PMID- 26658650
OWN - NLM
STAT- MEDLINE
DCOM- 20160930
LR  - 20220318
IS  - 1473-6527 (Electronic)
IS  - 0951-7375 (Print)
IS  - 0951-7375 (Linking)
VI  - 29
IP  - 1
DP  - 2016 Feb
TI  - The immunopathogenesis of cryptococcal immune reconstitution inflammatory 
      syndrome: understanding a conundrum.
PG  - 10-22
LID - 10.1097/QCO.0000000000000224 [doi]
AB  - PURPOSE OF REVIEW: Cryptococcal meningitis causes significant mortality among 
      HIV-infected patients, despite antifungal therapy and use of antiretroviral 
      therapy (ART). In patients with cryptococcal meningitis, ART is often complicated 
      by immune reconstitution inflammatory syndrome (IRIS), manifesting as unmasking 
      of previously unrecognized subclinical infection (unmasking CM-IRIS) or 
      paradoxical worsening of symptoms in the central nervous system after prior 
      improvement with antifungal therapy (paradoxical CM-IRIS). We review our current 
      understanding of the pathogenesis of this phenomenon, focusing on unifying innate 
      and adaptive immune mechanisms leading to the development of this often fatal 
      syndrome. RECENT FINDINGS: We propose that HIV-associated CD4 T-cell depletion, 
      chemokine-driven trafficking of monocytes into cerebrospinal fluid in response to 
      cryptococcal meningitis, and poor localized innate cytokine responses lead to 
      inadequate cryptococcal killing and clearance of the fungus. Subsequent 
      ART-associated recovery of T-cell signaling and restored cytokine responses, 
      characterized by IFN-gamma production, triggers an inflammatory response. The 
      inflammatory response triggered by ART is dysregulated because of impaired 
      homeostatic and regulatory mechanisms, culminating in the development of CM-IRIS. 
      SUMMARY: Despite our incomplete understanding of the immunopathogenesis of 
      CM-IRIS, emerging data exploring innate and adaptive immune responses could be 
      exploited to predict, prevent and manage CM-IRIS and associated morbid 
      consequences.
FAU - Meya, David B
AU  - Meya DB
AD  - aInfectious Disease Institute, Makerere University, Kampala, Uganda bDepartment 
      of Medicine, Center for Infectious Diseases and Microbiology Translational 
      Research, University of Minnesota, Minneapolis, Minnesota, USA cSchool of 
      Medicine, College of Health Sciences, Makerere University, Kampala, Uganda 
      dDivision of Infectious Diseases, Department of Medicine, Johns Hopkins 
      University, Baltimore, Maryland eMucosal and Vaccine Research Program Colorado 
      (MAVRC), University of Colorado Denver fDenver Veterans Affairs Medical Center, 
      Denver, Colorado, USA.
FAU - Manabe, Yukari C
AU  - Manabe YC
FAU - Boulware, David R
AU  - Boulware DR
FAU - Janoff, Edward N
AU  - Janoff EN
LA  - eng
GR  - T32AI055433/AI/NIAID NIH HHS/United States
GR  - U01 AI089244/AI/NIAID NIH HHS/United States
GR  - R21NS065713/NS/NINDS NIH HHS/United States
GR  - D43 TW009771/TW/FIC NIH HHS/United States
GR  - 087540/Wellcome Trust/United Kingdom
GR  - K24AI096925/AI/NIAID NIH HHS/United States
GR  - K24 AI096925/AI/NIAID NIH HHS/United States
GR  - R21 NS065713/NS/NINDS NIH HHS/United States
GR  - U01AI089244/AI/NIAID NIH HHS/United States
GR  - R01AI108479/AI/NIAID NIH HHS/United States
GR  - R01 AI078934/AI/NIAID NIH HHS/United States
GR  - AI108479/AI/NIAID NIH HHS/United States
GR  - T32 AI055433/AI/NIAID NIH HHS/United States
GR  - R01 AI108479/AI/NIAID NIH HHS/United States
GR  - R01AI078934/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.
PT  - Review
PL  - United States
TA  - Curr Opin Infect Dis
JT  - Current opinion in infectious diseases
JID - 8809878
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Antifungal Agents)
SB  - IM
MH  - AIDS-Related Opportunistic Infections/drug therapy/immunology/*physiopathology
MH  - Adaptive Immunity
MH  - Anti-HIV Agents/*therapeutic use
MH  - Antifungal Agents/*therapeutic use
MH  - CD4-Positive T-Lymphocytes/immunology
MH  - Humans
MH  - Immune Reconstitution Inflammatory Syndrome/drug 
      therapy/*immunology/physiopathology
MH  - Immunity, Innate
MH  - Meningitis, Cryptococcal/drug therapy/immunology/*physiopathology
MH  - Risk Factors
PMC - PMC4689618
MID - NIHMS738125
COIS- Conflict of Interest All authors have no conflict of interest to declare.
EDAT- 2015/12/15 06:00
MHDA- 2016/10/01 06:00
PMCR- 2017/02/01
CRDT- 2015/12/15 06:00
PHST- 2015/12/15 06:00 [entrez]
PHST- 2015/12/15 06:00 [pubmed]
PHST- 2016/10/01 06:00 [medline]
PHST- 2017/02/01 00:00 [pmc-release]
AID - 10.1097/QCO.0000000000000224 [doi]
PST - ppublish
SO  - Curr Opin Infect Dis. 2016 Feb;29(1):10-22. doi: 10.1097/QCO.0000000000000224.