American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Apr 2021
Comparative StudyAirspace Macrophages and Monocytes Exist in Transcriptionally Distinct Subsets in Healthy Adults.
Rationale: Macrophages are the most abundant immune cell in the alveoli and small airways and are traditionally viewed as a homogeneous population during health. Whether distinct subsets of airspace macrophages are present in healthy humans is unknown. Single-cell RNA sequencing allows for examination of transcriptional heterogeneity between cells and between individuals. ⋯ Resident macrophages make up the largest population and include novel subsets defined by inflammatory and metal-binding profiles. Monocyte-like cells within the airspaces are transcriptionally aligned with circulating blood cells and include a rare population defined by expression of cell-matrix interaction genes. This study is the first to delineate the conserved heterogeneity of airspace immune cells during health and identifies two previously unrecognized macrophage subsets.
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Am. J. Respir. Crit. Care Med. · Apr 2021
Comparative StudyEnhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection.
Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing. Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses. Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. ⋯ In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time. Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.
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Am. J. Respir. Crit. Care Med. · Apr 2021
ReviewSevere Adult Asthmas: Integrating Clinical Features, Biology and Therapeutics to Improve Outcomes.
Evaluation and effective management of asthma, and in particular severe asthma, remains at the core of pulmonary practice. Over the last 20-30 years, there has been increasing appreciation that "severe asthma" encompasses multiple different subgroups or phenotypes, each with differing presentations. Using clinical phenotyping, in combination with rapidly advancing molecular tools and targeted monoclonal antibodies (human knockouts), the understanding of these phenotypes, and our ability to treat them, have greatly advanced. ⋯ Despite these advances, little guidance is available to determine which class of biologic is appropriate for a given patient, and current "breakthrough" therapies remain expensive and even inaccessible to many patients. Many of the most severe asthmas, with and without T2-biomarker elevations, remain poorly understood and treated. Nevertheless, conceptual understanding of "the severe asthmas" has evolved dramatically in a mere 25 years, leading to dramatic improvements in the lives of many.
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Am. J. Respir. Crit. Care Med. · Apr 2021
Asthma in Adult Patients with COVID-19: Prevalence and Risk of Severe Disease.
Rationale: Health outcomes of people with coronavirus disease (COVID-19) range from no symptoms to severe illness and death. Asthma, a common chronic lung disease, has been considered likely to increase the severity of COVID-19, although data addressing this hypothesis have been scarce until very recently. Objectives: To review the epidemiologic literature related to asthma's potential role in COVID-19 severity. ⋯ We identified 150 studies worldwide that allowed us to compare the prevalence of asthma in patients with COVID-19 by region, disease severity, and mortality. The results of our analyses do not provide clear evidence of increased risk of COVID-19 diagnosis, hospitalization, severity, or mortality due to asthma. Conclusions: These findings could provide some reassurance to people with asthma regarding its potential to increase their risk of severe morbidity from COVID-19.
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Am. J. Respir. Crit. Care Med. · Apr 2021
Comparative StudyCharacteristics and Mechanisms of a Sphingolipid-associated Childhood Asthma Endotype.
Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elucidated. Objectives: To study the sphingolipid-associated childhood asthma endotype using multiomic data. Methods: We used untargeted liquid chromatography-mass spectrometry plasma metabolomic profiles at the ages of 6 months and 6 years from more than 500 children in the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood) birth cohort focusing on sphingolipids, and we integrated the 17q21 genotype and nasal gene expression of SPT (serine palmitoyl-CoA transferase) (i.e., the rate-limiting enzyme in de novo sphingolipid synthesis) in relation to asthma development and lung function traits from infancy until the age 6 years. ⋯ This relationship was dependent on the 17q21 genotype and nasal SPT gene expression, with significant interactions occurring between the genotype and the phosphosphingolipid concentrations and between the genotype and SPT expression, in which lower phosphosphingolipid concentrations and reduced SPT expression were associated with increasing numbers of at-risk alleles. However, the findings did not pass the false discovery rate threshold of <0.05. Conclusions: This exploratory study suggests the existence of a childhood asthma endotype with early onset and increased airway resistance that is characterized by reduced sphingolipid concentrations, which are associated with 17q21 genetic variants and expression of the SPT enzyme.