A Double-Blind, Randomized, Placebo-controlled Trial of Long-Term Doxycycline Therapy on Exacerbation Rate in Patients with Stable Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of morbidity and mortality, and preventing them is a key treatment target. Long-term macrolide treatment is effective at reducing exacerbations, but there is a paucity of evidence for other antibiotic classes. Objectives: To assess whether 12-month use of doxycycline reduces the exacerbation rate in people with COPD. Methods: People with moderate to very severe COPD and an exacerbation history were recruited from three UK centers and randomized to 12 months of doxycycline 100 mg once daily or placebo. The primary study outcome was the exacerbation rate per person-year. Results: A total of 222 people were randomized. Baseline mean FEV1 was 1.35 L (SD, 0.35 L), 52.5% predicted (SD, 15.9% predicted). The median number of treated exacerbations in the year before the study was 2 (SD, 1-4). A total of 71% of patients reported two or more exacerbations, and 81% were already prescribed inhaled corticosteroids at baseline. The COPD exacerbation rate did not differ between the groups (doxycycline/placebo rate ratio [RR], 0.86; 95% confidence interval [CI], 0.67-1.10; P = 0.23). No difference was seen if only treated exacerbations or hospitalizations were considered. In preplanned subgroup analysis, doxycycline appeared to better reduce the exacerbation rate among people with severe COPD (RR, 0.36; 95% CI, 0.15-0.85; P = 0.019) and in those with an eosinophil count <300 cells/µl (RR, 0.50; 95% CI, 0.29-0.84; P = 0.01). Health status measured by St. George's Respiratory Questionnaire was 5.2 points worse in the doxycycline group at 12 months (P < 0.007). Conclusions: Doxycycline did not significantly reduce the exacerbation rate, over 12 months, in participants with COPD who exacerbated regularly, but it may have benefitted those with more severe COPD or blood eosinophil counts <300 cells/µl. Clinical trial registered with www.clinicaltrials.gov (NCT02305940).

Contemporary Concise Review 2022: Chronic obstructive pulmonary disease.

International respiratory organizations now recommend using lower limit of normal and standardized residuals to diagnose airflow obstruction and COPD though using a fixed ratio <0.7 is simpler and robustly predicts important clinical outcomes. The most common COPD comorbidities are coronary artery calcification, emphysema and bronchiectasis. COPD patients with psychological (high anxiety and depression) and cachectic (underweight and osteoporotic) comorbidity have higher mortality and exacerbate more. Serum eosinophil count remains an important COPD biomarker and we have greater clarity about normal eosinophil levels in COPD and the wider population. Criteria for entry into COPD clinical trials continue to exclude many patients, in particular those at greater risk of exacerbation and death. The effect of hyperinflation on cardiac function impacts COPD mortality and is an important target for successful lung volume reduction procedures.

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).

Telemonitoring in Chronic Obstructive Pulmonary Disease (CHROMED). A Randomized Clinical Trial.

RATIONALE: Early detection of chronic obstructive pulmonary disease (COPD) exacerbations using telemonitoring of physiological variables might reduce the frequency of hospitalization. OBJECTIVES: To evaluate the efficacy of home monitoring of lung mechanics by the forced oscillation technique and cardiac parameters in older patients with COPD and comorbidities. METHODS: This multicenter, randomized clinical trial recruited 312 patients with Global Initiative for Chronic Obstructive Lung Disease grades II to IV COPD (median age, 71 yr [interquartile range, 66-76 yr]; 49.6% grade II, 50.4% grades III-IV), with a history of exacerbation in the previous year and at least one nonpulmonary comorbidity. Patients were randomized to usual care (n = 158) or telemonitoring (n = 154) and followed for 9 months. All telemonitoring patients self-assessed lung mechanics daily, and in a subgroup with congestive heart failure (n = 37) cardiac parameters were also monitored. An algorithm identified deterioration, triggering a telephone contact to determine appropriate interventions. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were time to first hospitalization (TTFH) and change in the EuroQoL EQ-5D utility index score. Secondary outcomes included: rate of antibiotic/corticosteroid prescription; hospitalization; the COPD Assessment Tool, Patient Health Questionnaire-9, and Minnesota Living with Heart Failure questionnaire scores; quality-adjusted life years; and healthcare costs. Telemonitoring did not affect TTFH, EQ-5D utility index score, antibiotic prescriptions, hospitalization rate, or questionnaire scores. In an exploratory analysis, telemedicine was associated with fewer repeat hospitalizations (-54%; P = 0.017). CONCLUSIONS: In older patients with COPD and comorbidities, remote monitoring of lung function by forced oscillation technique and cardiac parameters did not change TTFH and EQ-5D. Clinical trial registered with www.clinicaltrials.gov (NCT 01960907).

A Screening Study to Determine the Prevalence of Airway Disease in Heroin Smokers.

Over the last 20 years smoking has become the most common method of heroin use and increasing numbers of heroin smokers are presenting to local medical services, before the age of 40 years, with severe airway disease. To determine COPD prevalence we recruited 129 subjects from two local community drug services, of whom 107 were heroin smokers. We collected demographic, medical and treatment data, smoking history (including cannabis and opiates) and details of symptoms including MRC dyspnoea. Subjects completed the COPD Assessment Tool and spirometry. Thirty heroin smokers were identified as having COPD resulting in a COPD prevalence of 28%. Mean age was 43 (4) years and FEV1 was 2.71 (0.98) L; 70 (23) %predicted. Breathlessness and wheeze were more common in subjects with COPD (p < 0.04 and p < 0.05) but symptoms were common in all heroin smokers. MRC score was higher (3 vs. 2.4; p < 0.04) in those with COPD and health status appeared poorer (CAT 20.4 vs. 15.8; p < 0.07). Only 4 (11%) had previously been diagnosed with COPD and only 16 (53%) received any inhaled medication. Asthma prevalence was also high at 33% and asthmatic subjects had similar symptoms and health status compared with the COPD subjects, and were also significantly undertreated. COPD and asthma are common in current and former heroin smokers. They are often present at a young age and are underdiagnosed and undertreated. Awareness of this issue should be highlighted within drug services and in particular to heroin smokers. Screening this high-risk population with spirometry should be considered.

Improving the diagnosis and management of COPD.

COPD is a progressive condition. Therefore, earlier diagnosis allows earlier intervention in particular smoking cessation. Stopping smoking in early middle age where an individual has relatively mild COPD is associated with a slower decline in lung function and reduced mortality. Spirometry should be performed in symptomatic current or former smokers (typically ≥ 10 pack years) who are aged at least 35 where COPD is a likely differential diagnosis. Once airflow obstruction is proven and a diagnosis of COPD established then a measure of COPD severity can be made based on FEV1 expressed as a percentage of predicted value. When an individual with COPD is assessed it is vital that comorbid conditions are considered and management optimised. Cardiovascular disease and diabetes were seen most commonly in people enrolled in the active and sometimes sleep. The COPD Assessment Tool is a simple measure of health status that takes under five minutes to complete. Performing spirometry each year can identify patients with a rapid, progressive decline in lung function and allow this to be addressed. Inhaler technique should be checked at this review and also when a new type of inhaler is commenced.

Commentary: the British Thoracic Society guideline on pulmonary rehabilitation in adults.

The first British Thoracic Society guideline on pulmonary rehabilitation in adults is published in the accompanying Thorax supplement. Focusing on delivery of a quality pulmonary rehabilitation service, the evidenced-based guideline encompasses recommendations on the composition of the service, referral of patients and who benefits, the expected patient-related outcome measures and markers, pulmonary rehabilitation following exacerbations, the post-rehabilitation period and areas requiring further research. In this commentary, we introduce the guideline and discuss pulmonary rehabilitation in the wider context of chronic disease management of respiratory patients.

BronchUK: protocol for an observational cohort study and biobank in bronchiectasis.

Bronchiectasis has been a largely overlooked disease area in respiratory medicine. This is reflected by a shortage of large-scale studies and lack of approved therapies, in turn leading to a variation of treatment across centres. BronchUK (Bronchiectasis Observational Cohort and Biobank UK) is a multicentre, prospective, observational cohort study working collaboratively with the European Multicentre Bronchiectasis Audit and Research Collaboration project. The inclusion criteria for patients entering the study are a clinical history consistent with bronchiectasis and computed tomography demonstrating bronchiectasis. Main exclusion criteria are 1) patients unable to provide informed consent, 2) bronchiectasis due to known cystic fibrosis or where bronchiectasis is not the main or co-dominant respiratory disease, 3) age <18 years, and 4) prior lung transplantation for bronchiectasis. The study is aligned to standard UK National Health Service (NHS) practice with an aim to recruit a minimum of 1500 patients from across at least nine secondary care centres. Patient data collected at baseline includes demographics, aetiology testing, comorbidities, lung function, radiology, treatments, microbiology and quality of life. Patients are followed up annually for a maximum of 5 years and, where able, blood and/or sputa samples are collected and stored in a central biobank. BronchUK aims to collect robust longitudinal data that can be used for analysis into current NHS practice and patient outcomes, and to become an integral resource to better inform future interventional studies in bronchiectasis.

Opportunistic case finding pivotal in diagnosing COPD.

The principle of COPD diagnosis is based on establishing the presence of obstructive post-bronchodilator spirometry in an at-risk individual with appropriate symptoms. Most individuals diagnosed with COPD have substantial cigarette smoke exposure, more than 10 and usually 20 pack years. Patients with COPD usually have symptoms of cough and phlegm, exertional breathlessness, wheezing, recurrent winter bronchitis or a combination of these symptoms. A current or ex-smoker, aged over 35, with respiratory symptoms should undergo spirometry testing. The hallmark of COPD is the presence of airflow obstruction after administration of a bronchodilator. However, while normal spirometry excludes COPD, obstructive spirometry is also seen in asthma and bronchiectasis emphasising the importance of clinical features. A significant change introduced in the 2010 NICE guideline is the new grading of COPD severity. A system based on FEV alone oversimplifies disease severity and full clinical assessment should include symptoms, frequency of exacerbations and impact of disease on functioning and health status. The most important single intervention is smoking cessation as this is proven to reduce decline in FEV1 and reduce mortality. All patients should also receive influenza and pneumococcal vaccination, weight management, pulmonary rehabilitation (if breathless) and short-acting bronchodilators. The evidence base for rehabilitation is very strong with positive effects shown on breathlessness, exercise capacity, activity level, exacerbation rate, leg muscle strength and quality of life.

Screening Heroin Smokers Attending Community Drug Clinics for Change in Lung Function: A Cohort Study.

BACKGROUND: Heroin smokers have high rates of COPD, respiratory morbidity, hospital admission, and mortality. We assessed the natural history of symptoms and lung function in this population over time. METHODS: A cohort of heroin smokers with COPD was followed for 18 to 24 months. At baseline and follow-up, respiratory symptoms were measured by the Medical Research Council Dyspnea Scale (MRC) and the COPD Assessment Tool (CAT), and postbronchodilator spirometry was performed. Frequency of health-care-seeking episodes was extracted from routine health records. Parametric, nonparametric, and linear regression models were used to analyze the change in symptoms and lung function over time. RESULTS: Of 372 participants originally recruited, 161 were assessed at follow-up (mean age, 51.0 ± 5.3 years; 74 women [46%]) and 106 participants completed postbronchodilator spirometry. All participants were current or previous heroin smokers, and 122 (75.8%) had smoked crack. Symptoms increased over time (MRC score increased by 0.48 points per year, P < .001; CAT score increased by 1.60 points per year, P < .001). FEV1 declined annually by 90 ± 190 mL (P < .001). This deterioration was not associated with change in tobacco or heroin smoking status or use of inhaled medications. CONCLUSIONS: Heroin smokers experience a high and increasing burden of chronic respiratory symptoms and a decline in FEV1 that exceeds the normal age-related decline observed among tobacco smokers with COPD and healthy nonsmokers. Targeted COPD diagnostic and treatment services hosted within opiate substitution services could benefit this vulnerable, relatively inaccessible, and underserved group of people.

Screening Heroin Smokers Attending Community Drug Services for COPD.

BACKGROUND: Heroin smoking is associated with deprivation, early onset severe emphysema, premature morbidity and mortality, and high use of health care, but individuals engage poorly with traditional health services. METHODS: In this cross-sectional study, we screened a population of heroin smokers, prescribed opiate substitution therapy by community drug services, for airway disease. We assessed drug exposure, respiratory symptoms, health status, and COPD prevalence. Subjects completed spirometry, completed Medical Research Council (MRC) Dyspnea Scale, COPD Assessment Tool (CAT) questionnaire, recorded drug exposure, and provided feedback. RESULTS: A total of 753 people (73% of those approached) completed screening, with 260 participants (35%) having COPD using FEV1/FVC < 0.7 and 293 (39%) participants having COPD using the lower limit of normal. A further 112 participants (15%) had asthma-COPD overlap (ACO) with features of COPD and asthma. Compared with those with normal spirometry, participants with COPD were more breathless (MRC score 3.1 vs 1.9; P < .001) and had worse health status (CAT score 22.9 vs 13.4; P < .001), respectively. Individuals with COPD had smoked cigarettes (P < .001), heroin (P < .001), and crack (P = .03) for longer and were more likely to still be smoking heroin (P < .01). Feedback was strongly positive, with 92% of respondents happy for other health-care appointments to be colocated with drug key worker appointments. CONCLUSIONS: Most heroin smokers had COPD or ACO, most commonly mild to moderate disease. In high-risk areas, screening this population provides an opportunity to reduce symptoms and risk. Anchoring respiratory health screening to drug center appointments delivers high completion and satisfaction and is an appropriate model for screening other hard-to-reach populations.

Non-typeable Haemophilus influenzae protein vaccine in adults with COPD: A phase 2 clinical trial.

Loss of airway microbial diversity is associated with non-typeable Haemophilus influenzae (NTHi) infection and increased risk of exacerbation in chronic obstructive pulmonary disease (COPD). We assessed the safety and immunogenicity of an investigational vaccine containing NTHi antigens, recombinant protein D (PD) and combined protein E and Pilin A (PE-PilA), and AS01 adjuvant in adults with moderate/severe COPD and prior exacerbations. In this phase 2, observer-blind, controlled trial (NCT02075541), 145 COPD patients aged 40-80 years randomly (1:1) received two doses of NTHi vaccine or placebo 60 days apart, on top of standard care. Reactogenicity in the 7-day post-vaccination period was higher following NTHi vaccine than placebo. Most solicited adverse events (AEs) were mild/moderate. At least one unsolicited AE was reported during the 30-day post-vaccination period by 54.8% of NTHi vaccine and 51.4% of placebo recipients. One serious AE (placebo group) was assessed by the investigator as vaccine-related. Anti-PD, anti-PE and anti-PilA geometric mean antibody concentrations increased up to 30 days after each NTHi vaccine dose, waned thereafter, but remained higher than baseline (non-overlapping confidence intervals) up to 13 months post-dose 2. The frequency of specific CD4+ T cells increased following two doses of NTHi vaccine and remained higher than baseline. Exploratory analysis showed a statistically non-significant lower yearly rate of moderate/severe exacerbations in the NTHi vaccine group than following placebo (1.49 versus 1.73) in the one-year period post-dose 2, with estimated vaccine efficacy of 13.3% (95% confidence interval -24.2 to 39.5; p = 0.44). The NTHi vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in adults with COPD.

The volumetric response to bronchodilators in stable chronic obstructive pulmonary disease.

A significant proportion of patients with COPD show post-bronchodilator improvement in lung volume even though this response is rarely considered when classifying subjects as having reversible or irreversible airway disease. We studied 266 patients with a clinical and physiological diagnosis of COPD who underwent pulmonary function testing and had their spirometric response to 5 mg salbutamol assessed. After the bronchodilator 125 (47%) patients increased their forced vital capacity by more than the known variability of the test while 60 (23%) showed only a volume response without improvement in expiratory flow. These 'volume responders' had greater degrees of airflow obstruction-lower FEV(1) (p < 0.001) and FEV(1)/FVC (p < 0.05)-and a higher residual volume at rest (p = 0.005) with similar degrees of emphysema measured by K(CO). Subjects with evidence of greater dynamic airway collapse, assessed by the ratio of early to mid expiratory flow, were less likely to have a flow response but more likely to have a volume response after salbutamol (p < 0.005). This would be compatible with volume response being commoner in patients who exhibit tidal expiratory flow limitation. We suggest that post-bronchodilator absolute change in FVC provides important additional physiological information when interpreting bronchodilator reversibility testing.

Effect of ß-blockade on lung function, exercise performance and dynamic hyperinflation in people with arterial vascular disease with and without COPD.

INTRODUCTION: ß Blockers are important treatment for ischaemic heart disease and heart failure; however, there has long been concern about their use in people with chronic obstructive pulmonary disease (COPD) due to fear of symptomatic worsening of breathlessness. Despite growing evidence of safety and efficacy, they remain underused. We examined the effect of ß-blockade on lung function, exercise performance and dynamic hyperinflation in a group of vascular surgical patients, a high proportion of who were expected to have COPD. METHODS: People undergoing routine abdominal aortic aneurysm (AAA) surveillance were sequentially recruited from vascular surgery clinic. They completed plethysmographically measured lung function and incremental cardiopulmonary exercise testing with dynamic measurement of inspiratory capacity while taking and not taking ß blocker. RESULTS: 48 participants completed tests while taking and not taking ß blockers with 38 completing all assessments successfully. 15 participants (39%) were found to have, predominantly mild and undiagnosed, COPD. People with COPD had airflow obstruction, increased airway resistance (Raw) and specific conductance (sGaw), static hyperinflation and dynamically hyperinflated during exercise. In the whole group, ß-blockade led to a small fall in FEV1 (0.1 L/2.8% predicted) but did not affect Raw, sGaw, static or dynamic hyperinflation. No difference in response to ß-blockade was seen in those with and without COPD. CONCLUSIONS: In people with AAA, ß-blockade has little effect on lung function and dynamic hyperinflation in those with and without COPD. In this population, the prevalence of COPD is high and consideration should be given to case finding with spirometry. TRIAL REGISTRATION NUMBER: NCT02106286.

The Association Between Heroin Inhalation and Early Onset Emphysema.

BACKGROUND: Inhalation/smoking has become the most common method of recreational opiate consumption in the United Kingdom and other countries. Although some heroin smokers appear to develop COPD, little is known about the association. METHODS: We present data from a cohort of 73 heroin smokers with clinician-diagnosed and spirometrically confirmed COPD, seen within our clinical service, where symptoms developed before the age of 40 years. RESULTS: The whole group mean age at diagnosis was 41 years, subjects had smoked heroin for 14 years, and mean FEV1 was 1.08 L (31.5% predicted), with mean FEV1/FVC of 0.4. No subject was found to have severe α1-antitrypsin deficiency. Forty-four subjects had either a high-resolution CT (HRCT) scan (32) or measurement of lung diffusion (12). Overall HRCT scan emphysema score averaged across the upper, middle, and lower part of the lung was 2.3 (5%-25% emphysema), with 47% subjects having an upper lobe emphysema score ≥ 3 (25%-50% emphysema). Median diffusing capacity of the lung for carbon monoxide was 48% of predicted value. CONCLUSIONS: Recreational smoking of heroin appears to lead to early onset COPD with a predominant emphysema phenotype. This message is important to both clinicians and the public, and targeted screening and education of this high-risk population may be justified.

Bronchodilator reversibility in chronic obstructive pulmonary disease: use and limitations.

The change in forced expiratory volume in 1 s (FEV1) after administration of a short-acting bronchodilator has been widely used to identify patients with chronic obstructive pulmonary disease (COPD) who have a potentially different disease course and response to treatment. Despite the apparent simplicity of the test, it is difficult to interpret or rely on. Test performance is affected by the day of testing, the severity of baseline lung-function impairment, and the number of drugs given to test. Recent data suggest that the response to bronchodilators is not enhanced in patients with COPD and does not predict clinical outcomes. In this Review we will discuss the insight that studies of bronchodilator reversibility have provided into the nature of the COPD, and how the abnormal physiology seen in patients with this disorder can be interpreted.