PMID- 25672566
OWN - NLM
STAT- MEDLINE
DCOM- 20150526
LR  - 20220317
IS  - 1474-4457 (Electronic)
IS  - 1473-3099 (Print)
IS  - 1473-3099 (Linking)
VI  - 15
IP  - 4
DP  - 2015 Apr
TI  - Immunological profiling of tuberculosis-associated immune reconstitution 
      inflammatory syndrome and non-immune reconstitution inflammatory syndrome death 
      in HIV-infected adults with pulmonary tuberculosis starting antiretroviral 
      therapy: a prospective observational cohort study.
PG  - 429-38
LID - S1473-3099(15)70008-3 [pii]
LID - 10.1016/S1473-3099(15)70008-3 [doi]
AB  - BACKGROUND: Patients co-infected with advanced HIV and tuberculosis are at risk 
      of tuberculosis-associated immune reconstitution inflammatory syndrome (IRIS) and 
      death soon after initiation of antiretroviral therapy (ART). 
      Tuberculosis-associated IRIS has been associated with quicker recovery of 
      cellular immune responses after ART initiation and early mortality with slower 
      recovery of these responses. We aimed to assess whether patients who have these 
      outcomes have distinct immunological profiles before and after ART initiation. 
      METHODS: We undertook this prospective cohort study at 22 public clinics and the 
      main public hospital in Gaborone, Botswana, in ART-naive adults (aged >/=21 years) 
      with advanced HIV (CD4 cell counts </=125 cells per muL) and pulmonary tuberculosis. 
      We obtained data for clinical variables and for levels of 29 plasma biomarkers, 
      quantified by Luminex assay. We classified patients as having 
      tuberculosis-associated IRIS, early mortality, or survival without a diagnosis of 
      tuberculosis-associated IRIS (controls), on the basis of outcomes recorded in the 
      6 months after ART initiation. We used rank-sum or chi(2) tests, and logistic 
      regression with odds ratios (OR) and 95% CIs, to assess the association between 
      variables measured before and 4 weeks after ART initiation with death and 
      tuberculosis-associated IRIS, compared with controls. FINDINGS: Between Nov 12, 
      2009, and July 3, 2013, we enrolled 201 participants. 31 (15%) patients left the 
      study before ART initiation, leaving 170 (85%) patients for analysis. Patients 
      with tuberculosis-associated IRIS had reduced pre-ART concentrations of several 
      pro-inflammatory biomarkers, including interleukin (IL)-6 (adjusted OR per 1 
      log10 increase 0.40 [95% CI 0.18-0.89]). However, patients with early death had 
      increased pre-ART concentrations of inflammatory biomarkers, including monocyte 
      chemoattractant protein-1 (adjusted OR 9.0 [95% CI 1.0-80.0]) and tumour necrosis 
      factor (TNF)alpha (7.8 [1.1-55.2]). At week 4 after ART initation, 
      tuberculosis-associated IRIS was independently associated with greater increases 
      in several inflammatory biomarkers, including IL-6 (adjusted OR 1.7 [95% CI 
      1.2-2.5]) and TNFalpha (1.5 [1.0-2.2]), versus controls. Death was likewise 
      associated with greater increases in systemic inflammatory markers, including 
      granulocyte colony-stimulating factor (adjusted OR 2.8 [95% CI 1.3-6.1]), 
      IL-12p40 (1.8 [1.0-3.4]), and IL-15 (2.0 [1.1-3.7]), versus controls. However, 
      changes in CD4 cell count during ART, which were similar between controls and 
      patients with tuberculosis-associated IRIS (p=0.45), were substantially lower in 
      patients who died (p=0.006). INTERPRETATION: Distinct immunological profiles 
      before and after ART initiation characterise patients with advanced HIV and 
      tuberculosis who have tuberculosis-associated IRIS and death. Interventions that 
      decrease inflammation while promoting cellular immune recovery during ART should 
      be considered in patients co-infected with HIV and tuberculosis. FUNDING: 
      National Institutes of Health and the Penn Center for AIDS Research.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Ravimohan, Shruthi
AU  - Ravimohan S
AD  - Department of Medicine, Division of Infectious Diseases, Perelman School of 
      Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Botswana-UPenn 
      Partnership, Gaborone, Botswana. Electronic address: shruthiravimohan@gmail.com.
FAU - Tamuhla, Neo
AU  - Tamuhla N
AD  - Botswana-UPenn Partnership, Gaborone, Botswana.
FAU - Steenhoff, Andrew P
AU  - Steenhoff AP
AD  - Department of Pediatrics, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA, USA; Botswana-UPenn Partnership, Gaborone, 
      Botswana; The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
FAU - Letlhogile, Rona
AU  - Letlhogile R
AD  - Botswana-UPenn Partnership, Gaborone, Botswana.
FAU - Nfanyana, Kebatshabile
AU  - Nfanyana K
AD  - Botswana-UPenn Partnership, Gaborone, Botswana.
FAU - Bellamy, Scarlett L
AU  - Bellamy SL
AD  - Department of Biostatistics and Epidemiology, Center for Clinical Epidemiology 
      and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, 
      Philadelphia, PA, USA.
FAU - MacGregor, Rob Roy
AU  - MacGregor RR
AD  - Department of Medicine, Division of Infectious Diseases, Perelman School of 
      Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
FAU - Gross, Robert
AU  - Gross R
AD  - Department of Medicine, Division of Infectious Diseases, Perelman School of 
      Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of 
      Biostatistics and Epidemiology, Center for Clinical Epidemiology and 
      Biostatistics, Perelman School of Medicine at the University of Pennsylvania, 
      Philadelphia, PA, USA; Botswana-UPenn Partnership, Gaborone, Botswana.
FAU - Weissman, Drew
AU  - Weissman D
AD  - Department of Medicine, Division of Infectious Diseases, Perelman School of 
      Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Botswana-UPenn 
      Partnership, Gaborone, Botswana.
FAU - Bisson, Gregory P
AU  - Bisson GP
AD  - Department of Medicine, Division of Infectious Diseases, Perelman School of 
      Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of 
      Biostatistics and Epidemiology, Center for Clinical Epidemiology and 
      Biostatistics, Perelman School of Medicine at the University of Pennsylvania, 
      Philadelphia, PA, USA; Botswana-UPenn Partnership, Gaborone, Botswana.
LA  - eng
GR  - P30 AI045008/AI/NIAID NIH HHS/United States
GR  - R01 AI080337/AI/NIAID NIH HHS/United States
GR  - AI045008/AI/NIAID NIH HHS/United States
GR  - R01AI080337/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Observational Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20150209
PL  - United States
TA  - Lancet Infect Dis
JT  - The Lancet. Infectious diseases
JID - 101130150
RN  - 0 (Biomarkers)
SB  - IM
CIN - Lancet Infect Dis. 2015 Apr;15(4):370-1. PMID: 25672567
EIN - Lancet Infect Dis. 2015 May;15(5):505. PMID: 25932576
MH  - Adult
MH  - Antiretroviral Therapy, Highly Active/*adverse effects
MH  - Biomarkers/*blood
MH  - Botswana
MH  - Cohort Studies
MH  - Coinfection/*immunology
MH  - Female
MH  - HIV Infections/*complications/*drug therapy/immunology
MH  - Humans
MH  - Immune Reconstitution Inflammatory Syndrome/*immunology
MH  - Male
MH  - Middle Aged
MH  - Prospective Studies
MH  - Tuberculosis/*complications/immunology
MH  - Young Adult
PMC - PMC4624391
MID - NIHMS675662
EDAT- 2015/02/13 06:00
MHDA- 2015/05/27 06:00
PMCR- 2016/04/01
CRDT- 2015/02/13 06:00
PHST- 2015/02/13 06:00 [entrez]
PHST- 2015/02/13 06:00 [pubmed]
PHST- 2015/05/27 06:00 [medline]
PHST- 2016/04/01 00:00 [pmc-release]
AID - S1473-3099(15)70008-3 [pii]
AID - 10.1016/S1473-3099(15)70008-3 [doi]
PST - ppublish
SO  - Lancet Infect Dis. 2015 Apr;15(4):429-38. doi: 10.1016/S1473-3099(15)70008-3. 
      Epub 2015 Feb 9.