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. 2012 Oct;55(7):1004-11.
doi: 10.1093/cid/cis577. Epub 2012 Jun 19.

Corticosteroid therapy, vitamin D status, and inflammatory cytokine profile in the HIV-tuberculosis immune reconstitution inflammatory syndrome

Anali Conesa-Botella  1 , Graeme Meintjes, Anna K Coussens, Helen van der Plas, Rene Goliath, Charlotte Schutz, Rodrigo Moreno-Reyes, Meera Mehta, Adrian R Martineau, Robert J Wilkinson, Robert Colebunders, Katalin A Wilkinson
Affiliations

Corticosteroid therapy, vitamin D status, and inflammatory cytokine profile in the HIV-tuberculosis immune reconstitution inflammatory syndrome

Anali Conesa-Botella et al. Clin Infect Dis. 2012 Oct.

Abstract

Background: Tuberculosis-immune reconstitution inflammatory syndrome (TB-IRIS) in patients coinfected with human immunodeficiency virus (HIV) and tuberculosis starting antiretroviral therapy (ART) is associated with hypercytokinemia. As adjunctive corticosteroid therapy and vitamin D have immunomodulatory properties, we investigated the relationship between cytokine/chemokine profiles, corticosteroid use, and vitamin D deficiency in TB-IRIS patients.

Methods: Plasma from 39 TB-IRIS and 42 non-IRIS patients was collected during a prospective study of HIV-associated tuberculosis patients starting ART. In total, 26% of patients received corticosteroid (CTC) therapy pre-ART for severe tuberculosis. Concentrations of total 25-hydroxyvitamin D (25(OH)D) and 14 cytokines/chemokines were determined at ART initiation and 2 weeks later.

Results: Patients prescribed concurrent CTC had lower interferon γ (IFN-γ), IP-10, tumor necrosis factor (TNF), interleukin (IL)-6, IL-8, IL-10, IL-12p40, and IL-18 pre-ART (P ≤ .02). TB-IRIS presented at 12 days (median) of ART, irrespective of CTC use. In patients who developed TB-IRIS (not on CTC) IL-6, IL-8, IL-12p40, IL-18, IP-10, and TNF increased during 2 weeks (P ≤ .04) of ART. Vitamin D deficiency (total 25(OH)D <75 nmol/L) was highly prevalent (89%) at baseline. Although vitamin D deficiency at either baseline or 2 weeks was not associated with TB-IRIS, in those not on CTC the median 25(OH)D decreased during 2 weeks (P = .004) of ART. Severe vitamin D deficiency (total 25(OH)D <25 nmol/L) was associated with higher baseline TNF, IL-6, and IL-8 irrespective of IRIS status.

Conclusions: CTC modifies the inflammatory profile of those who develop TB-IRIS. The association between severe vitamin D deficiency and elevated proinflammatory cytokines support a study of vitamin D supplementation in HIV-TB co-infected patients starting ART.

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Figures

Figure 1.
Figure 1.
Cytokine concentrations in immune reconstitution inflammatory syndrome (IRIS; filled circles) and non-IRIS (open circles) patients: A–H, not on CTC (nIRIS = 31, nnonIRIS = 26); I–L, on CTC therapy (nIRIS = 8, nnonIRIS = 12). Line at median. Statistical test: Mann-Whitney (not paired data) and Wilcoxon signed rank test (paired data); significant P values are indicated on the graph. Abbreviations: IFN, interferon; IL, interleukin; IP, inflammatory protein; LOD, limit of detection; MIP, macrophage inflammatory protein; TNF, tumor necrosis factor.
Figure 2.
Figure 2.
Baseline vitamin D status for all patients (n = 81). Dotted lines indicate the threshold for severe vitamin D deficiency (25(OH)D <25 nmol/L), moderate vitamin D deficiency (25(OH)D: 25–50 nmol/L), suboptimal 25(OH)D levels (25(OH)D: 50–75 nmol/L), and vitamin D sufficiency (25(OH)D >75 nmol/L).
Figure 3.
Figure 3.
25(OH)D concentration in patients who developed immune reconstitution inflammatory syndrome (IRIS; filled circles) or did not develop IRIS (open circles) at baseline and after 2 weeks on antiretroviral therapy (A) in patients who did not receive corticosteroids nIRIS = 31, nnonIRIS = 29 and (B) in patients prescribed corticosteroids nIRIS = 8, nnonIRIS = 13. Solid line at median; dotted line indicates severe vitamin D deficiency. Statistical test: Mann-Whitney (unpaired data) and Wilcoxon signed rank test (paired data); significant P values are indicated on the graph.
Figure 4.
Figure 4.
Cytokine concentrations stratified by severe vitamin D deficiency (25(OH)D <25 nmol/L, nbaseline = 15 immune reconstitution inflammatory syndrome (IRIS; filled triangles) and 11 non-IRIS (open triangles), nweek2 = 20 IRIS and 7 non-IRIS) or nonsevere vitamin D deficiency (25(OH)D >25 nmol/L, nbaseline = 15 IRIS and 15 non-IRIS, nweek2 = 10 IRIS and 19 non-IRIS) in patients who did not receive adjunctive corticosteroid therapy. Line at median. P values determined by Mann-Whitney test for medians. Abbreviations: IL, interleukin; LOD, limit of detection; TNF, tumor necrosis factor.
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