Quantitative analysis of efficacy and safety of LABA/LAMA fixed-dose combinations in the treatment of stable COPD

Objective: This study aimed to quantitatively compare the efficacy and safety of long-acting β2-agonist (LABA)/long-acting muscarinic antagonist (LAMA) fixed-dose combinations (FDCs) for the treatment of stable chronic obstructive pulmonary disease (COPD), especially in terms of their loss of efficacy in lung function. Methods: Randomized controlled clinical trials of LABA/LAMA FDCs for the treatment of stable COPD were comprehensively searched for in public databases. Pharmacodynamic models were established to describe the time course of the primary outcome [trough forced expiratory volume in the first second (FEV1)]. Secondary outcomes [COPD exacerbations, St. George’s Respiratory Questionnaire (SGRQ), Transition Dyspnoea Index (TDI), and rescue medication use] and safety outcomes [mortality, serious adverse events (SAEs), and withdrawals due to adverse events (AEs)] were also compared via a meta-analysis. Results: A total of 22 studies involving 16,486 participants were included in this study. The results showed that in terms of primary outcome (change from baseline in trough FEV1), the efficacy of vilanterol/umeclidinium was the highest, while the efficacy of formoterol/aclidinium was the lowest, with a maximum effect value (Emax) of 0.185 L [95% confidence interval (CI): 0.173–0.197 L] and 0.119 L (95% CI: 0.103–0.135 L), respectively. The efficacy of other drugs, such as formoterol/glycopyrronium, indacaterol/glycopyrronium, and olodaterol/tiotropium, were comparable, and their Emax values were 0.150–0.177 L. Except for vilanterol/umeclidinium, the other four LABA/LAMA FDCs showed a certain degree of loss of efficacy. Compared with the efficacy at 2 days, the trough FEV1 (L) relative to baseline at 24 weeks decreased by 0.029–0.041 L. In terms of secondary outcomes, the efficacy of different LABA/LAMA FDCs was similar in TDI and rescue medication use. However, formoterol/aclidinium was better in preventing the COPD exacerbations, while vilanterol/umeclidinium was the best in terms of SGRQ. In addition, different LABA/LAMA FDCs and placebo had similar safety outcomes. Conclusion: The present findings may provide necessary quantitative information for COPD medication guidelines.

Physiological predictors of cardiorespiratory fitness in children and adolescents with cystic fibrosis without ventilatory limitation

Objectives: [1] To investigate the cardiorespiratory fitness (CRF) levels in children and adolescents with cystic fibrosis (CF) with no ventilatory limitation (ventilatory reserve ⩾ 15%) during exercise, and [2] to assess which physiological factors are related to CRF. Methods: A cross-sectional study design was used in 8- to 18-year-old children and adolescents with CF. Cardiopulmonary exercise testing was used to determine peak oxygen uptake normalized to body weight as a measure of CRF. Patients were defined as having ‘low CRF’ when CRF was less than 82%predicted. Physiological predictors used in this study were body mass index z-score, P. Aeruginosa lung infection, impaired glucose tolerance (IGT) including CF-related diabetes, CF-related liver disease, sweat chloride concentration, and self-reported physical activity. Backward likelihood ratio (LR) logistic regression analysis was used. Results: Sixty children and adolescents (51.7% boys) with a median age of 15.3 years (25th–75th percentile: 12.9–17.0 years) and a mean percentage predicted forced expiratory volume in 1 second of 88.5% (±16.9) participated. Mean percentage predicted CRF (ppVO2peak/kg) was 81.4% (±12.4, range: 51%–105%). Thirty-three patients (55.0%) were classified as having ‘low CRF’. The final model that best predicted low CRF included IGT ( p = 0.085; Exp(B) = 6.770) and P. Aeruginosa lung infection (p = 0.095; Exp(B) = 3.945). This model was able to explain between 26.7% and 35.6% of variance. Conclusions: CRF is reduced in over half of children and adolescents with CF with normal ventilatory reserve. Glucose intolerance and P. Aeruginosa lung infection seem to be associated to low CRF in children and adolescents with CF.

Impact of COVID-19 on social determinants of health for adults with cystic fibrosis

Introduction: Outcomes in cystic fibrosis are influenced by multiple factors, including social determinants of health. Low socioeconomic status has been shown to be associated with lung function decline, increased exacerbation rates, increased health care utilization, and decreased survival in cystic fibrosis. The COVID-19 pandemic disrupted the US economy, placing people with cystic fibrosis at risk for negative impacts due to changes in social determinants of health. Methods: To characterize the impact of COVID-19-related changes in social determinants of health in the adult cystic fibrosis population, a social determinants of health questionnaire was designed and distributed to patients as part of a quality improvement project. Results: Of 132 patients contacted, 76 (57.6%) responses were received. Of these responses, 22 (28.9%) answered yes to at least one question that indicated an undesired change in social determinants of health. Patients with stable employment prior to COVID-19 were more likely to endorse undesired change in all domains of the questionnaire, and the undesired changes were most likely to be related to employment, insurance security, and access to medications. Patients receiving disability were more likely to report hardship related to utilities and food security compared with patients previously employed or unemployed. Of patients endorsing risk of socioeconomic hardship, 21 (95.5%) were contacted by a social worker and provided resources. Conclusion: Utilizing a social determinants of health questionnaire to screen for social instability in the context of COVID-19 is feasible and beneficial for patients with cystic fibrosis. Identifying social issues early during the pandemic and implementing processes to provide resources may help patients with cystic fibrosis mitigate social hardship and maintain access to health care and medications.

Diagnosis of tuberculosis pleurisy with three endoscopic features via pleuroscopy

Background: Tuberculosis (TB) is a constant threat even with a worldwide active public health campaign. Diagnosis of TB pleurisy is challenging in the case of pleural effusion of unknown origin after aspiration analysis. The study was designed to demonstrate a simple image interpretation technique to differentiate TB pleurisy from non-TB pleurisy using semi-rigid pleuroscopy. Methods: The study retrospectively enrolled 117 patients who underwent semi-rigid pleuroscopy from April 2016 to August 2018 in a tertiary hospital. We analyzed the possibility of TB pleurisy using three simple pleuroscopic images via semi-rigid pleuroscopy. Results: Among 117 patients, 28 patients (23.9%) were diagnosed with TB pleurisy. Sago-like nodules/micronodules, adhesion, and discrete distribution were noted in 20 (71.4%), 20 (71.4%), and 19 (67.9%) patients with TB pleurisy, respectively. Sago-like nodules/micronodules, adhesion, and discrete distribution were noted in six (6.7%), 37 (41.6%), and no (0.0%) patients with non-TB pleurisy, respectively. The positive and negative predictive values of any two out of three pleuroscopic patterns for TB pleurisy were 100.0% and 93.7%, respectively. Conclusions: A high positive predictive value for TB pleurisy was demonstrated by the presence of any two out of the three characteristic features. Absence of all three features had an excellent negative predictive value for TB pleurisy. Our diagnostic criteria reconfirm that pleuroscopic images can be used as predictors for TB pleurisy in patients with undiagnosed pleural effusion. The reviews of this paper are available via the supplementary material section.

Comparison of outcomes of high-flow nasal cannula and noninvasive positive-pressure ventilation in patients with hypoxemia and various APACHE II scores after extubation

Aims: The study aimed to compare and analyze the outcomes of high-flow nasal cannula (HFNC) and noninvasive positive-pressure ventilation (NPPV) in the treatment of patients with acute hypoxemic respiratory failure (AHRF) who had extubation after weaning from mechanical ventilation. Methods: A total 120 patients with AHRF were enrolled into this study. These patients underwent tracheal intubation and mechanical ventilation. They were organized into two groups according to the score of Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II); group A: APACHE II score <12; group B: 12⩽ APACHE II score <24. Group A had 72 patients and patients given HFNC were randomly assigned to subgroup I while patients given NPPV were assigned to subgroup II (36 patients in each subgroup). Group B had 48 patients and patients given HFNC were randomly assigned to subgroup I while patients given NPPV were assigned to subgroup II (24 patients in each subgroup). General information, respiratory parameters, endpoint event, and comorbidities of adverse effect were compared and analyzed between the two subgroups. Results: The incidence of abdominal distension was significantly higher in patients treated with NPPV than in those treated with HFNC in group A (19.44% versus 0, p = 0.005) and group B (25% versus 0, p = 0.009). There was no significant difference between the HFNC- and NPPV-treated patients in blood pH, oxygenation index, partial pressure of carbon dioxide, respiratory rate, and blood lactic acid concentration in either group ( p > 0.05). Occurrence rate of re-intubation within 72 h of extubation was slightly, but not significantly, higher in NPPV-treated patients ( p > 0.05). Conclusion: There was no significant difference between HFNC and NPPV in preventing respiratory failure in patients with AHRF with an APACHE II score <24 after extubation. However, HFNC was superior to NPPV with less incidence of abdominal distension. The reviews of this paper are available via the supplemental material section.

Respiratory viral infections in the elderly

With the global over 60-year-old population predicted to more than double over the next 35 years, caring for this aging population has become a major global healthcare challenge. In 2016 there were over 1 million deaths in >70 year olds due to lower respiratory tract infections; 13–31% of these have been reported to be caused by viruses. Since then, there has been a global COVID-19 pandemic, which has caused over 2.3 million deaths so far; increased age has been shown to be the biggest risk factor for morbidity and mortality. Thus, the burden of respiratory viral infections in the elderly is becoming an increasing unmet clinical need. Particular challenges are faced due to the interplay of a variety of factors including complex multimorbidities, decreased physiological reserve and an aging immune system. Moreover, their atypical presentation of symptoms may lead to delayed necessary care, prescription of additional drugs and prolonged hospital stay. This leads to morbidity and mortality and further nosocomial spread. Clinicians currently have limited access to sensitive detection methods. Furthermore, a lack of effective antiviral treatments means there is little incentive to diagnose and record specific non-COVID-19 viral infections. To meet this unmet clinical need, it is first essential to fully understand the burden of respiratory viruses in the elderly. Doing this through prospective screening research studies for all respiratory viruses will help guide preventative policies and clinical trials for emerging therapeutics. The implementation of multiplex point-of-care diagnostics as a mainstay in all healthcare settings will be essential to understand the burden of respiratory viruses, diagnose patients and monitor outbreaks. The further development of novel targeted vaccinations as well as anti-viral therapeutics and new ways to augment the aging immune system is now also essential. The reviews of this paper are available via the supplemental material section.

Clinical effectiveness of convalescent plasma in hospitalized patients with COVID-19: a systematic review and meta-analysis

Aims: Given the variability of previously reported results, this systematic review aims to determine the clinical effectiveness of convalescent plasma employed in the treatment of hospitalized patients diagnosed with COVID-19. Methods: We conducted a systematic review of controlled clinical trials assessing treatment with convalescent plasma for hospitalized patients diagnosed with SARS-CoV-2 infection. The outcomes were mortality, clinical improvement, and ventilation requirement. Results: A total of 51 studies were retrieved from the databases. Five articles were finally included in the data extraction and qualitative and quantitative synthesis of results. The overall risk of bias in the reviewed articles was established at low-risk only in two trials. The meta-analysis suggests that there is no benefit of convalescent plasma compared with standard care or placebo in reducing the overall mortality and the ventilation requirement. However, there could be a benefit for the clinical improvement in patients treated with plasma. Conclusion: Current results led to assume that the convalescent plasma transfusion cannot reduce the mortality or ventilation requirement in hospitalized patients diagnosed with SARS-CoV-2 infection. More controlled clinical trials conducted with methodologies that ensure a low risk of bias are still needed. The reviews of this paper are available via the supplemental material section.

The perplexing role of RAGE in pulmonary fibrosis: causality or casualty?

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease in which most patients die within 3 years of diagnosis. With an unknown etiology, IPF results in progressive fibrosis of the lung parenchyma, diminishing normal lung function, which results in respiratory failure, and eventually, death. While few therapies are available to reduce disease progression, patients continue to advance toward respiratory failure, leaving lung transplantation the only viable option for survival. As incidence and mortality rates steadily increase, the need for novel therapeutics is imperative. The receptor for advanced glycation endproducts (RAGE) is most highly expressed in the lungs and plays a significant role in a number of chronic lung diseases. RAGE has long been linked to IPF; however, confounding data from both human and experimental studies have left an incomplete and perplexing story. This review examines the present understanding of the role of RAGE in human and experimental models of IPF, drawing parallels to recent advances in RAGE biology. Moreover, this review discusses the role of RAGE in lung injury response, type 2 immunity, and cellular senescence, and how such mechanisms may relate to RAGE as both a biomarker of disease progression and potential therapeutic target in IPF. The reviews of this paper are available via the supplemental material section.

Improvements in lung function with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler versus dual therapies in patients with COPD: a sub-study of the ETHOS trial

Background: In the phase III, 52-week ETHOS study in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF), at two inhaled corticosteroid dose levels, resulted in significantly lower moderate/severe exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) and budesonide/formoterol fumarate (BFF). Here, we report results from the ETHOS pulmonary function test (PFT) sub-study, which assessed lung function in a subset of ETHOS patients. Methods: ETHOS (NCT02465567) was a randomized, double-blind, multi-center, parallel-group study in patients with moderate to very severe COPD who had experienced ⩾1 moderate/severe exacerbation in the previous year. Patients received BGF 320/18/9.6 µg, BGF 160/18/9.6 μg, GFF 18/9.6 µg, or BFF 320/9.6 µg twice daily via a single metered dose Aerosphere inhaler for 52 weeks. A subset of patients participated in the 4-hour PFT sub-study; primary endpoints were change from baseline in morning pre-dose trough forced expiratory volume in one second (FEV1) versus GFF and FEV1 area under the curve from 0 to 4 hours (AUC0–4) versus BFF at week 24. Results: The PFT modified intent-to-treat population included 3088 patients (mean age 64.4 years; mean reversibility post-albuterol 16.7%; mean post-albuterol FEV1% predicted 42.8). BGF 320/18/9.6 µg and 160/18/9.6 µg significantly improved morning pre-dose trough FEV1 at week 24 versus GFF ( p ⩽ 0.0035 for both). Improvements in trough FEV1 were also observed at week 52 for BGF 320/18/9.6 µg and 160/18/9.6 µg versus GFF ( p ⩽ 0.0005 for both). For FEV1 AUC0–4 at week 24, BGF 320/18/9.6 µg and 160/18/9.6 µg showed significant improvements versus BFF ( p < 0.0001 for both). Improvements were maintained at week 52 ( p < 0.0001). Conclusions: BGF 320/18/9.6 µg and 160/18/9.6 µg significantly improved trough FEV1 versus GFF and FEV1 AUC0–4 versus BFF at week 24. The lung function benefits with both doses of BGF were maintained following 52 weeks of treatment. The reviews of this paper are available via the supplemental material section.

Severe COVID-19 among patients with asthma and COPD: a report from the Swedish National Airway Register

Background: Patients with obstructive lung diseases may be at risk of hospitalization and/or death due to COVID-19. Aim: To estimate the frequency of severe COVID-19, and COVID-19-related mortality in a well-defined large population of patients with asthma and chronic inflammatory lung disease (COPD). Further to assess the frequency of asthma and COPD as registered comorbidities at discharge from hospital, and in death certificates. Methods: At the start of the pandemic, the Swedish National Airway Register (SNAR) included 271,404 patients with a physician diagnosis of asthma and/or COPD. In September 2020, after the first COVID-19 wave in Sweden, the database was linked with the National Patient Register (NPR), the Swedish Intensive Care Register and the Swedish Cause of Death Register, which all provide data about COVID-19 based on International Classification of Diseases (ICD-10) codes. Severe COVID-19 was defined as hospitalization and/or intensive care or death due to COVID-19. Results: Among patients in SNAR, 0.5% with asthma, and 1.2% with COPD were identified with severe COVID-19. Among patients < 18 years with asthma, only 0.02% were severely infected. Of hospitalized adults, 14% with asthma and 29% with COPD died. Further, of patients in SNAR, 56% with asthma and 81% with COPD were also registered in the NPR, while on death certificates the agreement was lower (asthma 24% and COPD 71%). Conclusion: The frequency of severe COVID-19 in asthma and COPD was relative low. Mortality for those hospitalized was double as high in COPD compared to asthma. Comorbid asthma and COPD were not always identified among patients with severe COVID-19.