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Background: Chronic obstructive pulmonary disease (COPD) remains a major cause of morbidity and mortality. Present-day diagnostic criteria are largely based solely on spirometric criteria. Accumulating evidence has identified a substantial number of individuals without spirometric evidence of COPD who suffer from respiratory symptoms and/or increased morbidity and mortality. There is a clear need for an expanded definition of COPD that is linked to physiologic, structural (computed tomography [CT]) and clinical evidence of disease. Using data from the COPD Genetic Epidemiology study (COPDGene ® ), we hypothesized that an integrated approach that includes environmental exposure, clinical symptoms, chest CT imaging and spirometry better defines disease and captures the likelihood of progression of respiratory obstruction and mortality., Methods: Four key disease characteristics - environmental exposure (cigarette smoking), clinical symptoms (dyspnea and/or chronic bronchitis), chest CT imaging abnormalities (emphysema, gas trapping and/or airway wall thickening), and abnormal spirometry - were evaluated in a group of 8784 current and former smokers who were participants in COPDGene ® Phase 1. Using these 4 disease characteristics, 8 categories of participants were identified and evaluated for odds of spirometric disease progression (FEV 1 > 350 ml loss over 5 years), and the hazard ratio for all-cause mortality was examined., Results: Using smokers without symptoms, CT imaging abnormalities or airflow obstruction as the reference population, individuals were classified as Possible COPD, Probable COPD and Definite COPD. Current Global initiative for obstructive Lung Disease (GOLD) criteria would diagnose 4062 (46%) of the 8784 study participants with COPD. The proposed COPDGene ® 2019 diagnostic criteria would add an additional 3144 participants. Under the new criteria, 82% of the 8784 study participants would be diagnosed with Possible, Probable or Definite COPD. These COPD groups showed increased risk of disease progression and mortality. Mortality increased in patients as the number of their COPD characteristics increased, with a maximum hazard ratio for all cause-mortality of 5.18 (95% confidence interval [CI]: 4.15-6.48) in those with all 4 disease characteristics., Conclusions: A substantial portion of smokers with respiratory symptoms and imaging abnormalities do not manifest spirometric obstruction as defined by population normals. These individuals are at significant risk of death and spirometric disease progression. We propose to redefine the diagnosis of COPD through an integrated approach using environmental exposure, clinical symptoms, CT imaging and spirometric criteria. These expanded criteria offer the potential to stimulate both current and future interventions that could slow or halt disease progression in patients before disability or irreversible lung structural changes develop., Competing Interests: The COPDGene® study is funded by National Heart, Lung, and Blood Institute grants U01 HL089897 and U01 HL089856. The COPDGene® study (NCT00608764) is also supported by the COPD Foundation through contributions made to an Industry Advisory Committee comprised of AstraZeneca, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion. While some individual authors of this manuscript were employed by one of the listed funders at the time the work of this study was conducted, these employment relationships did not constitute undue influence by funders. These funders have had no official role in the collection, management, analysis and interpretation of the data or design and conduct of the study. All authors have completed a Conflict of Interest form, disclosing any real or apparent financial relationships including receiving royalties, honoraria or fees for consulting, lectures, speakers’ bureaus, continuing education, medical advisory boards or expert testimony; receipt of grants; travel reimbursement; direct employment compensation. These disclosure forms have been filed with the Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation Editorial Office and are available for review, upon request, at COPDC@njhealth.org., (JCOPDF © 2019.)

Background: Acute exacerbations are a significant source of morbidity and mortality associated with chronic obstructive pulmonary disease. Among individuals with COPD, some patients suffer an inordinate number of exacerbations while others remain relatively protected. We undertook a study to determine the clinical factors associated with "frequent exacerbator" status within a population of subjects with severe COPD., Methods: Case-control cohort recruited from two Boston-area practices. All subjects had GOLD stage 3 or 4 (FEV(1) ≤ 50% predicted) COPD. "Frequent exacerbators" (n = 192) had an average of ≥2 moderate-to-severe exacerbations per year while "non-exacerbators" (n = 153) had no exacerbations in the preceding 12 months. Multivariate logistic regression was performed to determine the significant clinical predictors of "frequent exacerbator" status., Results: Physician-diagnosed asthma was a significant predictor of frequent exacerbations. Within a subset of our cohort, the modified Medical Research Council dyspnea score and FEF (25-75%) predicted were also significant clinical predictors of frequent exacerbator status (p < 0.05). Differences in exacerbation frequency were not found to be due to increased current tobacco use or decreased rates of maintenance medication use., Conclusions: Within our severe COPD cohort, a history of physician-diagnosed asthma was found to be a significant clinical predictor of frequent exacerbations. Although traditional risk factors such as decreased FEV(1)% predicted were not significantly associated with frequent exacerbator status, lower mid-expiratory flow rates, as assessed by FEF (25-75%) predicted, were significantly associated with frequent exacerbations in a subset of our cohort., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Objectives: To measure adherence to inhaled corticosteroid (ICS) therapy using prescription claims and a patient survey, to identify local adverse events (LAEs) from the patient perspective and from medical records, and to evaluate the association between LAEs and adherence to ICS therapy., Study Design: Survey administration and claims-based and medical record-abstracted data., Methods: Patients aged 6 to 64 years with persistent asthma (defined using an established algorithm) and at least 2 ICS prescriptions were selected from a claims database (1999-2006) of a central Massachusetts medical group practice. Prescription claims were used to calculate the ICS medication possession ratio (MPR). A survey obtained information about patient-reported adherence to ICSs using the Morisky scale and a visual analog scale (VAS) and about LAEs using the validated Inhaled Corticosteroid Questionnaire. Medical records of survey respondents were abstracted for LAEs., Results: Among 372 survey respondents, 2.7% met the claims-based measure of good adherence (MPR, > or =80%). Patient-reported adherence was much higher; 20.7% of patients were highly adherent based on the Morisky scale (score, 0) and 55.4% based on the VAS (score, > or =80%). Medical record review identified 27.2% of patients having at least 1 LAE within 1 year after the ICS index date, but 47.3% of patients reported being bothered at least "quite a lot" by LAEs. Multivariate analysis indicated that unpleasant taste was significantly related to lower adherence based on the Morisky scale (P = .02)., Conclusions: Patient-reported adherence and LAEs were higher than those measured from claims or medical records. Unpleasant taste seems to be associated with lower adherence based on the Morisky scale.

Objective: To determine the validity of work-related self-reported exacerbation of asthma using the findings from serial peak expiratory flow (PEF) measurements as the standard., Methods: Adults with asthma treated in a health maintenance organisation were asked to conduct serial spirometry testing at home and at work for 3 weeks. Self-reported respiratory symptoms and medication use were recorded in two ways: a daily log completed concurrently with the serial PEF testing and a telephone questionnaire administered after the PEF testing. Three researchers evaluated the serial PEF records and judged whether a work relationship was evident., Results: 95 of 382 (25%) working adults with asthma provided adequate serial PEF data, and 13 of 95 (14%) were judged to have workplace exacerbation of asthma (WEA) based on these data. Self-reported concurrent medication use was the most valid single operational definition, with a sensitivity of 62% and a specificity of 65%., Conclusions: A work-related pattern of self-reported asthma symptoms or medication use was usually not corroborated by serial PEF testing and failed to identify many people who had evidence of WEA based on the serial PEF measurements.

Objectives: Workplace conditions can potentially contribute to the worsening of asthma, yet it is unclear what percentage of adults with asthma experience workplace exacerbation of symptoms. The objective of this investigation was to determine the prevalence of workplace exacerbation of asthma (WEA)., Methods: Adults with asthma aged 18-44 were enrolled into the baseline survey of a longitudinal study. Members of a health maintenance organisation were considered candidates for participation if they fulfilled membership, diagnostic, and treatment criteria based on automated review of electronic billing, claims, and pharmacy records. Diagnosis and treatment were confirmed by manual review of medical records. A telephone questionnaire was administered. A work related symptom score was assigned to each participant based on responses to questions about work related asthma symptoms, medication use, and symptom triggers. Blinded to participants' answers to these questions, two researchers independently reviewed the self-reported work histories and assigned exposure ratings. A final exposure score was then calculated. Participants with sufficient evidence for work related symptoms and exposure were classified as having WEA., Results: Of the 598 participants with complete data, 557 (93%) were working, and 136 (23%) fulfilled the criteria for WEA. Those with WEA were more likely to be male and to report that they had been bothered by asthma symptoms during the past seven days., Conclusions: Workplace exacerbation of asthma was common in this study population, occurring in over a fifth of these adults with asthma. Physicians should consider that work can contribute to the exacerbation of symptoms when treating adults with asthma.

Background: HMO databases offer an opportunity for community based epidemiologic studies of asthma incidence, etiology and treatment. The incidence of asthma in HMO populations and the utility of HMO data, including use of computerized algorithms and manual review of medical charts for determining etiologic factors has not been fully explored., Methods: We identified adult-onset asthma, using computerized record searches in a New England HMO. Monthly, our software applied exclusion and inclusion criteria to identify an "at-risk" population and "potential cases". Electronic and paper medical records from the past year were then reviewed for each potential case. Persons with other respiratory diseases or insignificant treatment for asthma were excluded. Confirmed adult-onset asthma (AOA) cases were defined as those potential cases with either new-onset asthma or reactivated mild intermittent asthma that had been quiescent for at least one year. We validated the methods by reviewing charts of selected subjects rejected by the algorithm., Results: The algorithm was 93 to 99.3% sensitive and 99.6% specific. Sixty-three percent (n = 469) of potential cases were confirmed as AOA. Two thirds of confirmed cases were women with an average age of 34.8 (SD 11.8), and 45% had no evidence of previous asthma diagnosis. The annualized monthly rate of AOA ranged from 4.1 to 11.4 per 1000 at-risk members. Physicians most commonly attribute asthma to infection (59%) and allergy (14%). New-onset cases were more likely attributed to infection, while reactivated cases were more associated with allergies. Medical charts included a discussion of work exposures in relation to asthma in only 32 (7%) cases. Twenty-three of these (72%) indicated there was an association between asthma and workplace exposures for an overall rate of work-related asthma of 4.9%., Conclusion: Computerized HMO records can be successfully used to identify AOA. Manual review of these records is important to confirm case status and is useful in evaluation of provider consideration of etiologies. We demonstrated that clinicians attribute most AOA to infection and tend to ignore the contribution of environmental and occupational exposures.

Occupational asthma may account for a significant proportion of adult-onset asthma, but incidence estimates from surveillance of physician reports and workers' compensation data (0.9 to 15/100,000) are lower than expected from community-based cross-sectional studies of asthma patients. We conducted a prospective cohort study of 79,204 health maintenance organization members between the ages of 15 and 55 at risk for asthma. Computerized files, medical records, and telephone interviews were used to identify and characterize asthma cases. Evidence for asthma attributable to occupational exposure was determined from work-related symptoms and workplace exposure. The annual incidence of clinically significant, new-onset asthma was 1.3/1,000, and increased to 3.7/1,000 when cases with reactivation of previously quiescent asthma were included. Criteria for onset of clinically significant asthma attributable to occupational exposure were met by 21% (95% CI 12-32%) of cases giving an incidence of 71/100,000 (95% CI 43-111). Physicians documented asking about work-related symptoms in 15% of charts, and recorded suggestive symptoms in three cases, but did not obtain occupational medicine consultation, diagnose occupational asthma, report to the state surveillance program, or bill workers' compensation for any of them. These data suggest that the incidence of asthma attributable to occupational exposures is significantly higher than previously reported, and accounts for a sizable proportion of adult-onset asthma.

In order to characterise asthma management in a managed care setting, we identified 10,301 patients who were diagnosed with asthma between 1 January 1988 and 31 December 1991 at a group model health maintenance organisation in central Massachusetts, US. We obtained for these patients automated utilisation files containing data on medications, hospitalisations, emergency room visits, office visits, and estimated costs of these services. The medication dispensed to the greatest proportion of patients was beta 2 agonists either by inhalation (56%) or orally (21%). Theophylline was dispensed to 23% of the patients. Maintenance therapy was inhaled anti-inflammatory medication was uncommon, as inhaled corticosteroids (17%) and sodium cromoglycate (cromolyn sodium) [8%] were dispensed to fewer patients than other asthma medications. Among patients who had been hospitalised in the previous year, 36% were presently receiving inhaled corticosteroids, and among patients who used at least one beta 2 agonist metered-dose inhaler per month, 49% were presently receiving inhaled corticosteroids. Economic analyses showed that only 8% of the patients had either a hospital admission or an emergency room visit, but hospital costs among these patients accounted for 25% of the total costs of asthma care. In addition, the top 10% most expensive patients accounted for 42% of the total cost of asthma care. We conclude that a substantial proportion of patients at increased risk of a severe attack, by virtue of having a recent hospitalisation, do not receive maintenance anti-inflammatory therapy, and that hospitalisations among a relatively small proportion of asthma patients contribute significantly to the cost of asthma care.

The effects of treatment with a perfluorochemical emulsion plus carbogen on radiation pneumonitis were examined in a rat model system. Rats received thoracic irradiation (15 Gy) and radiation reactions in the lungs were assessed 25 and 35 days later using bronchoalveolar lavage and histologic assessments. The irradiated lungs showed the expected evidence of acute radiation pneumonitis, including protein leaks and also alveolar infiltrates and interstitial infiltrates. Administration of a perfluoro-chemical emulsion (Fluosol; 15 ml/kg) plus carbogen breathing for 30 min before and during irradiation did not enhance the reactions seen in the irradiated lungs.

A common side effect of radiotherapy is the development of fibrosis in the irradiated tissue. To study the mechanisms of this fibrogenic response, we developed a model system of whole-lung radiation in the rat and studied the evolution of injury by assessment of the cells and protein recovered by lavage. Once the pattern of injury was known, we attempted to modulate this reaction by administering the cytokine interferon-gamma (IFN-gamma). Rats received 15 Gy radiation to the whole thorax and were studied by lung lavage at intervals of 1 to 35 days after radiation. The effect of radiation was an initial (24 h) leak of protein, unaccompanied by cellular alterations, that resolved by 48 h. This was followed 2 wk later by a phase of inflammatory cell recruitment and more significant protein leak. A third phase of increase in inflammatory cells and further increase in protein flux was noted at Day 35. A significant cellular infiltrate was seen in lung sections obtained from animals treated in parallel experiments. IFN-gamma was given by osmotic pump from Day 0 to Day 35. This treatment significantly attenuated the PMN recruitment and protein leak (p < 0.002 and 0.01, respectively) at Days 25 and 35. Histologic sections demonstrated reduced alveolar cellularity and exudate at Day 25 (p < 0.05); however, significant numbers of inflammatory cells and exudate were present in irradiated and IFN-gamma-treated animals at Day 35. These data indicate that inflammatory cell recruitment may play a role in the lung injury following radiation. Furthermore, these preliminary data indicate that a cytokine blocks this reaction.

The use of radiation therapy is limited by the occurrence of the potentially fatal clinical syndromes of radiation pneumonitis and fibrosis. Radiation pneumonitis usually becomes clinically apparent from 2 to 6 months after completion of radiation therapy. It is characterized by fever, cough, dyspnea, and alveolar infiltrates on chest roentgenogram and may be difficult to differentiate from infection or recurrent malignancy. The pathogenesis is uncertain, but appears to involve both direct lung tissue toxicity and an inflammatory response. The syndrome may resolve spontaneously or may progress to respiratory failure. Corticosteroids may be effective therapy if started early in the course of the disease. The time course for the development of radiation fibrosis is later than that for radiation pneumonitis. It is usually present by 1 year following irradiation, but may not become clinically apparent until 2 years after radiation therapy. It is characterized by the insidious onset of dyspnea on exertion. It most often is mild, but can progress to chronic respiratory failure. There is no known successful treatment for this condition.

The purpose of this investigation was to evaluate the cardiovascular responses to rowing. In the first part of the study, heart rate (HR) and cardiac output (Q) were measured at rest and at three steady-state exercise levels on the variable-resistance rowing ergometer in 10 female and 11 male subjects. Q was determined non-invasively by the equilibration method of CO2 re-breathing, and stroke volume (SV) was calculated. Subjects varied in rowing ability from healthy, inexperienced rowers to competitive athletes. The linear relationships between Q and oxygen consumption for the women (r = 0.57; P less than 0.001; slope = 5.2 +/- 1.1) (mean +/- SD) and the men (r = 0.58; P less than 0.001; slope = 6.1 +/- 1.4) were similar to published values for other types of upright exercises. For both mean and women, SV increased from rest to the first level of exercise, and then reached a plateau at or before the second exercise intensity. Between the second and third levels of exercise, SV decreased significantly in the female subjects (107 +/- 18 vs 94 +/- 16 ml; P less than 0.05), but not in the male subjects (128 +/- 1 1 vs 126 +/- 15 ml; P = not statistically significant). In the second part of the study, HR, Q, and SV were compared on the cycle and rowing ergometers on successive days in eight additional subjects. At similar levels of oxygen consumption and Q, HR was significantly higher, and SV was significantly lower during rowing exercise than with cycle exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

The optimal time to begin oral anticoagulation therapy with warfarin sodium in the treatment of acute pulmonary embolism has not been defined. To evaluate the relative cost, efficacy, and safety of early initiation of warfarin therapy, we reviewed the medical records of 38 patients with angiographically proven pulmonary embolism. Patients were divided into two groups: those who received warfarin early (less than or equal to 3 days after initial heparin sodium bolus, n = 17) and those who were treated late (greater than 3 days after initial heparin bolus, n = 21). After three months of follow-up, there was a similar incidence of mortality, recurrent pulmonary embolism, and bleeding complications in both treatment groups. Length of hospitalization was substantially less in the early group (9.6 +/- 2.0 vs 11.8 +/- 2.1 days). Early warfarin therapy in the treatment of acute pulmonary embolism appears to be both cost-effective and safe. A prospective multicenter controlled trial should be performed.

To investigate the hypothesis that clinical methods and psychophysical testing provide different information about breathlessness, we compared dyspnea ratings from a modified Medical Research Council (MRC) scale, the Oxygen-Cost Diagram (OCD), and the Baseline Dyspnea Index (BDI) with the perceived magnitude of added loads in 24 patients with obstructive airway disease (OAD) who experienced dyspnea on exertion. Age of the patients was 55.8 +/- 13.7 yr (mean +/- SD), FEV1 was 1.77 +/- 0.81 L, and FEV1/FVC ratio was 52.6 +/- 10.5%. Dyspnea ratings were obtained for each clinical method by 2 independent observers; estimates of the magnitude of 5 resistive loads (10 to 85 cm H2O/L/s) were obtained using the Borg category scale (0 to 10). For comparative purposes, 12 age-matched (48.9 +/- 13.5 yr) healthy subjects were also studied. Clinical ratings of dyspnea obtained in patients for MRC (range, 0 to 4), OCD (range, 23 to 98), and BDI (range, 0.5 to 12.0) were all highly interrelated (rs = 0.79, -0.83, and -0.71; p less than 0.001 for all comparisons). Exponents of the psychophysical power function for resistive breathing loads were similar for patients with OAD (0.57 +/- 0.27) and control subjects (0.63 +/- 0.18) (p = NS). Clinical dyspnea scores were significantly correlated with both FEV1 and FVC; however, neither dyspnea ratings nor lung function were significantly related to the exponent for added breathing loads in the patient group. These comparisons indicate that in patients with symptomatic OAD, clinical methods for rating dyspnea are interrelated and are correlated with lung function, but are independent of perception of resistive breathing loads.(ABSTRACT TRUNCATED AT 250 WORDS)

Structural changes occur in the respiratory system with advancing age. Lung elasticity decreases, stiffness of the chest wall increases, and respiratory muscle strength declines. These alterations contribute to gradual, but progressive, reductions in forced vital capacity, expiratory flow rates, diffusing capacity, gas exchange, ventilatory drive, and respiratory sensation. Cigarette smoking accelerates the age-related decline in flow rates. Understanding the effects of aging on the lung is important in order to distinguish pathologic changes from changes that are part of the normal aging process.