Lung-function trajectories: relevance and implementation in clinical practice.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

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.

Respiratory Syncytial Virus-related Community Chronic Obstructive Pulmonary Disease Exacerbations and Novel Diagnostics: A Binational Prospective Cohort Study.

Rationale: Respiratory syncytial virus (RSV) is a common global respiratory virus that is 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 that has 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, United Kingdom, and Groningen, the Netherlands, beginning in 2017 and observed for three consecutive RSV seasons, during exacerbations, and at least twice yearly. RSV infections were detected by RT-PCR and serologic testing. Measurements and Main Results: A total of 377 patients with COPD attended 1,999 clinic visits and reported 310 exacerbations. There were 27 RSV-related exacerbations (8.7% of the total); of these, seven were detected only by PCR, 16 only by serology, and four by both methods. Increases in RSV-specific Nucleoprotein antibody were as sensitive as those in the antibody to Pre-Fusion or Post-Fusion for serodiagnosis of RSV-related exacerbations. Conclusions: RSV is associated with 8.7% of outpatient-managed COPD exacerbations in this study. Antibodies to RSV Nucleoprotein may have diagnostic value and are potentially important in a vaccinated population. The introduction of vaccines that prevent RSV is expected to benefit patients with COPD.

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).

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).

Treatment Trials in Young Patients with Chronic Obstructive Pulmonary Disease and Pre-Chronic Obstructive Pulmonary Disease Patients: Time to Move Forward.

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

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).

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.

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.

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.

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.

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. George's 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. George's 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.

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).

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

RATIONALE: Information 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. METHODS: Seventy-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 16,478 days, an average of 267 days 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. RESULTS: Colder weather below 22.5 °C, reduced daily step count by 43.3 steps day per °C (95% CI 2.14 to 84.4; p = 0.039) and activity was lower on rainy than dry days (p = 0.002) and on overcast compared to sunny days (p < 0.001). Daily step count was 434 steps per day lower on Sunday than Saturday (p < 0.001) and 353 steps per day lower on Saturday than Friday (p < 0.001). After allowance for these effects, higher O3 levels decreased activity during the whole week (-8 steps/ug/m3; p = 0.005) and at weekends (-7.8 steps/ug/m3; p = 0.032). Whilst, during the week PM10 reduced activity (p = 0.018) but not during the weekend. CONCLUSIONS: Inactivity 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.