27 March – 3 April 2022

COPD

1. Ann Am Thorac Soc. 2022 Apr 1. doi: 10.1513/AnnalsATS.202109-1042OC. Online ahead of print.
Lung Function and the Risk of Exacerbation in the BLOCK COPD (beta-blocker) TrialParekh TM(1), Helgeson ES(2), Connett J(3), Voelker H(4), Ling SX(5), Lazarus SC(6), Bhatt SP(7), MacDonald DM(8), Mkorombindo T(9), Kunisaki KM(10)(11), Fortis S(12), Kaminsky D(13), Dransfield MT(14).
RATIONALE: The Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK COPD) study found that metoprolol was associated with a higher risk of severe exacerbation.
OBJECTIVES: To determine the mechanism underlying these results, we compared changes in lung function over the course of the study between treatment groups and evaluated whether baseline bronchodilator response or early reduction in FEV1 or FVC was associated with exacerbation risk.
METHODS: We compared changes in lung function (FEV1 and FVC) over the treatment period between treatment groups using linear mixed-effect models. Cox proportional hazards models were used to evaluate the association between baseline bronchodilator responsiveness (FEV1, FVC, and combined FEV1 and FVC), early post-randomization (14 day) change in lung function, and the interaction between treatment assignment and these measures with risk of any or severe/very severe exacerbations. Negative binomial models were used to evaluate the relationship between bronchodilator responsiveness, the interaction between bronchodilator responsiveness and treatment assignment, and exacerbation rate.
RESULTS: Over the 336 day treatment period, individuals in the metoprolol group had a significantly greater decrease in log-FEV1, from baseline to visit day 28 compared to individuals in the placebo group. Individuals in the metoprolol group had a significantly greater decrease in FVC from baseline to visit day 14 and 28 and additionally a significantly greater decrease in log FVC from baseline to visits 42 and 112 than individuals in the placebo group. There were no associations between early lung function reduction, or interactions between lung function reduction and treatment assignment, and time to any or severe/very severe exacerbations. There were no interactions between treatment arm and baseline bronchodilator responsiveness measures on risk or rate of exacerbations. However, those with baseline FVC bronchodilator responsiveness had a higher rate of severe/very severe exacerbations (adjusted RR = 1.62, 95% CI, 1.04-2.48).
CONCLUSION: Metoprolol was associated with reduced lung function during the early part of the treatment period, but these effects were modest and did not persist. Early lung function reduction and baseline bronchodilator responsiveness did not interact with the treatment arm to predict exacerbations; however, baseline FVC bronchodilator responsiveness was associated with a 60% higher rate of severe/very severe exacerbations.

2. Am J Respir Crit Care Med. 2022 Apr 1. doi: 10.1164/rccm.202111-2630OC. Online ahead of print.
International Differences in the Frequency of COPD Exacerbations Reported in Three Clinical Trials.
Calverley PMA(1), Martinez FJ(2), Vestbo J(3)(4), Jenkins CR(5), Wise R(6), Lipson DA(7), Cowans NJ(8), Yates J(9), Crim C(10)(11), Celli BR(12).
RATIONALE: Exacerbations of chronic obstructive pulmonary disease are an important endpoint in multinational clinical treatment trials, but the observed event rate is often lower than anticipated and appears to vary between countries.
OBJECTIVES: We investigated whether systematic differences in national exacerbation rates might explain this observed variation.
METHODS: We reviewed data from three large multicenter international randomized trials conducted over an 18-year period with different designs and clinical severities of chronic obstructive pulmonary disease, comparing bronchodilator and/or inhaled corticosteroids with bronchodilators alone and/or placebo. Exacerbations were defined by antibiotic and/or oral corticosteroid use (moderate) or need for hospitalization (severe). We calculated crude exacerbation rates in the 30 countries contributing 30 or more patients to at least two trials. We grouped data by exacerbation rate based on their first study contribution.
MEASUREMENTS AND MAIN RESULTS: For the 29,756 patients in 41 countries analyzed, the mean exacerbation rate was 2-3-fold different between the highest and lowest tertiles of the recruiting nations. These differences were not explained by demographic features, study protocol, or reported exacerbation history at enrolment. Of the 18 countries contributing to all studies, half of those in the highest and half in the lowest tertiles of exacerbation history remained in these groups across studies. Severe exacerbations showed a different rank order internationally.
CONCLUSIONS: Countries contributing to chronic obstructive pulmonary disease trials differ consistently in their reporting of health care-defined exacerbations. These differences help explain why large studies have been needed to show differences between treatments that decrease exacerbation risk.
DOI: 10.1164/rccm.202111-2630OC
PMID: 35363593

3. Nature. 2022 Mar 30. doi: 10.1038/s41586-022-04552-0. Online ahead of print.
Human distal airways contain a multipotent secretory cell that can regenerate alveoli.
Basil MC(#)(1)(2), Cardenas-Diaz FL(#)(1)(2), Kathiriya JJ(3), Morley MP(1)(2)(4), Carl J(1)(2), Brumwell AN(3), Katzen J(1)(2), Slovik KJ(1)(2)(4), Babu A(1)(2)(4), Zhou S(1)(2), Kremp MM(1)(2), McCauley KB(5), Li S(1)(2), Planer JD(1)(2), Hussain SS(6), Liu X(7), Windmueller R(2)(8), Ying Y(1)(2), Stewart KM(1)(2), Oyster M(1), Christie JD(1)(2), Diamond JM(1), Engelhardt JF(7), Cantu E(2)(9), Rowe SM(6), Kotton DN(5)(10), Chapman HA(3)(11), Morrisey EE(12)(13)(14).
The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease.
© 2022. The Author(s), under exclusive licence to Springer Nature Limited.
DOI: 10.1038/s41586-022-04552-0
PMID: 35355013

4. Lung. 2022 Mar 29. doi: 10.1007/s00408-022-00521-6. Online ahead of print.
Identifying Patients with Group 3 Pulmonary Hypertension Associated with COPD or ILD Using an Administrative Claims Database.Heresi GA(1), Dean BB(2), Castillo H(3), Lee HF(4), Classi P(3), Stafkey-Mailey D(4), Kantorovich A(3), Morland K(3), Sketch MR(3), Wu BS(3), King CS(5).
BACKGROUND: Group 3 pulmonary hypertension (PH) describes a subpopulation of patients with PH due to chronic lung disease and/or hypoxia, with chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) being two large subgroups. Claims database studies provide insights into the real-world treatment patterns and outcomes among these patients. However, claims data do not provide sufficient detail to assign the clinical subtype of PH required for identifying these patients.
METHODS: A panel of PH clinical experts and researchers was convened to discuss methodologies to identify patients with Group 3 PH associated with COPD or ILD in retrospective claims databases. To inform the discussion, a literature review was conducted to identify claims-based studies of Group 3 PH associated with COPD or ILD published from 2010 through June 2020.
RESULTS: Targeted title and abstract review identified 11 claims-based studies and two conference abstracts (eight based in the United States [US] and five conducted outside the US) that met search criteria. Based on insights from the panel and literature review, the following components were detailed across studies in the identification of Group 3 PH associated with COPD and ILD: (a) COPD or ILD identification, (b) PH identification, (c) defining the sequence between COPD/ILD and PH, and (d) other PH Group and Group 3 PH exclusions.
CONCLUSION: This article provides recommended approaches and considerations for identifying and studying patients with Group 3 PH associated with COPD or ILD using administrative claims data that provide the foundation for future validation studies.
© 2022. The Author(s).
DOI: 10.1007/s00408-022-00521-6
PMID: 35348836

5. BMC Health Serv Res. 2022 Mar 28;22(1):408. doi: 10.1186/s12913-022-07778-w.
Healthcare costs of patients with chronic obstructive pulmonary disease in Denmark – specialist care versus GP care only.
Lykkegaard J(1), Nielsen JB(2), Storsveen MM(2), Jarbøl DE(2), Søndergaard J(2).
BACKGROUND: Many patients with chronic obstructive pulmonary disease (COPD) are treated in general practice only and have never received specialist care for COPD. They are seldom included in COPD cost studies but may account for a substantial proportion of the total costs.
OBJECTIVE: To estimate and specify the total healthcare costs of patients who are treated for COPD in Denmark comparing those who have- and have not had specialist care for COPD.
SETTING: Denmark, population 5.7 million citizens.
METHODS: Via national registers, we specified the total healthcare costs of all + 30-years-old current users of respiratory pharmaceuticals. We identified the patients with COPD and compared those with at least one episode of pulmonary specialist care to those with GP care only.
RESULTS: Among totally 329,428 users of respiratory drugs, we identified 46,084 with specialist-care- and 68,471 with GP-care-only COPD. GP-care-only accounted for 40% of the two populations’ total healthcare costs. The age- and gender-adjusted coefficient relating the individual total costs specialist-care versus GP-care-only was 2.19. The individual costs ranged widely and overlapped considerably (p25-75: specialist-care €2,175-€12,625, GP-care-only €1,110-€4,350). Hospital treatment accounted for most of the total cost (specialist-care 78%, GP-care-only 62%; coefficient 2.81), pharmaceuticals (specialist-care 16%, GP-care-only 27%; coefficient 1.28), and primary care costs (specialist-care 6%, GP-care-only 11%; coefficient 1.13). The total costs of primary care pulmonary specialists were negligible.
CONCLUSION: Healthcare policy makers should consider the substantial volume of patients who are treated for COPD in general practice only and do not appear in specialist statistics.

6. Clin Sci (Lond). 2022 Mar 31;136(6):405-423. doi: 10.1042/CS20210835.
Chronic obstructive pulmonary disease and atherosclerosis: common mechanisms and novel therapeutics.
Brassington K(1), Selemidis S(1), Bozinovski S(1), Vlahos R(1).
Chronic obstructive pulmonary disease (COPD) and atherosclerosis are chronic irreversible diseases, that share a number of common causative factors including cigarette smoking. Atherosclerosis drastically impairs blood flow and oxygen availability to tissues, leading to life-threatening outcomes including myocardial infarction (MI) and stroke. Patients with COPD are most likely to die as a result of a cardiovascular event, with 30% of all COPD-related deaths being attributed to cardiovascular disease (CVD). Both atherosclerosis and COPD involve significant local (i.e. lung, vasculature) and systemic inflammation and oxidative stress, of which current pharmacological treatments have limited efficacy, hence the urgency for the development of novel life-saving therapeutics. Currently these diseases must be treated individually, with no therapies available that can effectively reduce the likelihood of comorbid CVD other than cessation of cigarette smoking. In this review, the important mechanisms that drive atherosclerosis and CVD in people with COPD are explained and we propose that modulation of both the oxidative stress and the inflammatory burden will provide a novel therapeutic strategy to treat both the pulmonary and systemic manifestations related to these diseases.

7. Respir Med. 2022 Apr-May;195:106774. doi: 10.1016/j.rmed.2022.106774. Epub 2022 Feb 22.
Nasal and systemic inflammation in Chronic Obstructive Pulmonary Disease (COPD).
Obling N(1), Backer V(2), Hurst JR(3), Bodtger U(4).
Systemic inflammation is a well-established feature of Chronic Obstructive Pulmonary Disease, COPD, but less is known about inflammation in the upper airways in the disease. In the current study, we investigated the inflammatory profile in the upper airway and in serum in a cohort of patients with COPD. Patients were examined with inflammatory profiles measured on material from the upper airway and in serum using a 14-plex Bioplex multiplex immunoassay containing the following cytokines: IL-1-beta, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, IL-17, IL-18, Interferon-gamma, Tumour Necrosis Factor-alpha, Tumour Necrosis Factor beta, and GM-CSF. We evaluated COPD disease burden using the CAT questionnaire and symptoms from the upper airways with the nasal domain of the 22 items Sino Nasal Outcome Test (SNOT22nasal). We included 180 patients (female 55%, age 67 (±8) years, FEV1% 52.4 (±16.6). Using a SNOT22nasal threshold of ≥6, we divided patients into high upper airways symptoms (high UAS), n = 74 (41%) and low upper airway symptoms (low UAS), n = 106 (59%). High UAS was significantly associated with higher levels of IL-1 beta and IL-3 in nasal samples (p = 0.016 and 0.02, respectively) and higher serum levels of IL-1 beta (p = 0.003). Upper airway scores correlated positively with nasal levels of IL-3 (rho = 0.195, p = 0.01) and serum levels of IL-1 beta (rho = 0.226, p = 0.005). Patients with COPD and high upper airway symptoms displayed signs of eosinophilic and neutrophilic inflammation with elevated levels of IL-1 beta and IL-3 in the nose and elevated IL-1 beta in serum.

8. Respirology. 2022 Apr;27(4):258-259. doi: 10.1111/resp.14233. Epub 2022 Feb 23.
CT in COPD: To be or not to be.
Agusti A(1)(2)(3)(4), Faner R(2)(3)(4).
DOI: 10.1111/resp.14233
PMID: 35199426

9. Respirology. 2022 Apr;27(4):277-285. doi: 10.1111/resp.14222. Epub 2022 Feb 10.
The HUNT study: Association of comorbidity clusters with long-term survival and incidence of exacerbation in a population-based Norwegian COPD cohort.
Vikjord SAA(1)(2), Brumpton BM(3)(4)(5), Mai XM(6), Romundstad S(2)(7), Langhammer A(1)(2), Vanfleteren L(8).
BACKGROUND AND OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease often viewed as part of a multimorbidity complex. There is a need for better phenotyping of the disease, characterization of its interplay with other comorbidities and its association with long-term outcomes. This study aims to examine how clusters of comorbidities are associated with severe exacerbations and mortality in COPD.
METHODS: Participants with potential COPD were recruited from the second (1995-1997) and third (2006-2008) survey of the HUNT Study and followed up until April 2020. Ten objectively identified comorbidities were clustered using self-organizing maps. Severe COPD exacerbations requiring hospitalization were assessed using hospital data. All-cause mortality was collected from national registries. Multivariable Cox regression was used to calculate hazard ratios (HRs) with 95% CIs for the association between comorbidity clusters and all-cause mortality. Poisson regression was used to calculate incidence rate ratios (IRRs) with 95% CI for the cumulative number of severe exacerbations for each cluster.
RESULTS: Five distinct clusters were identified, including ‘less comorbidity’, ‘psychological’, ‘cardiovascular’, ‘metabolic’ and ‘cachectic’ clusters. Using the less comorbidity cluster as reference, the psychological and cachectic clusters were associated with all-cause mortality (HR 1.23 [1.04-1.45] and HR 1.83 [1.52-2.20], adjusted for age and sex). The same clusters also had increased risk of exacerbations (unadjusted IRR of 1.24 [95% CI 1.04-1.48] and 1.50 [95% CI 1.23-1.83], respectively).
CONCLUSION: During 25 years of follow-up, individuals in the psychological and cachectic clusters had increased mortality. Furthermore, these clusters were associated with increased risk of severe COPD exacerbations.
DOI: 10.1111/resp.14222
PMID: 35144315

10. Respirology. 2022 Apr;27(4):286-293. doi: 10.1111/resp.14223. Epub 2022 Feb 7.
Chest CT-assessed comorbidities and all-cause mortality risk in COPD patients in the BODE cohort.
Ezponda A(1), Casanova C(2)(3), Divo M(4), Marín-Oto M(5), Cabrera C(6), Marín JM(7), Bastarrika G(1), Pinto-Plata V(8), Martin-Palmero Á(9), Polverino F(10), Celli BR(4), de Torres JP(5)(9)(11).
BACKGROUND AND OBJECTIVE: The availability of chest computed tomography (CT) imaging can help diagnose comorbidities associated with chronic obstructive pulmonary disease (COPD). Their systematic identification and relationship with all-cause mortality have not been explored. Furthermore, whether their CT-detected prevalence differs from clinical diagnosis is unknown.
METHODS: The prevalence of 10 CT-assessed comorbidities was retrospectively determined at baseline in 379 patients (71% men) with mild to severe COPD attending pulmonary clinics. Anthropometrics, smoking history, dyspnoea, lung function, exercise capacity, BODE (BMI, Obstruction, Dyspnoea and Exercise capacity) index and exacerbations rate were recorded. The prevalence of CT-determined comorbidities was compared with that recorded clinically. Over a median of 78 months of observation, the independent association with all-cause mortality was analysed. A ‘CT-comorbidome’ graphically expressed the strength of their association with mortality risk.
RESULTS: Coronary artery calcification, emphysema and bronchiectasis were the most prevalent comorbidities (79.8%, 62.7% and 33.9%, respectively). All were underdiagnosed before CT. Coronary artery calcium (hazard ratio [HR] 2.09; 95% CI 1.03-4.26, p = 0.042), bronchiectasis (HR 2.12; 95% CI 1.05-4.26, p = 0.036) and low psoas muscle density (HR 2.61; 95% CI 1.23-5.57, p = 0.010) were independently associated with all-cause mortality and helped define the ‘CT-comorbidome’.
CONCLUSION: This study of COPD patients shows that systematic detection of 10 CT-diagnosed comorbidities, most of which were not detected clinically, provides information of potential use to patients and clinicians caring for them.
DOI: 10.1111/resp.14223
PMID: 35132732

11. Life Sci. 2022 Apr 1;294:120374. doi: 10.1016/j.lfs.2022.120374. Epub 2022 Feb 4.
Impact of chronic obstructive pulmonary disease, lung infection, and/or inhaled corticosteroids use on potential risk of lung cancer.
Patel B(1), Priefer R(2).
Chronic obstructive pulmonary disease is the 3rd leading cause of death worldwide. It not only affects current and former smokers, but non-smokers as well. Chronic inflammatory response in this disease state leads to the production of genotoxic free radicals and reactive oxygen species that could result in tumorigenesis. Inhaled corticosteroids are used for the management of inflammation in patients experiencing frequent exacerbation and/or have a high eosinophil count. However, these steroids are often prescribed off-label for symptom management. Using inhaled corticosteroids to combat inflammation in chronic obstructive pulmonary disease patients is suggested to be protective against lung cancer. However, immunomodulatory effects of these medications can pre-dispose patients to develop respiratory infections such as tuberculosis or pneumonia. These lung infections have shown to also increase the risk of developing lung cancer. Since chronic obstructive pulmonary disease is an independent risk factor for developing lung cancer, a subsequent infection could have an additive effect. Additionally, the aforementioned chemo-preventive effects of inhaled corticosteroids are inconsistent due to there being limited data on the long term effects of using inhaled corticosteroids in patients who do not meet the treatment recommendation guidelines. Hence, it is necessary to recognize the indirect connection between inhaled corticosteroids and lung cancer possibly via lung infections in chronic obstructive pulmonary disease patients. The rationale behind this review is to better understand the mechanistic links that connect these multiple disease states which could aid in guiding treatment with inhaled corticosteroids in specific sub-groups. This review discusses possible pathways that could lead to the lung carcinogenesis and the cumulative impact of chronic obstructive pulmonary disease, inhaled corticosteroids use, and pulmonary infections on the risk of lung cancer.
DOI: 10.1016/j.lfs.2022.120374
PMID: 35131234 [Indexed for MEDLINE]

12. Curr Opin Allergy Clin Immunol. 2022 Apr 1;22(2):73-79. doi: 10.1097/ACI.0000000000000817.
Occupational causes of chronic obstructive pulmonary disease: an update.
De Matteis S(1).
PURPOSE OF REVIEW: This brief narrative review aims to highlight relevant recent updates on occupational causes of chronic obstructive pulmonary disease (COPD).
RECENT FINDINGS: The most recent literature has been searched for any new relevant association between occupational exposures and COPD. Only large epidemiological studies of high quality have been included. Beyond the more traditional exposures, such as mineral or organic dusts, new chemicals have emerged as potential occupational causal agents for COPD. In particular, pesticides and cleaning products, including disinfectants, that have shown also positive exposure-response trends. For cleaning products, some specific chemicals have been identified, but for pesticides the identification of specific causal compounds is more challenging. The biological underlying mechanisms are still under study.
SUMMARY: In the recent literature, occupational exposure to pesticides and cleaning products has emerged as potential cause of COPD. Awareness on occupational causes of COPD should increase among all stakeholders, from health professionals to public to prevent the associated public health burden. More studies on identifying the specific causal agents and mechanisms are needed to focus preventive strategies.
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
DOI: 10.1097/ACI.0000000000000817
PMID: 35125392

13. Am J Prev Med. 2022 Apr;62(4):492-502. doi: 10.1016/j.amepre.2021.12.001. Epub 2022 Feb 2.
Smoking Cessation Among U.S. Adult Smokers With and Without Chronic Obstructive Pulmonary Disease, 2018.
Liu Y(1), Greenlund KJ(2), VanFrank B(3), Xu F(2), Lu H(2), Croft JB(2).
INTRODUCTION: More than 3 of 5 U.S. adults who have ever smoked cigarettes have quit. This study assesses the latest estimates of smoking cessation among U.S. adults with and without chronic obstructive pulmonary disease who have ever smoked cigarettes (ever smokers).METHODS: Data from 161,233 ever smokers (12.8% with chronic obstructive pulmonary disease) in the 2018 Behavioral Risk Factor Surveillance System were analyzed in 2020. Weighted percentages of quit ratios (percentage of ever smokers who quit smoking), past-year quit attempts (≥1 day), and recent successful cessation (quit ≥6 months ago) by self-reported physician-diagnosed chronic obstructive pulmonary disease status were obtained from multivariable logistic regression analyses, with adjustment for sociodemographic characteristics, health risk behaviors, depression, and asthma.
RESULTS: Adults with chronic obstructive pulmonary disease who smoked had greater age-adjusted past-year quit attempts (68.8% vs 64.3%) but lower recent successful cessation (4.5% vs 5.8%) and quit ratio (53.2% vs 63.9%) than those without chronic obstructive pulmonary disease. After adjusting for covariates, adults with chronic obstructive pulmonary disease who smoked had a significantly higher percentage of past-year quit attempts but similar recent successful cessation and a significantly lower lifetime quit ratio than their counterparts without chronic obstructive pulmonary disease.
CONCLUSIONS: These findings suggest that individuals with chronic obstructive pulmonary disease who try to quit smoking may be less likely to succeed than those without chronic obstructive pulmonary disease. Evidence-based treatments for smoking cessation remain an important component of a comprehensive approach to helping all adults to quit and are a particularly important element of chronic obstructive pulmonary disease management and care.
DOI: 10.1016/j.amepre.2021.12.001
PMID: 35120768 [Indexed for MEDLINE]

14. ESC Heart Fail. 2022 Apr;9(2):1351-1359. doi: 10.1002/ehf2.13824. Epub 2022 Jan 27.
Inaccurate recognition of own comorbidities is associated with poor prognosis in elderly patients with heart failure.
Maeda D(1)(2), Matsue Y(1)(3), Kagiyama N(4)(5)(6), Jujo K(7), Saito K(8), Kamiya K(9), Saito H(1)(10), Ogasahara Y(11), Maekawa E(12), Konishi M(13), Kitai T(14)(15), Iwata K(15), Wada H(16), Hiki M(1), Dotare T(1), Sunayama T(1), Kasai T(1)(3), Nagamatsu H(17), Ozawa T(18), Izawa K(19), Yamamoto S(20), Aizawa N(21), Yonezawa R(22), Oka K(23), Momomura SI(24), Minamino T(1)(25).
AIMS: A patient’s understanding of his or her own comorbidities is part of the recommended patient education for those with heart failure. The accuracy of patients’ understanding of their comorbidities and its prognostic impact have not been reported.
METHODS AND RESULTS: Patients hospitalized for heart failure (n = 1234) aged ≥65 years (mean age: 80.1 ± 7.7 years; 531 females) completed a questionnaire regarding their diagnoses of diabetes, malignancy, stroke, hypertension, chronic obstructive pulmonary disease (COPD), and coronary artery disease (CAD). The patients were categorized into three groups based on the number of agreements between self-reported comorbidities and provider-reported comorbidities: low (1-2, n = 19); fair (3-4, n = 376); and high (5-6, n = 839) agreement groups. The primary outcome was a composite of all-cause mortality or heart failure rehospitalization at 1 year. The low agreement group had more comorbidities and a higher prevalence of a history of heart failure. The agreement was good for diabetes (κ = 0.73), moderate for malignancy (κ = 0.56) and stroke (κ = 0.50), and poor-to-fair for hypertension (κ = 0.33), COPD (κ = 0.25), and CAD (κ = 0.30). The fair and low agreement groups had poorer outcomes than the good agreement group [fair agreement group: hazard ratio (HR): 1.25; 95% confidence interval (CI): 1.01-1.56; P = 0.041; low agreement group: HR: 2.74: 95% CI: 1.40-5.35; P = 0.003].
CONCLUSIONS: The ability to recognize their own comorbidities among older patients with heart failure was low. Patients with less accurate recognition of their comorbidities may be at higher risk for a composite of all-cause mortality or heart failure rehospitalization.
DOI: 10.1002/ehf2.13824
PMCID: PMC8934983
PMID: 35088546 [Indexed for MEDLINE]

15. Eur Respir Rev. 2022 Jan 25;31(163):210150. doi: 10.1183/16000617.0150-2021. Print 2022 Mar 31.
Eosinophils and eosinophilic immune dysfunction in health and disease.
Jackson DJ(1)(2), Akuthota P(3), Roufosse F(4).
The functions ascribed to eosinophils have classically been limited to host defence against certain parasitic infections and potentially deleterious effects in the setting of specific diseases that are associated with elevated eosinophil counts in blood and/or tissue. The ability to induce eosinophil depletion either experimentally in animal models or through targeted therapies in humans has extended our understanding of the roles played by eosinophils in health and homeostasis as well as in disease pathogenesis. When associated with human disease aetiology, the eosinophil takes on a pathogenic rather than a protective role. This maladaptive response, called “eosinophilic immune dysfunction” herein, appears central to exacerbation pathogenesis and disease control in severe asthma and may be involved in the aetiology of other eosinophil-related conditions ranging from organ-system-limited diseases such as phenotypic subsets of chronic obstructive pulmonary disease and chronic rhinosinusitis with nasal polyposis to more broadly systemic diseases such as eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. In this review, we describe the evidence supporting eosinophilic functions related to health and homeostasis and explore the contribution of eosinophilic immune dysfunction to human disease.
DOI: 10.1183/16000617.0150-2021
PMID: 35082127 [Indexed for MEDLINE]

16. Br J Radiol. 2022 Apr 1;95(1132):20201005. doi: 10.1259/bjr.20201005. Epub 2021 Sep 19.
Functional imaging of COPD by CT and MRI.
Lynch DA(1).
This commentary reviews the contribution of imaging by CT and MRI to functional assessment in chronic obstructive pulmonary disease (COPD). CT can help individualize the assessment of COPD by quantifying emphysema, air trapping and airway wall thickening, potentially leading to more specific treatments for these distinct components of COPD. Longitudinal changes in these metrics can help assess progression or improvement. On hyperpolarized gas MRI, the apparent diffusion coefficient of provides an index of airspace enlargement reflecting emphysema. Perfusion imaging and measurement of pulmonary vascular volume on non-contrast CT provide insight into the contribution of pulmonary vascular disease to pulmonary impairment. Functional imaging is particularly valuable in detecting early lung dysfunction in subjects with inhalational exposures.
DOI: 10.1259/bjr.20201005
PMID: 34541865 [Indexed for MEDLINE]

17. Postgrad Med J. 2022 Apr;98(1158):258-263. doi: 10.1136/postgradmedj-2020-139341. Epub 2021 Jan 12.
Short-term and long-term impact of diagnosed and undiagnosed chronic obstructive pulmonary disease on coronary artery bypass grafting surgery.
Gatta F(1), Haqzad Y(2), Loubani M(3).
OBJECTIVES: This study sought to compare clinical outcomes between three categories of patients: non-chronic obstructive pulmonary disease (COPD), diagnosed COPD and undiagnosed COPD in coronary artery bypass grafting surgery.
METHODS: A single-centred retrospective study from January 2010 to December 2019. Primary outcomes were postoperative complications, length of ITU admission and in-hospital staying. Secondary outcomes were reintervention rate, in-hospital and long-term mortality.
RESULTS: A total of 4020 patients were analysed and divided into three cohorts: non-COPD (group A) (74.55%, n=2997), diagnosed COPD (group B) (14.78%, n=594) and undiagnosed COPD (group C) (10.67%, n=429). The rate of respiratory complications was noted in this order: group B>group C>group A (p 0.00000002). Periooperative acute kidney injury and wound complications were higher in group B (p 0.0004 and p 0.03, respectively). Prolonged in-hospital staying (days) resulted in group B (p 0.0009). Finally, long-term mortality was statistically higher in group B and C compared with group A (p 0.0004). No difference in long-term mortality was noted in relation to the expected FEV1% in group B (p 0.29) and group C (p 0.82).
CONCLUSIONS: In CABG surgery, COPD is a well-known independent risk factor for morbidity. Patients with preoperative spirometry results indicative of COPD result in the same outcomes of known patients with COPD. As a result of that, greater value should be given to the preoperative spirometry in the EuroSCORE. Finally, the expected FEV1% appears not be a predictor for long-term survival.
DOI: 10.1136/postgradmedj-2020-139341
PMID: 33436479 [Indexed for MEDLINE]
Conflict of interest statement: Competing interests: None declared.

ASTHMA

1: Couillard S, Steyerberg E, Beasley R, Pavord I. Blood eosinophils, fractionalexhaled nitric oxide and the risk of asthma attacks in randomised controlledtrials: protocol for a systemic review and control arm patient-level meta-analysis for clinical prediction modelling. BMJ Open. 2022 Apr 1;12(4):e058215.doi: 10.1136/bmjopen-2021-058215. PMID: 35365539.
Introduction: The reduction of the risk of asthma attacks is a major goal of guidelines. The fact that type-2 inflammatory biomarkers identify a higher risk, anti-inflammatory responsive phenotype is potentially relevant to this goal. We aim to quantify the relation between blood eosinophils, exhaled nitric oxide (FeNO) and the risk of severe asthma attacks.
Methods and analysis: A systematic review of randomised controlled trials (RCTs) will be conducted by searching MEDLINE from January 1993 to April 2021. We will include RCTs that investigated the effect of fixed treatment(s) regimen(s) on severe asthma exacerbation rates over at least 24 weeks and reported a baseline value for blood eosinophils and FeNO. Study selection will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, and the methodological appraisal of the studies will be assessed by the Cochrane Risk-of-Bias Tool for RCTs. Study authors will be contacted to request anonymised individual participant data (IPD) for patients randomised to the trial’s control arm. An IPD meta-analysis will be performed for multivariable prognostic modelling with performance assessment (calibration plots and the c-statistic) in a cross-validation by study procedure. The outcome to predict is the absolute number of severe asthma attacks to occur in the following 12 months if anti-inflammatory therapy is not changed (ie, annualised number of attacks requiring ≥3 days of systemic corticosteroids and/or hospitalisation if the patient was randomised to the control arm of an RCT). A summary prognostic equation and risk stratification chart will be reported as a basis for further analyses of individualised treatment benefit.

2: Oppenheimer J, Leung DYM. Asthma 2022-moving toward precision medicine. AnnAllergy Asthma Immunol. 2022 Apr;128(4):343. doi: 10.1016/j.anai.2022.01.011.
PMID: 35365251.

3: Quint JK, Arnetorp S, Kocks JWH, Kupczyk M, Nuevo J, Plaza V, Cabrera C,Raherison-Semjen C, Walker B, Penz E, Gilbert I, Lugogo NL, van der Valk RJP;SABINA North American and European Study contributors. Short-actingβ<sub>2</sub>-agonist exposure and severe asthma exacerbations: SABINA findingsfrom Europe and North America. J Allergy Clin Immunol Pract. 2022 Mar29:S2213-2198(22)00285-9. doi: 10.1016/j.jaip.2022.02.047. Epub ahead of print.
PMID: 35364341.
Background: Expert national/global asthma management recommendations raise the issue whether a safe threshold of short-acting β2-agonist (SABA) use without concomitant inhaled corticosteroids (ICS) exists.
Objective: To examine SABA and maintenance therapy associations with severe asthma exacerbations across North America and Europe.
Methods: Observational analyses of 10 SABa use IN Asthma (SABINA) datasets involving 1,033,564 patients (≥12 years) from Canada, France, the Netherlands, Poland, Spain, United Kingdom (UK), and United States (US). Negative binomial models (incidence rate-ratio [95% confidence interval]) adjusted for prespecified-covariates]) evaluated associations between SABA and exacerbations.
Results: Across severities, 40.2% of patients were prescribed/possessed ≥3 SABA canisters/year. Per GINA-2018 definitions, step 3‒5-treated patients prescribed/possessing ≥3 vs. 1‒2 SABA experienced more severe exacerbations (between 1.08 [1.04‒1.13], US-Medicare; 2.11 [1.96‒2.27], Poland). This association was not observed in all step 1‒2-treated patients (the Netherlands 1.25 [0.91‒1.71]; US-commercial 0.92 [0.91‒0.93]; US-Medicare 0.74 [0.71‒0.76]). We hypothesize that this inverse association between SABA and severe exacerbations in the US datasets was attributable to the large patient population possessing <3 SABA and no maintenance therapy and receiving oral corticosteroid bursts without face-to-face healthcare provider encounters. In US SABA monotherapy-treated patients, ≥3 SABA was associated with more emergency/outpatient visits and hospitalizations (1.31 [1.29‒1.34]). Most GINA 2‒5-treated study patients (60.6%) did not have maintenance therapy for up to 50% of the time; however, the association of ≥3 SABA and severe exacerbations persisted (1.32 [1.18‒1.49]) after excluding these patients and the independent effect was further confirmed when UK SABA data was analyzed as a continuous variable in patients with up to 100% annual coverage for ICS-containing medications.
Conclusions: Increasing SABA exposure is associated with severe exacerbation risk, independent of maintenance therapy. As addressed by GINA, based on studies across asthma severities where as-needed fast-acting bronchodilators with concomitant ICS decrease severe exacerbations compared with SABA, our findings highlight the importance of avoiding a rescue/reliever paradigm utilizing SABA monotherapy.

4: Wechsler ME, Menzies-Gow A, Brightling CE, Kuna P, Korn S, Welte T, GriffithsJM, Sałapa K, Hellqvist Å, Almqvist G, Lal H, Kaur P, Skärby T, Colice G; SOURCE
study group. Evaluation of the oral corticosteroid-sparing effect of tezepelumabin adults with oral corticosteroid-dependent asthma (SOURCE): a randomised,
placebo-controlled, phase 3 study. Lancet Respir Med. 2022 Mar
29:S2213-2600(21)00537-3. doi: 10.1016/S2213-2600(21)00537-3. Epub ahead of
print. PMID: 35364018.
Background: Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma.
Methods: We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078.
Findings: Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per μL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per μL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group.
Interpretation: We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per μL.

5: Bapat SP, Whitty C, Mowery CT, Liang Y, Yoo A, Jiang Z, Peters MC, Zhang LJ,
Vogel I, Zhou C, Nguyen VQ, Li Z, Chang C, Zhu WS, Hastie AT, He H, Ren X, Qiu
W, Gayer SG, Liu C, Choi EJ, Fassett M, Cohen JN, Sturgill JL, Crotty Alexander
LE, Suh JM, Liddle C, Atkins AR, Yu RT, Downes M, Liu S, Nikolajczyk BS, Lee IK,
Guttman-Yassky E, Ansel KM, Woodruff PG, Fahy JV, Sheppard D, Gallo RL, Ye CJ,
Evans RM, Zheng Y, Marson A. Obesity alters pathology and treatment response in
inflammatory disease. Nature. 2022 Mar 30. doi: 10.1038/s41586-022-04536-0. Epub
ahead of print. PMID: 35355021.
Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

6: Coker RK, Armstrong A, Church AC, Holmes S, Naylor J, Pike K, Saunders P,
Spurling KJ, Vaughn P. BTS Clinical Statement on air travel for passengers with
respiratory disease.
Thorax. 2022 Apr;77(4):329-350. doi:
10.1136/thoraxjnl-2021-218110. Epub 2022 Feb 28. PMID: 35228307.

7: Abrams EM. Coronavirus disease 2019 and pediatric asthma: friend or foe? Curr
Opin Allergy Clin Immunol. 2022 Apr 1;22(2):95-100. doi:
10.1097/ACI.0000000000000809. PMID: 35197430.
Purpose of review: The interplay of asthma and coronavirus disease 2019 (COVID-19) in children is yet unknown. The purpose of this review is to determine the interplay of asthma and asthma therapeutics and COVID-19.
Recent findings: There is no evidence to date that asthma is a risk factor for more severe COVID-19 outcomes, especially in children. There is actually some basis to suggest that children with atopic asthma may be at reduced risk of asthma exacerbations during COVID-19. The impact of asthma therapeutics on COVID-19 outcomes is unclear, but guidance is relatively uniform in recommending that those with asthma remain on current asthma medications. A focus on social determinants of health may be increasingly important during the pandemic and beyond.
Summary: Asthma in children appears to be more friend, than foe, during COVID-19.

8: Al-Ahmad M, Webb D. A prospective study of switching asthma patients from a
Fixed-Dose Combination (FDC) Inhaled Corticosteroid [ICS]/Long-Acting Beta
Agonist [LABA] therapy delivered by Dry Powder Inhaler (DPI) to ICS/LABA
delivered by pressurised Metered Dose Inhaler (pMDI)
. Respir Med. 2022
Apr;194:106771. doi: 10.1016/j.rmed.2022.106771. Epub 2022 Feb 12. PMID:
35180515.
Background: Previous real-world studies have suggested that in comparison to a dry powder inhaler (DPI), the rate of critical errors is lower with a pressurised metered dose inhaler (pMDI), and inhaled corticosteroid/long-acting bronchodilator (ICS/LABA) delivered by pMDI is more likely to achieve asthma control.
Objectives: To evaluate the acceptability, efficacy, safety and cost-effectiveness of switching asthma patients from an ICS/LABA DPI to an ICS/LABA pMDI in a real-world population in Kuwait.
Methods: This was a 12-month, observational, nonblinded, prospective, real world study. Patients with asthma for ≥1 year with 2 or more asthma exacerbations in the last year were assigned to either switch to ICS/LABA pMDI, or to continue with ICS/LABA DPI.
Results: A total of 239 patients were treated with either ICS/LABA pMDI (Switch cohort; n = 119) or ICS/LABA DPI (Maintenance cohort; n = 120). The majority of patients (99/119; 83.2%) in the Switch cohort remained on ICS/LABA pMDI over 12 months of follow-up. Both cohorts experienced an improvement in their FEV1 levels, with mean values in the Switch group reaching normal levels (>80% predicted). On average, at 3 and 12 months, the Switch cohort had significantly better FEV1 values than patients in the Maintenance cohort (p = 0.001). At 12 months, the proportion of patients with controlled asthma increased in the Switch group, but did not change significantly in the Maintenance group.
Conclusions: In patients with asthma symptoms that are not well controlled with an ICS/LABA DPI, switching to an ICS/LABA pMDI provides an alternative choice that may improve asthma control.

9: Persaud YK. Using Telemedicine to Care for the Asthma Patient. Curr Allergy
Asthma Rep. 2022 Apr;22(4):43-52. doi: 10.1007/s11882-022-01030-5. Epub 2022 Feb
2. PMID: 35107807; PMCID: PMC8807679.
Purpose of review: To review the data supporting the use of telemedicine (TM) and to provide practical guidance for practitioners to optimize the care of their asthmatic patients.
Recent findings: Previous to the pandemic, TM was little used in various aspects of asthma care. Since the pandemic, TM has been increasingly used in new ways to care for asthma patients at various locations. In addition to direct-to-consumer visits for asthma care, other forms of telehealth visits have been increasing such as facilitated visits, asynchronous, remote patient monitoring, e-consults, and mHealth. Moreover, patient and provider satisfaction with the use of TM has been increasing and is comparable at times with face-to-face visits. In this review, best practices for starting a telemedicine asthma service with patients at home, distant clinic sites, and various other locations, including school-based asthma programs, are reviewed. TM is a valuable adjunct to face-to-face visits for asthma care. Following the recommended best practices can strengthen the implementation of a telemedicine asthma program (TMAP) into clinical practice. Providers must be vigilant in keeping current with the various nuances required for asthma telemedicine care in preparation for the post-pandemic environment.

10: Wang E, Wechsler ME. A rational approach to compare and select biologic
therapeutics in asthma. Ann Allergy Asthma Immunol. 2022 Apr;128(4):379-389.
doi: 10.1016/j.anai.2022.01.024. Epub 2022 Jan 31. PMID: 35093555.
Objective: To review key literature on asthma biologic therapeutics-currently available and under investigation-to inform a rational approach to select biologics for the management of people with severe asthma by precision medicine.
Data sources: We used the PubMed database to review literature on biologic therapeutics in asthma.
Study selections: We included published randomized control trials and real-world studies on biologic therapeutics, available in English, through September 2021.
Results: Increased understanding of asthma endotypes and the roles of various inflammatory mechanisms has led to therapeutic agents that inhibit specific cytokines or immune pathways. Currently available biologic therapeutics target type 2-high asthma. Grouped by mechanisms of action, there are the following 3 types: (1) anti-immunoglobulin E, (2) anti-interleukin (IL)-5 or IL-5 receptor, and (3) anti-IL-4 receptor α. There are also various potential future biologic therapeutics currently under investigation. Although there remains a paucity of data regarding prospective direct head-to-head comparisons of biologic therapeutics in asthma, there are some retrospective and indirect comparison data available.
Conclusion: Precision medicine guides selection of biologic therapeutics along with shared decision-making. Biomarkers, although not comprehensive, allow approximations of likely mechanisms. Use of biomarkers, to include historical levels and trends, in addition to consideration of key clinical characteristics and comorbidities can greatly help guide biologic selection. Efficacy, safety, potential adverse effects, indications for other key comorbidities, and logistics should also be considered.

11: Busse WW, Kraft M. Current unmet needs and potential solutions to
uncontrolled asthma. Eur Respir Rev. 2022 Jan 25;31(163):210176. doi:
10.1183/16000617.0176-2021. PMID: 35082128.
Despite the availability of effective inhaled therapies, many patients with asthma have poor asthma control. Uncontrolled asthma presents a significant burden on the patient and society, and, for many, remains largely preventable. There are numerous reasons why a patient may remain uncontrolled despite access to therapies, including incorrect inhaler technique, poor adherence to treatment, oversight of triggers and suboptimal medical care. Shared decision-making, good patient-clinician communication, supported self-management, multidisciplinary patient education, new technology and risk stratification may all provide solutions to this major unmet need in asthma. Novel treatments such as biologics could benefit patients’ lives, while the investigations into biomarkers, non-Type 2 asthma, treatable traits and disease modification give an exciting glimpse into the future of asthma care.
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12: Mummy DG, Dunican EM, Carey KJ, Evans MD, Elicker BM, Newell JD Jr, Gierada
DS, Nagle SK, Schiebler ML, Sorkness RL, Jarjour NN, Denlinger LC, Fahy JV, Fain
SB. Mucus Plugs in Asthma at CT Associated with Regional Ventilation Defects at
<sup>3</sup>He MRI. Radiology. 2022 Apr;303(1):184-190. doi:
10.1148/radiol.2021204616. Epub 2021 Dec 21. PMID: 34931858.
Background Airway mucus plugs in asthma are associated with exacerbation frequency, increased eosinophilia, and reduced lung function. The relationship between mucus plugs and spatially overlapping ventilation abnormalities observed at hyperpolarized gas MRI has not been assessed quantitatively. Purpose To assess regional associations between CT mucus plugs scored by individual bronchopulmonary segment and corresponding measurements of segmental ventilation defect percentage (VDP) at hyperpolarized helium 3 (3He) MRI. Materials and Methods In this secondary analysis of a Health Insurance Portability and Accountability Act-compliant prospective observational cohort, participants in the Severe Asthma Research Program (SARP) III (NCT01760915) between December 2012 and August 2015 underwent hyperpolarized 3He MRI to determine segmental VDP. Segmental mucus plugs at CT were scored by two readers, with segments scored as plugged only if both readers agreed independently. A linear mixed-effects model controlling for interpatient variability was then used to assess differences in VDP in plugged versus plug-free segments. Results Forty-four participants with asthma were assessed (mean age ± standard deviation, 47 years ± 15; 29 women): 19 with mild-to-moderate asthma and 25 with severe asthma. Mucus plugs were observed in 49 total bronchopulmonary segments across eight of 44 patients. Segments containing mucus plugs had a median segmental VDP of 25.9% (25th-75th percentile, 7.3%-38.3%) versus 1.4% (25th-75th percentile, 0.1%-5.2%; P < .001) in plug-free segments. Similarly, the model estimated a segmental VDP of 18.9% (95% CI: 15.7, 22.2) for mucus-plugged segments versus 5.1% (95% CI: 3.3, 7.0) for plug-free segments (P < .001). Participants with one or more mucus plugs had a median whole-lung VDP of 11.1% (25th-75th percentile, 7.1%-18.9%) versus 3.1% (25th-75th percentile, 1.1%-4.4%) in those without plugs (P < .001). Conclusion Airway mucus plugging at CT was associated with reduced ventilation in the same bronchopulmonary segment at hyperpolarized helium 3 MRI, suggesting that mucus plugging may be an important cause of ventilation defects in asthma. © RSNA, 2021 Online supplemental material is available for this article.

13: Agusti A, Fabbri L, Lahousse L, Singh D, Papi A. Single inhaler triple
therapy (SITT) in asthma: Systematic review and practice implications. Allergy.
2022 Apr;77(4):1105-1113. doi: 10.1111/all.15076. Epub 2021 Sep 15. PMID:
34478578.
A significant number of patients with asthma remain uncontrolled despite treatment with inhaled corticosteroids (ICS) and long-acting β2 adrenergic bronchodilators (LABA). The addition of long-acting antimuscarinic agents (LAMA) can improve the management of asthma in these patients. Recently, three novel triple therapy (ICS/LABA/LAMA) formulations in a single-inhaler device (SITT) have been investigated in patients with uncontrolled asthma despite ICS/LABA treatment. Here, we review systematically the evidence available to date in relation to SITT in patients with uncontrolled asthma despite ICS-LABA treatment and conclude that SITT is a safe and effective therapeutic alternative in these patients. We also discuss how to position this new therapeutic alternative in their practical clinical management as well as the opportunities and challenges that it may generate for patients, physicians, and payers.

14: Krings JG, Wenzel SE, Castro M. The emerging role of quantitative imaging in
asthma. Br J Radiol. 2022 Apr 1;95(1132):20201133. doi: 10.1259/bjr.20201133.
Epub 2020 Dec 3. PMID: 33242252.
Quantitative imaging of the lung has proved to be a valuable tool that has improved our understanding of asthma. CT, MRI, and positron emission tomography have all been utilized in asthma with each modality having its own distinct advantages and disadvantages. Research has now demonstrated that quantitative imaging plays a valuable role in characterizing asthma phenotypes and endotypes, as well as potentially predicting future asthma morbidity. Nonetheless, future research is needed in order to minimize radiation exposure, standardize reporting, and further delineate how imaging can predict longitudinal outcomes. With future work, quantitative imaging may make its way into the clinical care of asthma and change our practice

RHINITIS-ALLERGY-ALLERGIC ASTHMA

1: Son DS, Cho MS, Kim DK. Chronic Rhinosinusitis and the Increased Incidence of
Atopic Dermatitis. Am J Rhinol Allergy. 2022 Mar 29:19458924221090050. doi:
10.1177/19458924221090050. Epub ahead of print. PMID: 35345892.
Background: Chronic rhinosinusitis (CRS) is often associated with other comorbidities due to chronic inflammation. However, no population-based, longitudinal study has investigated the relationship between CRS and chronic skin inflammation.
Objective: To investigate the potential relationship between CRS and chronic skin inflammatory diseases, such as atopic dermatitis (AD), vitiligo, and psoriasis.
Methods: A total of 5638 patients with CRS and 11 276 without CRS as a comparison group, were included from the Korean National Health Insurance Service database from 2002-2013. A propensity score matching (1:2) was performed using the nearest neighbor matching method, sociodemographic factors, and enrollment year. The Cox proportional hazards model was used to analyze the hazard ratio of CRS for AD, vitiligo, and psoriasis.
Results: Results from this study showed that patients with CRS had no significant risk of the subsequent development of vitiligo or psoriasis compared to patients without CRS. However, we found a significantly higher incidence of AD in CRS patients than in those without CRS. The incidence of AD was 63.59 per 1000 person-years in the CRS group and 45.38 per 1000 person-years in the comparison group. Additionally, young and middle-aged CRS patients were independently associated with a higher incidence of subsequent AD events, but we could not find a significantly higher incidence of AD events in the elderly group.
Conclusions: Our findings suggest there are no significant differences in the overall risk of vitiligo and psoriasis events in patients with CRS; however, we detected a higher risk of AD in young and middle-aged CRS patients. Therefore, clinicians should consider the risk of developing AD in specific patients who are newly diagnosed with CRS.

2: Farraia M, Paciência I, Castro Mendes F, Cavaleiro Rufo J, Shamji M, Agache
I, Moreira A. Allergen immunotherapy for asthma prevention: A systematic review
and meta-analysis of randomized and non-randomized controlled studies. Allergy.
2022 Mar 28. doi: 10.1111/all.15295. Epub ahead of print. PMID: 35342949.
Background: Allergen immunotherapy (AIT) is a disease-modifying treatment for IgE-mediated diseases. Randomized controlled trials (RCTs) support AIT’s potential role in asthma prevention but evidence from non-randomized studies of interventions (NRSI) and longitudinal observational studies has been poorly addressed. Therefore, we aimed to conduct a systematic review and meta-analysis to assess clinical data from all study types to evaluate quantitatively the preventive role of AIT in asthma onset.
Methods: We search three databases. Studies were screened, selected and evaluated for quality using risk-of-bias (ROB) tools. Data were descriptively summarized and meta-analysed using random effects. We performed a sensitivity, influence and subgroup analyses. Publication bias and heterogeneity were assessed.
Results: From the 4549 identified studies, 24 (12 RCTs and 12 NRSI) were included in the qualitative synthesis and 18 underwent meta-analysis. One study was at low ROB, seven had moderate ROB, and 15 were proven of high ROB. Random-effects analysis showed a significant decrease in the risk of developing asthma following AIT by 25% (RR, 95% CI: 0.75, 0.64-0.88). This effect was not significant in the sensitivity analysis. Publication bias raised concerns, together with the moderate heterogeneity between studies (I2 = 58%). Subgroup analysis showed a remarkable preventive effect of AIT in children (RR, 95% CI: 0.71, 0.53-0.96), when completing 3 years of therapy (RR, 95% CI: 0.64, 0.47-0.88), and in mono-sensitized patients (RR, 95% CI: 0.49, 0.39-0.61).
Conclusions: Our findings support a possible preventive effect of AIT in asthma onset and suggest an enhanced effect when administered in children, mono-sensitized, and for at least 3 years, independently of allergen type.

3: De Corso E, Seccia V, Ottaviano G, Cantone E, Lucidi D, Settimi S, Di Cesare
T, Galli J. Clinical Evidence of Type 2 Inflammation in Non-allergic Rhinitis
with Eosinophilia Syndrome: a Systematic Review. Curr Allergy Asthma Rep. 2022
Apr;22(4):29-42. doi: 10.1007/s11882-022-01027-0. Epub 2022 Feb 9. PMID:
35141844.
Purpose of review: Non-allergic rhinitis (NAR) includes different subtypes, among which NAR with eosinophilia syndrome (NARES) is the most important because of severity of symptoms and the high risk of comorbidities. Its pathophysiology is still object of debate, but a crucial role of chronic eosinophilic inflammation has been recognized. The aim of this review is to critically analyze the current evidence regarding the hypothesis that NARES may be considered a type 2 inflammatory disorder.
Recent findings: The definition and diagnostic criteria for NARES are not universally shared and adopted, thus generating difficulties in reproducing the results. At present, there is extreme heterogeneity in sampling methods and disagreement in the cut-off of local eosinophilic count to determine a diagnosis of NARES. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) standard was applied to identify English-language experimental and clinical articles regarding NARES. The search was performed in April 2021. Twenty-six articles were included. Our data suggest a particular heterogeneity regarding sampling and specific cut-offs adopted for diagnosis of NARES and consensus should be reached. We suggest that eosinophil count should be reported as an absolute value for at least 10 observed rich fields in order to increase the level of standardization. Consensus among authors on this topic should be reached with particular attention to the cut-off for diagnosis. In the future, this limitation may be overcome by the identification of repeatable biomarkers to refine diagnosis and prognosis of NARES. Furthermore, our data strongly suggest that NARES have numerous similarities with clinical features of the most common type 2 diseases such as eosinophilic asthma and chronic rhinosinusitis with nasal polyps (CRSwNP): late onset, association with type 2 comorbidities, selective eosinophilic tissue infiltration, remarkable response to oral and intranasal corticosteroids, and progression in a type 2 CRSwNP.

4: Li S, Wu W, Wang G, Zhang X, Guo Q, Wang B, Cao S, Yan M, Pan X, Xue T, Gong
J, Duan X. Association between exposure to air pollution and risk of allergic
rhinitis: A systematic review and meta-analysis. Environ Res. 2022 Apr
1;205:112472. doi: 10.1016/j.envres.2021.112472. Epub 2021 Dec 1. PMID:
34863689.
Background: Allergic rhinitis (AR) is one of the most common allergic diseases in the world, and usually persists throughout the activity. Epidemiological studies have shown a positive association between air pollution and allergic rhinitis. However, we could not find any meta-analysis of the risk of air pollutants (PM2.5, PM10, NO2, SO2, O3 and CO) on the prevalence of AR in people of all ages.
Objectives: Carry out a meta-analysis on the results of recent studies (up to 2020) to present valid information about exposure to air pollution and risk of prevalence of AR.
Methods: We systematically searched three databases for studies up to December 17, 2020, including air pollution and AR. Random effect models were conducted to estimate the pooled odds ratios (ORs) and 95% confidence intervals (95% CIs). Subgroup analysis, funnel plot, Egger’s test, and the trim-and-fill method were also conducted.
Results: Thirty-five studies across 12 countries, including a total of 453,470 participants, were included. The OR per 10 μg/m3 increase of pollutants was 1.13 (1.04-1.22) for PM10 and 1.12 (1.05-1.20) for PM2.5. The OR per 10 μg/m3 increment of gaseous pollutants were 1.13 (1.07-1.20) for NO2, 1.13 (1.04-1.22) for SO2 and 1.07 (1.01-1.12) for O3. No significant association was observed between CO and AR. Children or adolescents are more sensitive to air pollution than adults. The effects of PM10 and SO2 were significantly stronger in Europe than Asia. The effects of air pollutants were more significant and higher in developing countries than in developed countries, except for PM10. A significant difference of subgroup test was found between developed and developing countries of NO2.
Conclusion: This meta-analysis showed a positive association between air pollution and the prevalence of allergic rhinitis, and identified geographic area and economic level as the potential modifiers for the association.

5: Chen R, Zheng D, Zhang Y, Sima G. Efficacy and safety of twice-daily
olopatadine-mometasone combination nasal spray (GSP301) in the treatment of
allergic rhinitis: a systematic review and meta-analysis. Eur Arch
Otorhinolaryngol. 2022 Apr;279(4):1691-1699. doi: 10.1007/s00405-021-07085-w.
Epub 2021 Sep 30. PMID: 34591150.
Purpose: GSP301 is a fixed-dose combination of olopatadine hydrochloride (antihistamine) and mometasone furoate (corticosteroid). This meta-analysis aims to evaluate the efficacy and safety of GSP301 in the treatment of allergic rhinitis.
Methods: A systematic review and meta-analysis were conducted. The data were collected from PubMed, Cochrane Central Register of Controlled Trials and Embase databases till June 2021. In patients with AR, short-term (2/6 weeks) and long-term (52 weeks) effects of GSP301 were assessed. Average morning and evening 12-h reflective total nasal symptom score (rTNSS), instantaneous total nasal symptom score (iTNSS), reflective total ocular symptom score (rTOSS), instantaneous total ocular symptom score(iTOSS), Physician-assessed nasal symptom score (PNSS), rhinoconjunctivitis quality of life (RQLQ), rhinitis control assessment test (RCAT) and adverse events (AEs) were measured.
Results: Five randomized controlled trials were included. GSP301 showed greatly improvement in rTNSS (MD = – 0.99; [95% CI – 1.19 to – 0.79]; P < 0.01; I2 = 0), iTNSS (MD = – 1.05; [95% CI – 1.44 to – 0.67]; P < 0.01; I2 > 50%), rTOSS (MD = – 0.50; [95% CI – 0.72 to – 0.29]; P < 0.01; I2 = 0), iTOSS (MD = – 0.64; [95% CI – 1.02 to – 0.26]; P < 0.01; I2 > 50%), PNSS (MD = – 1.01; [95% CI – 1.32 to – 0.69]; P < 0.01; I2 = 22.13%), RQLQ (MD = – 0.43; [95% CI – 0.57 to – 0.30]; P < 0.01; I2 = 0%) and RCAT (MD = 1.94; [95% CI 1.43-2.45]; P < 0.01; I2 = 0%) in the short term. No statistical difference was observed in the outcome of long-term PNSS, RQLQ and RCAT.
Conclusion: GSP301 is a safe and well-tolerated medication. It showed short-term benefits for seasonal and perennial AR, but may not help to improve patients’ quality of life and rhinitis control in the long run

Posted in Libra Journal Club.