Showing papers in "American Journal of Respiratory and Critical Care Medicine in 1997"

Noninvasive Measurement of Airway Responsiveness in Allergic Mice Using Barometric Plethysmography

Abstract: To study the mechanisms and kinetics underlying the development of increased airway responsiveness (AR) after allergic sensitization, animal models have been invaluable. Using barometric whole-body plethysmography and increases in enhanced pause (Penh) as an index of airway obstruction, we measured responses to inhaled methacholine in conscious, unrestrained mice after sensitization and airway challenge with ovalbumin (OVA). Sensitized and challenged animals had significantly increased AR to aerosolized methacholine compared with control animals. AR measured as Penh was associated with increased IgE production and eosinophil lung infiltration. In a separate approach we confirmed the involvement of the lower airways in the response to aerosolized methacholine using tracheotomized mice. Increases in Penh values after methacholine challenge were also correlated with increased intrapleural pressure, measured via an esophageal tube. Lastly, mice demonstrating AR using a noninvasive technique also demonstrated ...

Respiratory effects are associated with the number of ultrafine particles.

Abstract: The association between fine and ultrafine particles and respiratory health was studied in adults with a history of asthma in Erfurt, Eastern Germany. Twenty-seven nonsmoking asthmatics recorded their peak expiratory flow (PEF) and respiratory symptoms daily. The size distribution of ambient particles in the range of 0.01 to 2.5 microm was determined with an aerosol spectrometer during the winter season 1991-1992. Most of the particles (73%) were in the ultrafine fraction (smaller than 0.1 microm in diameter), whereas most of the mass (82%) was attributable to particles in the size range of 0.1 to 0.5 microm. Because these two fractions did not have similar time courses (correlation coefficient r = 0.51), a comparison of their health effects was possible. Both fractions were associated with a decrease of PEF and an increase in cough and feeling ill during the day. Health effects of the 5-d mean of the number of ultrafine particles were larger than those of the mass of the fine particles. In addition, the effects of the number of the ultrafine particles on PEF were stronger than those of particulate matter smaller than 10 microm (PM10). Therefore, the present study suggests that the size distribution of ambient particles helps to elucidate the properties of ambient aerosols responsible for health effects.

Interpreting Small Differences in Functional Status: The Six Minute Walk Test In Chronic Lung Disease Patients

Abstract: Functional status measurements are often difficult to interpret because small differences may be statistically significant but not clinically significant. How much does the Six Minute Walk test (6MW) need to differ to signify a noticeable difference in walking ability for patients with chronic obstructive pulmonary disease (COPD)? We studied individuals with stable COPD (n = 112, mean age = 67 yr, mean FEV1 = 975 ml) and estimated the smallest difference in 6MW distances that was associated with a noticeable difference in patients' subjective comparison ratings of their walking ability. We found that the 6MW was significantly correlated with patients' ratings of their walking ability relative to other patients (r = 0.59, 95% confidence interval [CI]: 0.54 to 0.63). Distances needed to differ by 54 m for the average patient to stop rating themselves as "about the same" and start rating themselves as either "a little bit better" or "a little bit worse" (95% CI: 37 to 71 m). We suggest that differences in functional status can be statistically significant but below the threshold at which patients notice a difference in themselves relative to others; an awareness of the smallest difference in walking distance that is noticeable to patients may help clinicians interpret the effectiveness of symptomatic treatments for COPD.

The comet-tail artifact. An ultrasound sign of alveolar-interstitial syndrome.

Abstract: Can ultrasound be of any help in the diagnosis of alveolar-interstitial syndrome? In a prospective study, we examined 250 consecutive patients in a medical intensive care unit: 121 patients with radiologic alveolar-interstitial syndrome (disseminated to the whole lung, n = 92; localized, n = 29) and 129 patients without radiologic evidence of alveolar-interstitial syndrome. The antero-lateral chest wall was examined using ultrasound. The ultrasonic feature of multiple comet-tail artifacts fanning out from the lung surface was investigated. This pattern was present all over the lung surface in 86 of 92 patients with diffuse alveolar-interstitial syndrome (sensitivity of 93.4%). It was absent or confined to the last lateral intercostal space in 120 of 129 patients with normal chest X-ray (specificity of 93.0%). Tomodensitometric correlations showed that the thickened sub-pleural interlobular septa, as well as ground-glass areas, two lesions present in acute pulmonary edema, were associated with the presence of the comet-tail artifact. In conclusion, presence of the comet-tail artifact allowed diagnosis of alveolar-interstitial syndrome.

Bronchoscopic evaluation of severe asthma. Persistent inflammation associated with high dose glucocorticoids.

Abstract: The role of inflammation in the pathogenesis of severe asthma chronically treated with high doses of glucocorticoids is poorly understood. Despite this, treatment has been aimed at advancing anti-inflammatory and immunomodulator therapy. This study was designed to evaluate both the presence and type of airway inflammation in patients with severe asthma. A prospective bronchoscopic study evaluated 14 severe, high-dose oral glucocorticoid dependent asthmatics. Bronchoalveolar lavage fluid was analyzed for cytology and inflammatory mediators. Endobronchial and transbronchial biopsies were performed in selected patients for morphometric evaluation of macrophage/monocytes, neutrophils, eosinophils and lymphocytes. These results were compared with lavage and endo- and transbronchial biopsy studies in normal controls and patients with moderate asthma. The concentration of eosinophils in bronchoalveolar lavage fluid was highest in the moderate asthmatics not on glucocorticoids, with very little difference between normal controls and severe asthmatics (significant difference among the groups, p = 0.007). In contrast, the severe asthmatics demonstrated a twofold higher concentration of neutrophils in lavage than either the mild-moderate asthmatics, or the normal controls (p = 0.032 among the groups, p < 0.05 between the severe asthmatics and both controls). Similar results were obtained in the endobronchial and transbronchial biopsy specimens, which consistently showed significantly higher numbers of neutrophils in the severe asthmatics than in the control groups. The eicosanoid mediators, thromboxane and leukotriene B4, were also highest in the severe asthma group (differences among the groups, p = 0.019 and p = 0.023, respectively). These findings suggest that inflammation remains in severe symptomatic asthmatics despite treatment with high dose glucocorticoids which may be due to the severity of disease, glucocorticoid treatment, or other as yet undefined factors.

Inflammation in bronchial biopsies of subjects with chronic bronchitis: inverse relationship of CD8+ T lymphocytes with FEV1.

Abstract: In order to determine whether the airway inflammatory cells of chronic obstructive pulmonary disease (COPD) are different from those seen in asthma, we have studied a subepithelial zone, 100 microns deep to the epithelial reticular basement membrane in bronchial biopsies taken from five normal nonsmoking subjects without chronic bronchitis or asthma (FEV1 percentage of predicted [mean +/- SD] 105.7 +/- 25.3), 11 subjects with chronic bronchitis alone (FEV1 percentage of predicted 98.5 +/- 12.9), and 13 subjects with chronic bronchitis in whom there was also evidence of airflow limitation (i.e., COPD; FEV1 percentage of predicted 59.7 +/- 10.0). Using immunohistochemical markers, we counted distinct types of inflammatory cell and expressed them as [median and range] per mm basement membrane. When there was airflow limitation we found significantly increased numbers of CD3+ T lymphocytes (COPD 22.3 [2.6 to 68.2] versus normal 3.7 [1.5 to 16.3]; p < 0.05), an increased number of CD8+ cells (COPD 19.3 [1.8 to...

Increasing incidence of withholding and withdrawal of life support from the critically ill

Abstract: To determine whether limits to life-sustaining care are becoming more common, we attempted to quantify the incidence of recommendations to withhold or withdraw life support from critically ill patients, to describe how patients respond to these recommendations, and to examine how conflicts over these recommendations are resolved. In 1992 and 1993 we prospectively enrolled 179 consecutive patients from two intensive care units (ICUs) for whom a recommendation was made to withhold or withdraw life support. Where possible, we compared results with data collected in the same units over a similar time period in 1987 and 1988. Recommendations to withhold or withdraw life support preceded 179 of 200 deaths (90%) in 1992 and 1993, compared with 114 of 224 deaths (51%) in 1987 and 1988 (chi2 = 73.76, p < 0.001]. Cardiopulmonary resuscitation was initiated in 10% of deaths in 1992 and 1993 as compared with 49% in 1987 and 1988. Ninety percent of patients agreed within less than 5 d, and only eight patients (4%) ref...

Extubation Outcome after Spontaneous Breathing Trials with T-Tube or Pressure Support Ventilation

Abstract: A 2-h T-tube trial of spontaneous breathing was used in selecting patients ready for extubation and discontinuation of mechanical ventilation. However, some doubt remains as to whether it is the most appropriate method of performing a spontaneous breathing trial. We carried out a prospective, randomized, multicenter study involving patients who had received mechanical ventilation for more than 48 h and who were considered by their physicians to be ready for weaning according to clinical criteria and standard weaning parameters. Patients were randomly assigned to undergo a 2-h trial of spontaneous breathing in one of two ways: with a T-tube system or with pressure support ventilation of 7 cm H 2 O. If a patient had signs of poor tolerance at any time during the trial, mechanical ventilation was reinstituted. Patients without these features at the end of the trial were extubated. Of the 246 patients assigned to the T-tube group, 192 successfully completed the trial and were extubated; 36 of them required reintubation. Of the 238 patients in the group receiving pressure support ventilation, 205 were extubated and 38 of them required reintubation. The percentage of patients who remained extubated after 48 h was not different between the two groups (63% T-tube, 70% pressure support ventilation, p 5 0.14). The percentage of patients failing the trial was significantly higher when the T-tube was used (22 versus 14%, p 5 0.03). Clinical evolution during the trial was not different in patients reintubated and successfully extubated. ICU mortality among reintubated patients was significantly higher than in successfully extubated patients (27 versus 2.6%, p , 0.001). Spontaneous breathing trials with pressure support or T-tube are suitable methods for successful discontinuation of ventilator support in patients without problems to resume spontaneous breathing.

The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects.

Abstract: A humanized murine monoclonal antibody directed to the Fc epsilonR1-binding domain of human IgE (rhuMAb-E25) has been shown to inhibit the binding of IgE to mast cells without provoking mast cell activation. To examine the effects of neutralizing IgE on allergic airway responses, we assessed the effects of 9 wk of treatment with rhuMAb-E25 in a parallel group, randomized, double-blind, placebo-controlled study of 19 allergic asthmatic subjects. We found that treatment with rhuMAb-E25 reduced serum IgE, increased the dose of allergen needed to provoke an early asthmatic response, reduced the mean maximal fall in FEV1 during the early response (30 +/- 10% at baseline to 18.8 +/- 8%, versus 33 +/- 8% at baseline to 34 +/- 4% after placebo; p = 0.01), and reduced the mean maximal fall in FEV1 during the late response (24 +/- 20% at baseline to 9 +/- 10% versus 20 +/- 17% at baseline to 18 +/- 17% after placebo; p = 0.047). We conclude that an anti-IgE monoclonal antibody, which inhibits binding of IgE to its ...

Cigarette smoking: a risk factor for idiopathic pulmonary fibrosis.

Abstract: We conducted a multicenter case-control study of clinically and histologically diagnosed idiopathic pulmonary fibrosis (IPF), a chronic diffuse interstitial lung disease of unknown cause. The study included 248 cases, and 491 control subjects identified through random-digit dialing, matched to cases in sex, age, and geographic region. Telephone interviews were conducted with both cases and controls to collect information on potential risk factors for IPF, including smoking and household, occupational, and environmental exposures. Pulmonary function tests, X-rays, computed tomographic (CT) scans of the chest, and lung biopsy reports were submitted by referring centers to support the diagnoses. An a priori hypothesis that smoking is associated with IPF was examined with conditional logistic regression analyses. More cases (72%) than control subjects (63%) had a history of ever smoking. The odds ratio (OR) for ever smoking was 1.6 (95% CI: 1.1 to 2.4). Risk was significantly elevated for former smokers (OR =...

A National Estimate of the Economic Costs of Asthma

Abstract: This cost of illness analysis examines national cost and resource utilization by persons with asthma using a single, comprehensive data source, the 1987 National Medical Expenditure Survey. Direct medical expenditures included payments for ambulatory care visits, hospital outpatient services, hospital inpatient stays, emergency department visits, physician and facility payments, and prescribed medicines. Indirect medical costs included costs resulting from missed work or school and days with restricted activity at work. Point estimates and 95% confidence intervals (CI) were calculated and inflated to 1994 dollars. The total estimated cost was $5.8 billion (95% CI, $3.6 to $8 billion). The estimated direct expenditures were $5.1 billion (95% CI, $3.3 to $7.0 billion), and indirect expenditures were valued at $673 million (95% CI, $271 to $1,076 million). Hospitalization accounted for more than half of all expenditures. More than 80% of resources were used by 20% of the population (defined as 'high-cost patients'). The estimated annual per patient cost for those high-cost patients was $2,584, in contrast with $140 for the rest of the sample. Findings from this study indicate that future asthma research and intervention efforts directed at hospitalizations and high-cost patients could help to decrease health care resource use and provide cost savings.

Effects of inhaled and oral glucocorticoids on inflammatory indices in asthma and COPD.

Abstract: The role of glucocorticoids in the treatment of chronic obstructive pulmonary disease (COPD) is controversial. We have previously described high numbers of neutrophils and high concentrations of the inflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha), and of the cell activation markers eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), myeloperoxidase (MPO), and human neutrophil lipocalin (HNL) in COPD patients as compared with controls, and have postulated that the cytokines TNF-alpha and IL-8 play a role in propagating the inflammatory response in COPD. We have now studied the effects of inhaled and oral glucocorticoids on these inflammatory indices in induced sputum. Initially, we studied the effect of a 2-wk course of inhaled budesonide (800 mg twice daily for 2 wk) in 13 patients with severe COPD (mean FDV1: 35% predicted). There was no clinical benefit in either lung function or symptom scores, and no significant change in the inflammatory indices as measured by total and differential cell counts and concentrations of TNF-alpha eosinophil activation markers ECP and EPO, and neutrophil activation markers MPO and HNL. Because the lack of anti-inflammatory effect might have been due to poor drug delivery as a result of severe airflow limitation, we undertook a study examining the antiinflammatory effect of oral prednisolone (30 mg daily for 2 wk) in patients with COPD and undertook the same measurements in 10 patients with atopic asthma. Sputum eosinophil numbers, ECP, and EPO were significantly reduced in the asthmatic patients but were not modified in COPD. This confirms the clinical impression that inhaled steroids have little antiinflammatory effect, at least in the short term in this group of patients, and suggests that the inflammatory process in COPD is resistant to the antiinflammatory effect of glucocorticoids.

Transforming Growth Factor- β Expression in Mucosal Biopsies in Asthma and Chronic Bronchitis

Abstract: We assessed whether transforming growth factor- β (TGF- β ), a fibrogenic growth factor, may be involved in remodeling of asthma and chronic bronchitis; its expression was compared with that of epidermal growth factor (EGF) and granulocyte macrophage colony-stimulating factor (GM-CSF) in bronchial mucosal biopsies from 13 normal subjects, 24 asthmatics, and 19 patients with chronic bronchitis. TGF- β immunoreactivity was highly increased in epithelium and submucosa of those with bronchitis and to a lesser extent in asthmatics. By comparison, with normal subjects, EGF immunoreactivity was significantly increased in the epithelium of bronchitic subjects and submucosa of asthmatics, and, GM-CSF immunoreactivity was increased in both epithelial and submucosal cells of asthmatics and to a lesser extent in submucosa of bronchitics. A significant correlation was found between the number of epithelial or submucosal cells expressing TGF- β in both asthma and chronic bronchitis and basement membrane thickness and f...

Racial differences in sleep-disordered breathing in African-Americans and Caucasians.

Abstract: In this case-control family study of sleep-disordered breathing (SDB), we describe the distributions of SDB and SDB risk factors in African-Americans and Caucasians. A total of 225 African-Americans and 622 Caucasians, ages 2 to 86 yr, recruited as members of families with an individual with known sleep apnea (85 index families) or as members of neighborhood control families (63 families) were studied with an overnight home sleep-study, questionnaires, and physical measurements. A subsample underwent cephalometry. Outcome measures were the respiratory disturbance index (RDI) and a binary variable indicating the presence of increased apneic activity (IAA). In both races, a strong relationship was demonstrated between the (log transformed) RDI and age and age2. African-Americans with SDB were younger than Caucasians with SDB (37.2 +/- 19.5 versus 45.6 +/- 18.7 yr, p < 0.01). In subjects < or = 25 yr, RDI level and IAA prevalence were higher in African-Americans (odds ratio, adjusted for obesity, sex, proban...

Quality of life changes in COPD patients treated with salmeterol.

Abstract: Changes in health-related quality of life (HRQoL) were evaluated in patients with chronic obstructive pulmonary disease (COPD) following treatment with placebo, salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler Patients completed the disease-specific St George's Respiratory Questionnaire (SGRQ) and the Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 16 wk of treatment Data from 283 patients (95 patients in the placebo group and 94 in each salmeterol group) were available for HRQoL analysis Apart from a small difference in ages, all treatment groups were well matched at baseline in terms of forced expiratory volume in one second (FEV1) and HRQoL scores Compared with placebo, salmeterol 50 microg twice a day was associated with significant improvements in SGRQ "Total" and "Impacts" scores which exceeded the threshold for a clinically significant change This was not seen with salmeterol 100 microg twice a day Changes in SGRQ and SF-36 scores correlated They also showed a weak but significant relationship with FEV1 This study has shown that a modest change in lung function may be associated with clinically significant gain in health and well-being in COPD patients

Marked flow-dependence of exhaled nitric oxide using a new technique to exclude nasal nitric oxide.

Abstract: Exhaled nitric oxide (NO) may aid in monitoring pulmonary disease. The single-breath NO profile (subjects with nose clip) was described as a NO peak followed by a plateau (NO(PLAT)). Published exhaled NO values vary greatly, possibly due to contamination with nasal NO and differing respiratory maneuvers. We developed a technique to measure pulmonary NO, without nasal NO, by having the subject maintain a positive expiratory pressure (ensuring vellum closure), and we examined the variation in NO(PLAT) over a range of expiratory flows (4.2 to 1,550 ml/s). NO(PLAT) values rose almost 35-fold (3.2 +/- 1.4 ppb to 110.5 +/- 54.8 ppb) with decreasing flow, described by NO(PLAT) = 208.6795 x (flow rate)(-0.5995). However, NO excretion showed an almost 11-fold rise as flow increased. In summary, we present a simple technique for measuring exhaled NO without contamination by nasal NO. There is a marked flow dependence of exhaled NO concentration and excretion. Exhaled pulmonary NO is best measured at very low flow r...

The Value of Routine Microbial Investigation in Ventilator-Associated Pneumonia

Abstract: The use of microbiologic investigations in routine clinical practice, their value in guiding antibiotic prescription, and their influence on outcome were prospectively studied in 113 consecutive adults who developed ventilator-associated pneumonia (VAP). Blood cultures were performed in 78.7% of cases, protected specimen brushing in 95.5%, and bronchoalveolar lavage in only 45.1%. No causative agent was identified in 13 episodes (11.5%), and results of microbial tests directed a change in therapy in 43 (38.0%). Bronchoscopic results revealed inadequate initial selection of antibiotic therapy in 27 cases (23.9%) and led to a change in antibiotic treatment. Inadequate initial selection was still associated with a significantly greater increase in related mortality than adequate initial therapy (37.0% versus 15.4%, p < 0.05), although the change in therapy permitted clinical resolution in 17 (62.9%) of these 27 episodes, and 10 patients were discharged alive. Bronchoscopic results also permitted the reduction of the antibiotic spectrum in seven episodes (6.1%). This study suggests that in patients with VAP, bronchoscopic results are frequently associated with changes in antibiotic therapy. Nevertheless, our findings also emphasize the critical importance of an appropriate early antibiotic therapy.

Lower airway inflammation in infants and young children with cystic fibrosis

Abstract: Airway inflammation is an important component of cystic fibrosis (CF) lung disease. To determine whether this begins early in the illness, before the onset of infection, we examined bronchoalveolar lavage (BAL) fluid from 46 newly diagnosed infants with CF under the age of 6 mo identified by a neonatal screening program. These infants were divided into three groups: 10 had not experienced respiratory symptoms or received antibiotics and pathogens were absent in their BAL fluid; 18 had clear evidence of lower respiratory viral or bacterial ( ⩾ 105 CFU/ml) infection; and the remaining 18 had either respiratory symptoms, taken antibiotics, or had < 105 CFU/ml of respiratory pathogens. Their BAL cytology, interleukin-8, and elastolytic activity were compared with those from 13 control subjects. In a longitudinal study to assess if inflammation develops or persists in the absence of infection, the results of 56 paired annual BAL specimens from 44 CF infants were grouped according to whether they showed absence...

Airway smooth muscle, tidal stretches, and dynamically determined contractile states.

Abstract: In the classic theory of airway lumen narrowing in asthma, active force in airway smooth muscle is presumed to be in static mechanical equilibrium with the external load against which the muscle has shortened This theory is useful because it identifies the static equilibrium length toward which activated airway smooth muscle would tend if given enough time The corresponding state toward which myosin-actin interactions would tend is called the latch state But are the concepts of a static mechanical equilibrium and the latch state applicable in the setting of tidal loading, as occurs during breathing? To address this question, we have studied isolated, maximally contracted bovine tracheal smooth muscle subjected to tidal stretches imposed at 033 Hz We measured the active force (F) and stiffness (E), which reflect numbers of actin-myosin interactions, and hysteresivity ( η ), which reflects the rate of turnover of those interactions When the amplitude of imposed tidal stretch ( e ) was very small, 025

Matrix Metalloproteinase Expression and Production by Alveolar Macrophages in Emphysema

Abstract: The aim of this study was to examine the hypothesis that alveolar macrophages represent a significant source of matrix-degrading proteinases in the emphysematous lung. Macrophages from bronchoalveolar lavage fluid of 10 patients with emphysema and 10 normal volunteers were maintained in vitro for 24 h and assessed semiquantitatively for mRNA transcript levels of the matrix metalloproteinases (MMPs) gelatinases A and B, macrophage metalloelastase (MME), and interstitial collagenase. Release of these MMPs into the culture medium and secretion of neutrophil elastaselike activity was also assessed. Elevated levels of mRNA transcripts for gelatinase B (p < 0.0005) and interstitial collagenase (p < 0.0005) were observed in macrophages from emphysematous patients. Increased collagenase (p < 0.01) and neutrophil elastaselike activities (p < 0.001) were also measured in conditioned medium from patient macrophages. With gelatinase B, complexed forms of the enzyme were secreted by patient but not by control macrophages. No difference in transcript levels of gelatinase A or MME was observed between patient and control samples, and neither enzyme was detected in macrophage-conditioned media from either group. These results directly demonstrate that alveolar macrophages from the emphysematous lung produce elevated quantities of matrix-degrading enzymes with both elastolytic and collagenolytic activities.

Diesel Exhaust Particles Enhance Antigen-induced Airway Inflammation and Local Cytokine Expression in Mice

Abstract: Previous experimental studies have suggested that nasal instillation of diesel exhaust particles (DEP) can enhance nasal IgE response and cytokine production. However, there is no experimental evidence for the relation of DEP to allergic asthma. We investigated the effects of DEP inoculated intratracheally on antigen-induced airway inflammation, local expression of cytokine proteins, and antigen-specific immunoglobulin production in mice. DEP aggravated ovalbumin-induced airway inflammation characterized by infiltration of eosinophils and lymphocytes and an increase in goblet cells in bronchial epithelium. DEP with antigen markedly increased interleukin-5 (IL-5) protein levels in lung tissue and bronchoalveolar lavage supernatants compared with either antigen or DEP alone. The combination of DEP and antigen induced significant increases in local expression of IL-4, granulocyte macrophage-colony stimulating factor (GM-CSF), and IL-2, whereas expression of interferon-gamma was not affected. In addition, DEP...

Physiologic benefits of exercise training in rehabilitation of patients with severe chronic obstructive pulmonary disease.

Abstract: We determined the effect on exercise tolerance and physiological exercise responses of rigorous rehabilitative exercise training in chronic obstructive pulmonary disease (COPD). Fifteen men and 10 women (mean age, 68 +/- 6 yr; FEV1, 0.93 +/- 0.27 L) participated in a rehabilitation program with an exercise component of three per week 45-min sessions of cycle ergometer training for 6 wk with exercise intensity kept near maximal targets. Before and after rehabilitation, patients performed an incremental test and a constant work rate (CWR) test at 80% of the peak work rate in the preprogram incremental test. Ventilation (V(E)) and gas exchange were measured breath by breath; arterialized venous blood was analyzed for blood gas determinations and lactate. Rehabilitation yielded an average increase in peak work rate in the incremental test of 36% (p < 0.001), and in the duration of the CWR test of 77% (p < 0.001). In the CWR test, the kinetics of O2 uptake, CO2 output, V(E), and heart rate were markedly slower than those of healthy subjects. After training, mean response time decrease averaged 17, 22, 34, and 29%, respectively (p < 0.02), evidence of a physiologic training effect. Further, for identical CWR tasks, V(E) was 10% lower (p < 0.02) after training, attributable to altered breathing pattern: tidal volume increased by 8% and respiratory rate decreased by 19%, yielding lower V(D) /V(T) (0.46 versus 0.53 p < 0.005). Rigorous exercise training for patients with severe COPD yields more efficient exercise breathing pattern and lower V(E); this is associated with improved exercise tolerance.

Increased Vascularity of the Bronchial Mucosa in Mild Asthma

Abstract: Airway-wall remodeling leading to thickening of the bronchial wall in asthma has been invoked to account for airflow obstruction and increased bronchial reactivity to provocative stimuli. Bronchial-wall changes characteristic of asthma are thought to include increased vascularity with vasodilatation. The contention that inflammatory mediators cause bronchial vasodilatation and that growth factors may induce increased vascularity is based on little structural evidence. We took bronchoscopic biopsies from the major airways of 12 subjects with mild asthma and 11 control subjects, and evaluated bronchial vessel numbers and size, using computerized image analysis after staining for type IV collagen in vessel walls. The airways of asthmatic subjects were significantly more vascular (17.2 ± 4.2 versus 10.3 ± 1.9%, p < 0.001), with more vessels (738 ± 150 versus 539 ± 276 vessels/mm2 [mean ± SD], p < 0.05) than those of the controls. There were significantly more asthmatic bronchial than control vessels with a cr...

Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid.

Abstract: Airway wall remodeling is an established pathological feature in asthma. Its causes are not well understood, but one mediator of potential relevance is transforming growth factor-beta 1 (TGF-beta 1). We have measured levels of immunoreactive TGF-beta 1 in bronchoalveolar lavage (BAL) fluid from clinically stable atopic asthmatics and healthy control subjects. We have also examined the influence of allergen exposure on TGF-beta 1 release in the airways using a segmental bronchoprovocation model, with BAL performed at two time points following endobronchial allergen and sham saline challenges. Basal concentrations of TGF-beta 1 were significantly higher in asthmatics than control subjects (median 8.0 versus 5.5 pg/ml, p = 0.027). Following segmental bronchoprovocation, concentrations of TGF-beta 1 at the allergen- and saline-challenged sites were not significantly different after 10 min, (31.3 versus 25.0 pg/ml, p = 0.78), but after 24 h there were significantly higher TGF-beta 1 concentrations at the allergen-challenged sites (46.0 versus 21.5 pg/ml, p = 0.017). We conclude that basal TGF-beta 1 levels in the airways are elevated in atopic asthma and that these levels increase further in response to allergen exposure. These findings are consistent with the hypothesis that TGF-beta 1 is implicated in airway wall remodeling in asthma.

Qualitative aspects of exertional breathlessness in chronic airflow limitation: pathophysiologic mechanisms.

Abstract: We compared qualitative aspects of the sensory experience of exertional breathlessness in normal subjects and in patients with chronic airflow limitation (CAL) and sought a physiologic rationale for these. Twelve patients (66 +/- 2 yr of age, mean +/- SEM) with severe CAL (FEV1 = 37 +/- 5% predicted) and 12 age-matched normal subjects (FEV1 = 103 +/- 5% predicted) were studied. Perceived inspiratory difficulty (BorgIN), inspiratory effort (esophageal pressure expressed as a fraction of maximal esophageal pressure at isovolume [Pes/PImax]), breathing pattern, and operational lung volumes (end-expiratory/inspiratory lung volumes [EELV/EILV]) were measured during symptom-limited incremental cycle exercise testing and compared at a standard VO2 of 50% predicted maximum in normal subjects and in patients with CAL. Qualitative descriptors of breathlessness were selected immediately after exercise. Breathlessness was qualitatively different between normal subjects and patients with CAL. Both normal subjects and patients with CAL chose descriptors of increased "work/effort" and "heaviness" of breathing; however, only patients with CAL consistently chose descriptors denoting "increased inspiratory difficulty" (75%), "unsatisfied inspiratory effort" (75%), and "shallow breathing" (50%). Stepwise regression analysis identified the ratio of Pes/PImax to VT/predicted VC as the strongest correlate of standardized BorgIN (n = 24, r = 0.86, p < 0.001). This latter measurement, which reflects the relationship between effort and ventilatory output, correlated strongly with dynamic EELV/TLC at isotime (r = 0.78, p < 0.001). In conclusion, the qualitatively discrete respiratory sensations of exertional inspiratory difficulty peculiar to patients with CAL may have their origins in thoracic hyperinflation and the resultant disparity between inspiratory effort and ventilatory output.

Alternaria as a major allergen for asthma in children raised in a desert environment.

Abstract: The relationships of asthma and allergic rhinitis with individual immediate skin test responses were examined for preferential associations and for changes with age in children raised in a semiarid environment. Prevalence of physician-diagnosed asthma was 9.8% at age 6 (n = 948) and 15.5% at age 11 (n = 895). Immediate skin test responses to Bermuda grass were the most prevalent among children with allergic rhinitis and control subjects, whereas responses to the mold, Altenaria alternata, were the most prevalent among asthmatics. Skin test responses for crude house dust, Dermatophagoides farinae, and cat had low prevalences in all groups. By logistic regression, Alternaria was the only allergen independently associated with increased risk for asthma at both ages 6 and 11. Allergic rhinitis showed independent association with sensitization to Bermuda grass and mulberry tree pollen at age 11 but did not show an independent relation to any single allergen at age 6. Logistic regression further revealed that persistent asthma (diagnosed before age 6) was independently associated with Alternaria skin tests at both ages 6 and 11, whereas new asthma (diagnosed after age 6) was associated with Alternaria skin tests at age 6 but not at age 11. We conclude that Alternaria is the major allergen associated with the development of asthma in children raised in a semiarid environment and that skin test responses at age 6 are more closely linked to asthma than those at age 11.

Cigarette smoke induces interleukin-8 release from human bronchial epithelial cells

Abstract: Cigarette smoking causes the development of chronic bronchitis and chronic obstructive pulmonary disease. We hypothesized that exposure to cigarette smoke might initiate release of inflammatory mediators by bronchial epithelial cells. To evaluate this, the effect of cigarette smoke extract (CSE) on IL-8 release from cultured human bronchial epithelial cells was examined. CSE augmented IL-8 release from bronchial epithelial cells in a concentration- and time-dependent manner. Most of the augmenting activity of CSE on IL-8 release from bronchial epithelial cells was lost after volatilization or lyophilization treatment. Two major volatile factors in cigarette smoke, acrolein and acetaldehyde, augmented IL-8 release. Four cell strains were tested and showed increased IL-8 release in response to CSE. In addition, bronchoalveolar lavage was performed on 11 nonsmokers and 12 smokers. IL-8 concentration was greater in the proximal, bronchial samples than in distal, alveolar samples, and IL-8 in BAL from smokers was higher than in BAL from nonsmokers. There was a significant correlation between IL-8 concentration and neutrophil count in bronchial samples of BAL fluid. These data support the hypothesis that exposure to cigarette smoke may induce bronchial epithelial cells to release IL-8 and that this may contribute to airway inflammation in smokers.