The role of the bronchial microvasculature in the airway remodelling in asthma and COPD

In recent years, there has been increased interest in the vascular component of airway remodelling in chronic bronchial inflammation, such as asthma and COPD, and in its role in the progression of disease. In particular, the bronchial mucosa in asthmatics is more vascularised, showing a higher number and dimension of vessels and vascular area. Recently, insight has been obtained regarding the pivotal role of vascular endothelial growth factor (VEGF) in promoting vascular remodelling and angiogenesis. Many studies, conducted on biopsies, induced sputum or BAL, have shown the involvement of VEGF and its receptors in the vascular remodelling processes. Presumably, the vascular component of airway remodelling is a complex multi-step phenomenon involving several mediators. Among the common asthma and COPD medications, only inhaled corticosteroids have demonstrated a real ability to reverse all aspects of vascular remodelling. The aim of this review was to analyze the morphological aspects of the vascular component of airway remodelling and the possible mechanisms involved in asthma and COPD. We also focused on the functional and therapeutic implications of the bronchial microvascular changes in asthma and COPD

Correlation of exhaled breath temperature with bronchial blood flow in asthma

In asthma elevated rates of exhaled breath temperature changes (Δe°T) and bronchial blood flow (Q(aw)) may be due to increased vascularity of the airway mucosa as a result of inflammation. We investigated the relationship of Δe°T with Q(aw )and airway inflammation as assessed by exhaled nitric oxide (NO). We also studied the anti-inflammatory and vasoactive effects of inhaled corticosteroid and β(2)-agonist. Δe°T was confirmed to be elevated (7.27 ± 0.6 Δ°C/s) in 19 asthmatic subjects (mean age ± SEM, 40 ± 6 yr; 6 male, FEV(1 )74 ± 6 % predicted) compared to 16 normal volunteers (4.23 ± 0.41 Δ°C/s, p < 0.01) (30 ± 2 yr) and was significantly increased after salbutamol inhalation in normal subjects (7.8 ± 0.6 Δ°C/ s, p < 0.05) but not in asthmatic patients. Q(aw), measured using an acetylene dilution method was also elevated in patients with asthma compared to normal subjects (49.47 ± 2.06 and 31.56 ± 1.6 μl/ml/min p < 0.01) and correlated with exhaled NO (r = 0.57, p < 0.05) and Δe°T (r = 0.525, p < 0.05). In asthma patients, Q(aw )was reduced 30 minutes after the inhalation of budesonide 400 μg (21.0 ± 2.3 μl/ml/min, p < 0.05) but was not affected by salbutamol. Δe°T correlates with Q(aw )and exhaled NO in asthmatic patients and therefore may reflect airway inflammation, as confirmed by the rapid response to steroids

Partial pulmonary embolization disrupts alveolarization in fetal sheep

BACKGROUND: Although bronchopulmonary dysplasia is closely associated with an arrest of alveolar development and pulmonary capillary dysplasia, it is unknown whether these two features are causally related. To investigate the relationship between pulmonary capillaries and alveolar formation, we partially embolized the pulmonary capillary bed. METHODS: Partial pulmonary embolization (PPE) was induced in chronically catheterized fetal sheep by injection of microspheres into the left pulmonary artery for 1 day (1d PPE; 115d gestational age; GA) or 5 days (5d PPE; 110-115d GA). Control fetuses received vehicle injections. Lung morphology, secondary septal crests, elastin, collagen, myofibroblast, PECAM1 and HIF1 alpha abundance and localization were determined histologically. VEGF-A, Flk-1, PDGF-A and PDGF-R alpha mRNA levels were measured using real-time PCR. RESULTS: At 130d GA (term approximately 147d), in embolized regions of the lung the percentage of lung occupied by tissue was increased from 29 +/- 1% in controls to 35 +/- 1% in 1d PPE and 44 +/- 1% in 5d PPE fetuses (p < 0.001). Secondary septal crest density was reduced from 8 +/- 0% in controls to 5 +/- 0% in 1d PPE and 4 +/- 0% in 5d PPE fetuses (p < 0.05), indicating impaired alveolar formation. The deposition of differentiated myofibroblasts (23 +/- 1% vs 28 +/- 1%; p < 0.001) and elastin fibres (3 +/- 0% vs 4 +/- 0%; p < 0.05) were also impaired in embolized lung regions of PPE fetuses compared to controls. PPE did not alter the deposition of collagen or PECAM1. At 116d GA in 5d PPE fetuses, markers of hypoxia indicated that a small and transient hypoxic event had occurred (hypoxia in 6.7 +/- 1.4% of the tissue within embolized regions of 5d PPE fetuses at 116d compared to 0.8 +/- 0.2% of tissue in control regions). There was no change in the proportion of tissue labelled with HIF1 alpha. There was no change in mRNA levels of the angiogenic factors VEGF and Flk-1, although a small increase in PDGF-R alpha expression at 116d GA, from 1.00 +/- 0.12 in control fetuses to 1.61 +/- 0.18 in 5d PPE fetuses may account for impaired differentiation of alveolar myofibroblasts and alveolar development. CONCLUSIONS: PPE impairs alveolarization without adverse systemic effects and is a novel model for investigating the role of pulmonary capillaries and alveolar myofibroblasts in alveolar formation

Measuring routine childhood vaccination coverage in 204 countries and territories, 1980-2019: a systematic analysis for the Global Burden of Disease Study 2020, Release 1

Background: Measuring routine childhood vaccination is crucial to inform global vaccine policies and programme implementation, and to track progress towards targets set by the Global Vaccine Action Plan (GVAP) and Immunization Agenda 2030. Robust estimates of routine vaccine coverage are needed to identify past successes and persistent vulnerabilities. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2020, Release 1, we did a systematic analysis of global, regional, and national vaccine coverage trends using a statistical framework, by vaccine and over time. // Methods: For this analysis we collated 55 326 country-specific, cohort-specific, year-specific, vaccine-specific, and dose-specific observations of routine childhood vaccination coverage between 1980 and 2019. Using spatiotemporal Gaussian process regression, we produced location-specific and year-specific estimates of 11 routine childhood vaccine coverage indicators for 204 countries and territories from 1980 to 2019, adjusting for biases in country-reported data and reflecting reported stockouts and supply disruptions. We analysed global and regional trends in coverage and numbers of zero-dose children (defined as those who never received a diphtheria-tetanus-pertussis [DTP] vaccine dose), progress towards GVAP targets, and the relationship between vaccine coverage and sociodemographic development. // Findings: By 2019, global coverage of third-dose DTP (DTP3; 81·6% [95% uncertainty interval 80·4–82·7]) more than doubled from levels estimated in 1980 (39·9% [37·5–42·1]), as did global coverage of the first-dose measles-containing vaccine (MCV1; from 38·5% [35·4–41·3] in 1980 to 83·6% [82·3–84·8] in 2019). Third-dose polio vaccine (Pol3) coverage also increased, from 42·6% (41·4–44·1) in 1980 to 79·8% (78·4–81·1) in 2019, and global coverage of newer vaccines increased rapidly between 2000 and 2019. The global number of zero-dose children fell by nearly 75% between 1980 and 2019, from 56·8 million (52·6–60·9) to 14·5 million (13·4–15·9). However, over the past decade, global vaccine coverage broadly plateaued; 94 countries and territories recorded decreasing DTP3 coverage since 2010. Only 11 countries and territories were estimated to have reached the national GVAP target of at least 90% coverage for all assessed vaccines in 2019. // Interpretation: After achieving large gains in childhood vaccine coverage worldwide, in much of the world this progress was stalled or reversed from 2010 to 2019. These findings underscore the importance of revisiting routine immunisation strategies and programmatic approaches, recentring service delivery around equity and underserved populations. Strengthening vaccine data and monitoring systems is crucial to these pursuits, now and through to 2030, to ensure that all children have access to, and can benefit from, lifesaving vaccines

Global mortality associated with 33 bacterial pathogens in 2019: a systematic analysis for the Global Burden of Disease Study 2019

Background Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential to identify the greatest threats to public health. To our knowledge, this is the first study to present global comprehensive estimates of deaths associated with 33 bacterial pathogens across 11 major infectious syndromes.Methods We estimated deaths associated with 33 bacterial genera or species across 11 infectious syndromes in 2019 using methods from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, in addition to a subset of the input data described in the Global Burden of Antimicrobial Resistance 2019 study. This study included 343 million individual records or isolates covering 11 361 study-location-years. We used three modelling steps to estimate the number of deaths associated with each pathogen: deaths in which infection had a role, the fraction of deaths due to infection that are attributable to a given infectious syndrome, and the fraction of deaths due to an infectious syndrome that are attributable to a given pathogen. Estimates were produced for all ages and for males and females across 204 countries and territories in 2019. 95% uncertainty intervals (UIs) were calculated for final estimates of deaths and infections associated with the 33 bacterial pathogens following standard GBD methods by taking the 2.5th and 97.5th percentiles across 1000 posterior draws for each quantity of interest.Findings From an estimated 13.7 million (95% UI 10.9-17.1) infection-related deaths in 2019, there were 7.7 million deaths (5.7-10.2) associated with the 33 bacterial pathogens (both resistant and susceptible to antimicrobials) across the 11 infectious syndromes estimated in this study. We estimated deaths associated with the 33 bacterial pathogens to comprise 13.6% (10.2-18.1) of all global deaths and 56.2% (52.1-60.1) of all sepsis-related deaths in 2019. Five leading pathogens-Staphylococcus aureus, Escherichia coli, Streptococcus pneumoniae, Klebsiella pneumoniae, and Pseudomonas aeruginosa-were responsible for 54.9% (52.9-56.9) of deaths among the investigated bacteria. The deadliest infectious syndromes and pathogens varied by location and age. The age-standardised mortality rate associated with these bacterial pathogens was highest in the sub-Saharan Africa super-region, with 230 deaths (185-285) per 100 000 population, and lowest in the high-income super-region, with 52.2 deaths (37.4-71.5) per 100 000 population. S aureus was the leading bacterial cause of death in 135 countries and was also associated with the most deaths in individuals older than 15 years, globally. Among children younger than 5 years, S pneumoniae was the pathogen associated with the most deaths. In 2019, more than 6 million deaths occurred as a result of three bacterial infectious syndromes, with lower respiratory infections and bloodstream infections each causing more than 2 million deaths and peritoneal and intra-abdominal infections causing more than 1 million deaths.Interpretation The 33 bacterial pathogens that we investigated in this study are a substantial source of health loss globally, with considerable variation in their distribution across infectious syndromes and locations. Compared with GBD Level 3 underlying causes of death, deaths associated with these bacteria would rank as the second leading cause of death globally in 2019; hence, they should be considered an urgent priority for intervention within the global health community. Strategies to address the burden of bacterial infections include infection prevention, optimised use of antibiotics, improved capacity for microbiological analysis, vaccine development, and improved and more pervasive use of available vaccines. These estimates can be used to help set priorities for vaccine need, demand, and development. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license