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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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.
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 FEV
and FVC trajectories between ages 43 and 60-64 years were influenced by smoking behavior.
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 FEV
at 43 years. Within smoker-stratified models, there were FEV
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. FEV
decline was greater in smokers (P < 0.001), but there was no effect of any early-life exposure on FEV
decline. Neither smoking nor early-life exposures were associated with FVC decline.
Besides accelerating adult FEV
decline, cigarette smoking also modifies how early-life exposures impact on both midlife FEV
and FVC. These findings are consistent with smoking impairing pulmonary development during adolescence or early adulthood, thereby preventing catch-up from earlier acquired deficits.
: This document provides clinical recommendations for the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). It represents a collaborative effort on the part of a panel of ...expert COPD clinicians and researchers along with a team of methodologists under the guidance of the American Thoracic Society.
: Comprehensive evidence syntheses were performed on all relevant studies that addressed the clinical questions and critical patient-centered outcomes agreed upon by the panel of experts. The evidence was appraised, rated, and graded, and recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluation approach.
: After weighing the quality of evidence and balancing the desirable and undesirable effects, the guideline panel made the following recommendations:
) a strong recommendation for the use of long-acting β
-agonist (LABA)/long-acting muscarinic antagonist (LAMA) combination therapy over LABA or LAMA monotherapy in patients with COPD and dyspnea or exercise intolerance;
) a conditional recommendation for the use of triple therapy with inhaled corticosteroids (ICS)/LABA/LAMA over dual therapy with LABA/LAMA in patients with COPD and dyspnea or exercise intolerance who have experienced one or more exacerbations in the past year;
) a conditional recommendation for ICS withdrawal for patients with COPD receiving triple therapy (ICS/LABA/LAMA) if the patient has had no exacerbations in the past year;
) no recommendation for or against ICS as an additive therapy to long-acting bronchodilators in patients with COPD and blood eosinophilia, except for those patients with a history of one or more exacerbations in the past year requiring antibiotics or oral steroids or hospitalization, for whom ICS is conditionally recommended as an additive therapy;
) a conditional recommendation against the use of maintenance oral corticosteroids in patients with COPD and a history of severe and frequent exacerbations; and
) a conditional recommendation for opioid-based therapy in patients with COPD who experience advanced refractory dyspnea despite otherwise optimal therapy.
: The task force made recommendations regarding the pharmacologic treatment of COPD based on currently available evidence. Additional research in populations that are underrepresented in clinical trials is needed, including studies in patients with COPD 80 years of age and older, those with multiple chronic health conditions, and those with a codiagnosis of COPD and asthma.
Chronic mucus hypersecretion (CMH) is common among smokers and is associated with chronic obstructive pulmonary disease development and progression.
To understand how the relationships between ...smoking, CMH, and chronic obstructive pulmonary disease develop during adult life, and facilitate earlier disease detection and intervention.
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.
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).
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.
Patients with COPD are at risk for cardiovascular events. This is attributed to increased systemic inflammation. The course of COPD is punctuated by exacerbations, which further increase systemic ...inflammation, but the risk of vascular events in the postexacerbation period has never been defined.
We analyzed data from 25,857 patients with COPD entered in The Health Improvement Network database over a 2-year period. Exacerbations were defined using a health-care use definition of prescription of oral corticosteroids > 20 mg/d and/or selected oral antibiotics. The risk of myocardial infarction (MI) and stroke in the postexacerbation period was calculated relative to the patient's baseline risk using the self-controlled case series approach.
We identified 524 MIs in 426 patients and 633 ischemic strokes in 482 patients. The incidence rates of MI and stroke were 1.1 and 1.4 per 100 patient-years, respectively. There was a 2.27-fold (95% CI, 1.1-4.7; P = .03) increased risk of MI 1 to 5 days after exacerbation (defined by prescription of both steroids and antibiotics). This relative risk diminished progressively with time and was not significantly different from the baseline MI risk at any other postexacerbation time interval. One in 2,513 exacerbations was associated with MI within 1 to 5 days. There was a 1.26-fold (95% CI, 1.0-1.6; P = .05) increased risk of stroke 1 to 49 days after exacerbation.
The results suggest that exacerbations of COPD increase the risk of MI and stroke. This may have implications for therapy in both stable and exacerbated COPD.
Understanding the role of the airway microbiome in chronic obstructive pulmonary disease (COPD) inflammatory endotypes may help to develop microbiome-based diagnostic and therapeutic approaches.
To ...understand the association of the airway microbiome with neutrophilic and eosinophilic COPD at stability and during exacerbations.
An integrative analysis was performed on 1,706 sputum samples collected longitudinally from 510 patients with COPD recruited at four UK sites of the BEAT-COPD (Biomarkers to Target Antibiotic and Systemic COPD), COPDMAP (Chronic Obstructive Pulmonary Disease Medical Research Council/Association of the British Pharmaceutical Industry), and AERIS (Acute Exacerbation and Respiratory Infections in COPD) cohorts. The microbiome was analyzed using COPDMAP and AERIS as a discovery data set and BEAT-COPD as a validation data set.
The airway microbiome in neutrophilic COPD was heterogeneous, with two primary community types differentiated by the predominance of
. The
-predominant subgroup had elevated sputum IL-1β and TNFα (tumor necrosis factor α) and was relatively stable over time. The other neutrophilic subgroup with a balanced microbiome profile had elevated sputum and serum IL-17A and was temporally dynamic. Patients in this state at stability were susceptible to the greatest microbiome shifts during exacerbations. This subgroup can temporally switch to both neutrophilic
and eosinophilic states that were otherwise mutually exclusive. Time-series analysis on the microbiome showed that the temporal trajectories of
and
were indicative of intrapatient switches from neutrophilic to eosinophilic inflammation, in track with patient sputum eosinophilia over time. Network analysis revealed distinct host-microbiome interaction patterns among neutrophilic
-predominant, neutrophilic balanced microbiome, and eosinophilic subgroups.
The airway microbiome can stratify neutrophilic COPD into subgroups that justify different therapies. Neutrophilic and eosinophilic COPD are interchangeable in some patients. Monitoring temporal variability of the airway microbiome may track patient inflammatory status over time.
The time of year when patients experience exacerbations of chronic obstructive pulmonary disease is a much-overlooked feature of the disease. The higher incidence of exacerbations in winter has ...important consequences for patients in terms of increased morbidity and mortality. The seasonality also imposes a considerable burden on already-overloaded health care services, with both primary care consultations and hospital admissions increasing in number. The seasonality of exacerbations varies with latitude, and is greater in more temperate climates, where there may be less protection from outdoor and indoor cold exposure. The precise causes of the seasonality are unknown, but thought to be partly due to the increased prevalence of respiratory viral infections circulating in cold, damp conditions. Increased susceptibility to viral infection may also be a mechanism mediated through increased airway inflammation or possibly reduced vitamin D levels. The seasonality of exacerbations informs us about the triggers of exacerbations and suggests possible strategies to reduce their number.
Harhay and Donaldson provide guidance on statistical reporting to help authors improve the chances of a favorable statistical review. They state that over their tenure as the statistical editors of ...AJRCCM and AnnalsATS, they have observed recurrent methodological issues and reporting practices in submitted manuscripts that invariably lead to unfavorable reviews by statistical reviewers, content reviewers, and editorial board members
The Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) is an eight-item questionnaire designed to assess and quantify the impact of COPD symptoms on health status. COPD exacerbations ...impair quality of life and are characterized by worsening respiratory symptoms from the stable state. We hypothesized that CAT scores at exacerbation relate to exacerbation severity as measured by exacerbation duration, lung function impairment, and systemic inflammation.
To evaluate the usefulness of the CAT to assess exacerbation severity.
One hundred sixty-one patients enrolled in the London COPD cohort completed the CAT at baseline (stable state), exacerbation, and during recovery between April 2010 and June 2011.
Frequent exacerbators had significantly higher baseline CAT scores than infrequent exacerbators (19.5 ± 6.6 vs. 16.8 ± 8.0, P = 0.025). In 152 exacerbations, CAT scores rose from an average baseline value of 19.4 ± 6.8 to 24.1 ± 7.3 (P < 0.001) at exacerbation. Change in CAT score from baseline to exacerbation onset was significantly but weakly related to change in C-reactive protein (rho = 0.26, P = 0.008) but not to change in fibrinogen (rho = 0.09, P = 0.351) from baseline to exacerbation. At exacerbation, rises in CAT score were significantly associated with falls in FEV(1) (rho = -0.20, P = 0.032). Median recovery time as judged by symptom diary cards was significantly related to the time taken for the CAT score to return to baseline (rho = 0.42, P = 0.012).
The CAT provides a reliable score of exacerbation severity. Baseline CAT scores are elevated in frequent exacerbators. CAT scores increase at exacerbation and reflect severity as determined by lung function and exacerbation duration.
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