Efficacy of salmeterol xinafoate in the treatment of COPD.

STUDY OBJECTIVES: To examine and compare the efficacy and safety of salmeterol xinafoate, a long-acting inhaled beta2-adrenergic agonist, with inhaled ipratropium bromide and inhaled placebo in patients with COPD. DESIGN: A stratified, randomized, double-blind, double-dummy, placebo-controlled, parallel group clinical trial. SETTING: Multiple sites at clinics and university medical centers throughout the United States. PATIENTS: Four hundred eleven symptomatic patients with COPD with FEV1 < or = 65% predicted and no clinically significant concurrent disease. INTERVENTIONS: Comparison of inhaled salmeterol (42 microg twice daily), inhaled ipratropium bromide (36 microg four times a day), and inhaled placebo (2 puffs four times a day) over 12 weeks. RESULTS: Salmeterol xinafoate was significantly (p < 0.0001) better than placebo and ipratropium in improving lung function at the recommended doses over the 12-week trial. Both salmeterol and ipratropium reduced dyspnea related to activities of daily living compared with placebo; this improvement was associated with reduced use of supplemental albuterol. Analyses of time to first COPD exacerbation revealed salmeterol to be superior to placebo and ipratropium (p < 0.05). Adverse effects were similar among the three treatments. CONCLUSIONS: These collective data support the use of salmeterol as first-line bronchodilator therapy for the long-term treatment of airflow obstruction in patients with COPD.

The natural history of asthma.

Our understanding of the natural history of asthma is improving through the establishment of a more precise definition of asthma linked with information from large-scale longitudinal studies. Risk factors for the development of childhood asthma including sex, atopic status, genetic and familial factors, respiratory infections, and outdoor and indoor pollution are now more clearly understood. New information on the relation of viral wheezing episodes in infancy to later childhood asthma is evolving. We now know that children who start wheezing early in life and continue to wheeze at age 6 years are more likely to have a maternal history of asthma, elevated serum IgE levels, and normal lung function in the first year of life. However, at age 6 years they have both elevated serum IgE levels and diminished lung function. Approximately 50% of adults who report having had childhood asthma no longer have symptoms. Airway responsiveness in childhood tends to predict airway responsiveness in adulthood and to be greater in asthmatics with persistent symptoms. Studies of the natural history of asthma support the hypothesis that early therapeutic intervention in mild disease may lead to an improved clinical outcome. Adults exposed to specific occupational environments are at additional risk for the development of asthma. As we learn more about the natural history of asthma, we will have a better understanding of the effect of early diagnosis, environmental control, and therapy on the outcome of the disease.

Bronchial responsiveness to distilled water and methacholine and its relationship to inflammation and remodeling of the airways in asthma.

Although bronchial hyperresponsiveness in asthma is associated with inflammation within the airways, it is not known whether the degree and type of inflammation influence the response to different stimuli and whether pathologic changes of airway structure influence the bronchoconstrictive responses. Therefore, number of inflammatory cells in the epithelium and the lamina propria and the basement membrane thickness were estimated from bronchial biopsies taken in 27 asthmatic subjects (range percent predicted FEV1: 75.6 to 132.1, range of daily PEF variability: 1.9% to 20%) and related to the degree of bronchial responsiveness to ultrasonically nebulized distilled water (UNDW) and methacholine (M). PD20UNDW (provocative dose) was measurable in 15 of 27 patients and ranged between 1.01 and 20.4 ml. PC20M (provocative concentration) ranged between 0.15 and 31.7 mg/ml. In the 15 responders to UNDW, total inflammatory cells (p<0.04) and eosinophils (p<0.015) within the epithelium were higher than in 12 nonresponders to UNDW (PD20 > 34.8 ml). There was no correlation between PD20UNDW and any cell counts whereas negative correlations were found between PC20M and both total inflammatory cells (rs = -0.57; p<0.005) and eosinophils (rs = -0.63; p< 0.0015) within the epithelium. The degree of thickening of subepithelial layer ranged between 7 and 16 micrometers+ (n=26). Thickness correlates both with total inflammatory cells (rs = 0.49; p<0.025) and eosinophils (rs = 0.61; p< 0.003) within the epithelium. Moreover, it was correlated with baseline FEV1 (rs = -0.57; p<0.003) and daily peak expiratory flow (PEF) variability (rs = 0.51; p<0.01). A weak but significant correlation was also found between subepithelial layer thickness and PC20M (rs = -0.42; p<0.04). The results of this study demonstrate that eosinophilic inflammation of bronchial epithelium plays a role in determining UNDW and M responsiveness in asthma. Moreover, they suggest that remodeling of the airways such as thickening of subepithelial layer correlates with indices of asthma severity and could contribute to the degree of M but not to UNDW responsiveness.

Longitudinal evaluation of the association between pulmonary function and total serum IgE.

The role of immunoglobulin E (IgE) in the development and course of impaired ventilatory function and chronic obstructive pulmonary disease (COPD) required further study. This role has been examined in the longitudinal Tucson Epidemiological Study of Airways Obstructive Disease, which started in 1972. The association between IgE and longitudinal changes in pulmonary function measures was examined in subjects in the community population sample in Tucson who had an initial age of 35 or more. There were a total of 1,533 such subjects with lung function tests over the 20 yr period who also had IgE determinations. A significant inverse association was found between total serum IgE and FEV1/FVC that was independent of smoking and asthma status. The finding was statistically separate from the relation with age in all but elderly current smokers (age > 55). The magnitude of this effect in nonasthmatic subjects was relatively small. For asthmatic subjects, however, the inverse association was larger in both current and never smokers. Subjects excluded from the current analysis either did not have an IgE measurement and/or had no pulmonary function values after 35 yr of age. These findings suggest that higher IgE levels may indicate the presence of a disease process that may involve inflammation and/or other mechanisms related to IgE production, which impair lung function over time. However, in this study we were not able to account for possible parental or inheritance contributions to increases in total IgE, which have been shown to be important.

Findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample.

Forty elderly subjects who denied ever having asthma or emphysema on enrollment in a longitudinal epidemiologic study later reported consulting a doctor for asthma when they were older than 60 years of age. The average age at which the diagnosis was reported was 70.8 years, after a mean follow-up of 8.5 years. Findings on enrollment in the newly diagnosed subjects with asthma are compared with findings in the 1145 subjects who provided follow-up information when they were older than age 60 years but had never developed asthma. At the time of enrollment, most subjects later diagnosed as having asthma already had wheezing symptoms, suggesting at least a mild asthmatic state, and many subjects had impaired ventilatory function, a positive allergy skin test (especially in association with rhinitis), and blood eosinophilia. Thirty-five percent of the subjects recalled "respiratory trouble before age 16" despite denying prior asthma. The likelihood of a new asthma label was very closely related to the age-sex-standardized serum-IgE level before diagnosis. Newly diagnosed subjects with asthma demonstrated much greater rates of decline in FEV1 than control subjects or than subjects who already had known asthma on enrollment. We conclude that (1) symptoms suggesting asthma are usually present for many years before the diagnosis of the disease in elderly subjects, (2) the serum-IgE level is closely related to the likelihood of a subsequent asthma diagnosis, even in this age group, and (3) a rapid fall in lung function often occurs around the time of initial diagnosis.

Characteristics of asthma among elderly adults in a sample of the general population.

This article describes the characteristics and course of asthma among subjects who were older than 65 years at the time of enrollment in a longitudinal study of a general population sample. It was present in 3.8 percent of men and 7.1 percent of women. An additional 4.1 percent of men reported having "asthma," but they also had seen a physician for "emphysema" and had smoked significantly; their "asthma" diagnosis is regarded as highly questionable. They did not show the elevated rate of allergy skin test reactivity of high serum IgE levels that were characteristic of other asthmatics. Many of the elderly asthmatics (mean age, 72 years) had severe disease with marked ventilatory impairment. There was a close relationship between the severity of wheezing complaints and impairment of the FEV1. Of the 46 patients, 48 percent reported an onset before age 40 years. There was no relationship between severity and age of onset or duration of disease. A second diagnosis of "chronic bronchitis" was reported by 46 percent of the asthmatics, but this did not delineate a distinctive group with late-onset, smoking-related disease. Death rates in the asthmatics tended to be higher than in nonasthmatics (odds ratio, 1.9; CI, 0.998 to 3.70, after stratifying by sex). Over a mean follow-up of 7.44 years, most symptoms as well as the FEV1 remained relatively stable. Chronic productive cough did tend to remit (p less than 0.01), but this was noted in the nonasthmatics as well. We estimate that no more than 19 percent of the asthmatics went into complete remission during follow-up. Most of these had mild initial symptoms; there were no remissions in subjects with severe disease at the time of entry. We concluded that asthma in the elderly is not a rare disease and may be associated with severe symptoms and chronic airways obstruction. If severe, it rarely goes into complete remission but tends to remain a severe, disabling disorder.

The maternal immune response in coccidioidomycosis. Is pregnancy a risk factor for serious infection?

Seven subjects with prior coccidioidal disease and three with active Coccidioides immitis infection during their first trimester were studied during pregnancy and postpartum to determine their general and antigen-specific cell-mediated immune status. All ten were white and carried their pregnancies to term without incident. Decreases in total lymphocytes and T-helper and T-suppressor subsets were noted during the third trimester, presumably secondary to an increase in plasma volume. Lymphocyte responses to the mitogens phytohemagglutinin, concanavalin A, and pokeweed were mildly decreased late in pregnancy, with significant intrasubject and intersubject variation. Responses to tetanus antigen were consistently and significantly lower as pregnancy progressed, rising above first trimester levels by 12 weeks postpartum. A similar pattern of response was noted with spherulin antigen for the seven subjects with previously demonstrated coccidioidal immunity. The three subjects with active coccidioidomycosis either failed to mount a significant spherulin immune response or demonstrated an early response that fell as pregnancy progressed. This antigen-specific immune suppression continued for up to 16 months postpartum despite the fact that there was no clinical evidence of coccidioidal activity beyond the first trimester. Thus, while all three completed pregnancy without complication, the data suggest that significantly increased maternal risk may be present when active coccidioidomycosis and pregnancy occur together. This risk may be greatest among darker-skinned individuals who become infected during the latter half of pregnancy.

A longitudinal study of respiratory symptoms in a community population sample. Correlations with smoking, allergen skin-test reactivity, and serum IgE.

Chronic cough and/or phlegm, wheeze in the absence of colds, and rhinitis attributed to allergies are three of the most common respiratory symptoms encountered in community populations. In this study, we have determined the prevalence of these complaints in a random population sample (n = 1,109) using standardized questionnaires at two points in time, eight years apart. Cross-sectional prevalence and changes in symptom occurrence have been correlated with smoking status, allergen skin test reactivity, and total serum IgE levels. Our objective was to determine the individual and combined influence of these three variables on symptom prevalence. Initially, 19.2 percent of the population admitted to wheeze, 17.9 percent to cough, and 44.1 percent to allergic rhinitis. Cough and wheeze prevalence changed little over the eight-year period, while rhinitis increased 11 percent by the second survey. The occurrence of chronic cough was strongly correlated with smoking, and was not further influenced by either allergen skin reactivity or IgE level. Conversely, rhinitis prevalence was related to skin test reactivity with no additional association with smoking or IgE level. The occurrence of wheeze in the absence of colds was associated with both smoking and allergen skin reactivity. Among smokers, the prevalence was over 30 percent and was similar in both skin test positive (STP) and skin test negative (STN) individuals. However, on both surveys, STP ex-smokers and nonsmokers had significantly more wheeze than those who were STN. While the prevalence of wheeze in STN nonsmokers was low (6.8 percent), an IgE-wheeze relationship was also suggested on the second survey. In addition to these cross-sectional symptom relationships, changes in either smoking status or allergen skin reactivity during the study period were associated with changes in the prevalence of each symptom.

Lavage versus serum measurements of lysozyme, angiotensin converting enzyme and other inflammatory markers in pulmonary sarcoidosis.

The aim of this study was to explore whether amounts of angiotensin converting enzyme (ACE) and lysozyme produced within the lungs correlate more closely than serum levels of these enzymes, or other inflammatory markers, with chest radiographic profusion scores, lung function and therapy response in patients with pulmonary sarcoidosis. We have studied 25 patients, and levels in bronchoalveolar lavage (BAL) were used to determine "local" enzyme production by reference to serum and lavage albumin. Before treatment, serum lysozyme levels were elevated in more patients (80%) than serum ACE levels (40%). They also gave the best overall correlation with clinical measurements prior to treatment and falls in serum lysozyme closely parallelled improvement in lung function (transfer factor for carbon monoxide (DLCO)) on therapy. The only other markers showing significant correlations with disease severity were lavage neutrophil counts per ml and "local" ACE measurements prior to treatment. The value of pre-treatment levels of the different inflammatory markers in predicting response to corticosteroid therapy was explored and the only significant finding was that BAL lymphocyte percentages and numbers.ml-1 were initially higher in patients with lower post-treatment chest X-ray scores (p less than 0.01 and p less than 0.05, respectively). We conclude that serum lysozyme levels appear to be a more useful marker of overall disease activity in sarcoidosis than measurements of other inflammatory markers. However, BAL lymphocyte counts were the best predictive marker of radiographic response to corticosteroids.

Detection of fungi and other pathogens in immunocompromised patients by bronchoalveolar lavage in an area endemic for coccidioidomycosis.

Bronchoalveolar lavage (BAL) was performed in 51 adult immunocompromised patients (30 acquired immunodeficiency syndrome [AIDS] and 21 non-AIDS) as part of an extensive diagnostic evaluation for diffuse pulmonary infiltrates. Because multiple episodes occurred in several patients, a total of 60 BALs were performed. A diagnosis of fungal pneumonia was eventually made in 12 patients (24 percent). The organism was identified in BALs from seven of the 12, including five of seven cases of cocciodoidomycosis, one of two cases of aspergillosis, and one of three cases of cryptococcosis. Among the AIDS patients, only one case of coccidioidomycosis was diagnosed, whereas six such diagnoses were made from the 25 BALs performed on the 21 non-AIDS patients. This suggests that coccidioidomycosis is not as frequent an infection in AIDS patients in this endemic area as has been suggested previously. Candida-like organisms were identified in 23 BALs, but in no case were they clinically pathogenic. Their presence correlated with oral candidiasis (p = 0.01). Twenty-seven of 29 episodes related to Pneumocystis carinii were identified by Papanicolaou-stained cytocentrifuged BAL preparations, all but two of which were in AIDS patients. In addition, BALs detected six episodes of bacterial pneumonia and three of five cases of radiation pneumonitis. Overall, the diagnostic sensitivity of BAL was 52 of 60 or 87 percent. While examination of induced sputum for the presence of Pneumocystis may eliminate the need for bronchoscopy in some AIDS patients, BAL remains an excellent diagnostic procedure in the immunocompromised patient without AIDS.

Association of asthma with serum IgE levels and skin-test reactivity to allergens.

We investigated the association of self-reported asthma or allergic rhinitis with serum IgE levels and skin-test reactivity to allergens in 2657 subjects in a general-population study. Regardless of the subjects' status with respect to atopy or their age group, the prevalence of asthma was closely related to the serum IgE level standardized for age and sex (P less than 0.0001), and no asthma was present in the 177 subjects with the lowest IgE levels for their age and sex (greater than 1.46 SD below the mean). The log odds ratio increased linearly with the serum IgE level after we controlled for possible confounders and the degree of reactivity to skin tests. In contrast, allergic rhinitis appeared to be associated primarily with skin-test reactions to common aeroallergens, independently of the serum IgE level. We conclude that asthma is almost always associated with some type of IgE-related reaction and therefore has an allergic basis, although not all the allergic stimuli that cause asthma appear to have been included in the battery of common aeroallergens we used to assess atopic status. These findings challenge the concept that there are basic differences between so-called allergic ("extrinsic") and nonallergic ("intrinsic") forms of asthma.

Clinical usefulness of lymphocyte transformation in patients with coccidioidomycosis.

The development of an appropriate host defense in coccidioidomycosis is predicated on the presence of a positive delayed skin test reaction to coccidioidin. In severe and/or disseminated disease, coccidioidin reactions are routinely negative. By employing serial in vitro spherulin-induced lymphocyte blast transformation (LT) studies in a group of eight severely-ill coccidioidomycosis patients, prognostic clinical data were provided which could not have been obtained from their skin test status alone. Four of the eight demonstrated positive LT responses early in the course of their disease, quickly converted their skin tests to positive, and were cured of their disease. Two patients had negative LT responses until their skin test converted after several months of therapy. The final two have continued to demonstrate negative LT values despite several years of therapy and have experienced exacerbations of their disease when treatment was discontinued. The use of LT data in such patients can be very helpful in guiding therapeutic decisions in this difficult clinical problem.

A longitudinal study of serum IgE in a community cohort: correlations with age, sex, smoking, and atopic status.

A number of factors, including age, sex, smoking habits, and atopic status have been reported in cross-sectional studies to influence levels of serum IgE. We have examined the effects of these variables on serum IgE in a community population cohort of 1109 subjects during a longitudinal study in which two serum samples were obtained 8 years apart from each subject. For the entire cohort, mean serum IgE level changed little during the follow-up period (28.9 versus 26.0 IU/ml). Most of the decreases were observed in children and young adults. Subjects more than the age of 35 years demonstrated no systematic change in serum IgE levels. By the end of follow-up (when there were few subjects still less than 16 years of age), significant relationships of IgE to age could no longer be demonstrated in nonatopic subjects. Also, in the nonatopic subjects of this cohort, there were no significant differences in IgE levels between the sexes. Among atopic subjects, there was a clear tendency for IgE to decrease with age, with atopic women more than 35 years of age demonstrating greater declines in IgE levels during follow-up than men of comparable age. The IgE levels in atopic male subjects were significantly higher than in atopic female subjects after the age of 35 years. Smoking was associated with an elevation in serum IgE. In this cohort, the smoking effect appeared to be limited to male subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

The epidemiology of asthma.

As noted earlier, the clinician and the epidemiologist are in many respects in similar positions in terms of our current understanding of asthma. Through the efforts of the pharmaceutical industry the practitioner has a much wider range of therapeutic tools available to manage reversible airways disease. B-agonists are more specific, have a longer duration of action, minimizing the potential for abuse and coincident toxicity. Theophylline preparations are long-acting and therapeutic drug levels can be accurately assessed. Inhaled corticosteroids provide the opportunity to reduce the negative side aspects of hormonal therapy. Unfortunately, with all these tools, the morbidity and mortality of asthma have not been decreased. In fact, it may be that the disease is a greater worldwide health problem than it was a generation ago. Similarly, epidemiologic research has provided us with increasingly meaningful information, not only of the prevalence of the disease, but with recent longitudinal studies, the factors which impact upon disease remission and relapse. Whether we separate the wheezing syndromes into separate categories of wheezy bronchitis, asthmatic bronchitis, and asthma is probably less important than our understanding of a disease entity which is characterized by bronchial hyper-reactivity in response to a variety of stimuli. The most encouraging aspects of recent epidemiologic research have been the selection of representative populations, using standardized methods, from which significant conclusions can be drawn. At the least, these studies have confirmed and extended our knowledge of a disease that we still do not fully understand. Woolcock et al.[56], and others, have included inhalation challenge testing into their epidemiologic protocols in an attempt to add physiologic assessments to the more traditional symptom complexes. Unfortunately, even this addition has not solved the problem of an asthma diagnosis in the older adult population whose irreversible airways obstructive disease is a confounding variable. Even in younger subjects, as reported by Townley et al.[14], a gradation of responses to methacholine inhalation in atopic subjects, may make the identification of asthmatics more difficult than initially thought. The fact that ex-asthmatics appear to retain their hyper-responsiveness, however, could make inhalation challenge a valuable tool in longitudinal epidemiologic research. What can epidemiologic studies contribute in the future?.(ABSTRACT TRUNCATED AT 400 WORDS)

Longitudinal changes in allergen skin test reactivity in a community population sample.

A cohort of 1333 subjects, aged 3 years and older, was followed for a mean of 8.1 years to assess changes in allergen skin test reactivity. The overall prevalence of reactivity to the five antigen mixtures was 39.1% during the initial survey and 50.7% after the follow-up period. The greatest increase in prevalence occurred among children and teenagers (22.2% and 19.5%) with only minimal increases after the age of 65 years (6.0%). No difference in prevalence between male and female subjects was apparent, either initially or at the end of the follow-up period. In-migration to the Tucson area was a major factor in determining changes in reaction prevalence. Among subjects more than 35 years of age, recent in-migrants accounted for most of the increased prevalence. Comparisons of atopy among consistent smoking groups confirmed the previous observation that smokers are less atopic than either nonsmokers or exsmokers, probably because of a self-selection process. In contrast, exsmokers were generally the most atopic, both initially and at the end of the longitudinal observation period. The high overall prevalence of allergen reactivity in this population is believed to be due in large measure to high year-round concentrations of multiple aeroallergens in the Tucson environment.

Evaluation of methodologic variables of the in vitro lymphocyte transformation assay.

Optimum methodologic variables for assessing cellular immunity by in vitro lymphocyte transformation (LT) were determined using spherulin and coccidioidin antigens. This study was conducted in an area endemic for coccidioidomycosis and included healthy, coccidioidomycosis skin test positive (STP) and negative (STN) subjects, and patients with mild, acute disease. The authors examined the relationship between coccidioidin (1:100) and spherulin (low dose) skin test reactivity and lymphocyte transformation (LT) responses to the same antigens. Counts per minute (CPM) and stimulation index (SI) as methods of expressing tritiated thymidine uptake were compared. The LT assays were set up in duplicate test systems using autologous and homologous plasma. Both antigens differentiated between STP and STN groups (P less than or equal to 0.001-0.004), but values obtained with spherulin-induced LT were greater than those using coccidioidin (P less than 0.001). Values in CPM and SI were greater in the spherulin-induced LT assay using autologous compared with AB plasma. Specifically, for detecting cellular immunity to coccidioidomycosis, the combination of spherulin-induced LT using autologous plasma and expressing the results in CPM gave the best discrimination between STP and STN subjects. Based on epidemiologic data, the latter method also appeared more sensitive than the skin test in detecting cellular immunity to coccidioidomycosis. In general, these data illustrate the variable effectiveness of different antigens for inducing LT responses and further show how different plasma sources affect the LT response. Finally, these data suggest that lymphocyte blast transformation results expressed as CPM may give more consistent values and better discrimination between immune and nonimmune subjects than results expressed as stimulation indices.

The prevalence of cellular immunity to coccidioidomycosis in a highly endemic area.

Intradermal skin test reactivity to spherulin and coccidioidin and in vitro spherulin-induced lymphocyte transformation were used to assess cellular immunity in healthy subjects and patients with acute, self-limited coccidioidomycosis (cocci). The objectives of this study were to evaluate the relative sensitivities of the two assays in assessing cellular immunity to cocci, especially in long-term residents of an endemic area (Tucson) and, based on data from both assays, determine the prevalence of detectable cellular immunity to cocci in this highly endemic area. The lymphocyte transformation assay appeared to be more sensitive than the skin test in assessing long-term immune status, and the prevalence of detectable immunity to cocci in this highly endemic area was only 75% in long-term residents. This is much lower than previous prevalence estimates (90%) in other endemic areas. The absence of a demonstrable cell-mediated immunity may indicate either no prior antigen exposure (infection) or previous remote exposure with a diminished immune response (no reexposure to boost immunity). A possible explanation for the lower prevalence of immunity to cocci in this endemic area may relate to the increased urbanization of the Southwest in the past several years. Therefore, the clinical suspicion of acute cocci should not be restricted to recent arrivals to endemic areas.

Methodological considerations of epidemiological diagnoses in respiratory diseases.

Since epidemiological research depends extensively on questionnaire responses, a comparison of such responses with a standardized medical evaluation was conducted. It was found that standardized questionnaires do well in comparison for certain kinds of information on chronic conditions. However, clinical evaluations will elicit more information, specifically of a milder nature. It was concluded that standardized epidemiological questionnaires are satisfactory for survey of chronic conditions.