Association of Dose of Inhaled Corticosteroids and Frequency of Adverse Events.

BACKGROUND: Inhaled corticosteroids (ICS) are the cornerstone of asthma treatment and significantly improve morbidity and mortality. Adverse effects of oral corticosteroids are well documented, but less is known about ICS. METHODS: We conducted observational studies in adults with asthma using two different UK nationwide datasets: Clinical Practice Research Datalink (CPRD) Aurum and CPRD GOLD. The exposure was incident ICS; the outcomes were major adverse cardiac events (MACE), arrhythmia, pulmonary embolism (PE) and pneumonia over 12-months. Our main analyses used a cohort method with stabilized inverse probability treatment weighting to balance confounding between exposed and unexposed patients. Secondary analyses included nested case-control studies, and self-controlled case series. ICS was treated both as a categorical and continuous variable. Absolute risk was estimated using weighted flexible parametric models. FINDINGS: From 162,202 patients in our main cohort, there was an association with all outcomes at medium daily ICS dose or higher (HR, 95%CI at 201-599mcg: MACE=2.63, 1.66-4.15, arrhythmia=2.21, 1.60-3.04, PE=2.10, 1.37-3.22, pneumonia=2.25, 1.77-2.85; at ≥600mcg: MACE=4.63, 2.62-8.17, arrhythmia=2.91, 1.72-4.91, PE=3.32, 1.69-6.50, pneumonia=4.09, 2.98-5.60). There were no associations with lower doses of ICS. Secondary analyses produced similar results. The number needed to harm (95%CI) using 12-months of ICS 201-599mcg: MACE=473 (344-754), arrhythmia=567 (395-1006), PE=1221 (744-3388) and pneumonia=230 (177-327) and using ICS ≥600mcg: MACE=224 (148-461), arrhythmia=396 (228-1523), PE=577 (309-4311), pneumonia=93 (69-141). INTERPRETATION: Short-term use of low dose ICS was not associated with adverse effects. Moderate-high daily ICS doses were associated with an increased risk, but low-frequency, of cardiovascular events, pulmonary embolism and pneumonia. It is important for clinicians to adhere to guideline recommendations to use the lowest effective ICS dose.

Accelerated Lung Function Decline and Mucus-Microbe Evolution in Chronic Obstructive Pulmonary Disease.

Rationale: Progressive lung function loss is recognized in chronic obstructive pulmonary disease (COPD); however, no study concurrently evaluates how accelerated lung function decline relates to mucus properties and the microbiome in COPD. Objectives: Longitudinal assessment of mucus and microbiome changes accompanying accelerated lung function decline in patients COPD. Methods: This was a prospective, longitudinal assessment of the London COPD cohort exhibiting the greatest FEV1 decline (n = 30; accelerated decline; 156 ml/yr FEV1 loss) and with no FEV1 decline (n = 28; nondecline; 49 ml/yr FEV1 gain) over time. Lung microbiomes from paired sputum (total 116 specimens) were assessed by shotgun metagenomics and corresponding mucus profiles evaluated for biochemical and biophysical properties. Measurements and Main Results: Biochemical and biophysical mucus properties are significantly altered in the accelerated decline group. Unsupervised principal component analysis showed clear separation, with mucus biochemistry associated with accelerated decline, whereas biophysical mucus characteristics contributed to interindividual variability. When mucus and microbes are considered together, an accelerated decline mucus-microbiome association emerges, characterized by increased mucin (MUC5AC [mucin 5AC] and MUC5B [mucin 5B]) concentration and the presence of Achromobacter and Klebsiella. As COPD progresses, mucus-microbiome shifts occur, initially characterized by low mucin concentration and transition from viscous to elastic dominance accompanied by the commensals Veillonella, Gemella, Rothia, and Prevotella (Global Initiative for Chronic Obstructive Lung Disease [GOLD] A and B) before transition to increased mucus viscosity, mucins, and DNA concentration together with the emergence of pathogenic microorganisms including Haemophilus, Moraxella, and Pseudomonas (GOLD E). Conclusions: Mucus-microbiome associations evolve over time with accelerated lung function decline, symptom progression, and exacerbations affording fresh therapeutic opportunities for early intervention.

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 hypothesized 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 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator 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 using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are 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. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Design of the SPIROMICS Study of Early COPD Progression: SOURCE Study.

The biological mechanisms leading some tobacco-exposed individuals to develop early-stage chronic obstructive pulmonary disease (COPD) are poorly understood. This knowledge gap hampers development of disease-modifying agents for this prevalent condition. Accord-ingly, with National Heart, Lung and Blood Institute support, we initiated the SPIROMICS Study of Early COPD Progression (SOURCE), a multicenter observational cohort study of younger individuals with a history of cigarette smoking and thus at-risk for, or with, early-stage COPD. Our overall objectives are to identify those who will develop COPD earlier in life, characterize them thoroughly, and by contrasting them to those not developing COPD, define mechanisms of disease progression. SOURCE utilizes the established SPIROMICS clinical network. Its goal is to enroll n=649 participants, ages 30-55 years, all races/ethnicities, with ≥10 pack-years cigarette smoking, in either Global Initiative for Chronic Obstructive Lung Disease (GOLD) groups 0-2 or with Preserved Ratio Impaired Spirometry (PRISm); and an additional n=40 never-smoker controls. Participants undergo baseline and three-year follow-up visits, each including high-resolution computed tomography; respiratory oscillometry and spirometry (pre- and post-bronchodilator administration), exhaled breath condensate (baseline only); and extensive biospecimen collection, including sputum induction. Symptoms, interim healthcare utilization, and exacerbations are captured every six months via follow-up phone calls. An embedded bronchoscopy sub-study involving n=100 participants (including all never-smokers) will allow collection of lower airway samples for genetic, epigenetic, genomic, immunological, microbiome, mucin analyses, and basal cell culture. SOURCE should provide novel insights into the natural history of lung disease in younger individuals with a smoking history, and its biological basis.

Using an electronic diary and wristband accelerometer to detect exacerbations and activity levels in COPD: a feasibility study.

Background: Early and accurate identification of acute exacerbations of COPD may lead to earlier treatment and prevent hospital admission. Electronic diaries have been developed for symptom monitoring and accelerometers to monitor activity. However, it is unclear whether this technology is usable in the COPD population. This study aimed to assess the feasibility of an electronic diary (eDiary) for symptom reporting using the MoreCare app and activity monitoring with the Garmin Vivofit 2 in COPD. Methods: Participants were recruited from the London COPD Cohort. Participants were provided a Garmin Vivofit 2 activity monitor and an android tablet with the MoreCare app for a period of 3 months. Results: 25 COPD patients were recruited (mean±sd age 70.8±7.1 years, forced expiratory volume in 1 s (FEV1) 49.8±14.8% predicted). Age, gender, disease severity and exacerbation frequency had no impact on eDiary compliance. There was a moderate positive correlation between median daily very active minutes and FEV1 % pred (ρ=0.62, p=0.005). Daily step counts decreased during the initial 7 days of exacerbation and recovery compared to a pre-exacerbation baseline. A decision-tree model identified change in sputum colour, change in step count, severity of cold, exacerbation history and use of rescue medication as the most important predictors of acute exacerbations of COPD in this cohort. Conclusions: Symptom and activity monitoring using digital technology is feasible in COPD. Further large-scale digital health studies are needed to assess whether eDiaries can be used to identify patients at risk of exacerbation and guide early intervention.

The prevention of COPD exacerbations by salmeterol/fluticasone propionate or tiotropium bromide.

Rationale: Exacerbations are key drivers of morbidity and mortality in chronicobstructive pulmonary disease (COPD).Objectives: We compared the relative efficacy of the long-acting inhaledbronchodilator/anti-inflammatory combination (salmeterol/fluticasone propionate) 50/500mcg bd and the long-acting bronchodilator (tiotropium) 18mcg od in preventing exacerbations and related outcomes in moderate severe COPD Methods: 1323 patients (mean age 64yr, forced expiratory volume in 1sec 39 per cent predicted) were randomized in 2-year, double blind, double-dummy, parallel study.Measurements and Main Results: Primary endpoint was healthcare utilization exacerbation rate. Other endpoints included health status measured by St. Georges Respiratory Questionnaire (SGRQ), mortality, adverse events and study withdrawal.Probability of withdrawing from the study was 29 per cent greater with tiotropium than salmeterol/fluticasone propionate (p=0.005). The modelled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group (rate ratio 0.967 [95 per cent CI: 0.836 to 1.119]; p=0.656). The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionateversus tiotropium (difference 2.1 units, 95 per cent CI: 0.1 to 4.0, p=0.038). Mortality was significantly lower in the salmeterol/fluticasone propionate group; 21 (3 per cent of patients in this group died compared to 38 (6 per cent) in the tiotropium group (p=0.032). Morepneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium (p=0.008).Conclusions: We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium. More patients failed to complete the study receiving tiotropium. A small statistically significant beneficial effect was found on health status, with an unexpected finding of lower deaths in salmeterol/fluticasone propionate treated patients.

Early therapy improves outcomes of exacerbations of Chronic Obstructive Pulmonary Disease

Treatment of chronic obstructive pulmonary disease (COPD) exacerbations improves outcomes; however, responses to treatment are variable, and patients with COPD often delay presentation or fail to seek therapy. The impact on exacerbation outcomes, hospitalization, and health status of delaying or failing to seek treatment is poorly understood. We studied between 1996 and 2002 a cohort of 128 patients with COPD, mean (SD) FEV1 of 1.07 (0.43) L. Patients recorded respiratory symptoms daily and reported exacerbations to the outpatient-based study team or to their primary care physician; 1,099 exacerbations were recorded by the patients, of which 658 were reported to a physician. The time between exacerbation onset and treatment was a median (interquartile range) of 3.69 (2.0–5.57) days, and the exacerbation recovery time was 10.7 (7.0–14.0) days. Earlier treatment was associated with a faster recovery (regression coefficient 0.42 days/day delay) (confidence interval, 0.19–0.65; p < 0.001). Patients who reported a higher proportion of exacerbations for treatment had better health-related quality of life than those patients with more untreated exacerbations (rho = –0.22, p = 0.018). Failure to report exacerbations was associated with an increased risk of emergency hospitalization (rho = 0.21, p = 0.04). Patient recognition of exacerbation symptoms and prompt treatment improves exacerbation recovery, reduces risks of hospitalization, and is associated with a better health-related quality of life

Airway and systemic inflammation and decline in lung function in patients with COPD

Study objective: Patients with COPD experience lower airway and systemic inflammation, and an accelerated decline in FEV. There is no evidence on whether this inflammation changes over time, or if it is associated with a faster decline FEV. Patient and design: a cohort of 148 COPD patients (100 men) was monitored daily for a median 2.9 years (interquartile range [IQR], 2.1 to 4.8). At recruitment median age was 68.5 years (IQR, 62.5 to 73.6) and FEV as percentage of predicted (FEV percent Pred) was 38.5 percent (IQR, 27.7 to 50.3). Results: During the study, the patients experienced 1,389 exacerbations, a median of 2.52/yr (IQR 1.48 to 3.96) and FEV declined by 40.2 mL/yr or as FEV percent Pred by 1.5 percent/yr. Concerning inflammatory markers, sputum interlukin (IL)-6 rose by 9 pg/mL, sputum neutrophil count rose by 1.64 x 10,000,000 cells per gram sputum per year, and plasma fibrinogen rose by 0.10 g/L/yr (all p, 0.05). Patients with frequent exacerbations (less than or equal to 2.52/yr) had a faster rise over time in plasma fibrinogen and sputum IL-6 of 0.063 g/L/yr (p= 0.046, n= 130) and 29.5 pg/mL/yr (p< 0.001, n=98), respectively, compared to patients with infrequent exacerbations (<2.52/yr). Using the earliest stable (nonexacerbation) measured marker, patients whose IL-6 exceeded the group median had a faster FEV percentPred decline of 0.97 percent/yr (p=0.001 and .40 percent/yr (p=0.014). respectively. Conclusions: In COPD, airway and systemic inflammatory markers increase over time; high levels of these markers are associated with a faster decline in lung function (AU)