James Allinson

Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease

Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.

The Presence of Chronic Mucus Hypersecretion across Adult Life in Relation to Chronic Obstructive Pulmonary Disease Development

RATIONALE Chronic mucus hypersecretion (CMH) is common among smokers and is associated with chronic obstructive pulmonary disease development and progression. OBJECTIVES To understand how the relationships between smoking, CMH, and chronic obstructive pulmonary disease develop during adult life, and facilitate earlier disease detection and intervention. METHODS We analyzed data on CMH, smoking, and lung function prospectively collected by the Medical Research Council National Survey of Health and Development, a nationally representative British cohort followed since birth in 1946. We analyzed the longitudinal relationships between smoking and CMH, how symptoms during life related to airflow limitation at 60-64 years, and how CMH duration between ages 43 and 60-64 years related to concurrent FEV1 decline. MEASUREMENTS AND MAIN RESULTS From 5,362 individuals enrolled at birth, 4,427 contributed data between ages 20 and 64 years (52% male; 63% ever-smoker). Among smokers CMH prevalence escalated between ages 36 and 43 from 7.6 ± 2.0% to 13.0 ± 2.6%. At these ages, symptoms were associated with a higher risk of subsequent airflow limitation (odds ratio [95% confidence interval], 3.70 [1.62-8.45] and 4.11 [1.85-9.13], respectively). Across adult life, CMH followed a dynamic remitting-relapsing course. Symptom prevalence following smoking cessation returned to levels seen among never-smokers. The longer CMH was present across three occasions (ages 43, 53, and 60-64 yr), the greater the concurrent FEV1 decline, corresponding to an additional decrement of 3.6 ± 2.5 ml/yr per occasion that CMH was present (P = 0.005). CONCLUSIONS CMH among middle-aged smokers represents an early developmental phase of chronic obstructive pulmonary disease. Smoking-related CMH usually resolves following smoking cessation but the longer its duration the greater the FEV1 lost, suggesting the course of CMH across adult life may reflect the underlying course of airway disease activity.

Impact of Prolonged Exacerbation Recovery in Chronic Obstructive Pulmonary Disease

RATIONALE Exacerbations are important and heterogeneous events in the natural history of chronic obstructive pulmonary disease (COPD). OBJECTIVES To examine the consequences of prolonged exacerbation recovery in patients with COPD. METHODS A cohort of 384 patients with COPD (FEV1 % predicted 45.8 [SD, 16.6] and a median exacerbation rate of 2.13 per year [interquartile range, 1.0-3.2]) were followed for 1,039 days (interquartile range, 660-1,814) between October 1995 and January 2013. Patients recorded daily worsening of respiratory symptoms and peak expiratory flow (PEF), and when stable underwent spirometry every 3 months, and completed the St. Georges Respiratory Questionnaire annually. Exacerbations were diagnosed as 2 consecutive days with one major symptom plus another respiratory symptom. Exacerbation duration was defined as the time from onset to the day preceding 2 consecutive symptom-free days and recovery in PEF as return to preexacerbation levels. MEASUREMENTS AND MAIN RESULTS A total of 351 patients had one or more exacerbations. Patients with a longer symptom duration (mean, 14.5 d) had a worse St. Georges Respiratory Questionnaire total score (0.2 units per 1 day; P = 0.040). A longer symptomatic duration was associated with a shorter interval between exacerbation recovery and onset of the next exacerbation (hazard ratio, 1.004; P = 0.013). For 257 (7.3%) exacerbations, PEF did not recover within 99 days. These exacerbations were associated with symptoms of a viral infection (cold and sore throat). Patients with these nonrecovered exacerbations showed a 10.8 ml/yr (P < 0.001) faster decline in FEV1. CONCLUSIONS Prolonged exacerbation symptomatic duration is associated with poorer health status and a greater risk of a new event. Exacerbations where lung function does not recover are associated with symptoms of viral infections and accelerated decline in FEV1.

Combined Impact of Smoking and Early-Life Exposures on Adult Lung Function Trajectories

Rationale: Both adverse early‐life exposures and adult smoking can negatively influence adult lung function trajectory, but few studies consider how the impact of early‐life exposures may be modified by subsequent smoking. Methods: The Medical Research Council National Survey of Health and Development is a nationally representative cohort, initially of 5,362 individuals, followed since enrollment at birth in March 1946. Using data collected prospectively across life and multilevel modeling, we investigated how the relationships between early‐life exposures (infant lower respiratory infection, manual social class, home overcrowding, and pollution exposure) and FEV1 and FVC trajectories between ages 43 and 60‐64 years were influenced by smoking behavior. Measurements and Main Results: Among 2,172 individuals, there were synergistic interactions of smoking with infant respiratory infection (P = 0.04) and early‐life home overcrowding (P = 0.009), for FEV1 at 43 years. Within smoker‐stratified models, there were FEV1 deficits among ever‐smokers associated with infant lower respiratory infection (−108.2 ml; P = 0.001) and home overcrowding (−89.2 ml; P = 0.002), which were not evident among never‐smokers (−15.9 ml; P = 0.69 and −13.7 ml; P = 0.70, respectively). FVC modeling, including 1,960 individuals, yielded similar results. FEV1 decline was greater in smokers (P < 0.001), but there was no effect of any early‐life exposure on FEV1 decline. Neither smoking nor early‐life exposures were associated with FVC decline. Conclusions: Besides accelerating adult FEV1 decline, cigarette smoking also modifies how early‐life exposures impact on both midlife FEV1 and FVC. These findings are consistent with smoking impairing pulmonary development during adolescence or early adulthood, thereby preventing catch‐up from earlier acquired deficits.

Effects of different antibiotic classes on airway bacteria in stable COPD using culture and molecular techniques: a randomised controlled trial

Background Long-term antibiotic therapy is used to prevent exacerbations of COPD but there is uncertainty over whether this reduces airway bacteria. The optimum antibiotic choice remains unknown. We conducted an exploratory trial in stable patients with COPD comparing three antibiotic regimens against placebo. Methods This was a single-centre, single-blind, randomised placebo-controlled trial. Patients aged ≥45 years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400 mg daily for 5 days every 4 weeks, doxycycline 100 mg/day, azithromycin 250 mg 3 times a week or one placebo tablet daily for 13 weeks. The primary outcome was the change in total cultured bacterial load in sputum from baseline; secondary outcomes included bacterial load by 16S quantitative PCR (qPCR), sputum inflammation and antibiotic resistance. Results 99 patients were randomised; 86 completed follow-up, were able to expectorate sputum and were analysed. After adjustment, there was a non-significant reduction in bacterial load of 0.42 log10 cfu/mL (95% CI −0.08 to 0.91, p=0.10) with moxifloxacin, 0.11 (−0.33 to 0.55, p=0.62) with doxycycline and 0.08 (−0.38 to 0.54, p=0.73) with azithromycin from placebo, respectively. There were also no significant changes in bacterial load measured by 16S qPCR or in airway inflammation. More treatment-related adverse events occurred with moxifloxacin. Of note, mean inhibitory concentrations of cultured isolates increased by at least three times over placebo in all treatment arms. Conclusions Total airway bacterial load did not decrease significantly after 3 months of antibiotic therapy. Large increases in antibiotic resistance were seen in all treatment groups and this has important implications for future studies. Trial registration number clinicaltrials.gov (NCT01398072).

Physical activity and exercise capacity in patients with moderate COPD exacerbations.

Little is known about changes in physical activity during moderate (out-patient managed) exacerbations. 6-min walking distance (6MWD) was measured during 50 exacerbations when the patients were stable, and at 3 and 7 days post-exacerbation presentation. At similar time points, quadriceps maximum voluntary contraction (QMVC) was measured during 47 different exacerbations. Physical activity (SenseWear; Bodymedia Inc., Pittsburgh, PA, USA) was recorded over 2 consecutive-week periods post-presentation. 6MWD fell from a median 422 m when stable to 373 m on day 3 (p=0.001). Similarly, QMVC fell from 32.6 versus 29.7 kg (p=0.026). Falls in 6MWD were associated with a rise in C-reactive protein (r= −0.364; p=0.041) and increased Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) (r= −0.44; p=0.013). Light physical activity was 2.18 h·day−1 during the first week post-exacerbation and was less over week 2 (1.98 h·day−1; p=0.009). Patients who had attended pulmonary rehabilitation had smaller changes in 6MWD than those who had not attended (−35.0 versus −114.9 m; p=0.013). Falls in physical activity were correlated with higher depression scores (rho= −0.51; p=0.006). These findings indicate that exercise capacity and muscle strength fall at exacerbation in chronic obstructive pulmonary disease patients who are treated at home and are free to maintain normal activity. Falls in physical capacity and muscle strength during COPD exacerbations managed in the community http://ow.ly/ZtU45

Upper Respiratory Symptoms Worsen over Time and Relate to Clinical Phenotype in Chronic Obstructive Pulmonary Disease

RATIONALE How nasal symptoms in patients with chronic obstructive pulmonary disease (COPD) change over time and resolve during naturally occurring exacerbations has not been described previously. OBJECTIVES To evaluate the evolution and impact of upper airway symptoms in a well-defined COPD cohort when stable and at exacerbation. METHODS Patients in the London COPD cohort were asked about the presence of nasal symptoms (nasal discharge, sneezing, postnasal drip, blocked nose, and anosmia) over an 8-year period (2005-2013) every 3 months at routine clinic visits while in a stable state and daily during exacerbations with the use of diary cards. Data were prospectively collected, and, in a subgroup of patients, COPD Assessment Test scores and human rhinovirus identification by polymerase chain reaction were available. Patients were also defined as having infrequent or frequent exacerbations (<2 or ≥2 exacerbations/yr, respectively). MEASUREMENTS AND MAIN RESULTS At an aggregate of 4,368 visits, 209 patients with COPD were asked about their nasal symptoms. At 2,033 visits when the patients were stable, the odds ratio (OR) for nasal discharge increased by 1.32% per year (95% confidence interval [CI], 1.19-1.45; P < 0.001); the OR for sneezing increased by 1.16% (95% CI, 1.05-1.29; P = 0.005); the OR for postnasal drip increased by 1.18% (95% CI, 1.03-1.36; P = 0.016); and the OR for anosmia increased by 1.19% (95% CI, 1.03-1.37; P = 0.015). At visits when the patients were having exacerbations, nasal discharge was present for 7 days and blocked nose, sneezing, and postnasal drip increased for just 3 days. Anosmia did not change. Nasal discharge was more likely in patients with frequent exacerbations (OR, 1.96; 95% CI, 1.17-3.28; P = 0.011), and COPD Assessment Test scores were higher by 1.06 units (95% CI, 0.32-1.80; P = 0.005) when patients were stable and higher by 1.30 units (95% CI, 0.05-2.57; P = 0.042) during exacerbations. CONCLUSIONS Upper airway symptoms increase over time in patients with COPD and are related to the frequent exacerbation phenotype. These longitudinal changes may be due to increasing airway inflammation or to progression of COPD.

Community-based recruitment of patients with COPD into clinical research

Abstract Identifying subjects for clinical trials is difficult and the evidence base for recruitment strategies is limited, particularly in the field of COPD. We compared the efficiency and patient characteristics of different community-based recruitment strategies during a non-commercial COPD trial in the UK. Recruiting from general practice COPD registers was less efficient and identified patients with significantly milder disease than recruiting through pulmonary rehabilitation and patient groups. We report our experience and propose that pulmonary rehabilitation and patient groups may represent an enriched pool of COPD patients to recruit into clinical trials. Trial registration number: EudraCT 2011-001063-43

Update in Chronic Obstructive Pulmonary Disease 2016

Chronic obstructive pulmonary disease (COPD) describes a predominantly smokinginduced small airway and/or emphysematous disease associated with airflow limitation. Considered progressive, irreversible, and responsible for substantial morbidity and mortality worldwide, COPD remains the subject of vigorous study, and advances made during 2016 are already reflected in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines (1). Researchers continue to explore strategies, pharmacological or otherwise, to improve the lives of those who have developed this condition; and it is hoped, by improving phenotyping of this heterogeneous disease, that we might ultimately deliver personalized medicine. Debate remains over how to identify undiagnosed COPD in individuals who would benefit from intervention, while avoiding overdiagnosis, and these controversies perhaps highlight shortcomings in accepted disease definitions. Not unrelatedly, renewed interest has emerged in explaining why some individuals develop COPD and identifying the formative stages of COPD development.

Sputum microbiome temporal variability and dysbiosis in chronic obstructive pulmonary disease exacerbations: an analysis of the COPDMAP study

Background Recent studies suggest that lung microbiome dysbiosis, the disease associated disruption of the lung microbial community, might play a key role in chronic obstructive pulmonary disease (COPD) exacerbations. However, characterising temporal variability of the microbiome from large longitudinal COPD cohorts is needed to better understand this phenomenon. Methods We performed a 16S ribosomal RNA survey of microbiome on 716 sputum samples collected longitudinally at baseline and exacerbations from 281 subjects with COPD at three UK clinical centres as part of the COPDMAP consortium. Results The microbiome composition was similar among centres and between stable and exacerbations except for a small significant decrease of Veillonella at exacerbations. The abundance of Moraxella was negatively associated with bacterial alpha diversity. Microbiomes were distinct between exacerbations associated with bacteria versus eosinophilic airway inflammation. Dysbiosis at exacerbations, measured as significant within subject deviation of microbial composition relative to baseline, was present in 41% of exacerbations. Dysbiosis was associated with increased exacerbation severity indicated by a greater fall in forced expiratory volume in one second, forced vital capacity and a greater increase in CAT score, particularly in exacerbations with concurrent eosinophilic inflammation. There was a significant difference of temporal variability of microbial alpha and beta diversity among centres. The variation of beta diversity significantly decreased in those subjects with frequent historical exacerbations. Conclusions Microbial dysbiosis is a feature of some exacerbations and its presence, especially in concert with eosinophilic inflammation, is associated with more severe exacerbations indicated by a greater fall in lung function. Trial registration number Results, NCT01620645.