Clinical utilization of airway inflammatory biomarkers in the prediction and monitoring of clinical outcomes in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) accounts for 545 million people living with chronic respiratory disorders and is the third leading cause of morbidity and mortality around the world. COPD is a progressive disease, characterized by episodes of acute worsening of symptoms such as cough, dyspnea, and sputum production. AREAS COVERED: Airway inflammation is a prominent feature of COPD. Chronic airway inflammation results in airway structural remodeling and emphysema. Persistent airway inflammation is a treatable trait of COPD and plays a significant role in disease development and progression. In this review, the authors summarize the current and emerging biomarkers that reveal the heterogeneity of airway inflammation subtypes, clinical outcomes, and therapeutic response in COPD. EXPERT OPINION: Airway inflammation can be broadly categorized as eosinophilic (type 2 inflammation) and non-eosinophilic (non-type 2 inflammation) in COPD. Currently, blood eosinophil counts are incorporated in clinical practice guidelines to identify COPD patients who are at a higher risk of exacerbations and lung function decline, and who are likely to respond to inhaled corticosteroids. As new therapeutics are being developed for the chronic management of COPD, it is essential to identify biomarkers that will predict treatment response.

A Novel Air Trapping Segment Score Identifies Opposing Effects of Obesity and Eosinophilia on Air Trapping in Asthma.

Rationale: Density thresholds in computed tomography (CT) lung scans quantify air trapping (AT) at the whole-lung level but are not informative for AT in specific bronchopulmonary segments. Objectives: To apply a segment-based measure of AT in asthma to investigate the clinical determinants of AT in asthma. Methods: In each of 19 bronchopulmonary segments in CT lung scans from 199 patients with asthma, AT was categorized as present if lung attenuation was less than -856 Hounsfield units at expiration in ⩾15% of the lung area. The resulting AT segment score (0-19) was related to patient outcomes. Measurements and Main Results: AT varied at the lung segment level and tended to persist at the patient and lung segment levels over 3 years. Patients with widespread AT (⩾10 segments) had more severe asthma (P < 0.05). The mean (±SD) AT segment score in patients with a body mass index ⩾30 kg/m2 was lower than in patients with a body mass index <30 kg/m2 (3.5 ± 4.6 vs. 5.5 ± 6.3; P = 0.008), and the frequency of AT in lower lobe segments in obese patients was less than in upper and middle lobe segments (35% vs. 46%; P = 0.001). The AT segment score in patients with sputum eosinophils ⩾2% was higher than in patients without sputum eosinophilia (7.0 ± 6.1 vs. 3.3 ± 4.9; P < 0.0001). Lung segments with AT more frequently had airway mucus plugging than lung segments without AT (48% vs. 18%; P ⩽ 0.0001). Conclusions: In patients with asthma, air trapping is more severe in those with airway eosinophilia and mucus plugging, whereas those who are obese have less severe trapping because their lower lobe segments are spared.

Peroxisome proliferator-activated receptor gamma gene variants modify human airway and systemic responses to indoor dibutyl phthalate exposure.

BACKGROUND: Single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptor gamma (PPAR-γ; gene: PPARG) and oxidative stress genes are associated with asthma risk. However, whether such variants modulate responses to dibutyl phthalate (DBP), a common plasticizer associated with increased asthma development, remains unknown. The purpose of this study is to investigate how SNPs in PPARG and oxidative stress genes, as represented by two separate genetic risk scores, modify the impact of DBP exposure on lung function and the airway and systemic response after an inhaled allergen challenge. METHODS: We conducted a double-blinded human crossover study with sixteen allergen-sensitized participants exposed for three hours to DBP and control air on distinct occasions separated by a 4-week washout. Each exposure was followed by an allergen inhalation challenge; subsequently, lung function was measured, and blood and bronchoalveolar lavage (BAL) were collected and analyzed for cell counts and allergen-specific immunoglobulin E (IgE). Genetic risk scores for PPAR-γ (P-GRS; weighted sum of PPARG SNPs rs10865710, rs709158, and rs3856806) and oxidative stress (OS-GRS; unweighted sum of 16 SNPs across multiple genes) were developed, and their ability to modify DBP effects were assessed using linear mixed-effects models. RESULTS: P-GRS and OS-GRS modified DBP effects on allergen-specific IgE in blood at 20 h (interaction effect [95% CI]: 1.43 [1.13 to 1.80], p = 0.005) and 3 h (0.99 [0.98 to 1], p = 0.03), respectively. P-GRS also modified DBP effects on Th2 cells in blood at 3 h (- 25.2 [- 47.7 to - 2.70], p = 0.03) and 20 h (- 39.1 [- 57.9 to - 20.3], p = 0.0005), and Th2 cells in BAL at 24 h (- 4.99 [- 8.97 to - 1.01], p = 0.02). An increasing P-GRS associated with reduced DBP effect on Th2 cells. Neither GRS significantly modified DBP effects on lung function parameters. CONCLUSIONS: PPAR-γ variants modulated several airway and systemic immune responses to the ubiquitous chemical plasticizer DBP. Our results suggest that PPAR-γ variants may play a greater role than those in oxidative stress-related genes in airway allergic responses to DBP. TRIAL REGISTRATION: This study reports results from The Phthalate-Allergen Immune Response Study that was registered on ClinicalTrials.gov with identification NCT02688478.

Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children.

BACKGROUND: People with asthma may experience exacerbations, or 'attacks', during which their symptoms worsen and additional treatment is required. Written action plans sometimes advocate a short-term increase in the dose of inhaled corticosteroids (ICS) at the first sign of an exacerbation to reduce the severity of the attack and to prevent the need for oral steroids or hospital admission. OBJECTIVES: To compare the clinical effectiveness and safety of increased versus stable doses of ICS as part of a patient-initiated action plan for the home management of exacerbations in children and adults with persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register, which is derived from searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and CINAHL (Cumulative Index to Nursing and Allied Health Literature), and handsearched abstracts to 20 December 2021. We also searched major trial registries for ongoing trials. SELECTION CRITERIA: We included parallel and cross-over randomised controlled trials (RCTs) that allocated people with persistent asthma to take a blinded inhaler in the event of an exacerbation which either increased their daily dose of ICS or kept it stable (placebo). DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, assessed quality, and extracted data. We reassessed risk of bias for all studies at the result level using the revised risk of bias tool for RCTs (Risk of Bias 2), and employed the GRADE approach to assess our confidence in the synthesised effect estimates. The primary outcome was treatment failure, defined as the need for rescue oral steroids in the randomised population. Secondary outcomes were treatment failure in the subset who initiated the study inhaler (treated population), unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, serious and non-serious adverse events, and duration of exacerbation. MAIN RESULTS: This review update added a new study that increased the number of people in the primary analysis from 1520 to 1774, and incorporates the most up-to-date methods to assess the likely impact of bias within the meta-analyses. The updated review now includes nine RCTs (1923 participants; seven parallel and two cross-over) conducted in Europe, North America, and Australasia and published between 1998 and 2018. Five studies evaluated adult populations (n = 1247; ≥ 15 years), and four studies evaluated child or adolescent populations (n = 676; < 15 years). All study participants had mild to moderate asthma. Studies varied in the dose of maintenance ICS, age, fold increase of ICS in the event of an exacerbation, criteria for initiating the study inhaler, and allowed medications. Approximately 50% of randomised participants initiated the study inhaler (range 23% to 100%), and the included studies reported treatment failure in a variety of ways, meaning assumptions were required to permit the combining of data. Participants randomised to increase their ICS dose at the first signs of an exacerbation had similar odds of needing rescue oral corticosteroids to those randomised to a placebo inhaler (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.76 to 1.25; 8 studies; 1774 participants; I2 = 0%; moderate quality evidence). We could draw no firm conclusions from subgroup analyses conducted to investigate the impact of age, time to treatment initiation, baseline dose, smoking history, and fold increase of ICS on the primary outcome. Results for the same outcome in the subset of participants who initiated the study inhaler were unchanged from the previous version, which provides a different point estimate with very low confidence due to heterogeneity, imprecision, and risk of bias (OR 0.84, 95% CI 0.54 to 1.30; 7 studies; 766 participants; I2 = 42%; random-effects model). Confidence was reduced due to risk of bias and assumptions that had to be made to include study data in the intention-to-treat and treated-population analyses. Sensitivity analyses that tested the impact of assumptions made for synthesis and to exclude cross-over studies, studies at overall high risk of bias, and those with commercial funding did not change our conclusions. Pooled effects for unscheduled physician visits, unscheduled acute care, emergency department or hospital visits, and duration of exacerbation made it very difficult to determine where the true effect may lie, and confidence was reduced by risk of bias. Point estimates for both serious and non-serious adverse events favoured keeping ICS stable, but imprecision and risk of bias due to missing data and outcome measurement and reporting reduced our confidence in the effects (serious adverse events: OR 1.69, 95% CI 0.77 to 3.71; 2 studies; 394 participants; I² = 0%; non-serious adverse events: OR 2.15, 95% CI 0.68 to 6.73; 2 studies; 142 participants; I² = 0%). AUTHORS' CONCLUSIONS: Evidence from double-blind trials of adults and children with mild to moderate asthma suggests there is unlikely to be an important reduction in the need for oral steroids from increasing a patient's ICS dose at the first sign of an exacerbation. Other clinically important benefits and potential harms of increased doses of ICS compared with keeping the dose stable cannot be ruled out due to wide confidence intervals, risk of bias in the trials, and assumptions that had to be made for synthesis. Included studies conducted between 1998 and 2018 reflect evolving clinical practice and study methods, and the data do not support thorough investigation of effect modifiers such as baseline dose, fold increase, asthma severity and timing. The review does not include recent evidence from pragmatic, unblinded studies showing benefits of larger dose increases in those with poorly controlled asthma. A systematic review is warranted to examine the differences between the blinded and unblinded trials using robust methods for assessing risk of bias to present the most complete view of the evidence for decision makers.

Global and regional estimates of maternal near miss: a systematic review, meta-analysis and experiences with application.

INTRODUCTION: Maternal near miss (MNM) is a useful means to examine quality of obstetric care. Since the introduction of the WHO MNM criteria in 2011, it has been tested and validated, and is being used globally. We sought to systematically review all available studies using the WHO MNM criteria to develop global and regional estimates of MNM frequency and examine its application across settings. METHODS: We conducted a systematic review by implementing a comprehensive literature search from 2011 to 2018 in six databases with no language restrictions. The predefined data collection tool included sections on study characteristics, frequency of near-miss cases and study quality. Meta-analysis was performed by regional groupings. Reported adaptations, modifications and remarks about application were extracted. RESULTS: 7292 articles were screened by title and abstract, and 264 articles were retrieved for full text review for the meta-analysis. An additional 230 articles were screened for experiences with application of the WHO MNM criteria. Sixty studies with near-miss data from 56 countries were included in the meta-analysis. The pooled global near-miss estimate was 1.4% (95% CI 0.4% to 2.5%) with regional variation in MNM frequency. Of the 20 studies that made adaptations to the criteria, 19 were from low-resource settings where lab-based criteria were adapted due to resource limitations. CONCLUSIONS: The WHO MNM criteria have enabled the comparison of global and sub-national estimates of MNM frequency. There has been good uptake in low-resource countries but contextual adaptations are necessary.

Asthma-COPD Overlap: What Are the Important Questions?

Asthma-COPD overlap (ACO) is a heterogeneous condition that describes patients who show persistent airflow limitation with clinical features that support both asthma and COPD. Although no single consensus definition exists to diagnose this entity, common major criteria include a strong bronchodilator reversibility or bronchial hyperreactivity, a physician diagnosis of asthma, and a ≥ 10-pack-year cigarette smoking history. The prevalence of ACO ranges from 0.9% to 11.1% in the general population, depending on the diagnostic definition used. Notably, patients with ACO experience greater symptom burden, worse quality of life, and more frequent and severe respiratory exacerbations than those with asthma or COPD. The underlying pathophysiologic features of ACO have been debated. Although emerging evidence supports the role of environmental and inhalational exposures in its pathogenesis among patients with a pre-existing airway disease, biomarker profiling and genetic analyses suggest that ACO may be a heterogeneous condition, but with definable characteristics. Early-life factors including childhood-onset asthma and cigarette smoking may interact to increase the risk of airflow obstruction later in life. For treatment options, the population with ACO historically has been excluded from therapeutic trials; therefore strong, evidence-based recommendations are lacking beyond first-line inhaler therapies. Advanced therapies in patients with ACO are selected according to disease phenotypes and are based on extrapolated data from asthma and COPD. Research focused on defining biomarkers and evidence-based treatment options for ACO is needed urgently.

The Prevalence of Chronic Obstructive Pulmonary Disease (COPD) and the Heterogeneity of Risk Factors in the Canadian Population: Results from the Canadian Obstructive Lung Disease (COLD) Study.

PURPOSE: To determine the spirometric-based prevalence of COPD across different regions in Canada and to evaluate the site heterogeneity of risk factors. PATIENTS AND METHODS: In this cross-sectional, population-based study, random samples of non-institutionalized adults aged ≥40 years were generated by random digit dialling. Participants answered an interviewer-administered questionnaire and performed spirometry before and after bronchodilator administration. COPD was defined as post-bronchodilator FEV1/FVC <0.70 (fixed ratio, FR) and as FEV1/FVC <5th percentile (lower limits of normal, LLN). Separate logistic regression models were used to compute the risk (adjusted odds ratio, aOR) for COPD. I2 and Tau2 analyses were used to evaluate heterogeneity. RESULTS: Out of 5176 (95%) participants, 4893 (47% male with mean age 56.6 years (95% confidence interval, 56.0-57.2)) had spirometry that satisfied ATS criteria. The population prevalence of COPD was 16.2% (95% CI, 14.5-17.8) by FR and 11.2% (95% CI, 9.7-12.6) by LLN. Male predominance in prevalence was shown by FR but not by LLN criteria. Patient characteristics associated with an increased risk of COPD included: age (OR 1.56; 95% CI 1.33-1.84); history of physician-diagnosed asthma (OR 3.30; 95% CI 2.42-4.49); and childhood hospitalization for respiratory illness (OR 1.81; 95% CI 1.17-2.80). In terms of smoking-related risk factors, current smoking status had the highest odds ratio (OR 3.49; 95% CI 2.55-4.80). Variance in prevalence among sites was significantly reduced by adjusting for risk factors in Tau2 analyses. Higher odds of exposure for each risk factor was found in more severe COPD, suggesting that a higher risk could be linked to the development of severe disease. CONCLUSION: This study reports the population prevalence of COPD in nine urban cities which collectively represent the majority of the Canadian population and demonstrates that heterogeneity in prevalence among sites is substantially explained by variation in associated risk factors for COPD.

Structural and functional variations in human bronchial epithelial cells cultured in air-liquid interface using different growth media.

The human bronchial epithelium is an important barrier tissue that is damaged or pathologically altered in various acute and chronic respiratory conditions. To represent the epithelial component of respiratory disease, it is essential to use a physiologically relevant model of this tissue. The human bronchial epithelium is a highly organized tissue consisting of a number of specialized cell types. Primary human bronchial epithelial cells (HBEC) can be differentiated into a mucociliated tissue in air-liquid interface (ALI) cultures using appropriately supplemented media under optimized growth conditions. We compared the histology, ciliary length, and function, diffusion, and barrier properties of HBEC from donors with no respiratory disease grown in two different media, PneumaCult-ALI or Bronchial Epithelial Differentiation Medium (BEDM). In the former group, HBEC have a more physiological pseudostratified morphology and mucociliary differentiation, including increased epithelial thickness, intracellular expression of airway-specific mucin protein MUC5AC, and total expression of cilia basal-body protein compared with cells from the same donor grown in the other medium. Baseline expression levels of inflammatory mediators, thymic stromal lymphopoietin (TSLP), soluble ST2, and eotaxin-3 were lower in PneumaCult-ALI. Additionally, the physiological cilia beat frequency and electrical barrier properties with transepithelial electrical resistance were significantly different between the two groups. Our study has shown that these primary cell cultures from the same donor grown in the two media possess variable structural and functional characteristics. Therefore, it is important to objectively validate primary epithelial cell cultures before experimentation to ensure they are appropriate to answer a specific scientific question.

Current Practice in the Management of Pulmonary Nodules Detected on Computed Tomography Chest Scans.

Lung cancer is associated with high mortality. It can present as one or more pulmonary nodules identified on computed tomography (CT) chest scans. The National Lung Screening Trial has shown that the use of low-dose CT chest screening can reduce deaths due to lung cancer. High adherence to appropriate follow-up of positive results, including imaging or interventional approaches, is an important aspect of pulmonary nodule management. Our study is one of the first to evaluate the current practice in managing pulmonary nodules and to explore potential causes for nonadherence to follow-up. This is a retrospective analysis at St. Paul's Hospital, a tertiary healthcare center in Vancouver, British Columbia, Canada. We first identified CT chest scans between January 1 to June 30, 2014, that demonstrated one or more pulmonary nodules equal to or greater than 6 mm in diameter. We then looked for evidence of interventional (surgical resection or biopsy, or bronchoscopy for transbronchial biopsy and cytology) and radiological follow-up of the pulmonary nodule by searching on the province-wide CareConnect eHealth Viewer patient database. A total of 1614 CT reports were analyzed and 139 (8.6%) had a positive finding. Out of the 97 patients who received follow-up, 54.6% (N = 53) was referred for a repeat CT chest scan and 36.1% (N = 35) and 9.3% (N = 9) were referred for interventional biopsy and surgical resection, respectively. In our study, 30.2% (N = 42) of the patients with pulmonary nodules were nonadherent to follow-up. Despite the radiologist's recommendation for follow-up within a certain time interval, only 36% had repeat imaging in a timely manner. Our findings reflect the current practice in the management of pulmonary nodules and suggest that there is a need for improvement at our academic center. Adherence to follow-up is important for the potentially near-future implementation of lung cancer screening.