FEV₁ and FVC and systemic inflammation in a spinal cord injury cohort

A growing literature supports inverse associations between levels of inflammatory markers and reductions in measures of pulmonary function in both the general population and among populations with chronic disease (e.g. chronic obstructive pulmonary disease (COPD), asthma, end-stage-renal disease) [1‐17]. The majority of these studies have been cross-sectional; however, these findings have also been reported in some, but not all, longitudinal studies [18‐24]. The consistency of observations across study populations suggests that systemic inflammation, and not pulmonary inflammation alone, may play a role in reductions in pulmonary function.

SCI is a chronic medical condition that is associated with a number of clinical characteristics that promote systemic inflammation, including increases in central fat, decreased mobility due to muscle paralysis, and recurrent infection mainly associated with skin ulcers and urinary tract infections [25‐32]. In two reports (n = 59 and n = 137 persons with chronic SCI) from an SCI cohort with data collected between 2003 and 2007 [13, 14], we observed inverse associations between systemic inflammatory biomarkers and forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC), but not the FEV1/FVC ratio. Due to the smaller sample sizes of our previous studies, we were unable to adjust for large numbers of potential confounders simultaneously and lacked information on others, leaving concerns regarding residual confounding. Our objective was to determine if these findings were generalizable to another SCI cohort with a larger sample size and information on additional potential confounders.

Participants were mostly male (84%) and white (91%) with a mean age of 54 years, had a wide range of injury levels, with a median injury duration of 14.1 years (Table 1). Most were current or former cigarette smokers with a median of 18 pack-years and were overweight. The majority of participants (90%) had at least two or three acceptable efforts with values of FEV₁ or FVC within 200 mL and an additional 7% (n = 21) had reproducible values of either FEV₁ or FVC. In 3% (n = 9), participants had only one acceptable effort.

The associations of CRP and IL-6 with FEV₁ are presented in Table 2. In basic models, increases in either inflammatory biomarker were associated with statistically significant reductions in FEV1. Although all adjusted models were attenuated relative to the basic model (Additional file 1: Table S1), the associations were robust to adjustment for potential confounders. In fully adjusted continuous models, each IQR increase in CRP (5.91 mg/L) was associated with a 55.85 (95% CI:-89.21, −22.49, p-value = 0.0012) mL decrease in FEV1, and each IQR increase in IL-6 (3.18 pg/mL) was associated with a 61.39 (95% CI: -115.47, −7.30, p-value = 0.027) mL decrease. Associations were similar in parsimonious adjusted models that included only age, sex, race, height, cigarette smoking status and pack-years, marijuana smoking status, doctor diagnosed COPD or asthma, level of injury and mobility mode (dichotomized into wheelchair vs walking aided or unaided), and use of inhaled steroids or long-acting bronchodilators.

Similar results were observed in models examining the associations of the inflammatory biomarkers with FVC (Table 3), although the models were slightly more sensitive to adjustment for potential confounders, especially mobility mode (Additional file 2: Table S2). In fully adjusted models, each IQR increase in CRP was associated with a 65.50 (95% CI: -106.61, −24.60, p-value = 0.0019) mL decrease in FVC and each IQR increase in IL-6 was associated with a 77.69 (95% CI: -143.93, −11.46, p-value = 0.0222) ml decrease. Adjustment for level of injury and mobility mode led to the largest attenuations in the effect estimates. Increases in CRP and IL-6 were not associated with the FEV₁/FVC ratio (Table 4), and adjustment for individuals confounders or groups of confounders had little impact (Additional file 3: Table S3) (all p-values > 0.34). In sensitivity analyses, adjusting for laboratory batch had no impact on the interpretation of any the final models (data not shown).

In this cohort of individuals with SCI, biomarkers of systemic inflammation (CRP, IL-6) were associated with decreases in FEV₁ and FVC, but not FEV₁/FVC. These findings were robust to adjustment for a number of potential confounders, including demographics and anthropometrics (age, race, sex, height, and BMI), lifestyle characteristics (cigarette and marijuana smoking status, medication use, and usual mobility mode), and disease characteristics (level of injury, history of COPD or asthma, history of chest operations or chest injuries).

In our previous analyses of 59 and 137 participants with SCI studied between 2003 and 2007, we observed similar associations between measures of inflammation and pulmonary function [13, 14]. In our pilot study of 59 individuals, IL-6 was inversely associated with percent-predicted FEV₁ (mean percent-predicted FEV₁ 92.4% in the least exposed quartile and 69.8% in the most exposed) and percent-predicted FVC (mean percent-predicted FVC 86.9% in the least exposed quartile and 71.5% in the most exposed) in unadjusted models, and in models adjusted for either SCI level, history of doctor diagnosed COPD, cigarette smoking status, or BMI (multivariable models were not possible). Similar decreases that did not reach statistical significance were observed between CRP and percent-predicted FEV₁ or percent-predicted FVC, and no associations were observed with FEV₁/FVC [13]. In a larger study of 137 individuals (54 of whom were also participants in the pilot study), we observed similar findings, even in multivariable models simultaneously adjusted for level of injury, BMI, cigarette smoking, statin use, and doctor-diagnosed COPD [14]. In our current study conducted in a larger SCI cohort enrolled between 2009 and 2015, we observed little confounding, and our parsimonious models included a different set of confounders than our previous studies (age, sex, race, height, cigarette smoking status and pack-years, marijuana smoking status, doctor diagnosed COPD, level or injury and mobility mode (dichotomized into wheelchair vs walking aided or unaided), and use of inhaled steroids or long-acting bronchodilators). Overall, we have observed consistent decreases in FEV₁ and FVC with increases in CRP and IL-6 among populations of individuals with SCI.

Our findings are also consistent with most other cross-sectional studies [1‐17]. Across a wide variety of populations, including individuals with and without chronic illnesses, increases in markers of systemic inflammation have been associated with declines in measures of pulmonary function. Similar to our study, the majority of the literature has focused on the impacts of CRP and IL-6 on FEV₁ and FVC.

This study has a number of limitations. First, due to its cross-sectional nature, we cannot determine the temporality of the associations between increased inflammation and decreased pulmonary function. A recent longitudinal study among a group of younger adults studied at ages 32 and 38 has suggested that reductions in pulmonary function lead to subsequent increases in inflammation, but that inflammation did not predict future decreases in lung function [24]. This is contrary to another longitudinal study that found CRP measured in young adults was predictive of pulmonary function measured 7 years later, and other studies that have suggested inflammation may be related to subsequent pulmonary function [18‐20].

Second, although we have considered an extensive number of potential confounders that were risk factors for pulmonary function and shown that our associations are robust to adjustment, residual confounding is always a concern in epidemiologic studies. Thirdly, the mechanism whereby systemic inflammation could influence pulmonary function in SCI is uncertain. Since chronic SCI is not known to be a condition characterized by pulmonary inflammation, it is likely that systemic inflammation following SCI is a function of decreased mobility, pressure ulcers, bladder dysfunction, and increased adipose tissue [32, 38]. Once these factors that occur after SCI are accounted for, we have previously found that level and completeness of SCI is not associated with CRP [32, 38]. However, since systemic inflammation is associated with muscle weakness and frailty, it is possible that systemic inflammation could adversely affect respiratory muscle performance and contribute to reduced pulmonary function [39‐42].

Lastly, our study population may not be broadly generalizable. We have small numbers of female and minority participants, reflecting the distribution in the population served at VA Boston. However, associations between inflammation and pulmonary function have been observed across a wide spectrum of populations.

Plasma CRP and IL-6 in individuals with chronic SCI is inversely associated with FEV₁ and FVC, independent of SCI severity, BMI, and other covariates. This finding suggests that systemic inflammation may contribute to reduced pulmonary function in chronic SCI.