Lower paraspinal muscle density is associated with small airway dysfunction in women with persistent asthma

Patients with asthma exhibit lower paraspinal muscle density (PSMD), which is reflective of increased skeletal muscle adiposity. Moreover, in women with persistent asthma, lower PSMD is associated with longitudinal decrease in spirometry.1Tattersall MC Lee KE Tsuchiya N et al.Skeletal muscle adiposity and lung function trajectory in the severe asthma research program.Am J Respir Crit Care Med. 2023; 207: 475-484Crossref PubMed Scopus (6) Google Scholar Notably, in the same study, however, there were no differences in baseline spirometry values according to PSMD. Pointedly, high intramuscular fat infiltration is associated with greater systemic leptin, lower systemic adiponectin, and increased expression of tumor necrosis factor α; all of which have been implicated in asthma.2Sood A Qualls C Li R et al.Lean mass predicts asthma better than fat mass among females.Eur Respir J. 2011; 37: 65-71Crossref PubMed Scopus (29) Google Scholar This is of particular interest given the targeted management of metabolic dysfunction provides another potential opportunity for reducing asthma exacerbations.3Foer D Beeler PE Cui J Karlson EW Bates DW Cahill KN Asthma exacerbations in patients with Type 2 diabetes and asthma on glucagon-like Peptide-1 receptor agonists.Am J Respir Crit Care Med. 2021; 203: 831-840Crossref PubMed Scopus (59) Google Scholar Compared with spirometry, airway oscillometry (AO) is an effort-independent tidal breathing test that assesses both total and peripheral airway resistance and reactance. We therefore hypothesized that women with asthma and lower PSMD might exhibit worse AO measurements as a measure of small airways dysfunction (SAD) because the latter is associated with poor asthma control and remodeling.4Manoharan A Anderson WJ Lipworth J Ibrahim I Lipworth BJ Small airway dysfunction is associated with poorer asthma control.Eur Respir J. 2014; 44: 1353-1355Crossref PubMed Scopus (55) Google Scholar,5Chan R Duraikannu C Thouseef MJ Lipworth B Impaired respiratory system resistance and reactance are associated with bronchial wall thickening in persistent asthma.J Allergy Clin Immunol Pract. 2023; 11: 1459-1462.e3Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar In total, 150 patients with persistent asthma attending our National Health Service specialist asthma clinic were included in this observational analysis. Two senior thoracic radiologists were blinded to all clinical data except that patients had Global Initiative for Asthma-defined moderate-to-severe asthma. High-resolution computed tomography (CT) scans were performed in volumetric mode with maximal inspiration, as per standard department protocol (128 slice CT Revolution EVO, GE Healthcare). Moreover, CT reconstruction was performed in the lung and mediastinal window with a slice thickness of 1 to 1.25 mm and no interval gap. Muscle attenuation was measured in the right and left erector spinae muscles at the 12th thoracic vertebra on a picture archiving and communication system workstation, using a defined region of interest with an area range of 300 to 500 mm2. The pooled average of right and left PSMD was then calculated. American Thoracic Society/European Respiratory Society guidelines were followed for spirometry (Micromedical, Chatham, United Kingdom) and AO (Impulse Oscillometry Masterscreen Carefusion, Hoechberg, Germany). Annual severe exacerbations requiring oral corticosteroids were recorded. Fractional exhaled nitric oxide (FeNO) values were obtained using NIOX VERO (Circassia, Oxford, United Kingdom) according to American Thoracic Society guidelines. All type 2 biomarkers (peripheral blood eosinophils and FeNO) were obtained, with none of the patients taking biologics at the time of any of the measurements. Independent t or Mann-Whitney U tests were performed using SPSS (IBM, United States) to identify any significant differences in clinical outcomes according to the median value for PSMD, with a 2-tailed α error of 0.05. The median value for PSMD was 48.2 and 47.5 Hounsfield units for the overall and female cohorts, respectively. Moreover, χ2 analysis was used for categorical variables. Interrater reliability was calculated using a 2-way mixed model with absolute agreement. Caldicott approval (IGTCAL-2023-002) was obtained before data collection. The overall interobserver reliability value (95% CI) for PSMD measurements was 0.94 (0.90, 0.96), P < .001. In the overall N = 150 cohort, patients with lower PSMD were older (data not shown). In a subset of n = 100 female patients, lower PSMD was significantly associated with older age, higher FeNO, and worse SAD, evident as peripheral resistance heterogeneity between 5 and 20 Hz (R5-R20) and area under reactance curve (AX) (Table 1). Pearson correlation coefficient was −0.27 (P < .01) between body mass index (BMI) and PSMD in this cohort.Table 1Patient Demographics and Clinical Outcomes According to Paraspinal Muscle Density (N = 100 Women)Clinical Feature<47.5 HUn = 50≥47.5 HUn = 50Age (y)57 (53-61)43 (40-47)aP < .001.BMI (kg/m2)32.6 (30.4-34.8)29.5 (27.3-31.8)ICS dose (µg)1748 (1627-1869)1690 (1563-1817)Nasal polyps (%)2016FEV1%83.4 (76.2-90.7)85.6 (80.0-91.2)R5-R20 (kPa/L/s)0.15 (0.12-0.19)0.09 (0.06-0.13)bP < .05.AX (kPa/L)1.60 (1.15-2.23)0.95 (0.66-1.37)bP < .05.FeNO (ppb)25 (28)18 (25)bP < .05.PBE (cells/µL)350 (250)380 (401)Exacerbations2 (4)1 (4)Abbreviations: AX, area under the reactance curve; BMI, body mass index; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; HU, Hounsfield units; ICS, inhaled corticosteroid; PBE, peripheral blood eosinophils; ppb, parts per billion; R5-R20, peripheral resistance heterogeneity between 5 and 20 Hz.Demographics and spirometry as arithmetic means (95% CI), R5-R20 and AX as geometric means (95% CI), and exacerbations as medians (IQR).a P < .001.b P < .05. Open table in a new tab Abbreviations: AX, area under the reactance curve; BMI, body mass index; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 second; HU, Hounsfield units; ICS, inhaled corticosteroid; PBE, peripheral blood eosinophils; ppb, parts per billion; R5-R20, peripheral resistance heterogeneity between 5 and 20 Hz. Demographics and spirometry as arithmetic means (95% CI), R5-R20 and AX as geometric means (95% CI), and exacerbations as medians (IQR). Herein, we have shown a significant association between lower PSMD and worse peripheral airway resistance (R5-R20) and compliance (AX) in women with persistent asthma. In the lower PSMD cohort, R5-R20 and AX exceeded values of 0.10 kPa/L/s or greater and 1.0 kPa/L or greater, respectively, which are predictive of poorer asthma control.6Chan R Lipworth BJ Determinants of asthma control and exacerbations in moderate to severe asthma.J Allergy Clin Immunol Pract. 2022; 10: 2758-2760.e1Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar This is perhaps unsurprising given higher BMI score is linked to SAD, presumably owing to extrinsic mechanical compression.7Chan R Lipworth B Clinical impact of obesity on oscillometry lung mechanics in adults with asthma.Ann Allergy Asthma Immunol. 2023; 131: 338-342.e3Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Therefore, this disconnect in terms of a clinically relevant difference in AO but not in spirometry provides further evidence that AO exhibits greater sensitivity for detecting subtle alterations in lung function. However, our findings cannot be entirely attributable to differences in BMI given there was only a weak albeit significant correlation with PSMD measurements in our female cohort, and there was no significant difference in BMI scores according to PSMD. Importantly, BMI also does not distinguish between excess fat, muscle, or bone mass, nor does it indicate fat distribution among individuals. In this regard, our patients with lower PSMD required numerically more frequent oral corticosteroid bursts, which in turn are associated with an increased propensity for metabolic syndrome. Lower PSMD was associated with significantly higher FeNO levels but not peripheral blood eosinophils in our study. It has previously been reported that elevated FeNO levels are associated with obesity and might be the missing link between asthma and obesity.8De Winter-de Groot KM Van der Ent CK Prins I Tersmette JM Uiterwaal CS Exhaled nitric oxide: the missing link between asthma and obesity?.J Allergy Clin Immunol. 2005; 115: 419-420Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Interleukin 13 mediates FeNO production and regulates mucus plugging and bronchoconstriction; both of which are closely associated with impaired lung function.9Chan R Duraikannu C Lipworth B Clinical associations of mucus plugging in moderate to severe asthma.J Allergy Clin Immunol Pract. 2023; 11: 195-199.e2Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Furthermore, there was a numerically greater prevalence of patients with nasal polyps, in keeping with its previous association with higher FeNO levels.10Chan R Lipworth B Impact of nasal polyps on endotype and phenotype in patients with moderate to severe asthma.Ann Allergy Asthma Immunol. 2021; 127: 548-552Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar We appreciate the potential limitations of our study, including its retrospective nature using data obtained from a single, specialist United Kingdom center. We also did not have longitudinal data because CT scans were performed at a solitary time point before patients were assessed for commencement on biologics. This is rationalized by reducing unnecessary ionizing radiation in conjunction with a low likelihood of changing clinical management with serial imaging. Future studies are warranted to explore the effects of varying intensities and types of exercise on skeletal muscle adiposity and asthma control. Supplementary data related to this article can be found at https://doi.org/10.1016/j.anai.2024.02.016. Dr Chan reports personal fees (talks) and support attending European Respiratory Society (ERS) from AstraZeneca, personal fees (consulting) from Vitalograph, and personal fees (talks) from Thorasys. Dr Lipworth reports nonfinancial support (equipment) from GlaxoSmithKline; grants, personal fees (consulting, talks, and advisory board), other support (attending American Thoracic Society and ERS), and from AstraZeneca; personal fees (talks and consulting) from Sanofi and personal fees (consulting, talks, and advisory board) from Circassia in relation to the submitted work; grants, personal fees (consulting, talks, and advisory board), other support (attending ERS) from Teva, personal fees (talks and consulting), grants and other support (attending ERS and British Thoracic Society) from Chiesi, personal fees (consulting) from Lupin, personal fees (consulting) from Glenmark, personal fees (consulting) from Dr Reddy, and personal fees (consulting) from Sandoz; grants, personal fees (consulting, talks, and advisory board), other support (attending British Thoracic Society) from Boehringer Ingelheim, and grants and personal fees (advisory board and talks) from Mylan outside of the submitted work; and the son of Dr Lipworth is presently an employee of AstraZeneca. The remaining authors have no conflicts of interest to report. The authors have no funding sources to report.