Gavin Donaldson

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

RATIONALEnChronic mucus hypersecretion (CMH) is common among smokers and is associated with chronic obstructive pulmonary disease development and progression.nnnOBJECTIVESnTo understand how the relationships between smoking, CMH, and chronic obstructive pulmonary disease develop during adult life, and facilitate earlier disease detection and intervention.nnnMETHODSnWe 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.nnnMEASUREMENTS AND MAIN RESULTSnFrom 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).nnnCONCLUSIONSnCMH 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

RATIONALEnExacerbations are important and heterogeneous events in the natural history of chronic obstructive pulmonary disease (COPD).nnnOBJECTIVESnTo examine the consequences of prolonged exacerbation recovery in patients with COPD.nnnMETHODSnA 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.nnnMEASUREMENTS AND MAIN RESULTSnA 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; Pu2009=u20090.040). A longer symptomatic duration was associated with a shorter interval between exacerbation recovery and onset of the next exacerbation (hazard ratio, 1.004; Pu2009=u20090.013). 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 (Pu2009<u20090.001) faster decline in FEV1.nnnCONCLUSIONSnProlonged 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.

Influence of weather and atmospheric pollution on physical activity in patients with COPD

RationaleInformation concerning how climate and atmospheric pollutants affects physical activity in COPD patients is lacking and might be valuable in determining when physical activity should be encouraged.MethodsSeventy-three stable COPD patients recorded on daily diary cards worsening of respiratory symptoms, peak expiratory flow rate, hours spent outside the home and the number of steps taken per day. Pedometry data was recorded on 16,478xa0days, an average of 267xa0days per patient (range 29-658). Daily data for atmospheric PM10 and ozone (O3) were obtained for Bloomsbury Square, Central London from the Air Quality Information Archive databases. Daily weather data were obtained for London Heathrow from the British Atmospheric Data Archive.ResultsColder weather below 22.5xa0°C, reduced daily step count by 43.3 steps day per°C (95 % CI 2.14 to 84.4; pu2009=u20090.039) and activity was lower on rainy than dry days (pu2009=u20090.002) and on overcast compared to sunny days (pu2009<u20090.001). Daily step count was 434 steps per day lower on Sunday than Saturday (pu2009<u20090.001) and 353 steps per day lower on Saturday than Friday (pu2009<u20090.001). After allowance for these effects, higher O3 levels decreased activity during the whole week (-8 steps/ug/m3; pu2009=u20090.005) and at weekends (-7.8 steps/ug/m3; pu2009=u20090.032). Whilst, during the week PM10 reduced activity (pu2009=u20090.018) but not during the weekend.ConclusionsInactivity of COPD patients is greatest on cold, wet and overcast days and at the weekends. This study also provides evidence of an independent effect of atmospheric pollution at high levels.

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 ≥45u2005years with COPD, FEV1<80% predicted and chronic productive cough were randomised to receive either moxifloxacin 400u2005mg daily for 5u2005days every 4u2005weeks, doxycycline 100u2005mg/day, azithromycin 250u2005mg 3 times a week or one placebo tablet daily for 13u2005weeks. 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 log10u2005cfu/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 3u2005months 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 7u2005days 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 422u2005m when stable to 373u2005m on day 3 (p=0.001). Similarly, QMVC fell from 32.6 versus 29.7u2005kg (p=0.026). Falls in 6MWD were associated with a rise in C-reactive protein (r=u200a−0.364; p=0.041) and increased Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) (r=u200a−0.44; p=0.013). Light physical activity was 2.18u2005h·day−1 during the first week post-exacerbation and was less over week 2 (1.98u2005h·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 −114.9u2005m; p=0.013). Falls in physical activity were correlated with higher depression scores (rho=u200a−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

Differential Effects of p38, MAPK, PI3K or Rho Kinase Inhibitors on Bacterial Phagocytosis and Efferocytosis by Macrophages in COPD

Pulmonary inflammation and bacterial colonization are central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Defects in macrophage phagocytosis of both bacteria and apoptotic cells contribute to the COPD phenotype. Small molecule inhibitors with anti-inflammatory activity against p38 mitogen activated protein kinases (MAPKs), phosphatidyl-inositol-3 kinase (PI3K) and Rho kinase (ROCK) are being investigated as novel therapeutics in COPD. Concerns exist, however, about off-target effects. We investigated the effect of p38 MAPK inhibitors (VX745 and SCIO469), specific inhibitors of PI3K α (NVS-P13K-2), δ (NVS-P13K-3) or γ (NVS-P13K-5) and a ROCK inhibitor PF4950834 on macrophage phagocytosis, early intracellular killing of bacteria and efferocytosis of apoptotic neutrophils. Alveolar macrophages (AM) obtained from broncho-alveolar lavage (BAL) or monocyte-derived macrophages (MDM) from COPD patients (GOLD stage II/III) enrolled from a well characterized clinical cohort (MRC COPD-MAP consortium) or from healthy ex-smoker controls were studied. Both COPD AM and MDM exhibited lower levels of bacterial phagocytosis (using Streptococcus pneumoniae and non-typeable Haemophilus influenzae) and efferocytosis than healthy controls. None of the inhibitors altered bacterial internalization or early intracellular bacterial killing in AM or MDM. Conversely PF4950834, but not other inhibitors, enhanced efferocytosis in COPD AM and MDM. These results suggest none of these inhibitors are likely to exacerbate phagocytosis-related defects in COPD, while confirming ROCK inhibitors can enhance efferocytosis in COPD.

Blood and sputum eosinophils in COPD; relationship with bacterial load

BackgroundSputum and blood eosinophil counts predict corticosteroid effects in COPD patients. Bacterial infection causes increased airway neutrophilic inflammation. The relationship of eosinophil counts with airway bacterial load in COPD patients is uncertain. We tested the hypothesis that bacterial load and eosinophil counts are inversely related.MethodsCOPD patients were seen at stable state and exacerbation onset. Sputum was processed for quantitative polymerase chain reaction detection of the potentially pathogenic microorganisms (PPM) H. influenzae, M. catarrhalis and S. pneumoniae. PPM positive was defined as total load ≥1u2009×u2009104copies/ml. Sputum and whole blood were analysed for differential cell counts.ResultsAt baseline, bacterial counts were not related to blood eosinophils, but sputum eosinophil % was significantly lower in patients with PPM positive compared to PPM negative samples (medians: 0.5% vs. 1.25% respectively, pu2009=u20090.01). Patients with PPM positive samples during an exacerbation had significantly lower blood eosinophil counts at exacerbation compared to baseline (medians: 0.17u2009×u2009109/L vs. 0.23u2009×u2009109/L respectively, pu2009=u20090.008), while no blood eosinophil change was observed with PPM negative samples.ConclusionsThese findings indicate an inverse relationship between bacterial infection and eosinophil counts. Bacterial infection may influence corticosteroid responsiveness by altering the profile of neutrophilic and eosinophilic inflammation.

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.

Patient Reported Outcomes for the Detection, Quantification and Evaluation of Chronic Obstructive Pulmonary Disease Exacerbations.

Abstract An exacerbation of chronic obstructive pulmonary disease (COPD) is an acute worsening of respiratory symptoms accompanied by a variable degree of physiological deterioration. The traditional assessment of an exacerbation consists of the reporting of symptoms by the patient to a clinician and subsequent clinical assessment. It would be valuable to also gather symptom reports directly from patients, and thus patient‐reported outcome (PRO) tools should be ideally suited to the evaluation of COPD exacerbations. However, most pharmaceutical industry‐ and large academy‐sponsored studies have used a healthcare resource use definition alone, which is based on sustained worsening of a patients condition from the stable state that requires a change in regular medication. This Review explores the use of PROs for the detection, quantification, and evaluation of COPD exacerbations. It examines symptom diary cards as exacerbation detection tools and their evolution into electronic diaries used in pharmaceutical trials. This paper also describes the development of specifically designed PROs that have been used in exacerbation settings, focusing on the Exacerbations and Symptoms in COPD e‐Diary, Exacerbations of Chronic Obstructive Pulmonary Disease Tool, COPD Assessment Test, and Chronic Respiratory Disease Questionnaire, highlighting the strengths and weaknesses of these instruments. We describe the effectiveness of these tools to enhance exacerbation reporting; quantify exacerbation characteristics, including the frequency, duration, and severity of events; and evaluate the outcome. We also explore the potential use of PROs in future studies to discriminate the effect of therapies on different exacerbation phenotypes and thus enhance personalized therapeutic approaches.