Relationship between pulmonary test variables and asthma and wheezing: a validation of self-report of asthma

We investigated the relationship between the pulmonary test variable measurements and self-reported asthma and wheezing from a cross-sectional study conducted in Saskatchewan. Based on the responses to the questionnaire, the subjects were classified into asthmatic, wheezing, and asymptomatic groups. For both male and female subjects the mean values of forced expiratory volume in 1 s (FEV1), forced expiratory flow during the middle half of the forced vital capacity (FEF25-75), and FEV1/FVC ratio were lowest in asthmatics, followed by wheezing and asymptomatic groups, respectively. This trend was also observed in forced vital capacity (FVC) for men but not for women. After adjusting for current smoking status, the trend in the means across the three groups was statistically significant in men for FEV1 (p = 0.03), FEF25-75 (p = 0.002), and FEV1/FVC ratio (p = 0.002) and in women for FEF25-75 (p < 0.001) and FEV1/FVC ratio (p < 0.001). The differences in the adjusted means of FVC, FEV1, FEF25-75, and FEV1/FVC ratio between asymptomatic subjects and the other two groups were significant in both male and female subjects. Significant differences were also observed between asthmatics and wheezing groups in the adjusted means of FEF25-75 and FEV1/FVC ratio in male and female subjects. We conclude that the self-report of asthma has a high level of validity against the criterion of concurrently measured pulmonary test variables.     

Bronchial obstruction and exhaled nitric oxide response during exercise in cold air

This study examines whether exhausting exercise in cold air induces bronchial obstruction and changes in exhaled [NO] and in exhaled NO output (V'NO). Thus, eight well-trained males performed two incremental exercise tests until exhaustion, followed by 5 min of recovery in temperate (22 degrees C) and cold (-10 degrees C) environments, at random. At -10 degrees C, they were dressed in warm clothes. Ventilation (V'E), oxygen consumption (V'O2), carbon dioxide production, cardiac frequency (fC), and [NO] and V'NO were measured continuously. Before and after each test, the subjects' maximal expiratory flow-volume curves and peak expiratory flow, forced expiratory volume in one second (FEV1) and forced expiratory flow at 25 (FEF25), 50 (FEF50) and 75% (FEF75) of forced vital capacity were determined. At -10 degrees C, significant decreases in FEV1 and FEF75 were observed after exercise. At rest and at the same submaximal intensity, V'O2, V'E and fC did not differ significantly. At rest and up to approximately 50% peak V'O2, [NO] and V'NO values were lower at -10 degrees C than at 22 degrees C. Thereafter, and during recovery, the V'NO response became similar at both -10 and 22 degrees C. This study confirms that considerable hyperpnoea in cold air causes a detectable airway obstruction. This airway cooling also induces an initial decrease in the exhaled NO response. Since endogenous NO-production is involved in bronchial dilation, it cannot be excluded that this lack of production may favour the appearance of airway obstruction.     

Reduced asthma symptoms with n-3 fatty acid ingestion are related to 5-series leukotriene production

Asthma may respond to dietary modification, thereby reducing the need for pharmacologic agents. This study determined the effectiveness of n-3 polyunsaturated fatty acid (PUFA) ingestion in ameliorating methacholine-induced respiratory distress in an asthmatic population. The ability of urinary leukotriene excretion to predict efficacy of n-3 PUFA ingestion was assessed. After n-3 PUFAs in ratios to n-6 PUFAs of 0.1:1 and 0.5:1 were ingested sequentially for 1 mo each; patient respiratory indexes were assessed after each treatment. Forced vital capacity (FVC), forced expiratory volume for 1 s (FEV1), peak expiratory flow (PEF), and forced expiratory flow 25-75% (FEF 25-75) were measured along with weekly 24-h urinary leukotriene concentrations. With low n-3 PUFA ingestion, methacholine-induced respiratory distress increased. With high n-3 PUFA ingestion, alterations in urinary 5-series leukotriene excretion predicted treatment efficacy. Elevated n-3 PUFA ingestion resulted in a positive methacholine bronchoprovocation dose change in > 40% of the test subjects (responders). The provocative dose to cause a 20% reduction (PD20) in FEV1, FVC, PEF, and FEF25-75 values could not be calculated because of a lack of significant respiratory reduction. Conversely, elevated n-3 PUFA ingestion caused some of the patients (nonresponders) to further lose respiratory capacity. Five-series leukotriene excretion with high n-3 PUFA ingestion was significantly greater for responders than for nonresponders. A urinary ratio of 4-series to 5-series leukotrienes < 1, induced by n-3 PUFA ingestion, may predict respiratory benefit.     

Should sperm donors be paid? A survey of the attitudes of the general public

Human immunodeficiency virus (HIV) infection has been associated with a wide spectrum of pulmonary disease. We report three HIV-seropositive patients with rapidly worsening airway obstruction associated with bronchiectasis. All subjects (age range 33-39 yrs) were cigarette smokers. Two had previously used intravenous drugs. The CD4 lymphocyte count ranged 40-250 cells x mm(-3). All individuals had complained of increasing dyspnoea for 3-6 months. Within 1 yr, they all developed severe airway obstruction with a decrease in both forced expiratory volume in one second (FEV1) and ratio of FEV1 to forced vital capacity (FEV1/FVC) to less than 60% of predicted value, and a decrease in mean forced expiratory flow at 25-75% of the forced vital capacity (FEF25-75) to less than 35% of predicted value. Computed tomography of the chest disclosed bilateral dilated and thickened bronchi. No classical causes of genetic or acquired bronchiectasis were identified in our patients. Recurrent bacterial bronchitis occurred in the follow-up period of the three patients. In conclusion, unusually rapid airway obstruction associated with bronchiectasis should be added to the wide spectrum of respiratory complications of human immunodeficiency virus infection.     

Lung function in Indian twin children: comparison of genetic versus environmental influence

The relative contributions of genetic and environmental components in the variability of lung function measurements were studied in 54 twin pairs. Thirty pairs of monozygote (MZ) twins and 24 pairs of dizygotic (DZ) twins were examined. All measurements were made with 9-litre closed-circuit-type expirographs using standard spirometric techniques, except for peak expiratory flow rate (PFER) which was recorded with a Wright peak flow meter. Within-pair variances for inspiratory capacity (IC), vital capacity (VC), forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), forced mid-expiratory flow (FEV25-75%), forced end-expiratory flow (FEF75-85%), maximum expiratory flow (FEF200-1200ml), forced maximum voluntary ventilation MVVF) and PEFR were significantly smaller (p < 0.01) in MZ twins than in DZ twins. Tidal volume (VT), inspiratory reserve volume (IRV), expiratory reserve volume (ERV), forced expiratory volume in 1 second as a percentage of forced vital capacity (FEV1%), and forced expiratory time (FET) were not significantly different. Within-pair correlations were all higher in MZ than DZ twins. All measurements except for VT and PEFR showed high levels of heritability (23-99%). All measurements were positively and significantly correlated with physical characteristics such as weight, standing height, surface area, arm-span, chest circumference and age, except FEV1% and FET. Residual values adjusted for physical characteristics showed similar results to unadjusted values in most cases. These data indicate that major lung function measurements are possibly influenced more by genetic than environmental factors. Genetically influenced measurements show higher levels of heritability estimates and suggest that genetic determination of lung function is possibly independent of the influence of physical characteristics.     

Methods development for epidemiologic investigations of the health effects of prolonged ozone exposure. Part I: Variability of pulmonary function measures

The acute and subacute effects of ambient concentrations of ozone on lung function have been studied extensively in a variety of settings. Such studies generally have focused on measures of function that reflect either lung volumes or flows that are influenced by the physiology of large and small airways (e.g., forced expiratory volume in one second [FEV1). Data from animal studies suggest that the effects of prolonged exposure to elevated ambient concentrations of ozone result in abnormalities in the centriacinar region of the lung; and dosimetry models for humans predict that long-term exposure to ozone could impact the same areas of the human lung. However, alterations in structure at this level of the lung are not well reflected by measuring FEV1 until substantial structural changes have occurred. Measures of the lung function that reflect the functional mechanics of airways smaller than 2 mm in diameter are considered to be more relevant. At least one epidemiologic study has provided evidence that small-airway functions may be relevant to effects of prolonged exposure to environments with high concentrations of oxidants. A considerable body of physiologic data has established that flow rates measured during the terminal portion of a maximum expiratory flow-volume (MEFV) curve are largely governed by airways smaller than 2 mm in diameter A similar interpretation has been given to changes in the slope of phase III (delta N2) of the single-breath nitrogen washout (SBNW) curve. Despite the attractiveness of these measures in relation to airway physiology, some data suggest that measurements of flow via the terminal portions of MEFV and SBNW curves have much greater within-subject variability than forced vital capacity (FVC and FEV1. The present study was undertaken as part of a larger feasibility study to develop methods to study the effects of prolonged exposure to elevated ambient ozone levels on lung function in adolescents. A convenience sample of 239 freshmen (ages 16-20 years) entering the University of California, Berkeley were recruited to participate in this protocol. All were lifelong residents of the San Francisco Bay Area or the Los Angeles Basin. Subjects were studied on two occasions five to seven days apart. At each test session, subjects performed up to eight forced expiratory maneuvers to produce three acceptable and reproducible MEFV curves by modified American Thoracic Society criteria. Tests of SBNW were then performed on the basis of detailed criteria for validity and reproducibility. Eight attempts to generate three curves were allowed. The delta N2 was obtained by a least-squares regression of nitrogen concentrations between the 750-mL and 1750-mL volume points. Instantaneous flow at 75% of expired volume (FEF75%), average flow between the 25% and 75% volume points (FEF25%-75%), and delta N2 were the principal outcomes. Variance components were estimated with a nested random effects model with adjustments for important covariates. The average within-subject coefficients of variation (+/-SD of distribution of means) for male subjects were: FEV1 1.2 (+/-0.8); FEF25%-75% 3.2 (+/-2.3); FEF75% 5.8 (+/-5.0); and delta N2 17.9 (+/-12.3); for female subjects they were: FEV1 1.4 (+/-0.9); FEF25%-75% 3.0 (+/-2.2); FEF75% 6.2 (+/-5.2); and delta N2 19.9 (+/-17.0). The variance attributed to test session was less than 1% for all measures. The percentages of variance due to within-subject variation for each measure (adjusted for sex, area of residence, ethnicity, and height) were: FVC 3.6%; FEV1 3.0%; FEF25%-75% 5.2%; FEF75% 8.9%; and delta N2 23.9%. Of all subjects tested, 234 (97.9%) could provide at least two acceptable MEFV curves, but only 218 (91.2%) could provide at least two acceptable SBNW curves. The results were unchanged by recent history of acute, respiratory illness.(ABSTRACT TRUNCATED)     

Accelerated lung function decline in swine confinement workers

We conducted a longitudinal study to determine the annual rate decline in pulmonary function measurements in male swine confinement workers. For comparison, a grain farming group and a nonfarming rural-dwelling control group were also chosen for the longitudinal study. Two hundred seventeen swine confinement workers, 218 grain farmers, and 179 nonfarming control subjects had valid pulmonary function measurements at the baseline observation conducted in 1990 to 1991 and at the second observation conducted in 1994 to 1995. The swine confinement workers were younger (mean age=38.3+/-11.7 [SD] years) than the nonfarming control subjects (42.6+/-10.4 years) and the grain farmers (44.5+/-11.9 years). When stratified by age, nonfarming control subjects had the lowest mean annual rate decline in FEV1 and FVC in all age categories. The swine confinement workers had the largest annual rate decline in FEV1 and FVC, and this was most obvious in the middle age categories. After controlling for age, height, smoking, and baseline pulmonary function, swine confinement workers had excess annual decline of 26.1 mL in FEV1 (p=0.0005), 33.5 mL in FVC (p=0.0002), and 42.0 mL/s in forced expiratory flow between 25% and 75% of FVC (FEF[25-75%]) (p=0.02) over nonfarming control subjects. Grain farmers had excess annual decline of 16.4 mL in FEV1 (p=0.03), 26.7 mL in FVC (p=0.002), and 11.2 mL/s in FEF(25-75%) (p=0.38) over control subjects. These findings suggest that workers engaged in the swine industry and grain farmers appear prone to accelerated yearly losses in lung function and may therefore be at risk for the future development of chronic airflow limitation.     

Passive smoking and evolution of lung function in young adults. An 8-year longitudinal study

The objective of the study was to examine the relation between exposure to environmental tobacco smoke (ETS) and the rate of change in ventilatory lung function in young adults during a study period of 8 years, with an additional aim to recognize susceptible subgroups. The study population consisted of 117 never smokers, who were 15-40 years of age at the time of an initial examination when they underwent spirometry and a standardized interviewer-administered questionnaire on respiratory health, and were re-examined 8 years later. Lifetime exposure to ETS at home and at work before the start of the study was ascertained at an early stage of the study, and exposure during the study period was recorded at the 8-year examination. The relations between home and work ETS exposure before and during the study period and the rate of change in forced expiratory volume in one second (delta FEV1 in ml/yr) and in mean forced expiratory flow during the middle half of the forced vital capacity (delta FEF25-75 in 1/sec/yr) were studied in linear regression models including potential confounders and other determinants of the outcome. There was no statistically significant relation between ETS exposure during or before the study period and evolution of FEV1 or FEF25-75. The 95% confidence intervals of the estimates indicated that ETS exposure was unlikely to have a physiologically relevant effect. A statistically significant but physiologically unimportant relation was observed between cumulative home ETS exposure before the study and delta FEV1 in the subgroup of subjects 25 years of age or younger. There was no evidence of modification by atopy, wheezing or gender. The results suggest that exposure to environmental tobacco smoke in young adulthood at home and in office work environment does not lead to a clinically important ventilatory impairment in such exposure levels as experienced in Canadian housing conditions. This does not refute the possibility that higher exposure due to more frequent smoking in smaller indoor spaces with lower rates of ventilation may be harmful.     

Exercise induced bronchial lability in normal men and women--a comparison

Normal male (n = 29) and female (n = 39) medical students with a mean age of 19.2 years who were nonsmokers, with no personal history of allergy were studied. The bronchial lability was assessed from peak expiratory flows and forced expiratory spirograms taken before, during and upto 45 minutes after a standard exercise using the Harvard steps. Women had a significantly lower (P < .001) resting FVC, FEV1, FEF 25-75% and PEF as compared to men. Although the exercise lability index was not significantly different in men and women, the latter showed a greater percent increase (P < .02) and a lesser percent decrease (P < .02) of PEF during and after the exercise respectively. They also showed a significantly (P < .005) faster recovery to normal. These results suggest that airway dynamics may be better in women than in men. This could account for the lower incidence and morbidity from respiratory allergic disease seen in women as compared to men.     

Relationship between external resistances, lung function changes and maximal exercise capacity

In upper airway obstruction (UAO) the relationship between the degree of obstruction, exercise limitation and lung function indices is not well established. Therefore, we investigated in nine healthy subjects (age 36+/-9 yrs) the effects of two added resistances at the mouth (R1 = added resistance with 7.8 mm diameter; R2 = 5.7 mm) on forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), airway resistance (Raw) and maximal breathing capacity (measured during 15 s = measured maximum breathing capacity (MBCm); calculated as FEV1x37.5 = calculated maximum breathing capacity (MBCc)) on the one hand, and maximum exercise capacity (W'max), minute ventilation (V'E) and CO2 elimination (V'CO2) on the other. We found that R1 had almost no influence on FEV1 but decreased PEF by approximately 35% and increased Raw by almost 300%; it decreased W'max by merely approximately 10% while maximal exercise ventilation (V'Emax) was only 65% of control and only reached approximately 40% MBCc and approximately 70% MBCm; yet V'E and V'CO2 were significantly reduced at high exercise levels indicating hypoventilation. With R2, FEV1 was reduced by 25% and PEF by 55%, and Raw was increased by 600%; W'max was approximately 60% of control, V'Emax was only 35% of control and reached approximately 30% MBCc and approximately 60% MBCm, V'E was already reduced at moderate exercise levels. We conclude that: 1) an upper airway obstruction of 6 mm diameter (but not of 8 mm) had a marked influence on maximum exercise capacity due to hypoventilation; 2) calculated maximum breathing capacity markedly overestimated measured maximum breathing capacity because the forced expiratory volume in one second is an insensitive index of upper airway obstruction and because it does not take inspiratory flow limitation into account; and 3) a 10% decrease in maximum exercise capacity was linearly related with a 7% decrease in the forced expiratory volume in one second and a 150% increase in airway resistance. A 10% decrease in maximal exercise ventilation was related to a 8.5% decrease in peak expiratory flow and 9% decrease in measured maximum breathing capacity.     

Eosinophil cationic protein in the asthmatic infant: correlation with the clinic and pulmonary function

PATIENTS AND METHODS: Serum eosinophil cationic protein (ECP) was measured in 99 chronic asthmatic patients (51 males and 48 females) with a mean age of 10.59 years and correlated with the number of eosinophils, lung function, symptoms in the last 6 months and clinical scoring (that reflecting the clinical situation during the last 15 days). RESULTS: Serum ECP showed a significant correlation with the total number of eosinophils (p < 0.001, R = 0.44), clinical scoring (p < 0.05, R = 0.26), number of inhaled beta 2-agonist doses needed in the last 15 days (p < 0.05, R = 0.26), forced expiratory volume during 1 second (FEV1; p < 0.01, R = -0.27), forced vital capacity (FVC; p < 0.05, R = -0.23), maximal mid-expiratory flow (FEF25-27; p < 0.001, R = -0.37). However, there was no significant correlation between the total number of eosinophils and the clinical situation of the children or the FEV1, but we found a significant correlation with the FEF25-27. Patients with ECP < 20 had better results on lung function tests than patients with ECP > 20 (FEV1: 108.89 +/- 17.7 vs 100.5 +/- 22 (p < 0.05), FEF25-27: 93.81 +/- 24.4 vs 75.21 +/- 24.5 (p < 0.001). CONCLUSIONS: The findings of this study suggest that the ECP level is a good marker of the situation of asthma in childhood. The levels of ECP will probably be able to help us to evaluate the degree of bronchial inflammation that neither the clinical state nor the lung function define completely.     

Evaluation of heliox in children hospitalized with acute severe asthma. A randomized crossover trial

STUDY OBJECTIVE: To determine whether breathing a blend of 70% helium:30% oxygen (heliox) would improve pulmonary function, decrease clinical score, and improve the sensation of dyspnea in children hospitalized with acute severe asthma. DESIGN: Prospective, randomized, double-blind, crossover study. SETTING: The inpatient pediatric service of a military, tertiary care, teaching hospital. PATIENTS: Children 5 to 18 years who required hospital admission for treatment of acute asthma. INTERVENTIONS: All patients received 5 mg of nebulized albuterol every 1 to 4 h, with a dose given within 30 min of the start of the study, and IV administered methylprednisolone. Patients breathed heliox and a 30% oxygen-enriched air mixture for 15 min each in random order. MEASUREMENTS AND RESULTS: Clinical score, dyspnea score, oxygen saturation, heart rate, and respiratory rate, followed by FVC, FEV1, peak expiratory flow rate (PEFR), and, mean midexpiratory flow rate (FEF25-75) were obtained at study entry, 15 min after breathing the first gas mixture (heliox or air per randomization), 15 min after breathing the second mixture, and again 15 min after stopping the second gas mixture (study end values). Eleven children were enrolled, and all completed the study. There were no significant differences between study entry and study end spirometric values. Using the paired t test, we found no significant differences between mean values (SD) of FEV1 and FVC obtained while breathing heliox vs air; FEV1-heliox, 53% (18%) of the predicted value; FEV1-air, 52% (16%) of the predicted value (p = 0.36); FVC-heliox, 69% (22%) of the predicted value; and FVC-air, 70% (21%) of the predicted value (p = 0.50). The differences in values for PEFSR and FEF25-75 while breathing heliox vs air were small but did reach statistical significance in favor of heliox: PEFR-heliox, 56% (20%) of the predicted value; PEFR-air, 50% (16%) of the predicted value (p = 0.04); FEF25-75-heliox, 32% (13%) of the predicted value; and FEF25-75-heliox, 29% (11%) of the predicted value (p = 0.006). Heliox had no effect on either clinical or dyspnea scores. CONCLUSION: The short-term inhalation of heliox did not benefit this group of children hospitalized with acute, severe asthma.     

Bronchial reactivity, lung function, and serum immunoglobulin E in smoking-discordant monozygotic twins

Smokers with chronic bronchitis and/or chronic obstructive pulmonary disease (COPD) have been reported to have an increased bronchial reactivity (BR). It has been discussed whether increased BR is a risk factor for the development of COPD in smokers. We studied 10 monozygotic twin pairs who were discordant for tobacco smoking by means of histamine provocation tests, lung function tests, and serum samples for total IgE. The smokers had a mild obstructive ventilatory impairment, with FEV1 significantly lower than that of the partner both when it was determined from the flow-volume loops (3.2 +/- 1.0 L for smokers and 3.4 +/- 0.8 L for nonsmokers) and by the Vitalograph spirometer (3.5 +/- 1.0 L for smokers and 3.8 +/- 0.8 L for nonsmokers). Forced midexpiratory flow (FEF25-75%) and forced expiratory flow at 75 to 85% of vital capacity (FEF75-85%) were both significantly lower in the smokers (p < 0.05). The alveolar plateau phase N2-delta test and lung clearing index in the multibreath nitrogen washout test were both significantly affected in the smokers (p < 0.05 and p < 0.01, respectively). We found no significant difference in histamine reactivity between smokers and nonsmokers and no correlation between differences in reactivity and differences in lung function within pairs. Total serum IgE was significantly higher in the smokers than in their nonsmoking siblings. These data suggest that obstructive ventilatory impairment and raised serum IgE are earlier and more constant manifestations of tobacco smoking than increased bronchial reactivity. Thus, bronchial hyperreactivity does not seem to be a major risk factor for the development of early airways obstruction in smokers.     

Monogenic determinants of familial Alzheimer''s disease: presenilin-2 mutations

An industry-wide pulmonary morbidity study was undertaken to evaluate the respiratory health of employees manufacturing refractory ceramic fibers at five US sites between 1987 and 1989. Refractory ceramic fibers are man-made vitreous fibers used for high temperature insulation. Of the 753 eligible current employees, 742 provided occupational histories and also completed the American Thoracic Society respiratory symptom questionnaire; 736 also performed pulmonary function tests. Exposure to refractory ceramic fibers was characterized by classifying workers as production or nonproduction employees and calculating the duration of time spent in production employment. The risk of working in the production of refractory ceramic fibers and having one or more respiratory symptoms was estimated by adjusted odds ratios and found to be 2.9 (95 percent confidence interval 1.4-6.2) for men and 2.4 (95 percent confidence interval 1.1-5.3) for women. The effect of exposure to refractory ceramic fibers on forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), the ratio of the two (FEV1/FVC), and forced expiratory flow (liters/second) between 25 percent and 75 percent of the FVC curve (FEF(25-75)) was evaluated by multiple regression analysis using transformed values adjusted for height, by dividing by the square of each individual's height. For men, there was a significant decline in FVC for current and past smokers of 165.4 ml (p < 0.01) and 155.5 ml (p = 0.04), respectively, per 10 years of work in the production of refractory ceramic fibers. For FEV1, the decline was significant (p < 0.01) only for current smokers at 134.9 ml. For women, the decline was greater and significant for FVC among nonsmokers, who showed a decrease of 350.3 ml (p = 0.05) per 10 years of employment in the production of refractory ceramic fibers. These findings indicate that there may be important sex differences in response to occupational and/or environmental exposure.     

Peak expiratory flow and certain spirometric indices in boys with bronchial asthma in the clinically silent period

An analysis between relationship of PEF (measured with Vitalograph meter) and dynamic volumes (FVC, FEV1 and PEFII), maximal expiratory flow volumes (MEF25%, MEF50%, MEF75%) measured with Pneumoscreen by Jaeger was carried out in 9 year old boys (26 with atypic asthma and 36 healthy volunteers). Statistical significant differences were seen between PEFI (p < 0.001), FVC (p < 0.05), FEV1 (p < 0.01), and MEF25% (p < 0.02) in healthy volunteers in comparison with boys with atopic asthma in the clinically silent period.     

Randomised, dose-ranging, placebo-controlled study of chimeric antibody to CD4 (keliximab) in chronic severe asthma

BACKGROUND: There is substantial circumstantial evidence that CD4 lymphocytes have a role in the pathogenesis of chronic asthma. We investigated the efficacy and safety in severe corticosteroid-dependent asthma of a single intravenous infusion of keliximab (IDEC CE9.1), a chimeric monoclonal antibody to CD4. METHODS: 22 patients were recruited from two asthma clinics. In an ascending-dose design, the first eight patients were assigned 0.5 mg/kg keliximab (six) or placebo (two); the next seven were assigned 1.5 mg/kg (five) or placebo (two); and the last seven were assigned 3.0 mg/kg (five) or placebo (two). Masked data on safety for each dose group were assessed before progression to the next dose. Patients kept a daily symptom diary and measured morning and evening peak expiratory flow (PEF) at home. PEF and forced expiratory volume in 1 s (FEV1) were measured at follow-up clinic visits. FINDINGS: Patients given 0.5 mg/kg or 1.5 mg/kg keliximab and placebo recipients did not differ in change from baseline of PEF, FEV1, or symptom score. Those given 3.0 mg/kg keliximab differed significantly from placebo recipients in change in morning PEF (median area under curve [AUC] 445 vs -82.5, p=0.005) and evening PEF (median AUC 548 vs -85, p=0.014). Symptom score showed the same pattern (though differences did not achieve significance), but there was no difference in clinic FEV1. There were no serious adverse effects related to treatment. Two patients had mild exacerbations of eczema and one developed a transient maculopapular rash. All doses of keliximab were associated with a reduction from baseline in CD4 count. INTERPRETATION: Our findings raise the possibility that T-cell-directed treatment may be an alternative approach to the treatment of severe asthma.     

Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction

BACKGROUND: The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear. METHODS: A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire. RESULTS: Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease. CONCLUSIONS: High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment.     

Respiratory findings in workers employed in the brick-manufacturing industry

We studied 233 male workers employed in two brick-manufacturing plants and 149 matched control workers. The mean age of the brick workers was 35 years, with a mean duration of employment in this industry of 16 years. The prevalence of chronic respiratory symptoms as well as acute symptoms during the work shift were recorded. Lung function was measured on Monday during the work shift by recording maximum expiratory flow-volume (MEFV) curves, from which the forced vital capacity (FVC), the one-second forced expiratory volume (FEV1) and flow rates at 50% and the last 75% of the FVC (FEF50, FEF75) were measured. The results of periodic chest roentgenograms were reviewed. There was a significantly higher prevalence of chronic cough (31.8%), chronic phlegm (26.2%), and chest tightness (24.0%) in exposed workers, compared with control workers (20.1%; 18.1%; 0%) (P < 0.05). This increased symptom frequency was also documented among nonsmokers studied by age and by length of employment, suggesting a work-related effect. Among work shift-related symptoms, high prevalences were noted for upper respiratory tract symptoms (e.g., dry throat, eye irritation, throat irritation). The measured FVC and FEV1 were significantly lower than predicted for brick workers and suggested a restrictive pattern. The mean FVC (as a percent of predicted) was 78.1% and FEV1 was 88.1%. The FEF50 and FEF25 were not significantly decreased. A multiple regression analysis with age, exposure, and smoking as predictors and lung function parameters as response variables showed a significant effect between exposure and FVC. Significant chest roentgenographic abnormalities were not documented. These findings of a restrictive lung function pattern in brick workers with normal chest roentgenograms may suggest early interstitial disease. Additionally, a bronchitic component, as suggested by the respiratory symptoms, may also be present.     

Discrepancies between diagnosed asthma, asthma-like symptoms and a test for abnormal lung function

For the diagnosis of asthma, it is neither clear to which degree various tests and symptoms identify the same subjects nor how these characteristics are best combined. We assessed the interrelationship between physician-diagnosed asthma, asthma-like symptoms and abnormal airway function in a population based sample of 495 12-15 year old schoolchildren. Participants filled in a questionnaire and underwent baseline spirometry (FEV1%), provocation with treadmill exercise (EXE) and with inhaled methacholine (PD15), and monitoring of peak expiratory flow (PEF) twice daily for two weeks. Most symptomatic subjects with any test positive were identified by PD15 alone (75%) or in combination with PEF monitoring (89%). Although interest agreement was weak (kappa < 0.40 for all pairs), significant associations were found between PD15 and EXE, between PEF and EXE and between FEV1% and PD15. However, PEF variability and methacholine responsiveness seem to identify different varieties of airway pathophysiology, and the combined use of the two tests may be helpful as an epidemiological screening tool for asthma.     

Intrasubject variability of maximal expiratory flow volume curve

Analysis of airflow in the terminal portion of the maximal expiratory flow volume curve has been suggested as a useful test for the early diagnosis of chronic airways obstruction. Whether such an analysis can identify early disease, and whether any subsequent action can prevent the progress of chronic airways obstruction, is unknown and will require prospective studies. As a precursor of such a study we have tried to establish the intrasubject variability of those tests of forced expiration which may be used for screening. We therefore measured expiratory flow volume curves of five healthy males and five healthy females aged 20-30 years as this is an age-group in which early detection of airways obstruction may be of value. Flow volume curves were obtained on the same day of the week for six weeks, and on three separate days during this period we carried out three flow volume curves every hour from 9 am to 6 pm. The data were subjected to analysis of variance to determine the variability of each measurement. Data were collected from forced expired volume in one second (FEV1) forced vital capacity (FVC), maximum expiratory flow rates at 50% and 75% of expired vital capacity, and forced expiratory time (FET). The results showed no consistent pattern of diurnal variation over the working day. The variation in any subject for FEV1 and FVC over the study period was considerably less than variations detected in the maximal expiratory flow rates at 50% and 75% of the expired vital capacity and FET. Our results suggest that the intrasubject variation found in flow rates of the terminal portion of the maximal expiratory flow volume curve and forced expiratory time may limit the usefulness of these tests in detecting early airways obstruction. FEV1 and FVC are more reproducible tests and are therefore particularly suited for cross-sectional screening. The more sensitive maximal expiratory flow volume curve may, however, be more useful for long-term studies in individuals when the onset of disease is sought, or for short-term challenge studies requiring the most sensitive index of change in airway characteristics.