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We investigated the hypothesis that asthmatic patients have an increased cholinergic tone by measuring tracheobronchial cross-sectional areas during transient voluntary apnea. This allowed us to assess bronchomotor tone without the influence of changes in lung recoil or lung volume. Three groups of subjects with potentially different levels of tracheobronchial tone were studied: 14 healthy volunteers (N), 18 stable asthmatic patients (A), and 10 double lung transplant recipients (T). Using the acoustic reflection technique, we measured changes in tracheobronchial cross-sectional areas during short periods (5 to 10 s) of voluntary apnea. In a subset of subjects, studies were repeated before and after the inhalation of the muscarinic antagonist ipratropium. During breath-holding, glottis and extrathoracic trachea remained unchanged but intrathoracic tracheal area decreased by 30 +/- 8% (mean +/- standard error of the mean) in N, by 27 +/- 3% in A, and by 9 +/- 4% in the T group. Bronchial areas decreased by 24 +/- 8% in N, by 45 +/- 3% in A, and by 10 +/- 4% in T. These differences among groups were statistically significant at the tracheal and bronchial levels (p < 0.05), and ipratropium significantly inhibited this airway constriction (p < 0.05) only in the asthmatic group. Assuming that changes in cross-sectional airway areas voluntary apnea reflect airway tone, these results support the view that in humans this tone is mainly vagally controlled and that it is significantly increased in asthmatic compared with nonasthmatic subjects.

SUMMARYWe analysed the T cell receptor (TCR) V°repertoire in BAL and peripheral blood (PBL) of three mild stable atopic asthmatics and two non-asthmatic controls. We used the polymerase chain reaction (PCR) to establish the expression of the four V°families, and to detect oligo or monoclonal expansion of°± T cells, we resolved the PCR products on denaturing and non-denaturing gels to find the extent of junctional diversity arising from differences in the lengths of the V(D)J junctions. We also subcloned and sequenced the PCR products to characterize fully the sequence diversity. BAL T lymphocytes from two asthmatic patients (treated with inhaled steroids) expressed only V°II and, in one of them, V°IIJ°u sage was restricted to J°P and J°P1 gene segments, contrasting with the V°J°repertoire found in his respective PBL. Analyses in denaturing and non-denaturing gels showed that the BAL V°IIJ°P and V°IIJ°P1 PCR products resolved into few bands, suggesting deletions at the junctions due to oligoclonal expansion. BAL T lymphocytes from the third asthmatic (not receiving inhaled steroids) expressed V°I, II and III, and the sequences of the in-frame TCR transcripts from this asthmatic and one healthy volunteer who expressed a similar BAL V°TCR repertoire showed clonal expansion of T cells expressing all three V°families. Our analyses showed that much of the°± T cell population found in BAL fluid of humans derives from clonally expanded T cells.

To assess the effects of isocapnic hypoxia on the pharynx, glottis, extrathoracic trachea (ET), intrathoracic trachea (IT), and main bronchi (MB), we measured the cross-sectional areas of these airways by acoustic reflection technique in 15 healthy volunteers. Measurements were made during tidal volume breathing while subjects were normoxic [arterial O2 saturation (SaO2) > 95%] or were made hypoxic by a rebreathing procedure. Under hypoxemic conditions, airway cross-sectional areas increased significantly at ET, IT, and MB levels (P < 0.001). The magnitude of this dilation was similar for both levels of hypoxemia studied (SaO2 80-85% and 70-75%); at the milder of the two hypoxemic conditions, ET cross-sectional area increased by 12.4 +/- 4.2% (SE), IT by 10.2 +/- 5.9%, and MB by 19.1 +/- 3.2%. No significant changes were found in the pharyngeal or glottic areas. Dilation was not produced by normoxic isocapnic hyperventilation, and the use of hypoxic airway gas mixtures did not artifactually alter acoustic reflection measurements in a mechanical model. Vagal airway tone, as reflected by airway constriction during pauses in tidal breathing, was unaffected by isocapnic hypoxia. We conclude that isocapnic hypoxia produces dilation of the trachea and major bronchi, an effect unaccounted for by an alteration in the ventilatory pattern.

To examine whether leukotrienes, histamine, and methacholine have different sites of bronchoconstrictor action, we studied 8 stable asthmatic subjects (mean age +/- SD, 26 +/- 5 yr) on 3 different days. On each day, a randomized challenge with LTC4, methacholine, or histamine was performed until the dose that provoked a fall of 20% in FEV1 (PC20) was obtained. Complete and partial flow-volume curves as well as area-distance profiles generated by the acoustic reflection technique (ART) at a fixed lung volume were obtained in all subjects before and after each inhalation challenge. No significant differences were found in pulmonary function or baseline cross-sectional airway areas for the different study days. The three agonists provoked significant (p less than 0.05) bronchoconstriction at the level of the main bronchi when identical falls of FEV1 were achieved. Similarly, equal reductions of V30p were elicited by the three agonists. However, LTC4 and methacholine induced additional tracheal constriction but histamine inhalation did not. These differences in the degree of tracheal constriction were statistically significant (p less than 0.05; ANOVA). These results may be explained by distinct pharmacologic properties of the agents used and may have relevance in the understanding of the pathophysiology of asthma.

We examined the effect of volume history on the dynamic relationship between airways and lung parenchyma (relative hysteresis) in 20 asthmatic subjects. The acoustic reflection technique was employed to evaluate changes in airway cross-sectional areas during a slow continuous expiration from total lung capacity to residual volume and inspiration back to total lung capacity. Lung volume was measured continuously during this quasi-static maneuver. We studied three anatomic airway segments: extra- and intrathoracic tracheal and main bronchial segments. Plots of airway area vs. lung volume were obtained for each segment to assess the relative magnitude and direction of the airway and parenchymal hysteresis. We also performed maximal expiratory flow-volume and partial expiratory flow-volume curves and calculated the ratio of maximal to partial flow rates (M/P) at 30% of the vital capacity. We found that 10 subjects (group I) showed a significant predominance of airway over parenchymal hysteresis (P < 0.005) at the extra- and intrathoracic tracheal and main bronchial segments; these subjects had high M/P ratios [1.53 +/- 0.27 (SD)]. The other 10 subjects (group II) showed similar airway and parenchymal hysteresis for all three segments and significantly lower M/P ratios (1.16 +/- 0.20, P < 0.01). We conclude that the effect of volume history on the relative hysteresis of airway and lung parenchyma and M/P ratio at 30% of vital capacity in nonprovoked asthmatic subjects is variable. We suggest that our findings may result from heterogeneous airway tone in asthmatic subjects.

The prevalence of patients with acute severe asthma appears to be increasing in many countries. In the present review, we summarize data in the literature relating to the prevention and treatment of fatality-prone asthmatics. The underlying assumption is that increased understanding of near-fatal asthma will increase our understanding of the pathophysiology of severe asthma, and lead to interventions that could reduce the mortality rate from asthma. Recognition of acute life-threatening asthma attacks by any physician is mandatory, since lack of such diagnosis and appropriate treatment has been shown to have devastating consequences. The characteristics that allow identification of asthmatics prone to die in ambulatory settings (i.e. previous admissions, type of therapy, etc.) as well as the principal precipitating factors of acute near-fatal and fatal attacks of asthma are reviewed. Predisposing factors, such as lack of appropriate treatment, lack of compliance or poor preventive measures are debated. Finally, we discuss current therapeutic approaches in emergency facilities, based on the major pathophysiological findings in near-fatal asthma.

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