11-18 April 2022

COPD

1: Xia J, Gu S, Lei W, Zhang J, Wei H, Liu C, Zhang H, Lu R, Zhang L, Jiang M,
Hu C, Cheng Z, Wei C, Chen Y, Lu F, Chen M, Bi H, Liu H, Yan C, Teng H, Yang Y,
Liang C, Ge Y, Hou P, Liu J, Gao W, Zhang Y, Feng Y, Tao C, Huang X, Pan P, Luo
H, Yun C, Zhan Q. High-flow nasal cannula versus conventional oxygen therapy in
acute COPD exacerbation with mild hypercapnia: a multicenter randomized
controlled trial. Crit Care. 2022 Apr 15;26(1):109. doi:
10.1186/s13054-022-03973-7. PMID: 35428349.
Background: High-flow nasal cannula (HFNC) can improve ventilatory function in patients with acute COPD exacerbation. However, its effect on clinical outcomes remains uncertain.
Methods: This randomized controlled trial was conducted from July 2017 to December 2020 in 16 tertiary hospitals in China. Patients with acute COPD exacerbation with mild hypercapnia (pH ≥ 7.35 and arterial partial pressure of carbon dioxide > 45 mmHg) were randomly assigned to either HFNC or conventional oxygen therapy. The primary outcome was the proportion of patients who met the criteria for intubation during hospitalization. Secondary outcomes included treatment failure (intolerance and need for non-invasive or invasive ventilation), length of hospital stay, hospital cost, mortality, and readmission at day 90.
Results: Among 337 randomized patients (median age, 70.0 years; 280 men [83.1%]; median pH 7.399; arterial partial pressure of carbon dioxide 51 mmHg), 330 completed the trial. 4/158 patients on HFNC and 1/172 patient on conventional oxygen therapy met the criteria for intubation (P = 0.198). Patients progressed to NPPV in both groups were comparable (15 [9.5%] in the HFNC group vs. 22 [12.8%] in the conventional oxygen therapy group; P = 0.343). Compared with conventional oxygen therapy, HFNC yielded a significantly longer median length of hospital stay (9.0 [interquartile range, 7.0-13.0] vs. 8.0 [interquartile range, 7.0-11.0] days) and a higher median hospital cost (approximately $2298 [interquartile range, $1613-$3782] vs. $2005 [interquartile range, $1439-$2968]). There were no significant differences in other secondary outcomes between groups.
Conclusions: In this multi-center randomized controlled study, HFNC compared to conventional oxygen therapy did not reduce need for intubation among acute COPD exacerbation patients with mild hypercapnia. The future studies should focus on patients with acute COPD exacerbation with respiratory acidosis (pH < 7.35). However, because the primary outcome rate was well below expected, the study was underpowered to show a meaningful difference between the two treatment groups.

2: Cho MH, Hobbs BD, Silverman EK. Genetics of chronic obstructive pulmonary
disease: understanding the pathobiology and heterogeneity of a complex disorder.
Lancet Respir Med. 2022 Apr 12:S2213-2600(21)00510-5. doi:
10.1016/S2213-2600(21)00510-5. Epub ahead of print. PMID: 35427534.
Chronic obstructive pulmonary disease (COPD) is a deadly and highly morbid disease. Susceptibility to and heterogeneity of COPD are incompletely explained by environmental factors such as cigarette smoking. Family-based and population-based studies have shown that a substantial proportion of COPD risk is related to genetic variation. Genetic association studies have identified hundreds of genetic variants that affect risk for COPD, decreased lung function, and other COPD-related traits. These genetic variants are associated with other pulmonary and non-pulmonary traits, demonstrate a genetic basis for at least part of COPD heterogeneity, have a substantial effect on COPD risk in aggregate, implicate early-life events in COPD pathogenesis, and often involve genes not previously suspected to have a role in COPD. Additional progress will require larger genetic studies with more ancestral diversity, improved profiling of rare variants, and better statistical methods. Through integration of genetic data with other omics data and comprehensive COPD phenotypes, as well as functional description of causal mechanisms for genetic risk variants, COPD genetics will continue to inform novel approaches to understanding the pathobiology of COPD and developing new strategies for management and treatment.

3: Agustí A, Melén E, DeMeo DL, Breyer-Kohansal R, Faner R. Pathogenesis of
chronic obstructive pulmonary disease: understanding the contributions of gene-
environment interactions across the lifespan. Lancet Respir Med. 2022 Apr
12:S2213-2600(21)00555-5. doi: 10.1016/S2213-2600(21)00555-5. Epub ahead of
print. PMID: 35427533.
The traditional view of chronic obstructive pulmonary disease (COPD) as a self-inflicted disease caused by tobacco smoking in genetically susceptible individuals has been challenged by recent research findings. COPD can instead be understood as the potential end result of the accumulation of gene-environment interactions encountered by an individual over the life course. Integration of a time axis in pathogenic models of COPD is necessary because the biological responses to and clinical consequences of different exposures might vary according to both the age of an individual at which a given gene-environment interaction occurs and the cumulative history of previous gene-environment interactions. Future research should aim to understand the effects of dynamic interactions between genes (G) and the environment (E) by integrating information from basic omics (eg, genomics, epigenomics, proteomics) and clinical omics (eg, phenomics, physiomics, radiomics) with exposures (the exposome) over time (T)-an approach that we refer to as GETomics. In the context of this approach, we argue that COPD should be viewed not as a single disease, but as a clinical syndrome characterised by a recognisable pattern of chronic symptoms and structural or functional impairments due to gene-environment interactions across the lifespan that influence normal lung development and ageing.

4: Yang IA, Jenkins CR, Salvi SS. Chronic obstructive pulmonary disease in
never-smokers: risk factors, pathogenesis, and implications for prevention and
treatment. Lancet Respir Med. 2022 Apr 12:S2213-2600(21)00506-3. doi:
10.1016/S2213-2600(21)00506-3. Epub ahead of print. PMID: 35427530.
Chronic obstructive pulmonary disease (COPD) was traditionally thought to be caused by tobacco smoking. However, recognition of the importance of non-smoking-related risk factors for COPD has increased over the past decade, with evidence on the burden, risk factors, and clinical presentations of COPD in never-smokers. About half of all COPD cases worldwide are due to non-tobacco-related risk factors, which vary by geographical region. These factors include air pollution, occupational exposures, poorly controlled asthma, environmental tobacco smoke, infectious diseases, and low socioeconomic status. Impaired lung growth during childhood, caused by a range of early-life exposures, is associated with an increased risk of COPD. Potential mechanisms for the pathogenesis of COPD in never-smokers include inflammation, oxidative stress, airway remodelling, and accelerated lung ageing. Compared with smokers who develop COPD, never-smokers with COPD have relatively mild chronic respiratory symptoms, little or no emphysema, milder airflow limitation, and fewer comorbidities; however, exacerbations can still be frequent. Further research-including epidemiological, translational, clinical, and implementation studies-is needed to address gaps in understanding and to advance potential solutions to reduce the burden of COPD in never-smokers.

5: Cotton S, Devereux G, Abbas H, Briggs A, Campbell K, Chaudhuri R, Choudhury
G, Dawson D, De Soyza A, Fielding S, Gompertz S, Haughney J, Lang CC, Lee AJ,
MacLennan G, MacNee W, McCormack K, McMeekin N, Mills NL, Morice A, Norrie J,
Petrie MC, Price D, Short P, Vestbo J, Walker P, Wedzicha J, Wilson A, Lipworth
BJ. Use of the oral beta blocker bisoprolol to reduce the rate of exacerbation
in people with chronic obstructive pulmonary disease (COPD): a randomised
controlled trial (BICS). Trials. 2022 Apr 14;23(1):307. doi:
10.1186/s13063-022-06226-8. PMID: 35422024.
Background: Chronic obstructive pulmonary disease (COPD) is associated with significant morbidity, mortality and healthcare costs. Beta blockers are well-established drugs widely used to treat cardiovascular conditions. Observational studies consistently report that beta blocker use in people with COPD is associated with a reduced risk of COPD exacerbations. The bisoprolol in COPD study (BICS) investigates whether adding bisoprolol to routine COPD treatment has clinical and cost-effective benefits. A sub-study will risk stratify participants for heart failure to investigate whether any beneficial effect of bisoprolol is restricted to those with unrecognised heart disease.
Methods: BICS is a pragmatic randomised parallel group double-blind placebo-controlled trial conducted in UK primary and secondary care sites. The major inclusion criteria are an established predominant respiratory diagnosis of COPD (post-bronchodilator FEV1 < 80% predicted, FEV1/FVC < 0.7), a self-reported history of ≥ 2 exacerbations requiring treatment with antibiotics and/or oral corticosteroids in a 12-month period since March 2019, age ≥ 40 years and a smoking history ≥ 10 pack years. A computerised randomisation system will allocate 1574 participants with equal probability to intervention or control groups, stratified by centre and recruitment in primary/secondary care. The intervention is bisoprolol (1.25 mg tablets) or identical placebo. The dose of bisoprolol/placebo is titrated up to a maximum of 4 tablets a day (5 mg bisoprolol) over 4-7 weeks depending on tolerance to up-dosing of bisoprolol/placebo-these titration assessments are completed by telephone or video call. Participants complete the remainder of the 52-week treatment period on the final titrated dose (1, 2, 3, 4 tablets) and during that time are followed up at 26 and 52 weeks by telephone or video call. The primary outcome is the total number of participant reported COPD exacerbations requiring oral corticosteroids and/or antibiotics during the 52-week treatment period. A sub-study will risk stratify participants for heart failure by echocardiography and measurement of blood biomarkers.
Discussion: The demonstration that bisoprolol reduces the incidence of exacerbations would be relevant not only to patients and clinicians but also to healthcare providers, in the UK and globally.

6: Congleton J. Urgent! A call to put the ‘O’ back in COPD. Drug Ther Bull. 2022
Apr 12:dtb-2021-000068. doi: 10.1136/dtb.2021.000068. Epub ahead of print. PMID:
35414593.
Chronic obstructive pulmonary disease (COPD) is the second most common long-term respiratory condition and it is estimated that exacerbations of COPD lead to over a million bed-days per year.1–3 In 2020/2021, the Quality and Outcomes Framework (QOF) data recorded 1.2 million people in England with a diagnosis of COPD and it is thought that an additional 2 million cases may be undiagnosed.1 2 The cause of COPD is inhalation of toxins, primarily cigarette smoke, which results in mucus hypersecretion and anatomical distortion in the large airways, fibrosis and obliteration of small airways and destruction of the parenchyma (emphysema). All three processes lead to ‘airflow obstruction’, that is, limitation of flow in expiration, particularly apparent when increased flow is required on exertion, leading to breathlessness and exercise limitation. The degree of airflow obstruction is an important predictor of complications such as exacerbations, respiratory failure and death …..
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NOT OPEN ACCESS

7: Choi N, Jang S, Yoo KH, Rhee CK, Kim Y. The Effectiveness and Harms of
Screening for Chronic Obstructive Pulmonary Disease: An Updated Systematic
Review and Meta-Analysis. J Korean Med Sci. 2022 Apr 11;37(14):e117. doi:
10.3346/jkms.2022.37.e117. PMID: 35411733.
Background: This study aimed to perform meta-analyses to update a previous systematic review (SR) conducted by the US Preventive Services Task Force (USPSTF) to evaluate the benefits and harms of screening for chronic obstructive pulmonary disease (COPD) in asymptomatic adults.
Methods: MEDLINE, EMBASE, Cochrane Library, and regional databases were searched from their inception to January 2020. Studies for diagnostic accuracy, preventive services effect, treatment efficacy, and treatment harms were included.
Results: Eighteen studies were included, and twelve of these were newly added in this update. In meta-analyses, the pooled sensitivity and specificity for COPD diagnosis using spirometry were 73.4% and 89.0%, respectively. The relative effect of smoking cessation intervention with screening spirometry, presented as abstinence rate, was not statistically significant (risk ratio [RR], 1.21; 95% confidence interval [CI], 0.87-1.67) when all selected studies were pooled, but screening on smoking cessation was effective (RR, 1.58; 95% CI, 1.14-2.19) when limited to studies with smoking cessation programs that provided smoking cessation medicines or intensive counseling at public health centers or medical institutions.
Conclusion: In this study, no direct evidence for the impact on health outcomes of screening asymptomatic adults for COPD was identified similar to the previous SR. Further research is necessary to confirm the benefits of COPD screening.

8: Singanayagam A, Footitt J, Marczynski M, Radicioni G, Cross MT, Finney LJ,
Trujillo-Torralbo MB, Calderazzo M, Zhu J, Aniscenko J, Clarke TB, Molyneaux PL,
Bartlett NW, Moffatt MF, Cookson WO, Wedzicha J, Evans CM, Boucher RC, Kesimer
M, Lieleg O, Mallia P, Johnston SL. Airway mucins promote immunopathology in
virus-exacerbated chronic obstructive pulmonary disease. J Clin Invest. 2022 Apr
15;132(8):e120901. doi: 10.1172/JCI120901. PMID: 35239513.
The respiratory tract surface is protected from inhaled pathogens by a secreted layer of mucus rich in mucin glycoproteins. Abnormal mucus accumulation is a cardinal feature of chronic respiratory diseases, but the relationship between mucus and pathogens during exacerbations is poorly understood. We identified elevations in airway mucin 5AC (MUC5AC) and MUC5B concentrations during spontaneous and experimentally induced chronic obstructive pulmonary disease (COPD) exacerbations. MUC5AC was more sensitive to changes in expression during exacerbation and was therefore more predictably associated with viral load, inflammation, symptom severity, decrements in lung function, and secondary bacterial infections. MUC5AC was functionally related to inflammation, as Muc5ac-deficient (Muc5ac-/-) mice had attenuated RV-induced (RV-induced) airway inflammation, and exogenous MUC5AC glycoprotein administration augmented inflammatory responses and increased the release of extracellular adenosine triphosphate (ATP) in mice and human airway epithelial cell cultures. Hydrolysis of ATP suppressed MUC5AC augmentation of RV-induced inflammation in mice. Therapeutic suppression of mucin production using an EGFR antagonist ameliorated immunopathology in a mouse COPD exacerbation model. The coordinated virus induction of MUC5AC and MUC5B expression suggests that non-Th2 mechanisms trigger mucin hypersecretion during exacerbations. Our data identified a proinflammatory role for MUC5AC during viral infection and suggest that MUC5AC inhibition may ameliorate COPD exacerbations.

ASTHMA

1: Holmes J, Heaney LG, McGarvey LPA. Objective and Subjective Measurement of
Cough in Asthma: A Systematic Review of the Literature. Lung. 2022 Apr 13. doi:
10.1007/s00408-022-00527-0. Epub ahead of print. PMID: 35416544.
Background: The extent to which objective and subjective tools has been used to measure the characteristics and burden of cough in patients with asthma has not been reported.
Objective: To review the large and extensive body of literature in asthma with the specific hypothesis that the characteristics of cough and clinical impact in this disease has only occasionally been studied.
Methods: For this systematic review, we searched EMBASE and MEDLINE databases using a combination of MeSH terms for “cough” and “asthma” for studies published up to and including end of August 2021. Studies included for analysis were confined to those undertaken in adult patients (≥ 18 years) with asthma of any severity where any tool or method to specifically measure cough was employed.
Results: Of 12,090 citations identified after our initial search, 112 full-text articles met criteria for inclusion in our analysis. We found that a broad range of objective and subjective measures have been used albeit with a lack of consistency between studies. Clinically important levels of cough associated with impaired health status were identified in patients with asthma.
Conclusion: Although cough is a common symptom in asthma, the clinical features and accompanying healthcare burden have been studied infrequently. In studies where cough was measured, the methods employed varied considerably. A more consistent use of cough-specific measurement tools is required to better determine the nature and burden of cough in asthma.

2: Duijts L, Fleming LJ, Bacharier LB, Pitrez PM, Reddel HK. Reply to Baraldi
and Piacentini: Global Initiative for Asthma 2021: Asthma in Preschool Children
and Short-Acting β<sub>2</sub>-Agonist-Only Treatment.
Am J Respir Crit Care
Med. 2022 Apr 15;205(8):972-973. doi: 10.1164/rccm.202112-2788LE. PMID:
35202561.

3: Baraldi E, Piacentini G. Global Initiative for Asthma 2021: Asthma in
Preschool Children and Short-Acting β<sub>2</sub>-Agonist-Only Treatment.
Am J
Respir Crit Care Med. 2022 Apr 15;205(8):971-972. doi:
10.1164/rccm.202111-2465LE. PMID: 35202554.

RHINITIS-ALLERGY-ALLERGIC ASTHMA

1: Chu NN, Huang K, Que LL, Ding Y, Gu XH, Zhang L, Wang JK, Chen XP, Sun ZG, He
Q. Safety, Tolerability, and Pharmacokinetic Study of 101BHG-D01 Nasal Spray, a
Novel Long-Acting and Selective Cholinergic M Receptor Antagonist, in Healthy
Chinese Volunteers: A Randomized, Double-Blind, Placebo-Controlled, Single-Dose
Escalation, First-In-Human Study. Eur J Drug Metab Pharmacokinet. 2022 Apr 16.
doi: 10.1007/s13318-022-00769-6. Epub ahead of print. PMID: 35429285.
Background and objective: 101BHG-D01 nasal spray is the first novel long-acting cholinergic M receptor antagonist under development to treat rhinorrhea in rhinitis. This first-in-human study aimed to evaluate the safety, tolerability, and pharmacokinetics of 101BHG-D01 nasal spray following single intranasal doses in healthy Chinese subjects.
Methods: A randomized, double-blind, placebo-controlled, single-dose escalation study was conducted in healthy Chinese volunteers after intranasal doses of 101BHG-D01 nasal spray or placebo ranging from 40 µg to 960 µg (total of six doses). Blood samples were collected at scheduled time points, and plasma concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method. A non-compartmental method was used to calculate the main pharmacokinetic parameters, including the area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC0-t), the area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), the maximum plasma concentration (Cmax), the time to maximum plasma concentration (Tmax), and the elimination half-life (t1/2). Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations, 12-lead electrocardiograms (ECGs), anterior rhinoscopy, ophthalmic examination, and ambulatory ECG monitoring.
Results: Following single intranasal dosing, 101BHG-D01 was rapidly absorbed with a median Tmax of 0.34-0.50 h and eliminated slowly with a mean t1/2 ranging from 4.29 to 46.76 h for different dose groups. The Cmax and AUC of 101BHG-D01 increased linearly across the examined dose range of 40-960 µg. 101BHG-D01 nasal spray was well tolerated, all AEs were mild, and no serious adverse events occurred during the study.
Conclusions: 101BHG-D01 nasal spray was safe and well tolerated in healthy Chinese subjects when administered intranasally in single escalating doses. The mean Cmax and AUC increased proportionally to the studied dose. The pharmacokinetic, safety, and tolerability profiles of 101BHG-D01 nasal spray indicate that it is a good candidate for further development as a treatment for rhinorrhea in rhinitis.

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