RSV-related Community COPD Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study.

RATIONALE: Respiratory syncytial virus (RSV) is a common global respiratory virus increasingly recognized as a major pathogen in frail older adults and as a cause of chronic obstructive pulmonary disease (COPD) exacerbations. There is no single test for RSV in adults with acceptable diagnostic accuracy. Trials of RSV vaccines have recently shown excellent safety and efficacy against RSV in older adults; defining the frequency of RSV-related community infections and COPD exacerbations is important for vaccine deployment decisions. OBJECTIVES: This prospective study aimed to establish the frequency of outpatient-managed RSV-related exacerbations of COPD in two well-characterized patient cohorts using a combination of diagnostic methods. METHODS: Participants were recruited at specialist clinics in London, UK and Groningen, NL from 2017 and observed for three consecutive RSV seasons, during exacerbations and at least twice yearly. RSV infections were detected by reverse transcription-polymerase chain reaction (RT-PCR) and serologic testing. MEASUREMENTS AND MAIN RESULTS: 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8·7% of total); of these, seven were detected only on PCR, 16 only on serology and 4 by both methods. Increases in RSV specific N-protein antibody were as sensitive as antibody to pre-F or post-F for serodiagnosis of RSV related exacerbations. CONCLUSIONS: RSV is associated with 8.7% of outpatient managed COPD exacerbations in this study. Antibodies to RSV-N protein may have diagnostic value, potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

RATIONALE: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. OBJECTIVES: We hypothesised that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. METHODS: We recruited 431 current smokers (median age 39 years, 16 pack-years smoked) and recorded symptoms by the COPD Assessment Test (CAT), spirometry and quantitative thoracic CT (QCT) scans at study entry. These scans results were compared to 67 never smoking controls. 368 participants were followed every six months with measurement of post-bronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age and sex was related to the initial QCT appearances and symptoms, measured with the CAT. MEASUREMENTS AND MAIN RESULTS: There were no material differences in demography or subjective CT appearances between the young smokers and controls, but 55.7% of the former had a CAT score above 10 and 24.2% reported chronic bronchitis. QCT assessments of Disease Probability-defined functional small airways disease, ground glass opacification, bronchovascular prominence and small blood vessel to total pulmonary vessel volume ratio were increased compared to controls and were all associated with a faster FEV1 decline as was a higher CAT score. CONCLUSIONS: Radiologic abnormalities on CT are already established in young smokers with normal lung function and is associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Selected updates on chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is preventable disease and yet it remains the third greatest cause of death worldwide. This review focuses on recent updates in COPD research which have had an impact on our understanding of the epidemiology and pathophysiology of COPD. RECENT FINDINGS: Epidemiological studies of COPD have moved towards trying to understand the global impact of COPD particularly in low- and middle-income countries where disease prevalence continues to increase. In addition, we are beginning to uncover the impact of air pollution on COPD development with recent work showing a relationship between air pollution and COPD exacerbations. Advances in understanding early origins and early development of COPD have the potential to intervene earlier in the disease course to prevent disease progression. Although biomarkers such as peripheral blood eosinophilia have led to trials of biologic agents in COPD suggesting we may be entering an exciting new biologic era in COPD. SUMMARY: Recent advances suggest there may be a relationship between air pollution and COPD exacerbations. This requires further research to influence environmental policy. New clinical trials of biologics targeting TH2 inflammation in COPD suggest that targeted treatments with biologics may be a possibility COPD.

The Effect of Inhaled Corticosteroids on Pneumonia Risk in Patients With COPD-Bronchiectasis Overlap: A UK Population-Based Case-Control Study.

BACKGROUND: Inhaled corticosteroids (ICS) increase the risk of pneumonia in COPD and commonly are used in patients with COPD-bronchiectasis overlap. RESEARCH QUESTION: Is the risk of pneumonia associated with ICS further heightened in COPD-bronchiectasis? STUDY DESIGN AND METHODS: Electronic health care records (from 2004-2019) were used to obtain a cohort of patients with COPD and a nested case-control group (age and sex matched 1:4). Analyses were conducted to determine the risk of hospitalization for pneumonia in COPD associated with ICS use in those with bronchiectasis. Findings were confirmed by several sensitivity analyses. Additionally, a smaller nested case-control group containing only patients with COPD-bronchiectasis overlap and those with recent blood eosinophil counts (BECs) was used to determine any association with BEC. RESULTS: Three hundred sixteen thousand six hundred sixty-three patients were eligible for the COPD cohort; bronchiectasis significantly increased the risk of pneumonia (adjusted hazard ratio, 1.24; 95% CI, 1.15-1.33). In the first nested case-control group of 84,316 patients with COPD, ICS was found to increase the odds of pneumonia (adjusted OR [AOR], 1.26; 95% CI, 1.19-1.32) only if used in the previous 180 days. However, bronchiectasis was a significant modifier such that ICS use did not augment further the already elevated bronchiectasis-associated pneumonia risk (COPD-bronchiectasis: AOR, 1.01; 95% CI, 0.8-1.28; no bronchiectasis: AOR, 1.27; 95% CI, 1.20-1.34). Several sensitivity analyses and a second smaller nested case-control group confirmed these findings. Finally, we found that BEC modified the ICS-associated pneumonia risk in COPD-bronchiectasis overlap, where lower BEC was associated significantly with pneumonia (BEC ≤ 3 × 109/L: AOR, 1.56; 95% CI, 1.05-2.31; BEC > 3 × 109/L: AOR, 0.89; 95% CI, 0.53-1.24). INTERPRETATION: ICS use does not augment further the already increased risk of hospitalization for pneumonia associated with concomitant bronchiectasis in patients with COPD.

Favipiravir in patients hospitalised with COVID-19 (PIONEER trial): a multicentre, open-label, phase 3, randomised controlled trial of early intervention versus standard care.

BACKGROUND: COVID-19 has overwhelmed health services globally. Oral antiviral therapies are licensed worldwide, but indications and efficacy rates vary. We aimed to evaluate the safety and efficacy of oral favipiravir in patients hospitalised with COVID-19. METHODS: We conducted a multicentre, open-label, randomised controlled trial of oral favipiravir in adult patients who were newly admitted to hospital with proven or suspected COVID-19 across five sites in the UK (n=2), Brazil (n=2) and Mexico (n=1). Using a permuted block design, eligible and consenting participants were randomly assigned (1:1) to receive oral favipiravir (1800 mg twice daily for 1 day; 800 mg twice daily for 9 days) plus standard care, or standard care alone. All caregivers and patients were aware of allocation and those analysing data were aware of the treatment groups. The prespecified primary outcome was the time from randomisation to recovery, censored at 28 days, which was assessed using an intention-to-treat approach. Post-hoc analyses were used to assess the efficacy of favipiravir in patients aged younger than 60 years, and in patients aged 60 years and older. The trial was registered with clinicaltrials.gov, NCT04373733. FINDINGS: Between May 5, 2020 and May 26, 2021, we assessed 503 patients for eligibility, of whom 499 were randomly assigned to favipiravir and standard care (n=251) or standard care alone (n=248). There was no significant difference between those who received favipiravir and standard care, relative to those who received standard care alone in time to recovery in the overall study population (hazard ratio [HR] 1·06 [95% CI 0·89-1·27]; n=499; p=0·52). Post-hoc analyses showed a faster rate of recovery in patients younger than 60 years who received favipiravir and standard care versus those who had standard care alone (HR 1·35 [1·06-1·72]; n=247; p=0·01). 36 serious adverse events were observed in 27 (11%) of 251 patients administered favipiravir and standard care, and 33 events were observed in 27 (11%) of 248 patients receiving standard care alone, with infectious, respiratory, and cardiovascular events being the most numerous. There was no significant between-group difference in serious adverse events per patient (p=0·87). INTERPRETATION: Favipiravir does not improve clinical outcomes in all patients admitted to hospital with COVID-19, however, patients younger than 60 years might have a beneficial clinical response. The indiscriminate use of favipiravir globally should be cautioned, and further high-quality studies of antiviral agents, and their potential treatment combinations, are warranted in COVID-19. FUNDING: LifeArc and CW+.

Clinical and survival differences during separate COVID-19 surges: Investigating the impact of the Sars-CoV-2 alpha variant in critical care patients.

A number of studies have highlighted physiological data from the first surge in critically unwell Covid-19 patients but there is a paucity of data describing emerging variants of SARS-CoV-2, such as B.1.1.7. We compared ventilatory parameters, biochemical and physiological data and mortality between the first and second COVID-19 surges in the United Kingdom, where distinct variants of SARS-CoV-2 were the dominant stain. We performed a retrospective cohort study investigating critically unwell patients admitted with COVID-19 across three tertiary regional ICUs in London, UK. Of 1782 adult ICU patients screened, 330 intubated and ventilated patients diagnosed with COVID-19 were included. In the second wave where B.1.1.7 variant was the dominant strain, patients were had increased severity of ARDS whilst compliance was greater (p<0.05) and d-dimer lower. The 28-day mortality was not statistically significant (1st wave: 42.2% vs 2nd wave: 39.8%). However, when adjusted for key covariates, the hazard ratio for 28-day mortality in those patients with B.1.1.7 was 3.79 (CI 1.04-13.8; p = 0.043) compared to the original strain. During the second surge in the UK, where the COVID-19 variant B.1.1.7 was most prevalent, significantly more patients presented to critical care with severe ARDS. Furthermore, mortality risk was significantly greater in our ICU population during the second wave of the pandemic in those patients with B.1.1.7. As ICUs are experiencing further waves (particularly by the delta (B.1.617.2) variant), we highlight the urgent need for prospective studies describing immunological and pathophysiological differences across novel emerging variants.

Impact of the UK lockdown on people at risk of COPD.

Impact of the UK lockdown on early COPD https://bit.ly/3laMsmi.

Virus-induced Volatile Organic Compounds Are Detectable in Exhaled Breath during Pulmonary Infection.

Rationale: Chronic obstructive pulmonary disease (COPD) is a condition punctuated by acute exacerbations commonly triggered by viral and/or bacterial infection. Early identification of exacerbation triggers is important to guide appropriate therapy, but currently available tests are slow and imprecise. Volatile organic compounds (VOCs) can be detected in exhaled breath and have the potential to be rapid tissue-specific biomarkers of infection etiology. Objectives: To determine whether volatile organic compound measurement could distinguish viral from bacterial infection in COPD. Methods: We used serial sampling within in vitro and in vivo studies to elucidate the dynamic changes that occur in VOC production during acute respiratory viral infection. Highly sensitive gas chromatography-mass spectrometry techniques were used to measure VOC production from infected airway epithelial-cell cultures and in exhaled breath samples from healthy subjects experimentally challenged with rhinovirus (RV)-A16 and from subjects with COPD with naturally occurring exacerbations. Measurements and Main Results: We identified a novel VOC signature comprising decane and other long-chain alkane compounds that is induced during RV infection of cultured airway epithelial cells and is also increased in the exhaled breath from healthy subjects experimentally challenged with RV and from patients with COPD during naturally occurring viral exacerbations. These compounds correlated with the magnitude of antiviral immune responses, viral burden, and exacerbation severity but were not induced by bacterial infection, suggesting that they represent a specific virus-inducible signature. Conclusions: Our study highlights the potential for measurement of exhaled breath VOCs as rapid, noninvasive biomarkers of viral infection. Further studies are needed to determine whether measurement of these signatures could be used to guide more targeted therapy with antibiotic/antiviral agents for COPD exacerbations.

Definition, Causes, Pathogenesis, and Consequences of Chronic Obstructive Pulmonary Disease Exacerbations.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are episodes of symptom worsening which have significant adverse consequences for patients. Exacerbations are highly heterogeneous events associated with increased airway and systemic inflammation and physiological changes. The frequency of exacerbations is associated with accelerated lung function decline, quality of life impairment and increased mortality. They are triggered predominantly by respiratory viruses and bacteria, which infect the lower airway and increase airway inflammation. A proportion of patients appear to be more susceptible to exacerbations, with poorer quality of life and more aggressive disease progression than those who have infrequent exacerbations. Exacerbations also contribute significantly to healthcare expenditure. Prevention and mitigation of exacerbations are therefore key goals of COPD management.

Repurposing Existing Drugs for the Treatment of COVID-19.

The rapid global spread and significant mortality associated with the coronavirus disease (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection has spurred an urgent race to find effective treatments. Repurposing existing drugs is a particularly attractive approach as pharmacokinetic and safety data already exist; thus, development can leapfrog straight to clinical trials of efficacy, generating results far more quickly than de novo drug development. This review summarizes the state of play for the principle drugs identified as candidates to be repurposed for treating COVID-19 grouped by broad mechanism of action: antiviral, immune enhancing, and antiinflammatory or immunomodulatory. Patient selection, particularly with regard to disease stage, is likely to be key. To date, only dexamethasone and remdesivir have been shown to be effective, but several other promising candidates are in trials.

Targeted Retreatment of Incompletely Recovered Chronic Obstructive Pulmonary Disease Exacerbations with Ciprofloxacin. A Double-Blind, Randomized, Placebo-controlled, Multicenter, Phase III Clinical Trial.

Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations are prone to nonrecovery, but there are no data about the effectiveness of retreatment for these prolonged events. We examined whether further therapy with ciprofloxacin for incompletely resolved COPD exacerbations prolonged the time until the next event.Objectives: To assess whether incompletely recovered COPD exacerbations benefit from additional treatment with ciprofloxacin, at Day 14.Methods: In a multicenter, randomized double-blind placebo-controlled trial, we studied retreatment with oral ciprofloxacin 500 mg or matched placebo twice daily for 7 days in patients with Global Initiative for Chronic Obstructive Lung Disease stage II-IV COPD and persistent symptoms and/or serum C-reactive protein ≥8 mg/L initiated 14 (±3) days after an index COPD exacerbation. The primary outcome was the time to the next exacerbation within a 90-day period.Measurements and Main Results: Among 826 patients screened at four centers, 144 eligible participants with incomplete recovery were randomized to receive ciprofloxacin (n = 72) or placebo (n = 72). Within 90 days of randomization, 57% of the patients in the ciprofloxacin group and 53% in the placebo group experienced one or more exacerbations. The median time to the next exacerbation was 32.5 days (interquartile range 13-50) in the placebo arm and 34 days (interquartile range 17-62) in the ciprofloxacin arm, which was not significantly different (adjusted hazard ratio, 1.07; 95% confidence interval, 0.68-1.68; P = 0.76). No significant differences were seen in quality-of-life scores or lung function between the treatment groups.Conclusions: In patients with persistent symptoms and/or raised C-reactive protein 14 days after a COPD exacerbation, an additional course of ciprofloxacin resulted in no additional benefit compared with placebo. This suggests that nonrecovered exacerbations are not driven by ongoing bacterial infection and may potentially be targeted with antiinflammatory therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02300220).

Role of microbiome in the pathophysiology and disease course of asthma.

PURPOSE OF REVIEW: The emergence of next-generation 16S rRNA sequencing techniques has facilitated a more detailed study of the body's microbiota and led to renewed interest in the association between microbial exposure and asthma inception. In this review, we evaluate the evidence that the respiratory tract and intestinal microbiota contribute to asthma pathogenesis and progression. RECENT FINDINGS: Human studies have revealed associations between the presence of potentially pathogenic bacteria in the respiratory tract in early life and subsequent risk of allergic sensitization and asthma. Similarly, alterations in the intestinal microbiota of neonates have also been shown to precede the development of asthma. Emerging evidence suggests that the lung microbiota is dysregulated in asthma with specific changes in bacterial diversity and community composition according to severity and phenotype. Studies using germ-free mice have been invaluable in moving our understanding from correlation to causation by demonstrating a mechanistic link between the neonatal microbiota and the development of allergic airway inflammation. SUMMARY: An expanding body of literature supports the hypothesis that early life microbial exposures and bacterial communities within the lung and/or intestine play an important role in shaping early immunological development. Perturbations in the microbiota may promote immune defects associated with the development of asthma and allergic sensitization.

Airway Epithelial Orchestration of Innate Immune Function in Response to Virus Infection. A Focus on Asthma.

Asthma is a very common respiratory condition with a worldwide prevalence predicted to increase. There are significant differences in airway epithelial responses in asthma that are of particular interest during exacerbations. Preventing exacerbations is a primary aim when treating asthma because they often necessitate unscheduled healthcare visits and hospitalizations and are a significant cause of morbidity and mortality. The most common cause of asthma exacerbations is a respiratory virus infection, of which the most likely type is rhinovirus infection. This article focuses on the role played by the epithelium in orchestrating the innate immune responses to respiratory virus infection. Recent studies show impaired bronchial epithelial cell innate antiviral immune responses, as well as augmentation of a pro-Th2 response characterized by the epithelial-derived cytokines IL-25 and IL-33, crucial in maintaining the Th2 cytokine response to virus infection in asthma. A better understanding of the mechanisms of these abnormal immune responses has the potential to lead to the development of novel therapeutic targets for virus-induced exacerbations. The aim of this article is to highlight current knowledge regarding the role of viruses and immune modulation in the asthmatic epithelium and to discuss exciting areas for future research and novel treatments.