Prolonged tuberculosis-associated immune reconstitution inflammatory syndrome: characteristics and risk factors.
BACKGROUND
In a proportion of patients with HIV-associated tuberculosis who develop paradoxical immune reconstitution inflammatory syndrome (IRIS), the clinical course of IRIS is prolonged necessitating substantial health care utilization for diagnostic and therapeutic interventions. Prolonged TB-IRIS has not been prospectively studied to date. We aimed to determine the proportion of patients with prolonged TB-IRIS, as well as the clinical characteristics and risk factors for prolonged TB-IRIS.


METHODS
We pooled data from two prospective observational studies and a randomized controlled trial conducted in Cape Town, South Africa, that enrolled patients with paradoxical TB-IRIS. We used the same diagnostic approach and clinical case definitions for TB-IRIS in the 3 studies. Prolonged TB-IRIS was defined as TB-IRIS symptoms lasting > 90 days. Risk factors for prolonged TB-IRIS were analysed using Wilcoxon rank sum test, Fisher's exact test, multivariate logistic regression and Cox proportional hazards models.


RESULTS
Two-hundred and sixteen patients with TB-IRIS were included. The median duration of TB-IRIS symptoms was 71.0 days (IQR 41.0-113.2). In 73/181 patients (40.3 %) with adequate follow-up data, IRIS duration was > 90 days. Six patients (3.3 %), mainly with lymph node involvement, had IRIS duration > 1 year. In univariate logistic regression analysis the following were significantly associated with IRIS duration > 90 days: lymph node involvement at initial TB diagnosis, drug-resistant TB, lymph node TB-IRIS, and not being hospitalised at time of TB-IRIS diagnosis. In our multivariate logistic regression model lymph node TB-IRIS (aOR 2.27, 95 % CI 1.13-4.59) and not being hospitalised at time of TB-IRIS diagnosis (aOR for being hospitalised 0.5, 95 % CI 0.25-0.99) remained significantly associated with prolonged TB-IRIS, and drug-resistant TB was of borderline significance (aOR 3.26, 95 % CI 0.97-12.99). The association of not being hospitalised with longer duration of IRIS might be related to 1 of the 3 cohorts in which all patients were hospitalised at ART initiation with close inpatient follow-up. This could have resulted in diagnosis of milder cases and earlier IRIS treatment potentially resulting in shorter TB-IRIS duration in these hospitalised patients.


CONCLUSIONS
Around 40 % of patients with TB-IRIS have symptoms for more than 90 days. Involvement of lymph nodes at time of TB-IRIS is an independent risk factor for prolonged TB-IRIS. Future studies should address whether more prompt anti-inflammatory treatment of lymph node TB-IRIS reduces the risk of prolonged TB-IRIS.


BACKGROUND
The randomized controlled trial was registered with Current Controlled Trials ISRCTN21322548 on 17 August 2005.
Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
Tasnim M
TM
Bana
Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
Maia
M
Lesosky
Critical Care Medicine Department, National Institutes of Health, Bethesda, MD, USA.
Dominique J
DJ
Pepper
Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
Helen
H
van der Plas
Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.|Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, South Africa.
Charlotte
C
Schutz
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, South Africa.
Rene
R
Goliath
Institute for Women's Health and Institute for Global Health, University College London, London, UK.
Chelsea
C
Morroni
Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
Marc
M
Mendelson
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.
Gary
G
Maartens
Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa.|Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, South Africa.|Francis Crick Institute, London, NW7 1AA, UK.|Department of Medicine, Imperial College London, London, W2 1PG, UK.
Robert J
RJ
Wilkinson
Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Observatory, 7925, South Africa. Graeme.meintjes@uct.ac.za.|Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, 7925, South Africa. Graeme.meintjes@uct.ac.za.|Department of Medicine, Imperial College London, London, W2 1PG, UK. Graeme.meintjes@uct.ac.za.
Graeme
G
Meintjes
Glucocorticoids; HIV; IRIS; Immune reconstitution inflammatory syndrome; Tuberculosis
Clin Infect Dis. 2005 May 1;40(9):1368-71
15825042
Future Microbiol. 2015;10(6):1077-99
26059627
Ann Intern Med. 2012 Sep 4;157(5):313-24
22944873
Antivir Ther. 2005;10(3):417-22
15918332
Clin Chest Med. 2009 Dec;30(4):797-810, x
19925968
J Acquir Immune Defic Syndr. 2012 Aug 1;60(4):377-83
22592586
Clin Dev Immunol. 2011;2011:239021
21197457
Int J Tuberc Lung Dis. 2002 Jan;6(1):71-5
11931404
Braz J Infect Dis. 2007 Oct;11(5):462-5
17962870
Acta Clin Belg. 2007 Mar-Apr;62(2):126-9
17547295
Clin Infect Dis. 2004 Dec 1;39(11):1709-12
15578375
PLoS One. 2013;8(2):e54145
23408935
AIDS. 2013 Oct 23;27(16):2577-86
24096631
J Transl Med. 2007 Oct 15;5:50
17937815
J Clin Invest. 2016 Mar 1;126(3):1093-108
26901813
J Acquir Immune Defic Syndr. 2014 Apr 1;65(4):423-8
24226057
Clin Infect Dis. 2005 Nov 15;41(10):1483-97
16231262
Int J Tuberc Lung Dis. 2007 Dec;11(12):1282-9
18229435
Clin Infect Dis. 2009 Mar 1;48(5):667-76
19191655
AIDS. 2014 Sep 10;28(14):2097-107
24977440
PLoS One. 2013 May 17;8(5):e63541
23691062
AIDS. 2010 Sep 24;24(15):2381-90
20808204
Lancet Infect Dis. 2008 Aug;8(8):516-23
18652998