• Simonetta Baldi, Paul E Jose, Claudio Bruschi, Gian Domenico Pinna, Roberto Maestri, Antonella Rezzani, Ezio Bellinzona, Claudio Fracchia, Elena Dacosto, Paola Crotti, and Silvia Montemartini.
• Department of Pneumology, Scientific Institute of Montescano, Salvatore Maugeri Foundation IRCCS, Montescano, Pavia, Italy.
• Int J Chron Obstruct Pulmon Dis. 2014 Jan 1;9:1091-9.

ObjectivesTo 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.DesignModerated mediation model.SettingAn inpatient pulmonary rehabilitation center in Italy.ParticipantsAll 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.MeasurementsAt 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.MethodsThe 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.ResultsFEV1 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).ConclusionThis 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.

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