No abstract

Dyspnea is a common, disabling symptom in chronic heart failure, yet the underlying mechanisms remain unknown. The respiratory muscle pump is composed of skeletal muscles whose strength directly influences the pump's performance. Respiratory muscle weakness is important in the dyspnea experienced by some patients with pulmonary disease; however, the role of the respiratory muscle pump in the dyspnea of chronic heart failure has not previously been examined. To assess respiratory muscle strength and its relation to dyspnea during daily activity, we measured maximum inspiratory and expiratory mouth pressures as indices of respiratory muscle strength and the baseline dyspnea index in nine stable, chronic cardiac pump failure patients who had no evidence of primary lung disease, and in nine age- and sex-matched healthy control subjects. The chronic heart failure patients, when compared with their matched control subjects, had reduced inspiratory and expiratory muscle strength, and both inspiratory and expiratory muscle strength were significantly correlated with dyspnea during daily activity (r2 = 0.80, p = 0.001 and r2 = 0.45, p = 0.05, respectively). Inspiratory muscle strength accounted for all of the variance in dyspnea that was correlated with respiratory muscle strength when the relative contributions of inspiratory and expiratory muscle strength were examined. There was no correlation between lung volumes or spirometry and dyspnea in the heart failure patients. These findings indicate that patients with stable chronic heart failure have inspiratory and expiratory muscle weakness and further suggest that the respiratory muscle pump significantly contributes to the dyspnea during the activities of daily living.

Canadian Thoracic Society (CTS) clinical guidelines for asthma and chronic obstructive pulmonary disease (COPD) specify that spirometry should be used to diagnose these diseases. Given the burden of asthma and COPD, most people with these diseases will be diagnosed in the primary care setting. The present CTS position statement was developed to provide guidance on key factors affecting the quality of spirometry testing in the primary care setting. The present statement may also be used to inform and guide the accreditation process for spirometry in each province. Although many of the principles discussed are equally applicable to pulmonary function laboratories and interpretation of tests by respirologists, they are held to a higher standard and are outside the scope of the present statement.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).