title: Clinical and mycological predictors of cryptococcosis-associated immune reconstitution inflammatory syndrome.
abstract: OBJECTIVE
  HIV-infected patients with treated cryptococcal meningitis are at risk for further neurological deterioration after commencing combination antiretroviral therapy (cART), mostly because of cryptococcosis-associated immune reconstitution inflammatory syndrome (C-IRIS). Identifying predictors of C-IRIS could enable risk stratification.
  
  
  METHODS
  Prospective, longitudinal cohort study for 24 weeks.
  
  
  METHODS
  Durban, South Africa.
  
  
  METHODS
  One hundred and thirty HIV-infected patients with first cryptococcal meningitis episode
  
  
  METHODS
  : Antifungal therapy (amphotericin 1 mg/kg median 14 days, followed by consolidation and maintenance fluconazole) and cART (commenced median of 18 days from cryptococcal meningitis diagnosis).
  
  
  METHODS
  Clinical, blood, and cerebrospinal fluid (CSF) markers associated with C-IRIS before and during cART and clinical significance of CSF cryptococcal culture negativity pre-cART commencement.
  
  
  RESULTS
  Of 106 patients commencing cART, 27 (25.5%) developed C-IRIS, 16 (15.1%) neurological deterioration-not C-IRIS, and 63 (59.4%) no neurological deterioration. On multivariable analysis, C-IRIS was associated with persistent CSF cryptococcal growth [hazard ratio (HR) 0.27, P=0.026] and lower CSF protein (HR 0.53, P=0.059) prior to cART and lower CD4 T-cell increases (HR 0.99, P=0.026) but not change in HIV viral load during cART. Using survival analysis, patients with a negative cryptococcal culture pre-cART commencement (n=51; 48.1%) experienced fewer episodes of neurological deterioration, C-IRIS, and cryptococcal relapse/persistence than patients with culture positivity (n=55; 51.9%, HR 0.33, 0.33, and 0.12 and P=0.0003, 0.0042, and 0.0004, respectively).
  
  
  CONCLUSIONS
  Persistent CSF cryptococcal growth at cART initiation and poor CD4 T-cell increases on cART are strong predictors of C-IRIS. Approaches aimed at achieving CSF culture negativity prior to cART should be evaluated as a strategy to reduce rates of C-IRIS.
authors.affiliation: aDepartment of Infectious Diseases, Alfred Hospital and Monash University, Melbourne, Australia bDepartment of Infectious Diseases, King Edward VIII Hospital cHIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa dCentre for Virology, Burnet Institute, Melbourne, Australia eDepartment of Medical Microbiology, National Health Laboratory Services, Inkosi Albert Luthuli Central Hospital Academic Complex fDepartment of Microbiology and Infection Control, School of Laboratory Medicine and Medical Sciences, University of KwaZulu-Natal, Durban, South Africa gCentre for Population Health, Burnet Institute, Melbourne, Australia hCentre for the AIDS Programme of Research in South Africa, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa iSchool of Pathology and Laboratory Medicine, University of Western Australia jDepartment of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Australia.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Chang
authors.forename: Afton A
authors.initials: AA
authors.lastname: Dorasamy
authors.forename: Bernadett I
authors.initials: BI
authors.lastname: Gosnell
authors.forename: Julian H
authors.initials: JH
authors.lastname: Elliott
authors.forename: Tim
authors.initials: T
authors.lastname: Spelman
authors.forename: Saleha
authors.initials: S
authors.lastname: Omarjee
authors.forename: Vivek
authors.initials: V
authors.lastname: Naranbhai
authors.forename: Yacoob
authors.initials: Y
authors.lastname: Coovadia
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Mohamed-Yunus S
authors.initials: MY
authors.lastname: Moosa
authors.forename: Sharon R
authors.initials: SR
authors.lastname: Lewin
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000008:administration & dosage*; D000935:Antifungal Agents / Q000008:administration & dosage; D015415:Biomarkers; D018791:CD4 Lymphocyte Count; D002555:Cerebrospinal Fluid / Q000382:microbiology; D015331:Cohort Studies; D003453:Cryptococcosis / Q000175:diagnosis* / Q000473:pathology*; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000175:diagnosis* / Q000473:pathology*; D008137:Longitudinal Studies; D008297:Male; D011446:Prospective Studies; D013019:South Africa
chemical_list: D044966:Anti-Retroviral Agents; D000935:Antifungal Agents; D015415:Biomarkers