form of IRIS; therefore, comparisons with existing literature could be made.
Two main research questions were explored: was there a distinctive profile of cytokines and chemokines during paradoxical and/or unmasking TB-IRIS events, and were there differences in biomarkers prior to ART that predicted subsequent paradoxical and/or unmasking TB-IRIS?
Abstract and Introduction
Abstract
Objective: To identify inflammatory biomarker profiles during paradoxical and unmasking tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS), and determine whether differences in biomarkers prior to antiretroviral therapy (ART) predict subsequent development of TB-IRIS.
Design: Case–control study within a cohort of patients initiating ART in South Africa (n = 498).
Methods: Participants were followed up for 24 weeks for development of TB-IRIS. Plasma samples were collected at baseline and presentation with symptoms. Groups of cases and controls were as follows: pre-ART TB and developed paradoxical TB-IRIS (n = 9); pre-ART TB but no IRIS (n = 12); no pre-ART TB but developed unmasking TB-IRIS (n = 13); no pre-ART TB and no TB or IRIS during treatment (n = 12). Concentrations of 18 cytokines and chemokines, and C-reactive protein (CRP), were measured and compared.
Results: Event samples were drawn a median of 28 days after ART initiation [interquartile range (IQR) 14–56 days]. During paradoxical TB-IRIS events, there were lower median concentrations of interleukin-10 [IL-10; 22.1 (IQR 15.3–34.9) vs. 82.2 (29.4–128.4) pg/ml, P = 0.047] and monocyte chemotactic protein-1 [MCP-1; 27.6 (20.0–29.7) vs. 71.4 (40.6–77.8) pg/ml, P = 0.005], and higher CRP: IL-10 ratio [2.2 × 10 (1.8–3.4) vs. 0.3 × 10 (0.2–0.5), P = 0.003] than in controls. Patients who developed unmasking TB-IRIS had higher median pre-ART levels of CRP [25 (8–47) vs. 6 (lower limit of detection, LLD–12) mg/l, P = 0.046] and interferon gamma (IFN-γ) [9.1 (4.4–24.7) vs. 0.9 (LLD–8.7) pg/ml, P = 0.032] than controls.
Conclusion: Patients with unmasking TB-IRIS had higher pre-ART levels of plasma IFN-γ and CRP, consistent with preexisting subclinical TB. Paradoxical TB-IRIS was associated with lower levels of biomarkers of monocyte and regulatory T-cell activity, and higher CRP.
Introduction
Ten to 25% of HIV-infected patients initiating antiretroviral therapy (ART) experience immune reconstitution inflammatory syndrome (IRIS), a clinical deterioration resulting from alterations in immune responses to preexisting antigens or pathogens. Tuberculosis (TB) is the second most common IRIS-associated disease in unselected studies of patients starting ART, accounting for 20% of reported IRIS cases overall, and is the commonest in resource-limited settings. TB-associated IRIS may present in two ways: 'paradoxical' worsening of symptoms of known disease, either at a new body site or at the original body site, with an incidence of 8–43% of TB-co-infected individuals starting ART; or 'unmasking' of occult Mycobacterium tuberculosis infection, in which infection was not clinically apparent prior to ART but presents floridly during ART, affecting around 5% among those starting ART without known TB infection in South Africa. The immunopathogenesis remains poorly understood, but clinical and pathological observations suggest that the mechanisms of IRIS vary according to the target antigen. Mycobacterial IRIS is characterized by suppuration, granuloma formation and delayed-type hypersensitivity responses.
Analysis of systemic cytokine levels can provide insight into immune pathways involved in IRIS. Circulating cytokines in IRIS may reflect 'spill over' of locally released molecules from the site of disease, or they may be part of an immunoregulatory milieu that influences tissue-specific activity. Several studies have assayed concentrations of effector cytokines in the plasma of individuals with IRIS. These studies were limited by small numbers of participants, restricted numbers of cytokines measured and delayed collection of samples, often some time after the occurrence of IRIS. Between-study comparisons are difficult due to the heterogeneity of opportunistic infections studied (including TB, Kaposi's sarcoma, human herpes virus infections,Mycobacterium avium complex and cryptococcosis) and variations in the time of specimen collection of up to 2 years after ART initiation. The main findings regarding paradoxical mycobacterial IRIS were elevations in interleukin (IL)-4, IL-6, IL-7, interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α) during clinical events, and no change in circulating IL-2 or IL-12.
Our aim was to compare plasma cytokine and chemokine levels and C-reactive protein (CRP) concentrations pre-ART and during clinical events between individuals who developed IRIS associated with tuberculosis (TB-IRIS) and ART-treated patients with non-IRIS clinical events. TB-IRIS was chosen as the focus of this substudy because one would expect to see changes in circulating biomarkers (in contrast to immune reconstitution folliculitis, for example), TB accounts for up to two-thirds of IRIS in developing countries and TB-IRIS is probably the best studied form of IRIS; therefore, comparisons with existing literature could be made.
Two main research questions were explored: was there a distinctive profile of cytokines and chemokines during paradoxical and/or unmasking TB-IRIS events, and were there differences in biomarkers prior to ART that predicted subsequent paradoxical and/or unmasking TB-IRIS?
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