title: Circulating inflammatory biomarkers can predict and characterize tuberculosis-associated immune reconstitution inflammatory syndrome.
abstract: OBJECTIVE
  To identify inflammatory biomarker profiles during paradoxical and unmasking tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS), and determine whether differences in biomarkers prior to antiretroviral therapy (ART) predict subsequent development of TB-IRIS.
  
  
  METHODS
  Case-control study within a cohort of patients initiating ART in South Africa (n = 498).
  
  
  METHODS
  Participants were followed up for 24 weeks for development of TB-IRIS. Plasma samples were collected at baseline and presentation with symptoms. Groups of cases and controls were as follows: pre-ART TB and developed paradoxical TB-IRIS (n = 9); pre-ART TB but no IRIS (n = 12); no pre-ART TB but developed unmasking TB-IRIS (n = 13); no pre-ART TB and no TB or IRIS during treatment (n = 12). Concentrations of 18 cytokines and chemokines, and C-reactive protein (CRP), were measured and compared.
  
  
  RESULTS
  Event samples were drawn a median of 28 days after ART initiation [interquartile range (IQR) 14-56 days]. During paradoxical TB-IRIS events, there were lower median concentrations of interleukin-10 [IL-10; 22.1 (IQR 15.3-34.9) vs. 82.2 (29.4-128.4) pg/ml, P = 0.047] and monocyte chemotactic protein-1 [MCP-1; 27.6 (20.0-29.7) vs. 71.4 (40.6-77.8) pg/ml, P = 0.005], and higher CRP: IL-10 ratio [2.2 × 10³ (1.8-3.4) vs. 0.3 × 10³ (0.2-0.5), P = 0.003] than in controls. Patients who developed unmasking TB-IRIS had higher median pre-ART levels of CRP [25 (8-47) vs. 6 (lower limit of detection, LLD-12) mg/l, P = 0.046] and interferon gamma (IFN-γ) [9.1 (4.4-24.7) vs. 0.9 (LLD-8.7) pg/ml, P = 0.032] than controls.
  
  
  CONCLUSIONS
  Patients with unmasking TB-IRIS had higher pre-ART levels of plasma IFN-γ and CRP, consistent with preexisting subclinical TB. Paradoxical TB-IRIS was associated with lower levels of biomarkers of monocyte and regulatory T-cell activity, and higher CRP.
authors.affiliation: Division of Infection, Immunity and Inflammatory Diseases, Centre for Sexual Health and HIV Research, King's College London, London, UK. lewis.haddow@ucl.ac.uk
authors.forename: Lewis J
authors.initials: LJ
authors.lastname: Haddow
authors.forename: Oliver
authors.initials: O
authors.lastname: Dibben
authors.forename: Mohamed-Yunus S
authors.initials: MY
authors.lastname: Moosa
authors.forename: Persephone
authors.initials: P
authors.lastname: Borrow
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Easterbrook
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism*; D002097:C-Reactive Protein / Q000378:metabolism*; D016022:Case-Control Studies; D016207:Cytokines / Q000378:metabolism*; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000821:virology; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome / Q000276:immunology* / Q000821:virology; D008297:Male; D011237:Predictive Value of Tests; D013019:South Africa; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D014376:Tuberculosis / Q000150:complications / Q000276:immunology* / Q000821:virology
chemical_list: D044966:Anti-Retroviral Agents; D015415:Biomarkers; D016207:Cytokines; D002097:C-Reactive Protein