Effects of randomized assignment to a smoking cessation intervention and changes in smoking habits on respiratory symptoms in smokers with early chronic obstructive pulmonary disease: the Lung Health Study.

PURPOSE: To evaluate the effects of randomly assigning smokers who have early chronic obstructive pulmonary disease (COPD) to a smoking-cessation intervention on the symptoms of chronic cough, chronic phlegm production, wheezing and shortness of breath, and to determine the effects of quitting smoking on these symptoms. SUBJECTS AND METHODS: A total of 5,887 male and female smokers 35 to 60 years of age with early COPD [defined as a forced expiratory volume in the first second (FEV1) of 55% to 90% of predicted and FEV1/forced vital capacity (FVC) <0.70] were enrolled in a 5-year clinical trial. Two-thirds of participants were randomly assigned to smoking-intervention groups and one-third to a usual-care group. The intervention groups attended 12 intensive smoking-cessation sessions that included behavior modification techniques and the use of nicotine chewing gum. One intervention group was treated with ipratropium bromide by inhaler; the other intervention group received placebo inhalers. The usual-care group was advised to stop smoking. All participants were followed annually. Smoking status was biochemically validated by salivary cotinine measurements or exhaled carbon monoxide values. RESULTS: Validated 5-year sustained smoking cessation occurred in 22% of participants in the intervention compared with only 5% of participants in the usual-care group. At the end of the study, the prevalence of each of the four symptoms in the two intervention groups was significantly less than in the usual-care group (P <0.0001). For example, among participants who did not report cough at baseline, 15% of those in the intervention groups had cough at least 3 months during the year, compared with 23% of those in usual care. Sustained quitters had the lowest prevalence of all four symptoms, whereas continuous smokers had the greatest prevalence of these symptoms. Changes in symptoms occurred primarily in the first year after smoking cessation. Respiratory symptoms were associated with greater declines in FEV1 during the study (P <0.001). Ipratropium bromide had no long-term effects on respiratory symptoms. CONCLUSIONS: In this prospective randomized trial using an intention-to-treat analysis, smokers with early COPD who were assigned to a smoking-cessation intervention had fewer respiratory symptoms after 5 years of follow-up.

Predictors of survival in subjects with chronic airflow limitation.

In a study of chronic airflow limitation, we followed 140 subjects living in Utah at altitudes of 1,300 to 1,500 meters for seven to 13 years. Twelve-year survival probabilities were determined and compared with an age- and sex-matched Utah population. The lowest 12-year survival probability was 0.40 for those patients with a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) of less than or equal to 0.40, indicating that there is much variability in survival. Other indicators of a lower survival probability (and increased death risk ratio) were an FEV1 percent predicted less than or equal to 50, an FEV1 less than or equal to 1.5 liters, male gender, partial pressure of oxygen (PO2) [exercise] less than or equal to 50 mm Hg, partial pressure of carbon dioxide (PCO2) [rest] greater than 39 mm Hg, PCO2 (exercise) greater than 39 mm Hg, FVC percent predicted less than or equal to 80, PO2 (rest) less than or equal to 55 mm Hg, and a carbon monoxide diffusing capacity (DLCO) percent predicted less than or equal to 80. Current smokers had a poorer survival probability than the reference population and an increased death risk when compared with the nonsmokers in the study. Pack/years of smoking also affected survival. Other variables associated with reduced survival were a diagnosis of chronic bronchitis combined with emphysema, more rapid annual declines in the FEV1 and/or FVC, low alpha 1-antitrypsin levels, a 20 percent improvement in FEV1 following the use of a bronchodilator aerosol, and a lower socioeconomic class. Differences between these findings and those noted in other studies are in the main due to differences in the characteristics (such as age, diagnosis, and extent of disease) of the patients in the study populations. The findings have relevance in estimating a patient's prognosis and for developing guidelines for disability determination purposes.

Variables associated with changes in spirometry in patients with obstructive lung diseases.

One hundred fifty subjects were enrolled in a long-term study of obstructive lung diseases; 84 of these were subjected to five or more spirometric studies over a period of two or more years. Stepdown regression analysis was performed to determine the association between many different variables and the annual rates of change in the forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). The following associations were noted to be significant (p less than 0.03); more favorable rates of change of the FVC and FEV1 were associated with a higher alpha1-antitrypsin level and older age. Less favorable changes were associated with more years of cigarette smoking, more airway reactivity and more frequent lower respiratory tract illnesses.

Acute exposure to environmental tobacco smoke and heart rate variability.

Environmental tobacco smoke (ETS) has been associated with cardiovascular mortality. Pathophysiologic pathways leading from ETS exposure to cardiopulmonary disease are still being explored. Reduced cardiac autonomic function, as measured by heart rate variability (HRV), has been associated with cardiac vulnerability and may represent an important pathophysiologic mechanism linking ETS and risk of cardiac mortality. In this study we evaluated acute ETS exposure in a commercial airport with changes in HRV in 16 adult nonsmokers. We conducted ambulatory electrocardiographic (ECG) monitoring for 8-hr periods while participants alternated 2 hr in nonsmoking and smoking areas. Nicotine and respirable suspended particle concentrations and participants' blood oxygen saturation were also monitored. We calculated time and frequency domain measures of HRV for periods in and out of the smoking area, and we evaluated associations with ETS using comparative statistics and regression modeling. ETS exposure was negatively associated with all measures of HRV. During exposure periods, we observed an average decrement of approximately 12% in the standard deviation of all normal-to-normal heart beat intervals (an estimate of overall HRV). ETS exposures were not associated with mean heart rate or blood oxygen saturation. Altered cardiac autonomic function, assessed by decrements in HRV, is associated with acute exposure to ETS and may be part of the pathophysiologic mechanisms linking ETS exposure and increased cardiac vulnerability.

The relationship between airways responsiveness and chronic airflow limitation.

In 84 subjects with varying degrees of chronic airflow limitation (CAL), airways responsiveness (AR) measured by the response to an inhaled bronchodilator was negatively correlated with pulmonary function. Correlation coefficients were AR and FEV1, r = -0.39, p less than .001; AR and FEV1 percent predicted, r = -0.41, p less than .001; and between AR and FVC percent predicted, r = -0.28, p less than .006. This confirms the findings of others who used bronchoprovocation techniques to measure AR. Previously reported associations between AR and annual rate of change (ARC) of the FVC and FEV1 were reevaluated to determine if they are independent of any relationship between AR and baseline pulmonary function. Baseline FVC and FEV1 were not significantly correlated with ARC, while AR retained its significant association when evaluated by Pearson correlation coefficients and partial correlation coefficients adjusting for baseline FVC and FEV1, and when baseline values were included in liner regression models. Thus, AR in these subjects is a predictor of ARC of the FVC and FEV1 independent of baseline pulmonary function values.

Bilateral vocal cord paralysis for 26 years with respiratory failure. Timing of restoration of tidal volume and serum electrolytes after tracheostomy.

A 31-year-old man had respiratory failure caused by bilateral vocal cord paralysis. He had had limited exercise tolerance since the age of five years, when he had had poliomyelitis. Respiratory failure was present for at least three months. Following relief of the upper airway obstruction by tracheostomy, the patient's tidal volume increased from 200 ml to 500 ml in two days, his carbon dioxide tension fell from 75 to 38 mm Hg, and his arterial bicarbonate level decreased from 39.8 to 25.6 mEq/L in five days. The patient is currently doing well with a permanent tracheostomy.

Chronic eosinophilic pneumonia. Ultrastructural evidence of marked immunoglobulin production plus macrophagic ingestion of eosinophils and eosinophilic lysosomes leading to intracytoplasmic Charcot-Leyden crystals.

A 60-year-old man was diagnosed as having chronic eosinophilic pneumonia by clinical presentation and open lung biopsy. Electron microscopic study of the tissue from biopsy revealed evidence of marked production of immunoglobulin, which may be part of the chemotactic process which attracted large numbers of eosinophils into the area. Also, there were macrophages which were phagocytosing degenerating eosinophils and eosinophilic lysosomes. Charcot-Leyden crystals were noted in the cytoplasm of many macrophages. The relationship of the production of immunoglobulin to the eosinophilia and the mechanism of intramacrophagic formation of Charcot-Leyden crystals is discussed.

Bronchocentric granulomatosis associated with rheumatoid arthritis.

A 49-year-old woman with biopsy-proved bronchocentric granulomatosis (BCG) had repeated exacerbations of seronegative rheumatoid arthritis and vasculitis of the skin concurrent with BCG. To our knowledge, there have been no prior reports of this form of systemic involvement in BCG. While its pathogenesis remains obscure, this case, along with another recent report of eye involvement, suggests that BCG is part of a widespread immunologic response and is not a distinct entity.

Antinuclear antibodies in Utah coal miners.

Antinuclear antibodies (ANA) were detected using a mouse kidney substrate in 69 of 238 (29 percent) underground Utah coal miners at a titer of 1:16. At titers of 1:4 and higher, 52 percent were positive. The majority had a speckled pattern and were not directed against any previously characterized antigens. Fifteen of 28 with high titer ANA had reduced complement. The ANA was more apt to be present in those with coal workers' pneumoconiosis (CWP), and as ANA titer increased, the percentage with CWP increased. The ANA increased with both age and coal mine dust exposure. It is hypothesized that ANA and CWP both result from long-term dust exposure, but that there is insufficient evidence to implicate ANA in the pathogenesis of CWP.

Chronic Obstructive Pulmonary Disease Early Intervention Trial (Lung Health Study). Baseline characteristics of randomized participants.

The Chronic Obstructive Pulmonary Disease Early Intervention Trial, or Lung Health Study, is a multicenter randomized clinical trial sponsored by the Division of Lung Diseases of the National Heart, Lung, and Blood Institute. The hypothesis being tested is that over a 5-year period, a comprehensive intervention program can reduce both the rate of decline in pulmonary function and the rates of respiratory morbidity and mortality in middle-aged smokers with mild to moderate airflow obstruction. The primary outcome variable of the trial is the annual rate of decline of maximum postbronchodilator FEV1. Secondary outcomes are the development of respiratory and nonrespiratory morbidity and mortality. After screening 73,694 cigarette smokers, aged 35 to 60 years, 5,887 participants were randomized into three equal groups: usual care, smoking intervention with daily use of a metered-dose inhaler with ipratropium bromide, and smoking intervention with inhalation of placebo. Eligible participants had a ratio of FEV1 to forced vital capacity (FVC) of 70 percent or less, were free of known life-limiting conditions, expressed willingness to enter the intervention program if so randomized, and gave written informed consent prior to entry into the trial. Spirometry, methacholine challenge, and questionnaires were strictly standardized within and across centers. The purpose of this report is to describe the characteristics of randomized participants at the time of entry into the study. For both sexes, three measures of lung function--average cross-sectional FEV1/FVC ratio, FEV1, and FEV1 percentage of predicted normal--showed slight downward trends for each successively older 5-year age cohort. The increase in FEV1 after isoproterenol was 15 percent or more in only 2.4 percent of men and 2.8 percent of women. A positive response to methacholine (defined as a fall in FEV1 of > 20 percent from baseline at concentrations up to 25 mg/ml) occurred in 63 percent of men and 87 percent of women. The cross-sectional prevalences of cough, phlegm, wheeze on most days or nights, and shortness of breath were 49 percent, 43 percent, 32 percent, and 43 percent, respectively. Respiratory symptoms were reported by a higher proportion of participants in the younger age groups than in the older age groups. Participants who reported cough, phlegm, and/or wheeze averaged lower FEV1 percent predicted and higher probability of positive response to methacholine than participants who did not. Shortness of breath appeared to be significantly associated with lower lung function and higher reactivity in men but not in women.(ABSTRACT TRUNCATED AT 400 WORDS)

Early intervention in chronic obstructive pulmonary disease. A review of the Lung Health Study results.

The major findings of the LHS that have been reported thus far are that an effective smoking cessation program can be developed that can produce more than a 20% success rate in getting smokers to give up the habit permanently, and that by stopping smoking, individuals with early COPD benefit by having an initial improvement in lung function and a slowing of the annual loss of their FEV1. The use of a bronchodilator has a short-term effect in improving the FEV1, but it does not affect long-term changes in lung function. AHR is common in patients with mild-to-moderate COPD. The reward for a smoker to give up the habit is an initial gain in FEV1 and a subsequent close to normal annual rate of decline of this pulmonary function parameter. These results should provide a positive incentive for smokers to quit and thereby decrease the morbidity and mortality caused by the use of tobacco.

Chronic eosinophilic pneumonia: a report of four cases and a review of the literature.

The clinical and radiological findings of four patients with chronic eosinophilic pneumonia are presented. This brings the total number of cases in the English literature to 27. A comparison of all 27 patients is given. The syndrome can readily be distinguished from other eosinophilic pneumonias. After appropriate evaluation, a therapeutic trial can often be initiated with corticosteroids without the necessity for histologic confirmation of the diagnosis.

Daily changes in oxygen saturation and pulse rate associated with particulate air pollution and barometric pressure.

Epidemiologic studies have linked fine particulate air pollution with increases in morbidity and mortality rates from cardiopulmonary complications. Although the underlying biologic mechanisms responsible for this increase remain largely unknown, potential pathways include transient declines in blood oxygenation and changes in pulse rate following exposures to particulate air pollution episodes. This study evaluated potential associations between daily measures of respirable particulate matter (PM) with pulse rate and oxygen saturation of the blood. Pulse rate and oxygen saturation (Spo2) using pulse oximetry were measured daily in 90 elderly subjects living near air pollution monitors during the winter of 1995-96 in Utah Valley. We also evaluated potential associations of oxygen saturation and pulse rate with barometric pressure. Small but statistically significant positive associations between day-to-day changes in Spo2 and barometric pressure were observed. Pulse rate was inversely associated with barometric pressure. Exposure to particulate pollution was not significantly associated with Spo2 except in male participants 80 years of age or older. Increased daily pulse rate, as well as the odds of having a pulse rate 5 or 10 beats per minute (bpm) above normal (normal is defined as the individual's mean pulse rate throughout the study period), were significantly associated with exposure to particulate pollution on the previous 1 to 5 days. The medical or biologic relevance of these increases in pulse rate following exposure to particulate air pollution requires further study.

Early intervention in COPD.

Much has been learned in the 35 years since the Dutch Hypothesis proposed early identification and intervention in those at risk for COPD. More has been accomplished in identification than in therapy. This is due in part to the powerful addiction of cigarette smoking and the continued search for effective pharmacologic means to prevent the accelerated loss in lung function. The Dutch Hypothesis states that airways hyperresponsiveness predicts future acceleration of the rate of lung function decline, particularly in susceptible smokers. In the Lung Health Study, heightened bronchoconstrictor response to methacholine did, indeed, strongly predict an adverse longitudinal decline in lung function. Further, airway hyperresponsiveness was more common than previously suspected, particularly in women. In this subgroup of cigarette smokers, selected because of early COPD, the incidence of hyperresponsiveness was 62% in men and 87% in women, rather than the anticipated 20%. In addition, in the Lung Health Study data recently released, female continuous smokers with the greatest degree of airway hyperresponsiveness exhibited the fastest rate of decline in lung function. However, cigarette smoking had a greater negative impact than hyperresponsiveness. Those with the greatest responsiveness who quit smoking declined more slowly than those with the least responsiveness who continued to smoke. The evidence continues to mount that smoking cessation should be the first and single most important intervention to prevent COPD. Many studies have demonstrated the beneficial effect of smoking cessation on declining lung function. In the comparison of the randomized groups, the Lung Health Study gives the strongest evidence to date that smoking cessation results in substantial benefit to lung function; the benefit continued to increase during the five year study. There was no evidence in the Lung Health Study that bronchodilator usage prevents the relentless decline in lung function in COPD. The increase of FEV1 among users of ipratroprium (even among the most-compliant) was not sustained when the bronchodilator was discontinued at the end of the study.

Bronchodilator response in the lung health study over 11 yrs.

Long-term changes in bronchodilator response in people with mild chronic obstructive pulmonary disease were assessed in this study. Changes in forced expiratory volume in one second (FEV1) in response to isoproterenol was measured in 4,194 participants in the Lung Health Study annually for 5 yrs, and again 11 yrs after study entry. Responses were quantitated in terms of mL (absolute), as per cent of the pre-bronchodilator value (relative), and as a per cent of the predicted normal value (% predicted). At baseline, the mean pre-bronchodilator FEV1 was 75.4% predicted, and responses were small. Relative and percentage predicted responses were similar in males and females; and correlated positively with methacholine reactivity, and negatively with smoking intensity and age. Baseline bronchodilator responses did not correlate with subsequent decline in FEV1. There was a substantial increase in response over the first year of the study, largely due to smoking cessation, with larger increases in those who stopped smoking. After the first year absolute responses changed little in those who maintained smoking cessation, but increased in those who did not. Mean relative and percentage predicted responses increased in all participants throughout the study. There was substantial annual variability of absolute response, and it was poorly reproducible in individual participants. In conclusion, smoking cessation increased bronchodilator response, and response did not predict the rate of decline of forced expiratory volume in one second.

The relationship between alveolar oxygen tension and the single-breath carbon monoxide diffusing capacity.

The effects of alveolar oxygen tension (PAO2) on the single-breath carbon monoxide diffusing capacity (DLCO) were quantified and a factor was derived to accommodate for differences in PAO2 over commonly encountered altitudes and/or varying concentrations of oxygen in the test gas mixture (FIO2) We performed duplicate measurements of DLCO in 7 normal subjects with 6 different oxygen fractions (0.176, 0.196, 0.211, 0.22, 0.25, and 0.27). The PAO2 for each test was measured as the PO2 in the alveolar gas sample bag. DLCO varied inversely with PAO2 and changed by 0.35% for each mmHg change in PAO2 (r = -0.62, p less than 0.001). At an FIO2 of 0.25, PAO2 varied between subjects and was highly correlated with each subject's residual volume to total lung capacity ratio (r = -0.84, p less than 0.001). We suggest that laboratories can adjust the measured DLCO when PAO2 is not congruent to 120 mmHg by the following formula: DLCO (corrected = DLCO (measured) x [1.0 + 0.0035 (PAO2 - 120)].

Bullous emphysema in monozygotic twins.

Monozygotic twins who developed bullous emphysema are described. This occurrence suggests that there is a genetic component that predisposes to the development of this disorder.