title: The mediating role of cytokine IL-6 on the relationship of FEV₁ upon 6-minute walk distance in chronic obstructive pulmonary disease.
abstract: OBJECTIVE
  To explore the mediating role of protein interleukin-6 (IL-6) on the relationship between forced expiratory volume in 1 second (FEV1) and 6-minute walk distance (6MWD) and, further, to determine whether status variables (such as age, sex, and body mass index [BMI]) operate as moderators of this mediation relationship.
  
  
  METHODS
  Moderated mediation model.
  
  
  METHODS
  An inpatient pulmonary rehabilitation center in Italy.
  
  
  METHODS
  All 153 patients involved in the screening of a randomized controlled clinical trial (ClinicalTrials.gov identifier: NCT01253941) were included in this study. All patients were Global initiative for chronic Obstructive Lung Disease (GOLD) stages I-IV and were aged 70.1±9.1 years.
  
  
  METHODS
  At run-in phase of the protocol, clinical and functional screening included BMI, fasting plasma levels of protein (IL-6), spirometry, and standardized 6-minute walking test, measured at the start of the respiratory rehabilitation program.
  
  
  METHODS
  The size of the indirect effect of the initial variable (FEV1) upon the outcome variable (6MWD) through the intervening variable (IL-6) was computed and tested for statistical significance. Moderated mediation analyses were subsequently conducted with age, sex, and BMI.
  
  
  RESULTS
  FEV1 averaged 53.4%±21.2%, and 6MWD 66.4%±41.3% of predicted. Median protein IL-6 was 6.68 pg/mL (interquartile range: 5.96). A bootstrapped mediation test supported the predicted indirect pathway (P=0.003). The indirect effect through IL-6 log units accounted for 17% of the total effect between FEV1 and 6MWD. Age functioned as a significant moderator of the mediational pattern. For individuals aged <70 years, the standardized indirect effect was significant (0.122, 95% confidence interval [CI]: 0.044-0.254, P=0.004), and for individuals >70 years it was not significant (0.04, 95% CI: -0.010 to 0.142, P=0.10).
  
  
  CONCLUSIONS
  This moderated mediation result based on concurrent data suggests, but does not prove, a causal role of systemic inflammatory syndrome on progression from functional impairment to "frailty" status and substantial disability in aging chronic obstructive pulmonary disease.
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Baldi
authors.affiliation: School of Psychology, Victoria University, Wellington, New Zealand.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Jose
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Bruschi
authors.affiliation: Department of Biomedical Engineering, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Gian Domenico
authors.initials: GD
authors.lastname: Pinna
authors.affiliation: Department of Biomedical Engineering, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Maestri
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Rezzani
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Bellinzona
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Fracchia
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Dacosto
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Crotti
authors.affiliation: Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Montemartini
mesh_terms: D000367:Age Factors; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D005080:Exercise Test; D017079:Exercise Tolerance; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood*; D007297:Inpatients; D015850:Interleukin-6 / Q000097:blood*; D007558:Italy; D008168:Lung / Q000276:immunology / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D029424:Pulmonary Disease, Chronic Obstructive / Q000097:blood* / Q000276:immunology / Q000503:physiopathology* / Q000534:rehabilitation; D012047:Rehabilitation Centers; D012720:Severity of Illness Index; D013147:Spirometry; D013997:Time Factors; D016138:Walking
chemical_list: D015415:Biomarkers; C508600:IL6 protein, human; D018836:Inflammation Mediators; D015850:Interleukin-6
keywords: COPD; aging; chronic airflow obstruction; mediation analysis