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. PDF ATTACHED 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

20-27 March 2022

COPD

1: Tavares N, Jarrett N, Wilkinson T, Hunt K. Clinician Perspectives on How to Hold Earlier Discussions About Palliative and End-of-Life Care With Chronic Obstructive Pulmonary Disease Patients: A Qualitative Study. J Hosp Palliat Nurs. 2022 Mar 24. doi: 10.1097/NJH.0000000000000858. Epub ahead of print. PMID: 35334479.
Chronic obstructive pulmonary disease is associated with progressive symptoms and increased treatment burden, especially at the end of life. However, most patients do not receive palliative care until late in their lives or discuss their end-of-life preferences with clinicians. This study explored clinicians’ perspectives on the timing and nature of palliative care discussions. Qualitative interviews were conducted with 7 physicians and 7 nurses working in primary and secondary care settings. Data were analyzed using a thematic analysis. Participants advocated for early, gradual, and informed palliative and future care discussions, because these discussions were thought to be less traumatic and better accepted by patients. Despite this, patient- and clinician-related barriers severely affected clinicians’ ability to start discussions at earlier stages. Participants felt many patients were not ready for these discussions and feared damaging hope if the subject was broached. Therefore, clinicians delayed discussions until patients approached the end of life. Stand-alone conversations about and near the end of life were described as current practice; however, clinicians believed these discussions reduced patients’ hope and were potentially upsetting. Instead, individualized early, regular, and gradual discussions about immediate and long-term care plans were thought to be less negative and be better accepted.

2: Phillips DB, Elbehairy AF, James MD, Vincent SG, Milne KM, de-Torres JP, Neder JA, Kirby M, Jensen D, Stickland MK, Guenette JA, Smith BM, Aaron SD, Tan WC, Bourbeau J, O’Donnell DE; CanCOLD Collaborative Research Group and the Canadian Respiratory Research Network. Impaired Ventilatory Efficiency, Dyspnea and Exercise Intolerance in Chronic Obstructive Pulmonary Disease: Results from the CanCOLD Study. Am J Respir Crit Care Med. 2022 Mar 25. doi: 10.1164/rccm.202109-2171OC. Epub ahead of print. PMID: 35333135.
Rationale: Impaired exercise ventilatory efficiency (high ventilatory requirements for CO2 [V̇E/V̇CO2]) provides an indication of pulmonary gas exchange abnormalities in chronic obstructive pulmonary disease (COPD).
Objectives: To determine: 1) the association between high V̇E/V̇CO2 and clinical outcomes (dyspnea and exercise capacity) and its relationship to lung function and structural radiographic abnormalities; and 2) its prevalence in a large population-based cohort.
Methods: Participants were recruited randomly from the population and underwent clinical evaluation, pulmonary function, cardiopulmonary exercise testing and chest computed tomography (CT). Impaired exercise ventilatory efficiency was defined by a nadir V̇E/V̇CO2 above the upper limit of normal (V̇E/V̇CO2>ULN), using population-based normative values.
Measurements and main results: Participants included 445 never-smokers, 381 ever-smokers without airflow obstruction, 224 with GOLD 1 COPD, and 200 with GOLD 2-4 COPD. Participants with V̇E/V̇CO2>ULN were more likely to have activity-related dyspnea (Medical Research Council dyspnea scale≥2, odds ratio=1.77[1.31-2.39]) and abnormally low peak oxygen uptake (V̇O2peak<LLN, odds ratio=4.58[3.06-6.86]). The carbon monoxide transfer coefficient (KCO) had a stronger correlation with nadir V̇E/V̇CO2 (r=-0.38, p<0.001) than other relevant lung function and CT metrics. The prevalence of V̇E/V̇CO2>ULN was 24% in COPD (similar in GOLD 1 and 2-4), which was greater than in never-smokers (13%) and ever-smokers (12%).
Conclusions: V̇E/V̇CO2>ULN was associated with greater dyspnea and low VO2peak and was present in 24% of all participants with COPD, regardless of GOLD stage. The results show the importance of recognizing impaired exercise ventilatory efficiency as a potential contributor to dyspnea and exercise limitation, even in mild COPD.

3: Li H, Chen J, Hu P. Diagnostic value of pulmonary ultrasound in acute exacerbation of chronic obstructive pulmonary disease: A pilot study. Med Clin (Barc). 2022 Mar 21:S0025-7753(22)00081-1. English, Spanish. doi: 10.1016/j.medcli.2022.01.022. Epub ahead of print. PMID: 35331547.
Background: To evaluate the value of the pulmonary ultrasound for the diagnosis of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in emergency departments (EDs).
Materials and methods: Between January 2018 and December 2019, patients admitted to the ED of Shanxi Provincial People’s Hospital for suspected AECOPD were prospectively included in this study. Pulmonary ultrasound was performed using a linear transducer. The pulmonary ultrasound findings were evaluated for further discrimination for patients with AECOPD. Then, the diagnostic performance of pulmonary ultrasound was estimated and calculated. The clinical characteristics between groups with and without pneumonia were compared.
Results: A total of 53 patients with AECOPD were included in the final analysis. For diagnosis of AECOPD due to pneumonia, ultrasound findings, such as consolidation, slightly rough pleural line, or irregular and interrupted pleural line had a sensitivity of 92.3% and a specificity of 86.7%. For diagnosis of AECOPD complicating pulmonary fibrosis, fringed pleural line had a sensitivity of 100% and a specificity of 97.5%. In addition, patients with pleural effusion (n=19) or pneumothorax (n=1) were correctly identified and wavy or bulging pleural lines were common in patients with AECOPD (58.5%, 31/53).
Conclusion: Ultrasound findings could offer further discrimination for AECOPD complications and other pathological conditions, such as pneumonia, pulmonary fibrosis, pleural effusion, and pneumothorax in EDs.

4: Press VG, Randall K, Hanser A. Evaluation of COPD Chronic Care Management Collaborative to Reduce Emergency Department and Hospital Revisits Across U.S. Hospitals. Chronic Obstr Pulm Dis. 2022 Mar 23. doi: 10.15326/jcopdf.2022.0273. Epub ahead of print. PMID: 35322625.
Background: Chronic Obstructive Pulmonary Disease (COPD) is the third-leading cause of early readmissions. The Centers for Medicare and Medicaid instituted a financial penalty for excessive COPD readmissions galvanizing hospitals to implement effective strategies to reduce readmissions. We evaluated a 6-month COPD Chronic Care Management Collaborative to support hospitals to reduce preventable COPD-related revisits.
Methods: Sites were recruited among nearly 300 Vizient members. The Collaborative used performance improvement initiatives to assist with implementation of effective strategies. Participants submitted performance data for two outcome measures: emergency department (ED) and hospital revisits.
Results: Forty-seven members enrolled (Part I+II: n=33; Part I: n=3; Part II: n=11) of which 23 submitted data (n=23/47). The majority (n=19/23, 83%) reduced rates of COPD-related ED and/or hospital revisits. Among all 23 sites, the change in ED visits went from 11.05% to 10.87%; among 7 sites with reductions in ED visits, the reduction was 12.7% to 9%. Among all 23 sites, there were not reductions hospital readmissions (18.53% to 18.64%); among 7 sites with reductions, the readmission rate went from 20.1% to 15.6%. The mean reach across 17 hospitals reporting reach for their most successful measure at baseline was 35.2% (SD = 26.7%) and for the six reporting reach at follow-up was 73.8%% (SD = 18.3%); of note, only three sites submitted both baseline and follow-up data.
Conclusions: The Collaborative successfully supported the majority of sites to reduce COPD-related ED and/or hospital revisits using subject matter experts and coaching strategies to support hospitals’ implementation of COPD quality improvement interventions.

5: Rebordosa C, Farkas DK, Montonen J, Laugesen K, Voss F, Aguado J, Bothner U, Rothman KJ, Zint K, Mines D, Ehrenstein V. Cardiovascular Events and All-Cause Mortality in Patients With Chronic Obstructive Pulmonary Disease Using Olodaterol and Other Long-Acting Beta2-Agonists. Pharmacoepidemiol Drug Saf. 2022 Mar 23. doi: 10.1002/pds.5432. Epub ahead of print. PMID: 35320605.
Purpose: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored.
Methods: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias.
Results: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n=14,239) compared to users of other LABA (n=51,167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis.
Conclusions: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

6: Baalbaki N, Giuliano C, Hartner CL, Kale-Pradhan P, Johnson L. Azithromycin Versus Beta-lactams in Hospitalized Patients with Acute Exacerbations of COPD. J Gen Intern Med. 2022 Mar 22:1–6. doi: 10.1007/s11606-022-07486-5. Epub ahead of print. PMID: 35316516; PMCID: PMC8939242.
Background: There is a lack of data comparing azithromycin to alternative antibiotic choices in managing COPD exacerbations, making appropriate antibiotic selection controversial.
Objective: To compare treatment failure in hospitalized patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) receiving azithromycin or beta-lactams.
Design: Retrospective, multicenter cohort study using logistic regression for multivariable analysis. Patients were included if they were at least 18 years old, admitted with AECOPD, and received at least two consecutive days of either a beta-lactam or azithromycin. Patients were excluded if they received concomitant azithromycin and beta-lactam antibiotics during the first 2 days, had a history of other severe underlying pulmonary diseases, pregnancy, COVID-19, alpha-1 antitrypsin deficiency, or received a corticosteroid for a diagnosis other than COPD.
Participants: Five hundred ninety-five patients were included, of which 428 (72%) received azithromycin and 167 patients (28%) received a beta-lactam.
Main measures: The primary endpoint was treatment failure rate in patients receiving azithromycin versus beta-lactams, which was a composite endpoint defined as in-hospital mortality, admission to intensive care, initiation of invasive mechanical ventilation, initiation of a new antibiotic, steroid therapy escalation, or readmission due to AECOPD within 30 days.
Key results: The composite primary outcome occurred in 84 patients (19.6%) in the azithromycin group and 54 (32.3%) in the beta-lactam group (p<0.01). The difference in the composite outcome was a result of higher rates of new antibiotics during admission (12.6% vs 4.2%; p<0.01) and higher readmission within 30 days (19.3% vs 12.4%; p=0.032). After controlling for potential confounders, beta-lactams continued to demonstrate a higher risk for treatment failure (OR, 2.30; 95% CI, 1.46-3.63). There was no difference in adverse effects between the groups.
Conclusion: Azithromycin was associated with less treatment failure in AECOPD which was driven by lower readmission rates and prescription of new antimicrobials.

7: Hyodo K, Masuko H, Oshima H, Shigemasa R, Kitazawa H, Kanazawa J, Iijima H, Ishikawa H, Kodama T, Nomura A, Kagohashi K, Satoh H, Saito T, Sakamoto T, Hizawa N. Common exacerbation-prone phenotypes across asthma and chronic obstructive pulmonary disease (COPD). PLoS One. 2022 Mar 21;17(3):e0264397. doi: 10.1371/journal.pone.0264397. PMID: 35312711; PMCID: PMC8936473.
Background and objectives: Chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD), are complex syndromes with diverse clinical symptoms due to multiple pathophysiological conditions. In this study, using common and shared risk factors for the exacerbation of asthma and COPD, we sought to clarify the exacerbation-prone phenotypes beyond disease labels, and to specifically investigate the role of the IL4RA gene polymorphism, which is related to type 2 inflammation, in these exacerbation-prone phenotypes.
Methods: The study population comprised patients with asthma (n = 117), asthma-COPD overlap (ACO; n = 37) or COPD (n = 48) and a history of exacerbation within the previous year. Cluster analyses were performed using factors associated with both asthma and COPD exacerbation. The association of the IL4RA gene polymorphism rs8832 with each exacerbation-prone phenotype was evaluated by multinomial logistic analyses using non-asthma non-COPD healthy adults as controls (n = 1,529). In addition, the genetic influence of rs8832 was also examined in asthma patients with allergic rhinitis and no history of exacerbation (n = 130).
Results: Two-step cluster analyses identified five clusters that did not necessarily correspond to the diagnostic disease labels. Cluster 1 was characterized by high eosinophil counts, cluster 2 was characterized by smokers with impaired lung function, cluster 3 was characterized by the presence of gastroesophageal reflux, cluster 4 was characterized by non-allergic females, and cluster 5 was characterized by allergic rhinitis and elevated total immunoglobulin E levels. A significant association with rs8832 was observed for cluster 5 (odds ratio, 3.88 (1.34-11.26), p = 0.013) and also for the type 2 exacerbation-prone phenotypes (clusters 1 and 5: odds ratio, 2.73 (1.45-5.15), p = 1.9 × 10-3).
Discussion: Our results indicated that the clinical heterogeneity of disease exacerbation may reflect the presence of common exacerbation-prone endotypes across asthma and COPD, and may support the use of the treatable traits approach for the prevention of exacerbations in patients with chronic inflammatory airway diseases.

ASTHMA

1: McLaughlin K, Jensen M, Foureur M, Murphy VE. Are pregnant women with asthma receiving guideline-recommended antenatal asthma management? A survey of pregnant women receiving usual care in Australia. Women Birth. 2022 Mar 23:S1871-5192(22)00046-4. doi: 10.1016/j.wombi.2022.03.008. Epub ahead of print. PMID: 35339413.
Background: Asthma affects 12.7% of pregnant women in Australia. Key recommendations for asthma management during pregnancy include: 4-6 weekly review of lung function, medications, written asthma action plan, inhaler device technique, current asthma control and triggers; smoking cessation and vaccination advice. It is unknown if these key recommendations are provided to pregnant women with asthma in Australia.
Aim: To explore usual antenatal asthma management (usual care) in Australia and the inclusion of key recommendations.
Method: Pregnant women with asthma were invited to complete an online survey distributed in 2 antenatal clinics and via social media platforms from July 2017-Jan 2019.
Results: The survey was completed by 142 pregnant women with asthma. 87(61%) were enrolled in an asthma management clinical trial and were therefore not receiving ‘usual’ care. Data presented is from 55(39%) women receiving usual care at survey completion. Of these women, 36% did not have their asthma reviewed during their pregnancy, 31% had a written asthma action plan, 11% had lung function assessed, 38% had an asthma medication review and 35% had their inhaler technique reviewed. 65% were not questioned about their asthma symptoms, 85% were not asked about asthma triggers, 96% were not given information about vaccinations and 95% did not receive smoking cessation information.
Conclusions: Overall, the key recommendations for antenatal asthma management were not always provided for this sample of pregnant women receiving usual care. Improved knowledge and implementation of these key recommendations by health professionals may alter this situation and improve maternal and infant outcomes.

2: Li X, Zhang Y, Zhang R, Chen F, Shao L, Zhang L. Association Between E-Cigarettes and Asthma in Adolescents: A Systematic Review and Meta-Analysis. Am J Prev Med. 2022 Mar 22:S0749-3797(22)00098-8. doi: 10.1016/j.amepre.2022.01.015. Epub ahead of print. PMID: 35337694.
Introduction: Numerous studies have revealed the relationship between E-cigarettes and asthma but have shown inconsistent results. This study systematically evaluated the potential association between E-cigarette use and asthma in adolescents.
Methods: PubMed, Embase (Ovid), Cochrane Library, and the China Biological Medicine Database were searched for relevant articles published between database inception and February 28, 2021. The quality of included studies was evaluated using the Agency for Healthcare Research and Quality assessment, and a quantitative meta-analysis was conducted to pool outcomes of ORs with 95% CIs.
Results: A total of 10 cross-sectional studies incorporating a total of 483,948 participants were included. All the study participants were middle- and high-school students with a mean age of 15-16 years. The median prevalence of ever E-cigarette use was 11.2% (range=2.2%, 45%), and that of current use was 7.5% (range=2.7%, 25%). Overall, E-cigarette use was associated with significantly higher odds of having asthma (pooled OR=1.31, 95% CI=1.22, 1.42) than nonuse, and both current use (OR=1.36, 95% CI=1.26, 1.48) and ever use (OR=1.20, 95% CI=1.12, 1.28) showed similar associations.
Discussion: This study shows that both current and ever E-cigarette use have significant associations with asthma in adolescents. This knowledge might provide potential evidence for developing primary prevention strategies and serve as a reference for public health policy.

3: Menzella F, Fontana M, Ruggiero P, Livrieri F, Facciolongo N. Home-based treatment of biologics for asthma: who, what, where, when and why. Expert Rev Respir Med. 2022 Mar 24. doi: 10.1080/17476348.2022.2057301. Epub ahead of print. PMID: 35324362.
Introduction: The advent of biologic therapies for severe asthma has profoundly changed the management of this pathology. The introduction of home administration is therefore an important innovation to optimize the patients’ management, even if there are many aspects that need to be clarified and pointed out.
Areas covered: This review summarizes the path that led to the possibility of self-administration of biologics, and what the pandemic has changed in the management of these patients.
Expert opinion: The growing understanding of asthma phenotypes and endotypes is enabling the careful selection of patients suitable for biologics. In this context, the availability of reliable and simple self-injection devices is important in implementing self-administration. The transition to self-injection is also possible thanks to the high safety profile of biologics. With attention, most patients may potentially be suitable for self-administration. The transition process from hospital to home administration can therefore be carried out correctly by clinicians with adequate expertise in the field of severe asthma and biologic therapies, with the support of other health professionals, pharmacists, and general practitioners. Home administration is probably the best way to guarantee high adherence and high-level satisfaction of patients, even in the long term.

4: Aukstuolis K, Cooper JJ, Altman K, Lang A, Ayars AG. Hypereosinophilic syndrome presenting as coagulopathy. Allergy Asthma Clin Immunol. 2022 Mar 22;18(1):25. doi: 10.1186/s13223-022-00666-2. PMID: 35317854; PMCID: PMC8941788.
Background: Hypereosinophilic syndrome (HES) is an extremely uncommon group of disorders. It rarely presents with coagulopathy without cardiac involvement.
Case presentation: A 33-year-old previously healthy male with no history of atopic disease presented with abdominal pain, hematochezia, peripheral eosinophilia as high as 10,000 eos/µL, right and left portal vein, mesenteric, and splenic vein thrombi with ischemic colitis resulting in hemicolectomy and small bowel resection. Despite an extensive workup for primary and secondary etiologies of hypereosinophilia by hematology/oncology, infectious disease, rheumatology and allergy/immunology, no other clear causes were identified, and the patient was diagnosed with idiopathic HES. His eosinophilia was successfully treated with high-dose oral corticosteroids (OCS) and subsequently transitioned to anti-IL-5-receptor therapy with benralizumab. He has continued this treatment for over a year with no recurrence of eosinophilia or thrombosis while on benralizumab.
Conclusion: In patients with an unexplained coagulopathy and eosinophilia, eosinophilic disorders such as HES should be considered. Corticosteroid-sparing agents, such as benralizumab show promise for successfully treating these patients.

5: Kow CS, Ramachandram DS, Hasan SS. Early oxygen therapy may be beneficial to patients with COVID-19 and underlying pulmonary diseases. J Asthma. 2022 Mar 22:1-2. doi: 10.1080/02770903.2022.2056701. Epub ahead of print. PMID: 35315746.

6: Trischler J, von Blumroeder M, Donath H, Kluge S, Hutter M, Dreßler M, Zielen S. Antibiotic Use in Paediatric Patients Hospitalized with Acute Severe Asthma. Klin Padiatr. 2022 Mar 21. English. doi: 10.1055/a-1712-4225. Epub ahead of print. PMID: 35315003.
Background: Antibiotic use during asthma exacerbations in paediatric patients is not routinely recommended but common practise in out-patient and in-patient settings. Objective of this study was to analyse frequency of antibiotic use during acute severe asthma exacerbations, antibiotic classes utilized and clinical decision-making.
Methods: All in-patient admissions over 10 years in a single German Children’s University hospital due to acute severe asthma were included in this retrospective analysis. Age, length of stay, oxygen supplementation, treatment, laboratory parameters and chest x-rays of all patients ranging from 1 to 17 years were analysed.
Results: 580 hospital admissions were included in this study. Overall antibiotic use was high but decreased with age (1-5 years 69,6%, 6-11 years 57,6% and 12-17 years 39,7%, p<0.001). Analysis of antibiotic treatment without clear indication showed a consistently lower treatment rate of 28.3%, with macrolides being the most common antibiotic class. Younger age significantly decreased, whereas, increase of CrP value, use of oxygen supplementation and concomitant fever all significantly increased the odds ratio (OR 0.967; 4.366, 2.472 and 2.011 respectively) of receiving antibiotic treatment without clear indication.
Conclusion: Antibiotic treatment without clear indication during acute severe asthma is common in this German single-centre cohort. Clinical parameters of more severe disease affect clinician’s decision to administer antibiotics despite evidence of bacterial infection or improved outcome.

7: Kachroo P, Stewart ID, Kelly RS, Stav M, Mendez K, Dahlin A, Soeteman DI, Chu SH, Huang M, Cote M, Knilhtilä HM, Lee-Sarwar K, McGeachie M, Wang A, Wu AC, Virkud Y, Zhang P, Wareham NJ, Karlson EW, Wheelock CE, Clish C, Weiss ST, Langenberg C, Lasky-Su JA. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nat Med. 2022 Mar 21. doi: 10.1038/s41591-022-01714-5. Epub ahead of print. PMID: 35314841.
The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment.

8: Barber CM, Cullinan P, Feary J, Fishwick D, Hoyle J, Mainman H, Walters GI. British Thoracic Society Clinical Statement on occupational asthma. Thorax. 2022 Mar 21:thoraxjnl-2021-218597. doi: 10.1136/thoraxjnl-2021-218597. Epub ahead of print. PMID: 35314486.

9: Proceedings of the Canadian Society of Allergy and Clinical Immunology Annual Scientific Meeting 2021. Allergy Asthma Clin Immunol. 2022 Mar 22;18(Suppl 1):11. doi: 10.1186/s13223-022-00647-5. PMID: 35313976; PMCID: PMC8938214.

10: Hoffmann C, Maglakelidze M, von Schneidemesser E, Witt C, Hoffmann P, Butler T. Asthma and COPD exacerbation in relation to outdoor air pollution in the metropolitan area of Berlin, Germany. Respir Res. 2022 Mar 20;23(1):64. doi: 10.1186/s12931-022-01983-1. PMID: 35307034; PMCID: PMC8935815.
Background: Ambient air pollution poses a major risk for the development and aggravation of respiratory diseases. Evidence suggests that even in low-level air pollution environments there is a risk for an increase in adverse respiratory symptoms. We examined whether variations in daily air pollution levels of nitrogen dioxide, ozone, or particulate matter in Berlin, Germany were associated with hospital admissions of chronic obstructive pulmonary disease (COPD) and asthma patients in a time series analysis.
Methods: We calculated single and multi-pollutant models, investigated possible lags in effect, and analysed the influence of meteorological variables on the results. Data from January 2005 through December 2015 were used to quantify the concentration-response.
Results: The risk ratio for asthma patients to be hospitalised on the same day of NO2 exposure was 1.101 per 10 µg/m3 NO2 increase (95% CI: 1.013 to 1.195), for COPD patients 1.123 (95% CI: 1.081 to 1.168). Neither the exposure to ozone (95% CI: 0.904 to 1.020), PM10 (95% CI: 0.990 to 1.127), nor PM2.5 (95% CI: 0.981 to 1.148) was associated with an increased risk ratio for asthma patients to be hospitalised. Risk ratios for the hospital admission of COPD patients were also not increased due to ozone (95% CI: 0.981 to 1.033), PM10 (95% CI: 0.988 to 1.032), or PM2.5 (95% CI: 0.966 to 1.019) exposure. The presented risk ratios and confidence intervals relate to the day of exposure. We found no increased hospitalisation risks with a delayed occurrence on subsequent days.
Conclusions: A quantifiable, statistically significant increase in risk for asthma and COPD exacerbations owing to NO2 exposure at levels well below European regulatory limit values was observed.

11: Zhu Y, Yang T, Huang S, Li H, Lei J, Xue X, Gao Y, Jiang Y, Liu C, Kan H, Chen R. Cold temperature and sudden temperature drop as novel risk factors of asthma exacerbation: a longitudinal study in 18 Chinese cities. Sci Total Environ. 2022 Mar 25;814:151959. doi: 10.1016/j.scitotenv.2021.151959. Epub 2021 Nov 27. PMID: 34843761.
Background: Few studies have explored the role of ambient temperature in asthma exacerbation.
Objective: We aimed to explore the association of temperature with diurnal peak expiratory flow (PEF) variation and asthma exacerbation.
Method: We developed a longitudinal study among asthmatic adults in 18 Chinese cities. Subjects recorded PEF in dynamic pulmonary function monitoring from 2017 to 2020. Linear mixed-effect model and generalized additive model with distributed non-linear models were used to assess the effect of temperature and temperature change between neighboring days (TCN) on diurnal PEF variation and the risk of asthma exacerbation.
Result: We evaluated a total of 79,217 daily PEF monitoring records from 4467 adult asthmatic patients. There were significant increase of diurnal PEF variation and higher risk of asthma exacerbation with cold and sudden temperature drop. Compared with the referent temperature (99th percentile, 32 °C), exposure to moderate cold (25th percentile, 3 °C) and extreme cold (2.5th percentile, -7 °C) was associated with elevations of 1.28% and 1.16% in diurnal PEF variation over lag 0-2 days, respectively. The odds ratios of asthma exacerbation (determined by diurnal PEF variation >20%) at the two temperature cutoffs were 1.68 and 1.73. A sudden temperature drop (2.5th percentile of TCN, -5 °C) was associated with 1.13% elevation in diurnal PEF variation, and with increased risk of asthma exacerbation (odd ratio = 1.50) over lag 0-4 days.
Conclusion: This large multicenter study provided the first-hand empirical evidence that cold temperature and a temperature drop may increase the risk of asthma exacerbation.

RHINITIS-ALLERGY-ALLERGIC ASTHMA

1: Testera-Montes A, Palomares F, Jurado-Escobar R, Fernandez-Santamaria R, Ariza A, Verge J, Salas M, Campo P, Mayorga C, Torres MJ, Rondon C, Eguiluz- Gracia I. Sequential class switch recombination to IgE and allergen-induced accumulation of IgE+ plasmablasts occur in the nasal mucosa of local allergic rhinitis patients. Allergy. 2022 Mar 27. doi: 10.1111/all.15292. Epub ahead of print. PMID: 35340036.
Background: the involvement of allergen-specific (s)IgE in local allergic rhinitis (LAR) has been debated. Here, we investigate the effect of nasal allergen challenge with Dermatophagoides pteronyssinus (NAC-DP) in mucosal and peripheral B-cell subpopulations in LAR patients.
Methods: Nine LAR, 5 allergic rhinitis (AR) and 5 non-atopic healthy-control (HC) individuals were subjected to a 3-day NAC-DP protocol, and nasal biopsies and blood samples were collected before and after provocation. Nasal biopsies were used for immunohistochemistry and gene expression studies, whereas the frequency of lymphocyte subsets and basophil activation test (BAT) were analyzed in blood samples by flow cytometry. sIgG was measured in sera.
Results: NAC-DP induced an increase of IgE+ CD38+ plasmablasts in the nasal mucosa of LAR patients, but not in AR or HC individuals. Markers of sequential recombination to IgE (εCSR) (from IgG) were observed in 33% of LAR, 20% of AR and 0% of HC subjects. NAC-DP increased the proportion of peripheral CD19+ CD20+ CD38+ plasmablastsin AR and LAR patients, but not in HC. Expression of the mucosal homing receptor CXCR3 in peripheral CD19+ CD20+ CD38+ plasmablasts from LAR, AR and HC individuals was 7%, 5% and 0.5%, respectively. In vitro DP stimulation increased proliferating CD19+ CD20+ CD38+ plasmablasts in LAR and AR patients, but not in HC. Serum DP-sIgG was higher in LAR and AR patients as compared to HC. BAT was positive in 38%, 100% and 0% of LAR, AR and HC subjects, respectively.
Conclusion: These results suggest that allergen exposure induces the sequential εCSR of IgG+ CD19+ CD20+ CD38+ plasmablasts in the nasal mucosa of LAR patients

2: Ahlbeck L, Ahlberg E, Björkander J, Aldén C, Papapavlou G, Palmberg L, Nyström U, Retsas P, Nordenfelt P, Togö T, Johansen P, Rolander B, Duchén K, Jenmalm MC. Intralymphatic immunotherapy with one or two allergens renders similar clinical response in patients with allergic rhinitis due to birch and grass pollen. Clin Exp Allergy. 2022 Mar 25. doi: 10.1111/cea.14138. Epub ahead of print. PMID: 35332591.
Introduction: There is need for a fast, efficient, and safe way to induce tolerance in patients with severe allergic rhinitis. Intralymphatic immune therapy has been shown to be effective.
Methods: Patients with severe birch and timothy allergy were randomized and received three doses of 0.1 ml of birch and 5-grass allergen extracts (10,000 SQ units/ml, ALK-Abelló), or birch and placebo or 5-grass and placebo by ultrasound-guided injections into inguinal lymph nodes at monthly intervals. Rhinoconjunctivitis Total Symptom Score, Medication Score and Rhinoconjunctivitis Quality of Life Questionnaire were evaluated before treatment and after each birch and grass pollen season during three subsequent years. Circulating proportions of T helper subsets and allergen-induced cytokine and chemokine production were analyzed by flow cytometry and Luminex.
Results: The three groups reported fewer symptoms, lower use of medication and improved quality of life during the birch and grass pollen seasons each year after treatment at an almost similar rate independently of treatment with one or two allergens. Mild local pain was the most common adverse event. IgE levels to birch decreased, whereas birch-induced IL-10 secretion increased in all three groups. IgG4 levels to birch and timothy and skin prick test reactivity remained mainly unchanged. Conjunctival challenge tests with timothy extract showed a higher threshold for allergen. In all three groups, regulatory T cell frequencies were increased three years after treatment.
Conclusions: Intralymphatic immunotherapy with one or two allergens in patients with grass and birch pollen allergy was safe, effective, and may be associated with bystander immune modulatory responses.
Keywords: Allergy; Hypersensitivity; Intralymphatic; Intralymphatic immunotherapy; Rhinoconjunctivitis Immunotheraphy.

3: Han J, Wang W, Zhu Z, Wang L, Chen Y, Wang R, Guan K, Lv W. Profile of Tissue Immunoglobulin E in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps. Int Arch Allergy Immunol. 2022 Mar 21:1-8. doi: 10.1159/000522624. Epub ahead of print. PMID: 35313318.
Introduction: Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) exhibits a poorer prognosis than noneCRSwNP. The aim of this study was to analyze the potential of total immunoglobulin E (tIgE) and specific IgE (sIgE) levels in tissues for distinguishing and assessing eCRSwNP.
Methods: We enrolled 10 control and 88 CRSwNP patients. The clinical data of patients were collected before surgery. Nasal mucosa tissues were taken during surgery for measurements of tIgE, sIgE (weed pollen, epidermal and animal protein, mold, house dust, tree pollen), and subepithelial eosinophil (EOS) counts. The predictive significance of the potential predictors for eCRSwNP was assessed with receiver operating characteristic (ROC) curves.
Results: Nasal polyps tIgE and mold-sIgE were positively correlated with blood and tissue EOSs, comorbid allergic rhinitis and asthma, ethmoid score/total maxillary score ratio, visual analog scale, and CT score. The ROC curve analysis showed that tissue tIgE (p = 0.0004), mold-sIgE (p = 0.0030), blood EOS percentage (p = 0.0003), and absolute blood EOS count (p = 0.0010) acted as predictive factors for eCRSwNP. According to the cutoff value of tissue tIgE of 34.55 ku/L, patients with a high level were more likely to suffer from asthma (p = 0.016) and showed a significantly higher EOS count (p = 0.022), EOS percentage (p = 0.029), and tIgE (p = 0.002) in blood.
Conclusion: Tissue tIgE and mold-sIgE had a significant relationship with the clinical and pathological characteristics of CRSwNP patients and might be reliable for distinguishing and assessing eCRSwNP.

20 March 2022

COPD

Tang et al. Mucus Plugs Persist in Asthma and Changes in Mucus Plugs Associate with Changes in Airflow Over Time. AJRCCM 2022, March. On line + Editorial
Objectives: To determine if mucus plugs are a persistent asthma phenotype and if changes in mucus plugs over time associate with changes in lung function.
Methods: In a longitudinal analysis of baseline and year 3 CT lung scans in SARP-3 participants, radiologists generated mucus plug scores to assess mucus plug persistence over time. Changes in mucus plug score were analyzed in relation to changes in lung function and CT air trapping measures.
Measurements and Main Results: In 164 participants, the mean (range) mucus plug score was similar at baseline and year 3 (3.4 [0-20] vs 3.8 [0-20]). Participants and bronchopulmonary segments with a baseline plug were more likely to have plugs at year 3 than those without baseline plugs (RR 2.8, 95% CI 2.0-4.1, p<0.001 and RR 5.0, 95% CI 4.5-5.6, p<0.001, respectively). The change in mucus plug score from baseline to year 3 was significantly negatively correlated with change in FEV1% predicted (rp = – 0.35, p<0.001) and with changes in CT air trapping measures (all p values < 0.05).
Conclusions: Mucus plugs identify a persistent asthma phenotype and susceptibility to mucus plugs occurs at the subject and the bronchopulmonary segment level. The association between change in mucus plug score and change in airflow over time supports a causal role for mucus plugs in mechanisms of airflow obstruction in asthma.

Gelbman BD, Reed CR. An Integrated, Multimodal, Digital Health Solution for Chronic Obstructive Pulmonary Disease: Prospective Observational Pilot Study. JMIR Form Res. 2022 Mar 17;6(3):e34758. doi: 10.2196/34758. PMID: 35142291.

Dransfield M, Rowe S, Vogelmeier CF, Wedzicha J, Criner GJ, Han MK, Martinez FJ, Calverley P. Cystic Fibrosis Transmembrane Conductance Regulator: Roles in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2022 Mar 15;205(6):631-640. doi: 10.1164/rccm.202109-2064TR. PMID: 34982651.

Mannino D, Bogart M, Germain G, Huang SP, Ismaila AS, Laliberté F, Jung Y, MacKnight SD, Stiegler MA, Duh MS. Benefit of Prompt versus Delayed Use of Single-Inhaler FluticasoneFuroate/Umeclidinium /Vilanterol (FF/UMEC/VI) Following a COPD Exacerbation. Int J Chron Obstruct Pulmon Dis. 2022 Mar 5;17:491-504. doi: 10.2147/COPD.S337668. PMID: 35281476; PMCID: PMC8906822.

Lei J, Yang T, Liang C, Huang K, Wu S, Wang C. Comparison of Clinical Characteristics and Short-Term Prognoses Within Hospitalized Chronic Obstructive Pulmonary Disease Patients Comorbid With Asthma, Bronchiectasis, and Their Overlaps: Findings From the ACURE Registry. Front Med (Lausanne). 2022 Feb 25;9:817048. doi: 10.3389/fmed.2022.817048. PMID: 35280888; PMCID: PMC8914031.

ASTHMA

Niewodowski D, Langton D. Learning curve for bronchial thermoplasty. Respirology. 2022 Mar 16. doi: 10.1111/resp.14248. Epub ahead of print. PMID: 35293074.

Menzies-Gow A, Hoyte FL, Price DB, Cohen D, Barker P, Kreindler J, Jison M, Brooks CL, Papeleu P, Katial R. Clinical Remission in Severe Asthma: A Pooled Post Hoc Analysis of the Patient Journey with Benralizumab. Adv Ther. 2022 Mar 14. doi: 10.1007/s12325-022-02098-1. Epub ahead of print. PMID: 35287231.
ABSTRACT
Introduction: Consensus definitions for clinical remission and super-response were recently established for severe asthma. Benralizumab is an interleukin-5 (IL-5) receptor α-directed monoclonal antibody for severe, uncontrolled asthma; efficacy and safety were demonstrated in previous pivotal phase 3 trials (SIROCCO, CALIMA, ZONDA). This analysis applied a composite remission definition to characterize individual responses to benralizumab after 6 and 12 months.
Methods: In previous phase 3 studies, eligible patients were those with severe, uncontrolled asthma receiving medium- or high-dosage inhaled corticosteroids plus long-acting β2-agonists. This post hoc analysis included patients randomized to the approved benralizumab dose and not receiving oral corticosteroids (OCS) at baseline (SIROCCO/CALIMA) or OCS ≤ 12.5 mg per day (ZONDA). Individual remission components were zero exacerbations; zero OCS use; Asthma Control Questionnaire-6 (ACQ-6) score < 1.5 or ≤ 0.75; and pre-bronchodilator forced expiratory volume in 1 s (FEV1) increase ≥ 100 mL; clinical remission incorporated zero exacerbations, zero OCS use, ACQ-6 score ≤ 0.75, and pre-bronchodilator FEV1 increase ≥ 100 mL after 6 or 12 months.
Results: Overall, 609 patients (N = 301 and N = 308) and 586 patients (N = 293 and N = 293) receiving benralizumab in SIROCCO and CALIMA were included at 6 and 12 months, respectively; 40 ZONDA patients were included after 6 months. In SIROCCO/CALIMA, similar to 6-month findings, approx. 83% and approx. 49% receiving benralizumab, and 77% and 37% on placebo achieved ≥ 2 and ≥ 3 remission components after 12 months; 14.5% (85/586) on benralizumab and 7.7% (48/620) on placebo achieved clinical remission at 12 months. Among ZONDA patients, 75% and approx. 48% on benralizumab and 35% and 20% on placebo achieved ≥ 2 and ≥ 3 remission components at 6 months, respectively; 22.5% (9/40) on benralizumab and 7.5% on placebo achieved clinical remission.
Conclusions: This analysis demonstrates clinical remission is achievable by targeting the underlying drivers of inflammation. Precision medicines can help shift treatment paradigms toward treat-to-target, with clinical remission as the ultimate therapeutic goal in severe asthma.

RHINITIS-ALLERGY-ALLERGIC ASTHMA

Kum E, Guyatt GH, Munoz C, Beaudin S, Li SA, Abdulqawi R, Badri H, Boulet LP, Chen R, Dicpinigaitis P, Dupont L, Field SK, French CL, Gibson PG, Irwin RS, Marsden P, McGarvey L, Smith JA, Song WJ, O’Byrne PM, Satia I. Assessing cough symptom severity in refractory or unexplained chronic cough: findings from patient focus groups and an international expert panel. ERJ Open Res. 2022 Mar 14;8(1):00667-2021. doi: 10.1183/23120541.00667-2021. PMID: 35295233; PMCID: PMC8918938.

Badri H, Gibbard C, Denton D, Satia I, Al-Sheklly B, Dockry RJ, Holt K, McGuiness K, Treadway S, Whorwell P, Houghton L, Lee A, Escott KJ, Lee T, Wilkinson G, Holt A, Canning BJ, Smith JA. A double-blind randomised placebo-controlled trial investigating the effects of lesogaberan on the objective cough frequency and capsaicin-evoked coughs in patients with refractory chronic cough. ERJ Open Res. 2022 Mar 14;8(1):00546-2021. doi: 10.1183/23120541.00546-2021. PMID: 35295236; PMCID: PMC8918934.

Van Hulst G, Jorssen J, Jacobs N, Henket M, Louis R, Schleich F, Bureau F, Desmet CJ. Anti-IL5 mepolizumab minimally influences residual blood eosinophils in severe asthma. Eur Respir J. 2022 Mar 17;59(3):2100935. doi: 10.1183/13993003.00935-2021. PMID: 34475229.
ABSTRACT
Neutralising antibodies against the cytokine interleukin (IL)5 have become widely used for the control of severe eosinophilic asthma. Remarkably, patients receiving neutralising anti-IL5 biological therapies retain a very stable population of residual blood eosinophils. Whether these residual eosinophils are endowed with particular biological activity has not yet been studied, but is of importance in predicting potential long-term effects of IL5 neutralisation in patients. To tackle the effect of IL5 depletion on residual eosinophils, we used a comparative RNA-sequencing approach and compared the gene expression programme of eosinophils arising in IL5-depleted or IL5-replete human or murine hosts, at steady-state in vivo and following in vitro stimulation with the eosinophil-activating alarmin IL33. We compared blood eosinophils from patients with severe allergic eosinophilic asthma treated with anti-IL5 mepolizumab therapy to those of healthy controls and matched asthma patients receiving anti-IgE omalizumab therapy. We made similar comparisons on bone marrow eosinophils from mice genetically deficient or not for IL5. We report that restriction of IL5 availability did not elicit any detectable transcriptional response in steady-state residual eosinophils in mepolizumab-treated patients or IL5-deficient mice, and influenced only a handful of genes in their response to IL33. Together, these results support the notion that treatment with IL5 neutralising antibodies spares a pool of circulating residual eosinophils largely resembling those of healthy individuals.

Sharma V, Ricketts HC, Steffensen F, Goodfellow A, Cowan DC. Obesity affects type 2 biomarker levels in asthma. J Asthma. 2022 Mar 17:1-8. doi: 10.1080/02770903.2022.2051548. Epub ahead of print. PMID: 35260034.
ABSTRACT
Objective: Type 2 (T2) inflammation offers a therapeutic target for biologics. Previous trials suggest obesity influences T2-biomarker levels in asthma, though have not accounted for key variables, e.g. inhaled (ICS)/oral corticosteroid (OCS) use. We hypothesized that body mass index (BMI) would affect T2-biomarker levels, after adjusting for covariates.
Methods: A retrospective analysis of data from two recent local trials of 153 participants with asthma (102 difficult-to-treat, 51 mild). Measurements included BMI, fractional exhaled nitric oxide (FeNO) and eosinophils. Correlation and regression analysis were performed for each biomarker to describe their relationship with BMI. Data was analyzed overall, and by asthma severity, T2-status and BMI tertile.
Results: Increasing BMI was associated with reduction in FeNO when stratified by BMI tertile (25 ppb lowest tertile, 18 ppb highest tertile; p = 0.014). Spearmans rank showed a negative correlation between BMI and FeNO in difficult-to-treat asthma (ρ= -0.309, p = 0.002). Linear regression adjusting for sex, age, smoking, atopy, allergic/perennial rhinitis, ICS and OCS confirmed BMI as a predictor of FeNO overall (β= -2.848, p = 0.019). Eosinophils were reduced in the highest BMI tertile versus lowest in difficult-to-treat asthma (0.2×109/L, 0.3×109/L respectively; p = 0.02).
Conclusions: Increasing BMI is associated with lower FeNO in asthma when adjusted for relevant covariates, including steroid use. There also appears to be an effect on eosinophil levels. Obesity, therefore, affects T2 biomarker levels with implications for disease endotyping and determination of eligibility for biologic therapy. Whether this is due to masking of underlying T2-high status or development of a truly T2-low endotype requires further research.

14 March 2022

COPD

Casselbrant A, Fedorowski A, Frantz S, Engström G, Wollmer P, Hamrefors V. Common physiologic and proteomic biomarkers in pulmonary and coronary artery disease. PLoS One. 2022 Mar 9;17(3):e0264376. doi: 10.1371/journal.pone.0264376. PMID: 35263363

Kor CT, Li YR, Lin PR, Lin SH, Wang BY, Lin CH. Explainable Machine Learning Model for Predicting First-Time Acute Exacerbation in Patients with Chronic Obstructive Pulmonary Disease. J Pers Med. 2022 Feb 7;12(2):228. doi: 10.3390/jpm12020228. PMID: 35207716; PMCID: PMC8879653.

Liang H, Zhi H, Ye W, Wang Z, Liang J, Yi F, Kong X, Jiang M, Chen R, Lai K. Risk factors of chronic cough in China: a systematic review and meta-analysis. Expert Rev Respir Med. 2022 Mar 10. doi: 10.1080/17476348.2022.2049759. Epub ahead of print. PMID: 35271782.
Objectives: Risk factors of chronic cough in China have not been systematically analyzed and we hypothesized that risk factors of chronic cough might have distinct characteristics in China. Hence, we performed this meta-analysis focusing on the potential risk factors of chronic cough in China.
Methods: We searched 7 databases for studies published before May 8, 2021. This systematic review was performed in accordance with the PRISMA checklist.
Results: A total of 33 eligible articles were identified and included in this systematic review, and 28 studies were included in the meta-analysis. Our results showed that allergy (OR: 3.72; 95% CI: 1.85-7.47), nasal/sinusitis diseases (OR: 3.56; 95% CI: 2.02-6.29), family history of allergy (OR = 1.74; 95% CI: 1.59-1.90), family history of chronic respiratory diseases (OR = 1.67; 95% CI: 1.47-1.91), exposure to pollutants (OR = 1.60; 95% CI: 1.26-2.04), passive smoking (OR = 1.44; 95% CI: 1.32-1.57), and exposure to pets (OR = 1.37; 95% CI: 1.18-1.58) were risk factors for chronic cough in China.
Conclusions: Our study indicated some potential risk factors of chronic cough in China, which provides useful epidemiological information for managing chronic cough in China and is worthy as a reference for future global investigations

Xiao T, Wijnant SRA, van der Velpen I, Terzikhan N, Lahousse L, Ikram MK, Vernooij MW, Brusselle GG, Ikram MA. Lung function impairment in relation to cognition and vascular brain lesions: the Rotterdam Study. J Neurol. 2022 Mar 10. doi: 10.1007/s00415-022-11027-9. Epub ahead of print. PMID: 35267082.
Objective: To investigate the association of chronic obstructive pulmonary disease (COPD) and Preserved Ratio Impaired Spirometry (PRISm) with cognitive performance and presence of vascular brain lesions (VBL).
Methods: We determined both cross-sectional and longitudinal association of lung function impairment with cognition, as well as cross-sectional association of lung function impairment with VBL, in the general population. Between 2009 and 2014 we included 3,941 participants from the Rotterdam Study with spirometry tests, brain MRI scans and cognition tests, of whom 1815 had follow-up data on cognition.
Results: Our finding indicated that cross-sectionally, participants with PRISm or COPD GOLD2-4 had a worse global cognitive performance. We did not find differences in cognition over time between those with normal spirometry versus those with lung function impairment. In addition, PRISm and COPD GOLD2-4 were associated with a higher prevalence of lacunar infarcts compared to normal spirometry.
Conclusions: This study suggests that persons with COPD GOLD2-4 or restrictive lung function, defined as PRISm, are characterized by poorer global cognitive function and a higher prevalence of lacunar infarcts.

Antwi GO, Rhodes DL. Association between E-cigarette use and chronic obstructive pulmonary disease in non-asthmatic adults in the USA. J Public Health (Oxf). 2022 Mar 7;44(1):158-164. doi: 10.1093/pubmed/fdaa229. PMID: 33348361.
Background: Concern about the health impacts of e-cigarette use is growing; however, limited research exists regarding potential long-term health effects of this behavior. This study explored the relationship between e-cigarette use and COPD in a sample of US adults.
Methods: A secondary data analysis using data from the 2018 Behavioral Risk Factor Surveillance Survey in the USA was computed to examine associations between e-cigarette use and COPD controlling for conventional cigarette smoking status, past month leisure physical activity and demographic characteristics including age, sex, education, race, marital status and body mass index.
Results: Significant associations between e-cigarette use and COPD among former combustible cigarette smokers and those who reported never using combustible cigarettes were found. Compared with never e-cigarette users, the odds of having COPD were significantly greater for daily e-cigarette users (OR = 1.53; 95% CI: 1.11-2.03), occasional users (OR = 1.43, 95% CI: 1.13-1.80) and former users (OR = 1.46 95% CI: 1.28-1.67).
Conclusions: Findings from this study indicate a potential link between e-cigarette use and COPD. Further research to explore the potential effects of e-cigarette on COPD is recommended.

Ian R Reid, Emma O Billington Drug therapy for osteoporosis in older adults. Lancet 2022; 399: 1080–92
The goal of osteoporosis management is to prevent fractures. Several pharmacological agents are available to lower fracture risk, either by reducing bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used anti-resorptives, reducing bone turnover markers to low premenopausal concentrations and reducing fracture rates (vertebral by 50–70%, non-vertebral by 20–30%, and hip by ~40%). Bisphosphonates bind avidly to bone mineral and have an offset of effect measured in months to years. Long term, continuous use of oral bisphosphonates is usually interspersed with drug holidays of 1–2 years, to minimise the risk of atypical femoral fractures. Denosumab is a monoclonal antibody against RANKL that potently inhibits osteoclast development and activity. Denosumab is administered by subcutaneous injection every 6 months. Anti-fracture effects of denosumab are similar to those of the bisphosphonates, but there is a pronounced loss of anti-resorptive effect from 7 months after the last injection, which can result in clusters of rebound vertebral fractures. Two classes of anabolic drugs are now available to stimulate bone formation. Teriparatide and abaloparatide both target the parathyroid hormone-1 receptor, and are given by daily subcutaneous injection for up to 2 years. Romosozumab is an anti-sclerostin monoclonal antibody that stimulates bone formation and inhibits resorption. Romosozumab is given as monthly subcutaneous injections for 1 year. Head-to-head studies suggest that anabolic agents have greater anti-fracture efficacy and produce larger increases in bone density than anti-resorptive drugs. The effects of anabolic agents are transient, so transition to anti-resorptive drugs is required. The optimal strategy for cycling anabolics, anti-resorptives, and off-treatment periods remains to be determined.

ASTHMA

Helen K. Reddel, MB, BS, PhDa,*, Eric D. Bateman, MB, ChB, MDb,*, Michael Schatz, MD, MSc, Jerry A. Krishnan, MD, PhDd, and Michelle M. Cloutier, MDe A Practical Guide to Implementing SMART in Asthma Management. J Allergy Clin Immunol Pract 2022;10:S31-S8)

Achten NB, van Rossum AMC, Bacharier LB, Fitzpatrick AM, Hartert TV. Long-Term Respiratory Consequences of Early-Life Respiratory Viral Infections: A Pragmatic Approach to Fundamental Questions. J Allergy Clin Immunol Pract. 2021 Dec 20:S2213-2198(21)01367-2. doi: 10.1016/j.jaip.2021.12.005. Epub ahead of print. PMID: 34942383.

Jackson DJ. Rhinovirus Infections and Their Roles in Asthma: Etiology and Exacerbations. (J Allergy Clin Immunol Pract 2022;10:673-81

Fizpatrick A AND Busse WW. Perspectives in Respiratory Infections and the Lung. J Allergy Clin Immunol Pract 2022;10:694-6.

Griesel M, Wagner C, Mikolajewska A, Stegemann M, Fichtner F, Metzendorf MI, Nair AA, Daniel J, Fischer AL, Skoetz N. Inhaled corticosteroids for the treatment of COVID-19. Cochrane Database Syst Rev. 2022 Mar 9;3:CD015125. doi: 10.1002/14651858.CD015125. PMID: 35262185.
Background: Inhaled corticosteroids are well established for the long-term treatment of inflammatory respiratory diseases such as asthma or chronic obstructive pulmonary disease. They have been investigated for the treatment of coronavirus disease 2019 (COVID-19). The anti-inflammatory action of inhaled corticosteroids might have the potential to reduce the risk of severe illness resulting from hyperinflammation in COVID-19.
Objectives: To assess whether inhaled corticosteroids are effective and safe in the treatment of COVID-19; and to maintain the currency of the evidence, using a living systematic review approach.
Search methods: We searched the Cochrane COVID-19 Study Register (which includes CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 7 October 2021.
Selection criteria: We included randomised controlled trials (RCTs) evaluating inhaled corticosteroids for COVID-19, irrespective of disease severity, age, sex, or ethnicity. We included the following interventions: any type or dose of inhaled corticosteroids. We included the following comparison: inhaled corticosteroids plus standard care versus standard care (with or without placebo). We excluded studies examining nasal or topical steroids.
Data collection and analysis: We followed standard Cochrane methodology. For risk of bias assessment, we used the Cochrane RoB 2 tool. We rated the certainty of evidence using the GRADE approach for the outcomes of mortality, admission to hospital or death, symptom resolution, time to symptom resolution, serious adverse events, adverse events, and infections.
Main results: Inhaled corticosteroids plus standard care versus standard care (with/without placebo) People with a confirmed diagnosis of moderate-to-severe COVID-19 We found no studies that included people with a confirmed diagnosis of moderate-to-severe COVID-19. People with a confirmed diagnosis of asymptomatic SARS-CoV-2 infection or mild COVID-19 We included three RCTs allocating 3607 participants, of whom 2490 had confirmed mild COVID-19. We analysed a subset of the total number of participants recruited to the studies (2171, 52% female) as some trials had a platform design where not all participants were allocated to treatment groups simultaneously. The included studies were community-based, recruiting people who were able to use inhaler devices to deliver steroids and relied on remote assessment and self-reporting of outcomes. Most people were older than 50 years and had co-morbidities such as hypertension, lung disease, or diabetes. The studies were conducted in high-income countries prior to wide-scale vaccination programmes. A total of 1057 participants were analysed in the inhaled corticosteroid arm (budesonide: 860 participants; ciclesonide: 197 participants), and 1075 participants in the control arm. No studies included people with asymptomatic SARS-CoV-2 infection. With respect to the following outcomes, inhaled corticosteroids compared to standard care: – may result in little to no difference in all-cause mortality (at up to day 30) (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.22 to 1.67; 2132 participants; low-certainty evidence). In absolute terms, this means that for every nine deaths per 1000 people not receiving inhaled corticosteroids, there were six deaths per 1000 people who did receive the intervention (95% CI 2 to 16 per 1000 people); – probably reduces admission to hospital or death (at up to 30 days) (RR 0.72, 95% CI 0.51 to 0.99; 2025 participants; moderate-certainty evidence); – probably increases resolution of all initial symptoms at day 14 (RR 1.19, 95% CI 1.09 to 1.30; 1986 participants; moderate-certainty evidence); – may reduce the duration to symptom resolution (at up to day 30) (by -4.00 days, 95% CI -6.22 to -1.78 less than control group rate of 12 days; 139 participants; low-certainty evidence); – the evidence is very uncertain about the effect on serious adverse events (during study period) (RR 0.51, 95% CI 0.09 to 2.76; 1586 participants; very low-certainty evidence); – may result in little to no difference in adverse events (at up to day 30) (RR 0.78, 95% CI 0.47 to 1.31; 400 participants; low-certainty evidence); – may result in little to no difference in infections (during study period) (RR 0.88, 95% CI 0.30 to 2.58; 400 participants; low-certainty evidence). As studies did not report outcomes for subgroups (e.g. age, ethnicity, sex), we did not perform subgroup analyses.
Authors’ conclusions: In people with confirmed COVID-19 and mild symptoms who are able to use inhaler devices, we found moderate-certainty evidence that inhaled corticosteroids probably reduce the combined endpoint of admission to hospital or death and increase the resolution of all initial symptoms at day 14. Low-certainty evidence suggests that corticosteroids make little to no difference in all-cause mortality up to day 30 and may decrease the duration to symptom resolution. We do not know whether inhaled corticosteroids increase or decrease serious adverse events due to heterogeneity in the way they were reported across the studies. There is low-certainty evidence that inhaled corticosteroids may decrease infections. The evidence we identified came from studies in high-income settings using budesonide and ciclesonide prior to vaccination roll-outs. We identified a lack of evidence concerning quality of life assessments, serious adverse events, and people with asymptomatic infection or with moderate-to-severe COVID-19. The 10 ongoing and four completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review. We monitor newly published results of RCTs on inhaled corticosteroids on a weekly basis and will update the review when the evidence or our certainty in the evidence changes

Molina MF, Okoniewski W, Puranik S, Aujla S, Celedón JC, Larkin A, Forno E. Severe asthma in children: description of a large multidisciplinary clinical cohort. Pediatr Pulmonol. 2022 Mar 9. doi: 10.1002/ppul.25887. Epub ahead of print. PMID: 35261210.
Background: Children with severe asthma have substantial morbidity and healthcare utilization. Pediatric severe asthma is a heterogeneous disease, and a multidisciplinary approach can improve the diagnosis and management of these children.
Methods: We reviewed the electronic health records for patients seen in the Severe Asthma Clinic (SAC) at UPMC Children’s Hospital of Pittsburgh between August 2012 and October 2019.
Results: Of the 110 patients in whom we extracted data, 46% were female, 48% were Black/African American, and 41% had ≥1 admission to the pediatric intensive care unit (PICU) for asthma. Compared to patients without a PICU admission, those with ≥1 PICU admission were more likely to be non-White (64.4% vs 41.5%, P=0.031) and more atopic (eosinophil count geometric mean= 673 vs 319 cells/mm3 , P=0.002; total IgE geometric mean=754 vs 303 KU/L, P=0.003), and to have lower pre-bronchodilator FEV1 (58.6% [±18.1%] vs 69.9% [±18.7%], P=0.002) and elevated FeNO (60% vs 22%, P=0.02). In this cohort, 84% of patients were prescribed high-dose ICS/LABA and 36% were on biologics. Following enrollment in the SAC, severe exacerbations decreased from 3.2/year to 2.2/year (P<0.0001); compared to the year prior to joining the SAC, in the following year the group had 106 fewer severe exacerbations.
Conclusions: This large cohort of children with severe asthma had a high level of morbidity and healthcare utilization. Patients with a history of PICU admissions for asthma were more likely to be non-White and highly atopic, and to have lower lung function. Our data supports a positive impact of a multidisciplinary clinic on patients with severe childhood asthma. This article is protected by copyright. All rights reserved

Antonio Buendía J, Patiño DG. Fluticasone furoate plus vilanterol in patients with moderate persistent asthma: a cost-utility analysis. J Asthma. 2022 Mar 9:1-9. doi: 10.1080/02770903.2022.2051547. Epub ahead of print. PMID: 35261332.
Background: In recent years, the combination of fluticasone furoate and vilanterol (FF/VI) has emerged as an alternative therapy, since it is administered every 24 h, in contrast to other ICS/LABAs such as fluticasone propionate plus salmeterol (FP/Salm), which requires administration every 12 hrs. Concerns have arisen over whether the benefit generated by FF/VI justifies the additional costs it involves over FP/Salm. This study aimed at assessing the health and economic consequences of FF/VI in patients with moderate-severe persistent asthma.
Methods: A probabilistic Markov model was created to estimate the cost and quality-adjusted life-years (QALYs) of patients with persistent asthma. Total costs and QALYs for FF/VI and FP/Salm were calculated over a lifetime horizon. Multiple sensitivity analyses were conducted. Cost-effectiveness was evaluated at a willingness-to-pay value of $19,000.
Results: We estimated a gain of 16.8 and 10.7 QALYs per patient per year on FF/VI and FP/Salm, respectively. At the same time, we observed a difference of US$216 in total discounted cost per person-year on FF/VI with respect to FP/Salm. The incremental cost-effectiveness ratio (ICER) of FF/VI was USD $70 per QALY with respect to FP/Salm. In the deterministic and probabilistic sensitivity analyses, our base-case results were robust to variations in all assumptions and parameters.
Conclusion: FF/VI is more cost-effective than FP/Salm. The evidence supports using FF/VI therapy in Colombia, and the study should be replicated in other middle-income countries.

RHINITIS-ALLERGY-ALLERGIC ASTHMA

Phinyo P, Wongsa C, Sompornrattanaphan M, Thongngarm T. As-needed versus regular intranasal corticosteroid for allergic rhinitis: A systematic review and meta-analysis. Asian Pac J Allergy Immunol. 2022 Mar 12. doi: 10.12932/AP-091121-1269. Epub ahead of print. PMID: 35278059.
Background: Daily intranasal corticosteroid (INCS) is recommended for treating allergic rhinitis (AR). Nevertheless, patients are generally not adherent and use it on-demand. The data on the efficacy of as-needed INCS was insufficient.
Objective: We conducted a systematic review and meta-analysis to assess the efficacy of as-needed INCS compared with regular use for AR.
Methods: We searched PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) until May 2021. A pairwise meta-analysis used a random-effects model to estimate the pooled standardized mean difference (SMD). The primary outcome was the total nasal symptom score (TNSS) changes from baseline at 4 and 6 weeks. Secondary outcomes were the changes of individual nasal symptom score and quality-of-life (QoL) score.
Results: We identified five eligible RCTs with a total of 436 patients with AR. Only four studies had adequate data for quantitative synthesis. The TNSS changes of as-needed INCS were not significantly different from the regular use at both 4 (SMD 0.23 [95%CI: -0.14 to 0.60], p = 0.230) and 6 weeks (SMD 0.21 [95%CI: -0.02 to 0.44], p = 0.080). Most of the changes of individual nasal symptom scores and QoL scores were not significantly different between the two regimens. At 50% or more INCS dose of regular use, as-needed and regular INCS provided a similar efficacy. The treatment effect was, however, less sustained with as-needed INCS.

Ilaria Baiardini, PhDa,b, Salvatore Fasola, PhDc, Stefania La Grutta, MDc, Elisa Trucco, MDa, Giorgio Walter Canonica, MDb,d, and Fulvio Braido, MDaRhinitis and Asthma Patient Perspective (RAPP): Clinical Utility and Predictive Value. (J Allergy Clin Immunol Pract 2022;10:846-52)

Rodrigues Sousa S, Tenda A, Farinha I, Carvalho A, Chaves Loureiro C. Home administration of biological treatment in severe asthma in real-life experience: impact on asthma control and quality of life. Eur Ann Allergy Clin Immunol. 2022 Mar 10. doi: 10.23822/EurAnnACI.1764-1489.248. Epub ahead of print. PMID: 35261225.
Introduction. Several biological agents for the treatment of severe asthma have been approved for self-administration on an outpatient basis in the last years. However, data on the impact of home administration in outcomes such as asthma control and quality of life in real-life settings are sparse. Being this knowledge crucial for clinical practice, this study aimed to assess asthma control and quality of life in patients who transitioned from day hospital administration of biological therapy to home administration. Methods. A single-center prospective analysis of 33 patients treated with biologics for severe asthma, who switched from hospital to home treatment was performed. Asthma Control Test (ACT), Control of Allergic Rhinitis and Asthma Test (CARAT), Asthma Life Quality (ALQ) and the number of exacerbations were assessed 3 months before and 3 and 6 months after of home-use. Results. ACT and CARAT did not show statistical differences comparing to the baseline values (21.8 ± 2.7 and 23.8 ± 5.5) within 3 months (22.1 ± 2.4, p = 0.609; 23.2 ± 5.3, p = 0.572) or 6 months (23.4 ± 0.9, p = 0.553; 23.7 ± 6.2, p = 0.149) of home administration. Also, ALQ score did not show meaningful variations between baseline (9.5 ± 3.2) and after 3 months (11.2 ± 4.4, p = 0.275) and 6 months (10.3 ± 3.8, p = 0.209) of home-use. Regarding asthma exacerbations, we did not record a significant difference comparing to the baseline values of 3 months/patient exacerbations (0.2 ± 0.4) and after 3 months (0.2 ± 0.5, p = 0.786) or 6 months (0.2 ± 0.4, p = 1.000) of change in modality treatment. There was no cases of anaphylaxis or other serious adverse effects in those patients treated at home. Conclusions. Transition of day hospital administration of biologic treatment for severe asthma to home administration did not lead to any deterioration of asthma control or quality of life. Our results emphasized the efficacy and safety of home administration of biologic treatment and provide support on changing the paradigm of the administration of biological treatment in severe asthma.

Eide JG, Wu J, Stevens WW, Bai J, Hou S, Huang J, Rosenberg J, Utz P, Shintani-Smith S, Conley D, Welch K, Kern R, Hulse KE, Peters AT, Grammer LC, Zhao M, Lindholm P, Schleimer R, Tan BK. Antiphospholipid Antibodies are Elevated and Functionally Active in Chronic Rhinosinusitis with Nasal Polyps. Clin Exp Allergy. 2022 Mar 6. doi: 10.1111/cea.14120. Epub ahead of print. PMID: 35253284.
Background: Polyps from patients with chronic rhinosinusitis with nasal polyps (CRSwNP) contain increased levels of autoreactive antibodies, B cells, and fibrin deposition. Anti-phospholipid antibodies (APA) are autoantibodies known to cause thrombosis but have not been implicated in chronic rhinosinusitis (CRS).
Objective: To compare APA levels (anti-cardiolipin, anti-phosphatidylethanolamine (anti-PE), and anti-β2 -glycoprotein (anti-B2GP)) in nasal polyp (NP) tissue with tissue from control and CRS without nasal polyp (CRSsNP) patients, we tested whether NP antibodies affect coagulation, and correlate APAs with anti-dsDNA IgG and markers of coagulation.
Methods: Patient specimens were assayed for APA IgG, anti-dsDNA IgG, and thrombin-anti-thrombin (TaT) complex by ELISA. Antibodies from a subset of specimens were tested for modified activated partial thromboplastin time (aPTT) measured on an optical-mechanical coagulometer.
Results: Anti-cardiolipin IgG in NP was 5-fold higher than control tissue (p<0.0001). NP antibodies prolonged aPTT compared to control tissue antibodies at 400 μg/mL (36.7 sec vs 33.8 sec, p=0.024) and 600 μg/mL (40.9 sec vs 34.7 sec, p=0.0037). Anti-PE IgG antibodies were increased in NP (p=0.027), but anti-B2GP IgG was not significantly higher (p=0.084). All APAs correlated with anti-dsDNA IgG levels, which were also elevated (R=0.77, 0.71, and 0.54, respectively, for anti-cardiolipin, anti-PE, and anti-B2GP; all p<0.001), but only anti-cardiolipin (R=0.50, p=0.0185) and anti-PE (R=0.45, p=0.037) correlated with TaT complex levels.
Conclusions: APA IgG antibodies are increased in NP and correlate with autoreactive tissue antibodies. NP antibodies have in vitro anti-coagulant activity similar to those observed in anti-phospholipid syndrome, suggesting that they may have pro-coagulant effects in polyp tissue.

Rossi CM et al. Adult anaphylaxis: A state-of-the-art review. Eur J Intern Med 2022, March 8 , in press.
Anaphylaxis is the most severe among acute allergic diseases and potentially life threatening. Despite its increasing frequency and related burden, it remains often underdiagnosed and improperly managed. Its multisystemic involvement, protean clinical manifestations and its rapid onset are contributory factors. In recent years new acquisitions have shed light into its pathogenesis pathways (and related biomarkers), triggers, factors increasing its severity, along with peculiar clinical manifestations. These breakthrough discoveries have contributed to phenotyping and endotyping this disease, possibly paving the way to a personalized approach which is not available at present. Moreover, to disseminate awareness and standardize diagnostic criteria and management practices, several guidelines and consensus reports, albeit mainly intended for specialist care, have been issued. We here discuss the latest issues in the field of anaphylaxis from the perspective of the emergency and/or internal medicine physician, so to improve its early recognition and treatment in the acute setting and favor allergology referral to implement therapeutical and preventive strategies, such as allergen identification in unclear cases and desensitizing t

28 February 2022

COPD

Maqsood A, Imel LR. Plastic Bronchitis. N Engl J Med. 2022 Feb 24;386(8):780. doi: 10.1056/NEJMicm2111951. PMID: 35196430.

Cookson W, Moffatt M, Rapeport G, Quint J. A Pandemic Lesson for Global Lung Diseases: Exacerbations are Preventable. Am J Respir Crit Care Med. 2022 Feb 22. doi: 10.1164/rccm.202110-2389CI. Epub ahead of print. PMID: 35192447.

Siddharthan T, Pollard SL, Quaderi SA, Rykiel NA, Wosu AC, Alupo P, Barber JA, Cárdenas MK, Chandyo RK, Flores-Flores O, Kirenga B, Miranda JJ, Mohan S, Ricciardi F, Sharma AK, Das SK, Shrestha L, Soares MO, Checkley W, Hurst JR; GECo Study Investigators. Discriminative Accuracy of Chronic Obstructive Pulmonary Disease Screening Instruments in 3 Low- and Middle-Income Country Settings. JAMA. 2022 Jan 11;327(2):151-160. doi: 10.1001/jama.2021.23065. PMID: 35015039; PMCID: PMC8753498

Yawn BP, Leidy NK, Martinez F. Screening for Chronic Obstructive Pulmonary Disease: Unmet Needs and Future Considerations. JAMA. 2022 Jan 11;327(2):126-128. doi: 10.1001/jama.2021.23255. PMID: 35015050.

Tkacz J, Evans KA, Touchette DR, Portillo E, Strange C, Staresinic A, Feigler N, Patel S, Pollack M. PRIMUS – Prompt Initiation of Maintenance Therapy in the US: A Real-World Analysis of Clinical and Economic Outcomes Among Patients Initiating Triple Therapy Following a COPD Exacerbation. Int J Chron Obstruct Pulmon Dis. 2022 Feb 10;17:329-342. doi: 10.2147/COPD.S347735. PMID: 35177901; PMCID: PMC8843423.

Moslemi A, Kontogianni K, Brock J, Wood S, Herth F, Kirby M. Differentiating COPD and Asthma using Quantitative CT Imaging and Machine Learning. Eur Respir J. 2022 Feb 24:2103078. doi: 10.1183/13993003.03078-2021. Epub ahead of print. PMID: 35210316.

Bhatt SP. Rome Criteria for E-COPD: Not Built In A Day. Am J Respir Crit Care Med. 2022 Feb 23. doi: 10.1164/rccm.202110-2253LE. Epub ahead of print. PMID: 35196475.

Celli BR, Fabbri LM; all authors of An updated definition and severity classification of chronic obstructive pulmonary disease exacerbations: The Rome Proposal. Reply to Bhatt and Ramakrishnan, et al. Am J Respir Crit Care Med. 2022 Feb 23. doi: 10.1164/rccm.202112-2864LE. Epub ahead of print. PMID: 35196478.

ASTHMA

Shang W, Wang G, Wang Y, Han D. The safety of long-term use of inhaled corticosteroids in patients with asthma: A systematic review and meta-analysis. Clin Immunol. 2022 Feb 23:108960. doi: 10.1016/j.clim.2022.108960. Epub ahead of print. PMID: 35218965.

Garner O, Ramey JS, Hanania NA. Management of Life-Threatening Asthma: Severe Asthma Series. Chest. 2022 Feb 23:S0012-3692(22)00395-6. doi: 10.1016/j.chest.2022.02.029. Epub ahead of print. PMID: 35218742.

Baraldi E, Piacentini G. GINA 2021: Asthma in Pre-School Children and SABA-Only Treatment. Am J Respir Crit Care Med. 2022 Feb 24. doi: 10.1164/rccm.202111-2465LE. Epub ahead of print. PMID: 35202554.

Duijts L, Fleming LJ, Bacharier LB, Pitrez PM, Reddel HK; authors of “Global Initiative for Asthma (GINA) Strategy 2021 – Executive summary and rationale for key changes”.. Reply to: GINA 2021: Asthma in Pre-School Children and SABA-Only Treatment. Am J Respir Crit Care Med. 2022 Feb 24. doi: 10.1164/rccm.202112-2788LE. Epub ahead of print. PMID: 35202561.

McEvoy CT, Spindel ER. Childhood Wheeze Patterns- What Do They Tell Us? Am J Respir Crit Care Med. 2022 Feb 23. doi: 10.1164/rccm.202201-0108ED. Epub ahead of print. PMID: 35196479.

RHINITIS-ALLERGY

Duse M, Santamaria F, Verga MC, Bergamini M, Simeone G, Leonardi L, Tezza G, Bianchi A, Capuano A, Cardinale F, Cerimoniale G, Landi M, Malventano M, Tosca M, Varricchio A, Zicari AM, Alfaro C, Barberi S, Becherucci P, Bernardini R, Biasci P, Caffarelli C, Caldarelli V, Capristo C, Castronuovo S, Chiappini E, Cutrera R, De Castro G, De Franciscis L, Decimo F, Iacono ID, Diaferio L, Di Cicco ME, Di Mauro C, Di Mauro C, Di Mauro D, Di Mauro F, Di Mauro G, Doria M, Falsaperla R, Ferraro V, Fanos V, Galli E, Ghiglioni DG, Indinnimeo L, Kantar A, Lamborghini A, Licari A, Lubrano R, Luciani S, Macrì F, Marseglia G, Martelli AG, Masini L, Midulla F, Minasi D, Miniello VL, Del Giudice MM, Morandini SR, Nardini G, Nocerino A, Novembre E, Pajno GB, Paravati F, Piacentini G, Piersantelli C, Pozzobon G, Ricci G, Spanevello V, Turra R, Zanconato S, Borrelli M, Villani A, Corsello G, Di Mauro G, Peroni D. Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases. Ital J Pediatr. 2021 Apr 21;47(1):97. doi: 10.1186/s13052-021-01013-8. Erratum in: Ital J Pediatr. 2022 Feb 25;48(1):35. PMID: 33882987; PMCID: PMC8058583.

Duse M, Santamaria F, Verga MC, Bergamini M, Simeone G, Leonardi L, Tezza G, Bianchi A, Capuano A, Cardinale F, Cerimoniale G, Landi M, Malventano M, Tosca M, Varricchio A, Zicari AM, Alfaro C, Barberi S, Becherucci P, Bernardini R, Biasci P, Caffarelli C, Caldarelli V, Capristo C, Castronuovo S, Chiappini E, Cutrera R, De Castro G, De Franciscis L, Decimo F, Iacono ID, Diaferio L, Di Cicco ME, Di Mauro C, Di Mauro C, Di Mauro D, Di Mauro F, Di Mauro G, Doria M, Falsaperla R, Ferraro V, Fanos V, Galli E, Ghiglioni DG, Indinnimeo L, Kantar A, Lamborghini A, Licari A, Lubrano R, Luciani S, Macrì F, Marseglia G, Martelli AG, Masini L, Midulla F, Minasi D, Miniello VL, Del Giudice MM, Morandini SR, Nardini G, Nocerino A, Novembre E, Pajno GB, Paravati F, Piacentini G, Piersantelli C, Pozzobon G, Ricci G, Spanevello V, Turra R, Zanconato S, Borrelli M, Villani A, Corsello G, Di Mauro G, Peroni D. Correction: Inter-society consensus for the use of inhaled corticosteroids in infants, children and adolescents with airway diseases. Ital J Pediatr. 2022 Feb 25;48(1):35. doi: 10.1186/s13052-022-01231-8. Erratum for: Ital J Pediatr. 2021 Apr 21;47(1):97. PMID: 35216620.

23 February 2022

COPD

Phillips TM, Moloney C, Sneath E, Beccaria G, Issac H, Mullens AB, Gow J, Rana R, King A. Associated factors, assessment, management, and outcomes of patients who present to the emergency department for acute exacerbation of chronic obstructive pulmonary disease: A scoping review. Respir Med. 2022 Jan 21;193:106747. doi: 10.1016/j.rmed.2022.106747. Epub ahead of print. PMID: 35086024.
Objective: The purpose of the scoping review was to examine the extant literature for factors contributing to presentations of Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) to Emergency Departments (ED).
Methods: The review followed Arksey and O’Malley, and Levac’s frameworks supplemented with the PRISMA-ScR checklist. We searched Cochrane Library, CINAHL, JBI, and PubMed from January 1, 2008 to March 23, 2020 for inclusions. We included studies reporting ED presentations for AECOPD among adults (≥18 years). The investigation included: pre-hospital factors; ED-related assessment, management and referral practices; holistic management (i.e., interdisciplinary); patient outcomes, admission/discharge status, and readmission.
Results: Forty-four studies were included. Environmental factors (e.g., air pollution, seasonal change); social determinants (e.g., poor literacy, ethnicity); and physical health (e.g., comorbidities, obesity, poor exercise capacity) contributed to ED presentation/re-presentation, and admission to hospital. Cigarette smoking was associated with hospital admission. Mortality was associated with longer-term oxygen therapy, poor exercise capacity, age, and loss of consciousness. Compliance with clinical guideline recommendations were generally low or mixed. Further, there was a lack of appropriate referral practices upon discharge.
Conclusions: While there is considerable literature on factors contributing to AECOPD admission more research is required that investigates the impact that inter-professional care models can have on the discharge planning cycles for patients with COPD who are regular presenters to an ED.

Sheikh S, Hamilton FW, Nava GW, Gregson FKA, Arnold DT, Riley C, Brown J; AERATOR Group, Reid JP, Bzdek BR, Maskell NA, Dodd JW. Are aerosols generated during lung function testing in patients and healthy volunteers? Results from the AERATOR study. Thorax. 2022 Mar;77(3):292-294. doi: 10.1136/thoraxjnl-2021-217671. Epub 2021 Nov 2. PMID: 34728573.
SUGGESTED BY ANTONIO SPANEVELLO
Pulmonary function tests are fundamental to the diagnosis and monitoring of respiratory diseases. There is uncertainty around whether potentially infectious aerosols are produced during testing and there are limited data on mitigation strategies to reduce risk to staff. Healthy volunteers and patients with lung disease underwent standardised spirometry, peak flow and FENO assessments. Aerosol number concentration was sampled using an aerodynamic particle sizer and an optical particle sizer. Measured aerosol concentrations were compared with breathing, speaking and voluntary coughing. Mitigation strategies included a standard viral filter and a full-face mask normally used for exercise testing (to mitigate induced coughing). 147 measures were collected from 33 healthy volunteers and 10 patients with lung disease. The aerosol number concentration was highest in coughs (1.45-1.61 particles/cm3), followed by unfiltered peak flow (0.37-0.76 particles/cm3). Addition of a viral filter to peak flow reduced aerosol emission by a factor of 10 without affecting the results. On average, coughs produced 22 times more aerosols than standard spirometry (with filter) in patients and 56 times more aerosols in healthy volunteers. FENO measurement produced negligible aerosols. Cardiopulmonary exercise test (CPET) masks reduced aerosol emission when breathing, speaking and coughing significantly. Lung function testing produces less aerosols than voluntary coughing. CPET masks may be used to reduce aerosol emission from induced coughing. Standard viral filters are sufficiently effective to allow guidelines to remove lung function testing from the list of aerosol-generating procedures
Important message: lung function testing with filters not generating aerosol i.e. are safe

Kulbacka-Ortiz K, Triest FJJ, Franssen FME, Wouters EFM, Studnicka M, Vollmer WM, Lamprecht B, Burney PGJ, Amaral AFS, Vanfleteren LEGW. Restricted spirometry and cardiometabolic comorbidities: results from the international population based BOLD study. Respir Res. 2022 Feb 17;23(1):34. doi: 10.1186/s12931-022-01939-5. PMID: 35177082.

O’Driscoll JM, Giannoglou D, Bashar I, Kipourou K, Alati E, Madden B, Marciniak A, Sharma R. Undiagnosed Chronic Obstructive Pulmonary Disease is Highly Prevalent in Patients Referred for Dobutamine Stress Echocardiography with Shortness of Breath. Lung. 2022 Feb 15. doi: 10.1007/s00408-022-00512-7. Epub ahead of print. PMID: 35166905.
Purpose: Shortness of breath (SOB) is a common symptom referral for dobutamine stress echocardiography (DSE). Patients with SOB and a normal DSE have worse long-term outcome than the general population. This suggests multiple aetiologies are involved. The purpose of this study was to assess the prevalence and clinical significance of undiagnosed COPD amongst patients referred for a DSE with SOB.
Methods: We prospectively studied 114 patients referred for DSE with SOB without prior evidence of lung disease (mean age 64.9 ± 18.5 years, 60 male). Respiratory function testing using spirometry was performed on all patients on the day of their DSE. The study end-points were cardiac events and total mortality.
Results: Respiratory function testing and DSE was performed in all patients and COPD was highly prevalent (n = 93). Multivariate Cox regression analysis was used to estimate the effect of dyspnoea on non-fatal cardiac events (NFCE) and all-cause mortality. Over a mean follow-up of 4.5 ± 2.6 years, the composite end-point of NFCE and all-cause mortality occurred in 62.7% and 16.7% patients, respectively. COPD (HR 1.27; 95% CI 1.17-1.93), previous myocardial infarction (HR 1.84; 95% CI 1.06-3.2), myocardial ischaemia (HR 2.56; 95% CI 1.48-4.43), peak wall motion score index (HR 4.66; 95% CI 2.26-9.6), and mitral E/E’ (HR 1.21; 95% CI 1.1-1.33) were significantly associated with a NFCE. Myocardial ischaemia (HR 4.43; 95% CI 1.24-15.81) was the only independent predictor of all-cause mortality.
Conclusion: Undiagnosed COPD is highly prevalent and independently associated with worse outcome amongst patients with SOB referred for DSE. Symptom presentation is therefore an important consideration when interpreting DSE result

Singh D, Wild JM, Saralaya D, Lawson R, Marshall H, Goldin J, Brown MS, Kostikas K, Belmore K, Fogel R, Patalano F, Drollmann A, Machineni S, Jones I, Yates D, Tillmann HC. Effect of indacaterol/glycopyrronium on ventilation and perfusion in COPD: a randomized trial. Respir Res. 2022 Feb 10;23(1):26. doi: 10.1186/s12931-022-01949-3. PMID: 35144620; PMCID: PMC8832861.

Vikjord SAA, Brumpton BM, Mai XM, Romundstad S, Langhammer A, Vanfleteren L. The HUNT study: Association of comorbidity clusters with long-term survival and incidence of exacerbation in a population-based Norwegian COPD cohort. Respirology. 2022 Feb 10. doi: 10.1111/resp.14222. Epub ahead of print. PMID: 35144315.
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.
Keywords: COPD exacerbation; HUNT study; chronic obstructive pulmonary disease; clinical epidemiology; comorbidity cluster.

Pando-Sandoval A, Ruano-Ravina A, Candal-Pedreira C, Rodríguez-García C, Represas-Represas C, Golpe R, Fernández-Villar A, Pérez-Ríos M. Risk factors for chronic obstructive pulmonary disease in never-smokers: A systematic review. Clin Respir J. 2022 Feb 10. doi: 10.1111/crj.13479. Epub ahead of print. PMID: 35142054.

Putcha N, Woo H, McCormack MC, Fawzy A, Romero K, Davis MF, Wise RA, Diette GB, Koehler K, Matsui EC, Hansel NN. Home Dust Allergen Exposure Is Associated with Outcomes among Sensitized Individuals with Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2022 Feb 15;205(4):412-420. doi: 10.1164/rccm.202103-0583OC. PMID: 34752729.
Rationale: Environmental exposures have been associated with adverse outcomes in chronic obstructive pulmonary disease (COPD). Approximately one-third of individuals with COPD have allergic sensitization, but it is unknown whether exposure to allergens in the home is associated with outcomes. Objectives: To determine the prevalence and associations of allergen sensitization with exposure to common indoor allergens with symptoms and exacerbation risk in COPD. Methods: Allergen sensitization to five common indoor allergens was assessed in former smokers with COPD. Home settled dust was assessed for presence of corresponding allergens. Sensitization and exposure status was determined and associations evaluated in adjusted models with longitudinal outcomes including symptoms, lung function, and exacerbations. Interactions were assessed between sensitization/exposure status and lung function. Measurements and Main Results: One hundred eighty-three individuals studied were on average 67.3 years of age (SD, 8.22) with average FEV1 of 53.2% (SD, 17.6%). Seventy-seven percent of participants were exposed to at least one tested allergen, and 17% had sensitization with corresponding allergen exposure. After adjustment, sensitization with exposure was associated with lower lung function (β, -8.29; 95% confidence interval [CI], -14.80 to -1.77), higher St. George’s Respiratory Questionnaire Total Score (β, 6.71; 95% CI, 0.17 to 13.25), and higher exacerbation risk (odds ratio, 2.31; 95% CI, 1.11 to 4.79). Associations appeared to be more pronounced among individuals with lower lung function. Conclusions: Allergen exposures are common in COPD and associated with adverse outcomes among those with concomitant allergen sensitization. This study establishes allergens as an important home exposure that potentially could be addressed with comprehensive home environmental modification strategies to improve COPD

Mkorombindo T, Balmes JR, Custovic A, Dransfield MT. The Air We Breathe: Respiratory Impact of Indoor Air Quality in Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2022 Feb 15;205(4):378-380. doi: 10.1164/rccm.202112-2822ED. PMID: 35007496.

ASTHMA

Louis R, Satia I, Ojanguren I, Schleich F, Bonini M, Tonia T, Rigau D, Ten Brinke A, Buhl R, Loukides S, Kocks JWH, Boulet LP, Bourdin A, Coleman C, Needham K, Thomas M, Idzko M, Papi A, Porsbjerg C, Schuermans D, Soriano JB, Usmani OS. European Respiratory Society Guidelines for the Diagnosis of Asthma in Adults. Eur Respir J. 2022 Feb 15:2101585. doi: 10.1183/13993003.01585-2021. Epub ahead of print. PMID: 35169025.

Sparreman Mikus M ET AL. U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Disease outcome) Study Group and the BIOAIR (Longitudinal Assessment of Clinical Course and Biomarkers in Severe Chronic Airway Disease) Consortium. Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation. Eur Respir J. 2022 Feb 17;59(2):2100142. doi: 10.1183/13993003.00142-2021. PMID: 34737220; PMCID: PMC8850689.

Edgerley S, Zhu R, Quidwai A, Kim H, Jeimy S. Telemedicine in allergy/immunology in the era of COVID-19: a Canadian perspective. Allergy Asthma Clin Immunol. 2022 Feb 21;18(1):16. doi: 10.1186/s13223-022-00657-3. PMID: 35189969.

Hoy SM. Tezepelumab: First Approval. Drugs. 2022 Feb 20. doi: 10.1007/s40265-022-01679-2. Epub ahead of print. PMID: 35184265.
Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine implicated in the pathogenesis of asthma. Tezepelumab (tezepelumab-ekko; TEZSPIRE™) is a first-in-class human IgG2λ monoclonal antibody that inhibits the action of TSLP. Administered subcutaneously, it is being developed by Amgen and AstraZeneca for the treatment of asthma, chronic obstructive pulmonary disease (COPD), chronic rhinosinusitis with nasal polyps (CRSwNP), chronic spontaneous urticaria and eosinophilic oesophagitis. Tezepelumab received its first approval on 17 December 2021 as an add-on maintenance treatment for patients aged ≥ 12 years with severe asthma in the USA; it is the only biologic approved for severe asthma with no phenotype (e.g. eosinophilic or allergic) or biomarker limitations. A regulatory assessment of tezepelumab for the treatment of asthma is currently underway in the EU and Japan. Tezepelumab received orphan drug designation for the treatment of eosinophilic oesophagitis in October 2021 in the USA, and is undergoing clinical development for the treatment of COPD, CRSwNP and chronic spontaneous urticaria. This article summarizes the milestones in the development of tezepelumab leading to this first approval for the add-on maintenance treatment of patients aged ≥ 12 years with severe asthma

RHINITIS-ALLERGY

Wongsa C, Phinyo P, Sompornrattanaphan M, Krikeerati T, Lumkul L, Thongngarm T. Efficacy and safety of house dust mite sublingual immunotherapy tablet in allergic asthma: A systematic review of randomized controlled trials. J Allergy Clin Immunol Pract. 2022 Feb 15:S2213-2198(22)00133-7. doi: 10.1016/j.jaip.2022.01.046. Epub ahead of print. PMID: 35181547.
Background: House dust mite sublingual immunotherapy (HDM SLIT) effectively treats allergic rhinitis (AR). However, the evidence of HDM SLIT for allergic asthma remained limited.
Objective: To systematically review the efficacy and safety of HDM SLIT tablets in patients with allergic asthma.
Methods: We performed a systematic search through PubMed, Scopus, EMBASE, Web of Science, the Cochrane Center of Controlled Trials, and Google Scholar for randomized controlled trials (RCTs) that addressed the efficacy and safety of HDM SLIT tablets compared with placebo or no intervention in allergic asthma from their inception date until September 2021. The primary outcome was the reduction in inhaled corticosteroid (ICS) dose. Additional outcomes were asthma control, exacerbation, lung function, quality-of-life, and adverse events (AEs).
Results: There were seven RCTs, 5 studies in allergic asthma (4 in adults and one in children), and 2 in AR with or without asthma. The 6 SQ-HDM effectively reduced ICS dose in well- to partly-controlled mild-to-moderate asthma in 1 RCT. Two RCTs evaluated the efficacy of 6 SQ- and 12 SQ-HDM in reducing asthma exacerbation in partly-controlled moderate-to-severe asthma, and their results were inconsistent. One study in children with mild-to-moderate asthma found no benefit of HDM SLIT. Two RCTs in AR with or without mild-to-moderate asthma showed improvement of asthma symptoms. AEs were primarily local, and anaphylaxis treated with epinephrine was reported in 3 patients.
Conclusion: HDM SLIT tablets tend to effectively reduce ICS use in adults and adolescents with well- to partly-controlled mild-to-moderate allergic asthma with a favorable safety profile.

Sunde RB, Thorsen J, Pedersen CT, Stokholm J, Bønnelykke K, Chawes B, Bisgaard H. Prenatal tobacco exposure and risk of asthma and allergy outcomes in childhood. Eur Respir J. 2022 Feb 17;59(2):2100453. doi: 10.1183/13993003.00453-2021. PMID: 34244319.

Runnstrom MC, Morrison-Porter A, Ravindran M, Quehl H, Ramonell RP, Woodruff M, Patel R, Kim C, Haddad NS, Lee FE. Reduced COVID-19 Vaccine Response in Patients Treated with Biologic Therapies for Asthma. Am J Respir Crit Care Med. 2022 Feb 18. doi: 10.1164/rccm.202111-2496LE. Epub ahead of print. PMID: 35180044.

Sokolowska M, Rovati GE, Diamant Z, Untersmayr E, Schwarze J, Lukasik Z, Sava F, Angelina A, Palomares O, Akdis CA, O’Mahony L, Jesenak M, Pfaar O, Torres MJ, Sanak M, Dahlen SE, Woszczek G. Effects of non-steroidal anti-inflammatory drugs and other eicosanoid pathway modifiers on antiviral and allergic responses. EAACI task force on eicosanoids consensus report in times of COVID-19. Allergy. 2022 Feb 16. doi: 10.1111/all.15258. Epub ahead of print. PMID: 35174512.

Gurrola J 2nd, Borish L. Chronic rhinosinusitis: Endotypes, biomarkers, and treatment response. J Allergy Clin Immunol. 2017 Dec;140(6):1499-1508. doi: 10.1016/j.jaci.2017.10.006. Epub 2017 Oct 26. PMID: 29106996.
It is increasingly recognized that chronic rhinosinusitis (CRS) comprises a spectrum of different diseases with distinct clinical presentations and pathogenic mechanisms. Defining the distinct phenotypes and endotypes of CRS affects prognosis and, most importantly, is necessary as the basis for making therapeutic decisions. The need for individualized definitions of pathogenic mechanisms before initiating therapy extends to virtually all therapeutic considerations. This is clearly crucial with antibiotics, where, barring an influence from their off-target anti-inflammatory pharmacologic effects, an understanding of the role of the individual biome predicts likelihood of therapeutic benefit. However, this need for identifying individual phenotypes and endotypes also extends to the agent that is currently considered the mainstay of treatment of CRS, specifically glucocorticoids. As with asthma, it is recognized that a large minority of patients with CRS have a steroid-resistant phenotype, identification of which will preclude use of these agents with their potential side effects. Identification of endotypes is also becoming increasingly imperative because targeted biotherapeutic agents, such as anti-IgE and anticytokine antibodies, are becoming available. These agents are likely to benefit patients in whom the targeted mediator is not only expressed but demonstrably driving a central mechanism in that patient. In summary, the treatment of CRS is at an exciting crossroad. On the positive side, numerous therapeutics are in development that seem likely to have a positive effect in our patients with this condition. The challenge is that these therapies will require targeted individualized treatments based on identifying subjects with the relevant endotype. (J Allergy Clin Immunol 2017;140:1499-508.)

19 February 2022

COPD

Larsen CH, Bendstrup E, Neergaard MA. Screening Tools for Depression and Anxiety in Patients with Chronic Obstructive Pulmonary Disease – A Systematic Review. COPD. 2021 Dec;18(6):683-689. doi: 10.1080/15412555.2021.1972091. Epub 2021 Sep 5. PMID: 34486457.

Burki TK. Volcanic eruption in Tonga and effects on respiratory health. Lancet Respir Med. 2022 Feb 9:S2213-2600(22)00054-6. doi: 10.1016/S2213-2600(22)00054-6. Epub ahead of print. PMID: 35150609.

Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022 Feb 12;399(10325):629-655. doi: 10.1016/S0140-6736(21)02724-0. Epub 2022 Jan 19. PMID: 35065702.

Antoniou KM, Vasarmidi E, Russell AM, Andrejak C, Crestani B, Delcroix M, Dinh-Xuan AT, Poletti V, Sverzellati N, Vitacca M, Witzenrath M, Tonia T, Spanevello A. European Respiratory Society Statement on Long COVID-19 Follow-Up. Eur Respir J. 2022 Feb 10:2102174. doi: 10.1183/13993003.02174-2021. Epub ahead of print. PMID: 35144991.
RECOMMENDED BY ANTONIO SPANEVELLO
Patients diagnosed with COVID-19 associated with SARS-CoV-2 infection frequently experience symptom burden post-acute infection or post-hospitalisation. We aim to identify optimal strategies for follow-up care that may positively impact the patient’s quality-of-life (QOL).A European Respiratory Society (ERS) Task Force (TF) convened and prioritised eight clinical questions. A targeted search of the literature defined the timeline of long COVID-19 as one to six months post infection and identified clinical evidence in the follow-up of patients. Studies meeting the inclusion criteria report an association of characteristics of acute infection with persistent symptoms, thromboembolic events in the follow-up period and evaluations of pulmonary physiology and imaging. Importantly, this statement reviews QOL consequences, symptom burden, disability and home care follow-up. Overall, the evidence for follow-up care for patients with long COVID-19 is limited.

ASTHMA

Badi YE, Pavel AB, Pavlidis S, Riley JH, Bates S, Kermani NZ, Knowles R, Kolmert J, Wheelock CE, Worsley S, Uddin M, Alving K, Bakke PS, Behndig A, Caruso M, Chanez P, Fleming LJ, Fowler SJ, Frey U, Howarth P, Horváth I, Krug N, Maitland-van der Zee AH, Montuschi P, Roberts G, Sanak M, Shaw DE, Singer F, Sterk PJ, Djukanovic R, Dahlen SE, Guo YK, Chung KF, Guttman-Yassky E, Adcock IM; U-BIOPRED Study Group. Mapping atopic dermatitis and anti-IL-22 response signatures to type 2-low severe neutrophilic asthma. J Allergy Clin Immunol. 2022 Jan;149(1):89-101. doi: 10.1016/j.jaci.2021.04.010. Epub 2021 Apr 20. PMID: 33891981.
RECOMMENDED BY GE SENNA
Background: Transcriptomic changes in patients who respond clinically to biological therapies may identify responses in other tissues or diseases.
Objective: We sought to determine whether a disease signature identified in atopic dermatitis (AD) is seen in adults with severe asthma and whether a transcriptomic signature for patients with AD who respond clinically to anti-IL-22 (fezakinumab [FZ]) is enriched in severe asthma.
Methods: An AD disease signature was obtained from analysis of differentially expressed genes between AD lesional and nonlesional skin biopsies. Differentially expressed genes from lesional skin from therapeutic superresponders before and after 12 weeks of FZ treatment defined the FZ-response signature. Gene set variation analysis was used to produce enrichment scores of AD and FZ-response signatures in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes asthma cohort.
Results: The AD disease signature (112 upregulated genes) encompassing inflammatory, T-cell, TH2, and TH17/TH22 pathways was enriched in the blood and sputum of patients with asthma with increasing severity. Patients with asthma with sputum neutrophilia and mixed granulocyte phenotypes were the most enriched (P < .05). The FZ-response signature (296 downregulated genes) was enriched in asthmatic blood (P < .05) and particularly in neutrophilic and mixed granulocytic sputum (P < .05). These data were confirmed in sputum of the Airway Disease Endotyping for Personalized Therapeutics cohort. IL-22 mRNA across tissues did not correlate with FZ-response enrichment scores, but this response signature correlated with TH22/IL-22 pathways.
Conclusions: The FZ-response signature in AD identifies severe neutrophilic asthmatic patients as potential responders to FZ therapy. This approach will help identify patients for future asthma clinical trials of drugs used successfully in other chronic diseases.
Keywords: Fezakinumab; IL-22; atopic dermatitis; gene set variation analysis; severe asthma

Seys SF, Long MB. The quest for biomarkers in asthma: challenging the T2 versus non-T2 paradigm. Eur Respir J. 2022 Feb 17;59(2):2102669. doi: 10.1183/13993003.02669-2021. PMID: 35177484.

Bradding P. Mechanisms of Mast Cell Activation in Severe Asthma: Beyond IgE. Am J Respir Crit Care Med. 2022 Feb 15;205(4):375-377. doi: 10.1164/rccm.202110-2322ED. PMID: 34856107.

RHINITIS

Gevaert P, Bachert C, Maspero JF, Cuevas M, Steele D, Acharya S, Altman P. Phase 3b randomized controlled trial of fevipiprant in patients with nasal polyposis with asthma (THUNDER). J Allergy Clin Immunol. 2022 Jan 27:S0091-6749(21)02599-9. doi: 10.1016/j.jaci.2021.12.759. Epub ahead of print. PMID: 35094848.
Abstract
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with asthma, particularly of late onset. Current treatment options for CRSwNP have limitations, and there is an unmet need for other safe and effective therapies.
Objective: The aim of the THUNDER study was to determine the efficacy and safety of the prostaglandin D2 receptor 2 (DP2) antagonist fevipiprant in patients with CRSwNP and concomitant asthma, measured by improvement in nasal polyp score (primary end point), nasal congestion score, Sinonasal Outcome Test 22 score, and University of Pennsylvania Smell Identification Test score.
Methods: THUNDER was a phase 3b, randomized, multicenter, double-blind, placebo-controlled, parallel-group, 16-week study of fevipiprant 150 mg or 450 mg once daily versus placebo. All patients received intranasal mometasone furoate 200 μg daily.
Results: Ninety-eight patients were randomly assigned to fevipiprant 150 mg (n = 32), fevipiprant 450 mg (n = 34), or placebo (n = 32). Mean (SE) change from baseline in nasal polyp score at week 16 was 0.20 (0.224) for fevipiprant 150 mg, -0.10 (0.216) for fevipiprant 450 mg, and 0.14 (0.233) for placebo. Mean treatment difference was 0.05 (95% confidence interval, -0.59, 0.70; adjusted P = .979) for fevipiprant 150 mg versus placebo and -0.25 (95% confidence interval, -0.88, 0.39; adjusted P = .656) for fevipiprant 450 mg versus placebo. There was no meaningful difference in the secondary end points for fevipiprant versus placebo.
Conclusions: THUNDER provided no evidence of a role for fevipiprant in the treatment of patients with CRSwNP and asthma; future studies may establish a role for other DP2 antagonists, specifically in patients with aspirin-exacerbated respiratory disease.
Keywords: DP(2) receptor; Nasal polyposis; asthma; chronic rhinosinusitis; chronic rhinosinusitis with nasal polyps; fevipiprant; nasal polyps

2021IM PIPELINES SESSION

OPEN DISCUSSION ON PIPELINES OF EXPERIMENTAL TREATMENTS FOR ASTHMA, ALLERGY/RHINITIS, COPD, MULTIMORBIDITY: PANEL DISCUSSION OF RD DIRECTORS OF THE MAIN RESPIRATORY PHARMA INDUSTRIES
Conductors Leonardo M. Fabbri, Pierluigi Paggiaro, Alberto Papi and Giovanni Passalacqua

Introduzione

 

Mark Parry-Billings
Head of Corporate Drug Development
Chiesi Farmaceutici

 

Carmen Stabile
Respiratory Medical Lead
GlaxoSmithKline Spa – Pharmaceuticals

 

Andrea Rizzi
Medical Director Respiratory & Allergy and Diabetes
Ilaria Barisone
Clinical Research Medical Advisor
Novartis Italia

 

Devis Moretti
Medical Lead Immunology
Sanofi Genzyme

 

Berta Juliá de Páramo
Regional Director Medical Affairs (EUCAN)
Respiratory, MSD

 

Najy Alsayed
Global Therapeutic Area Head – Infectious Diseases
Menarini Group

 

Rita De Santis
Head Biotechnology Research and Development
Alfasigma

 

Maria Belvisi
SVP Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D
AstraZeneca

 

Discussione

 

2021IM – Progetto GOLD (BPCO)e MULTIMORBIDITÀ

Introduzione

 

Bartolome Celli
READY FOR A NEW DEFINITION OF COPD?

      Comunicato stampa

 

Discussione

 

Alvar Agusti
A NEW UNDERSTANDING OF COPD BEYOND SMOKING

 

Discussione

 

Eugenio Baraldi
EARLY EXPOSURE/EVENTS RESPONSIBLE FOR FUTURE DEVELOPMENT OF COPD?

 

Discussione

 

Stefano Gasparini
NOVEL DIAGNOSTIC AND THERAPEUTIC ENDOSCOPIC APPROACHES

 

Discussione

 

2021IM – Progetto GINA (Asma)

Introduzione

 

Helen K. Reddel
PRN ICS/FORMOTEROL VERSUS REGULAR LABA/ICS WITH SABA PRN IN ASTHMA

 

Discussione

 

Guy Brusselle
MANAGEMENT OF UNCONTROLLED SEVERE ASTHMA WITH THE NEW BIOLOGICS

 

Discussione

 

GROUP DISCUSSION: BREAKING NEWS IN GINA