Just breathe: a review of sex and gender in chronic lung disease

Chronic lung diseases are the third leading cause of death worldwide and are increasing in prevalence over time. Although much of our traditional understanding of health and disease is derived from study of the male of the species – be it animal or human – there is increasing evidence that sex and gender contribute to differences in disease risk, prevalence, presentation, severity, treatment approach, response and outcomes. Chronic obstructive pulmonary disease, asthma and bronchiectasis represent the most prevalent and studied chronic lung diseases and have key sex- and gender-based differences which are critical to consider and incorporate into clinical and research approaches. Mechanistic differences present opportunities for therapeutic development whereas behavioural and clinical differences on the part of patients and providers present opportunities for greater education and understanding at multiple levels. In this review, we seek to summarise the sex- and gender-based differences in key chronic lung diseases and outline the clinical and research implications for stakeholders.

Intracellular Drug Targets In Mycobacterium Tuberculosis Revealed By A Chemo-Genetic Approach

Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, is one of the most devastating infectious agents in the world. It causes chronic lung diseases to one third of the world’s population. Chemo-genetic characterization through in vitro evolution combined with whole genome sequencing analysis can identify novel drug targets and drug resistance genes in Mtb. We performed a genome analysis of 53 Mtb mutants resistant to 15 different hit compounds. We found nonsynonymous mutations/indels in 30 genes that may be associated with drug resistance acquisitions. Beyond confirming previously identified drug resistance mechanisms such as rpoB and lead targets reported in novel anti-tuberculosis drug screenings such as mmpL3, ethA, mbtA, we discovered several unrecognized candidate drug targets including prrB and TB18.5. The exploration of the M. tuberculosis chemical mutant genomes could help novel drug discovery and structural biology of compounds and asscoiated mechanisms of action relevant to tuberculosis treatment.

Transient Ascaris suum larval migration induces intractable chronic pulmonary disease and anemia in mice

Ascariasis is one of the most common infections in the world and associated with significant global morbidity. Ascaris larval migration through the host’s lungs is essential for larval development but leads to an exaggerated type-2 host immune response manifesting clinically as acute allergic airway disease. However, whether Ascaris larval migration can subsequently lead to chronic lung diseases remains unknown. Here, we demonstrate that a single episode of Ascaris larval migration through lungs induces a chronic pulmonary syndrome of type-2 inflammatory pathology and emphysema accompanied by pulmonary hemorrhage and chronic anemia in a mouse model. Our results reveal that a single episode of Ascaris larval migration through the host lungs leads to permanent lung damage with systemic effects. Remote episodes of ascariasis may drive non-communicable lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), and chronic anemia in parasite endemic regions.

Increased LGR6 Expression Sustains Long-Term Wnt Activation and Acquisition of Senescence in Epithelial Progenitors in Chronic Lung Diseases

Chronic lung diseases (CLDs) represent a set of disorders characterized by the progressive loss of proper lung function. Among severe CLDs, the incidence of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) has grown over the last decades, mainly in the elderly population. Several studies have highlighted an increased expression of senescence-related markers in the resident progenitor cells in COPD and IPF, possibly undermining epithelial integrity and contributing to the progression and the aggravation of both diseases. Recently, the chronic activation of the canonical Wnt/β-catenin pathway was shown to induce cellular senescence. Here, we investigated the localization and the expression of leucin-rich repeat-containing G-protein-coupled receptor 6 (LGR6), a protein that activates and potentiates the canonical Wnt signalling. Through immunohistochemical analyses, we identified a lesion-associated rise in LGR6 levels in abnormal lung epithelial progenitors in COPD and IPF when compared to histologically normal tissues. Moreover, in areas of aberrant regeneration, chronic damage and fibrosis, LGR6-expressing epithelial progenitors displayed a major increase in the expression of senescence-associated markers. Our study suggests the involvement of LGR6 in the chronic activation of the Wnt/β-catenin pathway, mediating the impairment and exhaustion of epithelial progenitors in COPD and IPF.

Prescription Patterns for Pulmonary Vasodilators in the Treatment of Pulmonary Hypertension Associated With Chronic Lung Diseases: Insights From a Clinician Survey

Background: Pulmonary hypertension is a complication of chronic lung diseases (PH-CLD) associated with significant morbidity and mortality. Management guidelines for PH-CLD emphasize the treatment of the underlying lung disease, but the role of PH-targeted therapy remains controversial. We hypothesized that treatment approaches for PH-CLD would be variable across physicians depending on the type of CLD and the severity of PH.Methods and Results: Between May and July 2020, we conducted an online survey of PH experts asking for their preferred treatment approach in seven hypothetical cases of PH-CLD of varying severity. We assessed agreement amongst clinicians for initial therapy choice using Fleiss' kappa calculations. Over 90% of respondents agreed that they would treat cases of severe PH in the context of mild lung disease with some form of PH-targeted therapy. For cases of severe PH in the context of severe lung disease, over 70% of respondents agreed to use PH-targeted therapy. For mild PH and mild lung disease cases, <50% of respondents chose to start PH-specific therapy. There was overall poor agreement between respondents in the choice to use mono-, double or triple combination therapy with PH-specific agents in all cases.Conclusion: Although management guidelines discourage the routine use of PH-targeted therapies to treat PH-CLD patients, most physicians choose to treat patients with some form of PH-targeted therapy. The choice of therapy and treatment approach are variable and appear to be influenced by the severity of the PH and the underlying lung disease.

Systemic diseases and their association with open-angle glaucoma in the population of Stockholm

Objective We aimed to study open-angle glaucoma in association with somatic comorbidities in the total population of adults in Region Stockholm. Methods The study population included all living persons aged 19 years and above who resided in Stockholm County, Sweden, on 1 January 2017 (N = 1 703 675). Subjects with specified diseases were identified with data from all registered consultations and hospital stays during 2008–2019. As outcome, the risk of being associated with a diagnosis of open-angle glaucoma was identified during 2012–2018. Analyses were performed by gender, controlling for age and socio-economic status. Age-adjusted odds ratios (ORs) with 95% confidence intervals (95% CI) for women and men with open-angle glaucoma, using individuals without this as referents, were calculated. Socio-economic status was assessed based on the neighbourhood the subjects lived in. Results In total, 16,299 cases of open-angle glaucoma were identified during 2012–2018, 9204 women and 7095 men. Higher fully adjusted OR (95% CI) for risk of being associated with open-angle glaucoma was for women and men with diabetes 1.138 (1.074–1.207) and 1.216 (1.148–1.289), cancer 1.175 (1.120–1.233) and 1.106 (1.048–1.166), hypertension 1.372 (1.306–1.440) and 1.243 (1.179–1.311); and for women with thyroid diseases 1.086 (1.030–1.146), chronic lung diseases 1.153 (1.093–1.216), and inflammatory arthropathies 1.132 (1.006–1.275). Higher glaucoma incidence was observed in individuals residing in high socio-economic status neighbourhoods. Conclusion The risk of glaucoma is increased in some somatic diseases, especially in individuals with diabetes, hypertension and cancer; and in higher socio-economic neighbourhoods as compared to lower socio-economic neighbourhoods.

Mitochondria in Focus: From Function to Therapeutic Strategies in Chronic Lung Diseases

Mitochondria are essential organelles for cell metabolism, growth, and function. Mitochondria in lung cells have important roles in regulating surfactant production, mucociliary function, mucus secretion, senescence, immunologic defense, and regeneration. Disruption in mitochondrial physiology can be the central point in several pathophysiologic pathways of chronic lung diseases such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and asthma. In this review, we summarize how mitochondria morphology, dynamics, redox signaling, mitophagy, and interaction with the endoplasmic reticulum are involved in chronic lung diseases and highlight strategies focused on mitochondrial therapy (mito-therapy) that could be tested as a potential therapeutic target for lung diseases.

The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD.Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance of Streptococcus pneumoniae (SP), Staphylococcus aureus (SA), Haemophilus influenzae (HI), and Moraxella catarrhalis (MC) at these timepoints. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance respectively.Of 347 (174 AZM, 173 placebo) participants (median age 15 years [IQR=13–18], females 49%),NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18% versus 41%, p<0.001), HI (7% versus 16%, p=0.01), and MC (4% versus 11%, p=0.02); SP resistance to AZM (62% [18/29] versus 13%[8/63], p<0.0001) or tetracycline (60%[18/29] versus 21%[13/63], p<0.0001) were higher in the AZM arm. Carriage of SA resistant to AZM (91% [31/34] versus 3% [1/31], p<0.0001), tetracycline (35% [12/34] versus 13% [4/31], p=0.05) and clindamycin (79% [27/34] versus 3% [1/31], p<0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa.The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation.

The Emerging Role of Proteases in Alpha-1 Antitrypsin Deficiency and Beyond

Alpha-1 Antitrypsin Deficiency (AATD) has been historically under-recognised and under-diagnosed; recently it has begun to receive greater interest in terms of attempts at deeper elucidation of pathology and treatment options. However, the concept of disease phenotypes within AATD (emphysema, chronic bronchitis, bronchiectasis, or a combination of phenotypes) has not been proposed or studied. Of the 3 Neutrophil Serine Proteases (NSPs), Neutrophil Elastase (NE) was historically believed to be the sole contributor to disease pathology in AATD. Recently, Proteinase-3 (PR3) has been increasingly studied as an equal, if not greater, contributor to the disease process. Cathepsin G (CG), however, has not been extensively evaluated in this area. Matrix metalloproteinases (MMPs) have also been mentioned in the pathogenesis of AATD but have not been widely explored. This article considers the available evidence for differential protease activity in patients with AATD, including the contribution to distinct phenotypes of the disease. Due to limited literature in this area, extrapolations from studies of other chronic lung diseases with similar phenotypes, including chronic obstructive pulmonary disease (COPD) and bronchiectasis have been made. We consider a new framework of understanding defined by protease driven endotypes of disease which may lead to new opportunities for precision medicine.

Effectiveness of Telemonitoring for Respiratory and Systemic Symptoms of Asthma and COPD: A Narrative Review

Asthma and chronic obstructive pulmonary diseases (COPD) are highly prevalent chronic lung diseases that require ongoing self-management, which itself is often suboptimal. Therefore, telemonitoring has been used to help patients measure their symptoms, share data with healthcare providers and receive education and feedback to improve disease management. In this study, we conducted a narrative review of recent evidence on the effectiveness of telemonitoring for asthma and COPD in adults. Of the thirteen identified studies, eleven focused on COPD and two focused on asthma. All studies were reviewed, and effects were compared between intervention and care as usual groups. Of the study interventions, seven showed a positive outcome on at least one outcome measure, and six had no significant results on any of the outcome measures. All of the interventions with a positive outcome included an educational component, while only one of the six interventions without positive outcomes included an educational component. We conclude that telemonitoring interventions for asthma and COPD seem more effective if they included an educational component regarding different aspects of self-management.