PMID- 21253011
OWN - NLM
STAT- MEDLINE
DCOM- 20110330
LR  - 20220330
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 7
IP  - 12
DP  - 2010 Dec 21
TI  - Clinical features and serum biomarkers in HIV immune reconstitution inflammatory 
      syndrome after cryptococcal meningitis: a prospective cohort study.
PG  - e1000384
LID - 10.1371/journal.pmed.1000384 [doi]
LID - e1000384
AB  - BACKGROUND: Although antiretroviral therapy (ART) improves survival in persons 
      with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune 
      reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly 
      inflammatory reaction that complicates recovery from immunodeficiency. The 
      pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible. 
      METHODS AND FINDINGS: We prospectively followed 101 ART-naive Ugandans with AIDS 
      and recent CM for one year after initiating ART, and used Luminex multiplex 
      assays to compare serum cytokine levels in participants who did or did not 
      develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, 
      including 30% with central nervous system (CNS) manifestations. The median time 
      to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% 
      without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 
      1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher 
      median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher 
      pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis 
      factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), 
      granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular 
      endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses 
      (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum 
      biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low 
      risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of 
      C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were 
      associated with increasing hazard of IRIS by time-to-event analysis (each 
      p</=0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses 
      were present, including CRP and IL-6. Mortality was predicted by pre-ART 
      increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). 
      Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% 
      CI 2.7-25.6, p<0.001). CONCLUSIONS: Pre-ART increases in Th(17) and Th(2) 
      responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses 
      (e.g., TNF-alpha, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, 
      perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. 
      Although requiring validation, these biomarkers might be an objective tool to 
      stratify the risk of CM-IRIS and death, and could be used clinically to guide 
      when to start ART or use prophylactic interventions.
FAU - Boulware, David R
AU  - Boulware DR
AD  - Division of Infectious Diseases & International Medicine, Department of Medicine, 
      University of Minnesota, Minneapolis, Minnesota, USA. boulw001@umn.edu
FAU - Meya, David B
AU  - Meya DB
FAU - Bergemann, Tracy L
AU  - Bergemann TL
FAU - Wiesner, Darin L
AU  - Wiesner DL
FAU - Rhein, Joshua
AU  - Rhein J
FAU - Musubire, Abdu
AU  - Musubire A
FAU - Lee, Sarah J
AU  - Lee SJ
FAU - Kambugu, Andrew
AU  - Kambugu A
FAU - Janoff, Edward N
AU  - Janoff EN
FAU - Bohjanen, Paul R
AU  - Bohjanen PR
LA  - eng
GR  - K23AI073192/AI/NIAID NIH HHS/United States
GR  - R34 AI081554-01/AI/NIAID NIH HHS/United States
GR  - R03 AI078750/AI/NIAID NIH HHS/United States
GR  - L30 AI066779/AI/NIAID NIH HHS/United States
GR  - L30 AI066779-04/AI/NIAID NIH HHS/United States
GR  - L30AI066779/AI/NIAID NIH HHS/United States
GR  - K12 RR023247/RR/NCRR NIH HHS/United States
GR  - T32 AI055433/AI/NIAID NIH HHS/United States
GR  - K23 AI073192/AI/NIAID NIH HHS/United States
GR  - K12RR023247-04/RR/NCRR NIH HHS/United States
GR  - T32AI055433-03/AI/NIAID NIH HHS/United States
GR  - K23 AI073192-01A2/AI/NIAID NIH HHS/United States
GR  - K23 AI073192-02/AI/NIAID NIH HHS/United States
GR  - R34 AI081554/AI/NIAID NIH HHS/United States
GR  - R03AI078750/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20101221
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Interleukin-17)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 143011-72-7 (Granulocyte Colony-Stimulating Factor)
RN  - 207137-56-2 (Interleukin-4)
RN  - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor)
SB  - IM
MH  - Cohort Studies
MH  - Granulocyte Colony-Stimulating Factor/blood
MH  - Granulocyte-Macrophage Colony-Stimulating Factor/blood
MH  - HIV Infections/*complications/microbiology
MH  - Humans
MH  - Immune Reconstitution Inflammatory Syndrome/*blood/*diagnosis
MH  - Interleukin-17/blood
MH  - Interleukin-4/blood
MH  - Meningitis, Cryptococcal/*complications
MH  - Prospective Studies
MH  - Tumor Necrosis Factor-alpha/blood
PMC - PMC3014618
COIS- The authors have declared that no competing interests exist.
EDAT- 2011/01/22 06:00
MHDA- 2011/03/31 06:00
PMCR- 2010/12/21
CRDT- 2011/01/22 06:00
PHST- 2010/05/25 00:00 [received]
PHST- 2010/11/10 00:00 [accepted]
PHST- 2011/01/22 06:00 [entrez]
PHST- 2011/01/22 06:00 [pubmed]
PHST- 2011/03/31 06:00 [medline]
PHST- 2010/12/21 00:00 [pmc-release]
AID - 10-PLME-RA-5056R3 [pii]
AID - 10.1371/journal.pmed.1000384 [doi]
PST - epublish
SO  - PLoS Med. 2010 Dec 21;7(12):e1000384. doi: 10.1371/journal.pmed.1000384.