Proliferation is not increased in airway myofibroblasts isolated from asthmatics.

Airway mesenchymal cells, such as myofibroblasts and airway smooth muscle cells, contribute to inflammation, airway remodelling and hyperresponsiveness in asthma by excessive proliferation and inflammatory mediator production. Using endobronchial biopsies obtained from both nonasthmatic and asthmatic subjects, in situ proliferation was assessed by immunostaining for cyclin D1. The number of immunoreactive cells increased with asthma severity and was restricted to the epithelium and subepithelial connective tissue. Despite increases in smooth muscle area, cyclin D1 was not detected in cells in intact muscle bundles. Biopsy-derived cell cultures were characterised as predominantly myofibroblasts, and were assessed to determine whether proliferation and cytokine production varied with asthma status. Cell enumeration showed that basal proliferation was similar in cells from nonasthmatics and asthmatics, and mitogenic responses to fibroblast growth factor-2, thrombin or serum were either reduced or unchanged in cells from asthmatics. Interleukin (IL)-1-dependent granulocyte-macrophage colony-stimulating factor and IL-8 release was increased in cell supernatants from asthmatics. Thus, increased rates of cellular proliferation identified in situ in the asthmatic airway occurred outside the expanded smooth muscle compartment. Although reduced proliferative responses were observed in cultured myofibroblasts from asthmatics, the increased cytokine production by these cells suggests that this contributes to and may perpetuate ongoing inflammation in asthma.

Therapeutic efficacy of granulocyte-macrophage colony-stimulating factor in patients with idiopathic acquired alveolar proteinosis.

Alveolar proteinosis (AP) is characterized by excessive surfactant accumulation, and most cases are of unknown etiology. Standard therapy for AP is whole-lung lavage, which may not correct the underlying defect. Because the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is required for normal surfactant homeostasis, we evaluated the therapeutic activity of GM-CSF in patients with idiopathic AP. Fourteen patients received 5 microg/kg/d GM-CSF for 6 to 12 wk with serial monitoring of the alveolar-arterial oxygen gradient ([A-a]DO2), diffusing capacity of carbon monoxide, computed tomographic scans, and exercise testing. Patients not responding to 5 microg/kg/d GM-CSF underwent stepwise dose escalation, and responding patients were retreated at disease recurrence. Stored pretreatment sera were assayed for GM-CSF-neutralizing autoantibodies. According to prospective criteria, five of 14 patients responded to 5 microg/kg/d GM- CSF, and one of four patients responded after dose escalation (20 microg/kg/d). The overall response rate was 43% (mean improvement in [A-a]DO2 = 23.2 mm Hg). Responses lasted a median of 39 wk, and were reproducible with retreatment. GM-CSF was well-tolerated, with no late toxicity seen. The only treatment-related factor predictive of response was GM-CSF-induced eosinophilia (p = 0.01). Each of 12 patients tested had GM-CSF-neutralizing autoantibodies present in pretreatment serum. We conclude that GM- CSF has therapeutic activity in idiopathic AP, providing a potential alternative to whole-lung lavage.

Concentrations of major grass group 5 allergens in pollen grains and atmospheric particles: implications for hay fever and allergic asthma sufferers sensitized to grass pollen allergens.

BACKGROUND: Grass pollen allergens are the most important cause of hay fever and allergic asthma during summer in cool temperate climates. Pollen counts provide a guide to hay fever sufferers. However, grass pollen, because of its size, has a low probability of entering the lower airways to trigger asthma. Yet, grass pollen allergens are known to be associated with atmospheric respirable particles. OBJECTIVE: We aimed (1) to determine the concentration of group 5 major allergens in (a) pollen grains of clinically important grass species and (b) atmospheric particles (respirable and nonrespirable) and (2) to compare the atmospheric allergen load with clinical data to assess different risk factors for asthma and hay fever. METHODS: We have performed a continuous 24 h sampling of atmospheric particles greater and lower than 7.2 microm in diameter during the grass pollen season of 1996 and 1997 (17 October 1996-16 January 1997) by means of a high volume cascade impactor at a height of about 15 m above ground in Melbourne. Using Western analysis, we assessed the reactivity of major timothy grass allergen Phl p 5 specific monoclonal antibody (MoAb) against selected pollen extracts. A MoAb-based ELISA was then employed to quantify Phl p 5 and cross-reactive allergens in pollen extracts and atmospheric particles larger and smaller than 7.2 microm. RESULTS: Phl p 5-specific MoAb detected group 5 allergens in tested grass pollen extracts, indicating that the ELISA employed here determines total group 5 allergen concentrations. On average, 0.05 ng of group 5 allergens were detectable per grass pollen grain. Atmospheric group 5 allergen concentrations in particles > 7.2 microm were significantly correlated with grass pollen counts (rs = 0.842, P < 0. 001). On dry days, 37% of the total group 5 allergen load, whereas upon rainfall, 57% of the total load was detected in respirable particles. After rainfall, the number of starch granule equivalents increased up to 10-fold; starch granule equivalent is defined as a hypothetical potential number of airborne starch granules based on known pollen count data. This indicates that rainfall tended to wash out large particles and contributed to an increase in respirable particles containing group 5 allergens by bursting of pollen grains. Four day running means of group 5 allergens in respirable particles and of asthma attendances (delayed by 2 days) were shown to be significantly correlated (P < 0.001). CONCLUSION: Here we present, for the first time, an estimation of the total group 5 allergen content in respirable and nonrespirable particles in the atmosphere of Melbourne. These results highlight the different environmental risk factors for hay fever and allergic asthma in patients, as on days of rainfall following high grass pollen count, the risk for asthma sufferers is far greater than on days of high pollen count with no associated rainfall. Moreover, rainfall may also contribute to the release of allergens from fungal spores and, along with the release of free allergen molecules from pollen grains, may be able to interact with other particles such as pollutants (i.e. diesel exhaust carbon particles) to trigger allergic asthma.

Patients prefer sedation for fibreoptic bronchoscopy.

This study was carried out in order to determine if intravenous (i.v.) sedation with diazepam, at the time of procedure, made fibreoptic bronchoscopy more tolerable and if these perceptions persisted on later questioning. Methodology consisted of a sequential, parallel group design comparing sedation with no sedation for bronchoscopy in a tertiary referral hospital. Patient comfort and sedation desired for hypothetical repeat bronchoscopy were assessed both immediately and after at least 1 month. Patients who received sedation rated bronchoscopy as more comfortable (P = 0.01). Those who received sedation were also more likely to want no change in sedation if the bronchoscopy were repeated (P < 0.01). These differences were more evident at later questioning. Sedation was not associated with an increased complication rate but was associated with a prolonged recovery room stay (no sedation, 19.2 min (SEM 3.8) compared with sedation, 76.1 min (5.4), P < 0.001). In contrast to previous studies, our patients found bronchoscopy more comfortable with i.v. diazepam sedation. This was supported by patients who received sedation being less likely to want any change in future sedation if a repeat bronchoscopy were required. The benefit seen with sedation was more marked at later questioning supporting a previously postulated amnesic effect. However, sedation was associated with a prolonged room stay and potentially greater attendant cost.

Perception of natural fluctuations in peak flow in asthma: clinical severity and psychological correlates.

Two methods of defining perception of asthma-related changes in airflow were compared, and relationships to clinical opinions of severity and assessments of psychological functioning were investigated. Perceived breathlessness (VAB) and peak expiratory flow (PEF) were recorded by 100 subjects for 28 days. Perception was defined by correlation of the two values and by the ratio of maximum change in PEF and related change in VAB. The latter method defined 24 poor perceivers (PP) and 13 exaggerated perceivers (EP), in whom presence of a psychological disorder was high (30% of PP, 54% of EP, compared to 8% of the remainder). Clinical severity in EP was assessed as greater than appeared warranted.

Chronic lung diseases and the perception of breathlessness: a clinical perspective.

Breathlessness is an extremely common symptom. Its genesis is incompletely understood but is known to be largely determined by many of the mechanical factors associated with the act of breathing. As with all subjective sensations various other factors including volition, behavioural style and other cortical and subcortical factors play a part in its genesis. The relief of breathlessness is primarily directed at the underlying disorder. In those conditions and situations where specific therapy has little to offer or little impact it is reasonable to consider ways of reducing the perception of breathlessness by pharmacological means. However, to date there is no convincing evidence that use of drugs in the pursuit of the relief of breathlessness has any specific effect in modifying the perception of this often distressing symptom. Any reduction in breathlessness achieved in this way can be adequately explained in terms of a reduction in ventilation and other indices of respiratory mechanics.

The lack of distensibility of asthmatic airways.

Asthma is characterized by chronic endobronchial inflammation and the deposition of collagen below the epithelial basement membrane. The functional significance of collagen deposition is unknown, but it can lead to loss of airway distensibility and hence to eventual loss of bronchodilator response. In this study we examined the volume of airway dead space by a single-breath, nitrogen-plateau method at a range of lung volumes during inspiration. Participants were 10 asthmatics and 10 control subjects who were matched for lung volumes and age. The asthmatics increased their dead space by 27.0 ml/L compared with 37.3 ml/L in the control subjects (p = 0.014). The dead-space volumes at 50% TLC were no different (29.3 ml/L lung volume in asthma versus 26.9 ml/L in control subjects, p = 0.25). Loss of airway distensibility did not correlate, however, with loss of bronchodilator responsiveness, implying that factors other than mechanical airway distensibility may act to determine pharmacologic reversibility of airflow obstruction.

Oxygen dissociation curve in the adult respiratory distress syndrome.

The oxygen tension for half saturation (P50) was determined for venous blood in thirteen patients with the adult respiratory distress syndrome undergoing intensive therapy. The mean value for P50 was found to be significantly lower than the value found in ten normal control subjects (22.9 mmHg and 26.7 mmHg respectively; t = 3.03, P < 0.01). The extent of reduction in P50 was not related to serum phosphate level nor was it a predictor of short-term outcome. It is unlikely that the slight left-shifted oxygen-haemoglobin dissociation curve contributes in a major way to an oxygen delivery deficiency and its cause is unexplained.

Atopy in subjects with asthma followed to the age of 28 years.

The relationship between markers of asthma and atopy was examined in 323 subjects at the age of 28 years who have been followed since the age of 7 years. Hay fever was common in all groups with severe asthma, increasing from 25% of the control group to 67% of the group with the most severe asthma, class V. Eczema was uncommon at this age in all groups. IgE levels, peripheral blood eosinophil counts, and skin reactions were significantly (p less than 0.05) higher in class V than in the control group. Increasing age was associated with a progressive fall in eosinophil counts and an increase in skin reactivity to common allergens. No change in IgE levels was observed from 21 to 28 years. A general relationship between bronchial hyperreactivity and atopic markers was found. However, only the occurrence of hay fever was significantly related to reactivity when account was taken of severity of asthma. The results indicate that the relationship between asthma and atopy observed at earlier reviews continues into adult life and that bronchial hyperreactivity and atopy are not directly linked.

Panic disorder, the ventilatory response to carbon dioxide and respiratory variables.

Increased sensitivity of the central carbon dioxide chemoreceptors to carbon dioxide has been hypothesized as a biologic determinant of panic attacks in panic disorder and on voluntary inhalation of carbon dioxide mixtures. The ventilatory response to carbon dioxide, a measure of sensitivity, was assessed in 12 patients with panic disorder and 12 matched normal controls. While mean sensitivity was similar for both groups, for the panic disorder patients, mean sensitivity due to the tidal volume component was significantly less than for the normal controls, and mean sensitivity due to the frequency component was significantly greater than for the normal controls. The interpretation of the effects of carbon dioxide inhalation as a neurobiologic and behavioral probe may be enhanced if the components of the ventilatory response are examined separately.

Childhood asthma and adult lung function.

An age-matched group of 247 subjects who had had asthma as children and 39 control subjects were studied with lung function and bronchial reactivity testing at the age of 28 years. Lung function of those who had ceased wheezing was essentially normal, but lung function was increasingly abnormal in those who continued to wheeze. Those with frequent wheezing at 28 demonstrated a greater decline in their respiratory function since the age of 7 years than the other groups. Methacholine provocation testing was performed in 91% of the group and was associated with frequency of wheezing and evidence of small airways obstruction. No association was found between reactivity and loss of ventilatory capacity since 21 years of age.

The efficacy of nedocromil sodium (Tilade) in asthma.

Nedocromil sodium is a new antiasthmatic drug with properties similar to sodium cromoglycate. We examined the efficacy of nedocromil sodium compared to placebo in 71 asthmatic patients in a three-centre double-blind parallel group study over 12 weeks. During the study the patients' maintenance inhaled corticosteroids were progressively withdrawn. Nedocromil sodium had an advantage over placebo in the number of withdrawals related to uncontrolled asthma, 14 and 24 respectively (p = 0.03). Changes in symptom scores, peak flow rates and bronchodilator use favoured nedocromil sodium occasionally during the study. The unusual taste of the active drug was reported frequently. Nedocromil sodium is more efficacious than placebo in asthma maintenance, but does not replace inhaled corticosteroids.

Childhood asthma in adult life: a further study at 28 years of age.

A group of 323 subjects who had wheezed in childhood and 48 control subjects of the same age were studied prospectively from 7 to 28 years of age. A classification system based on wheezing frequency was found to correlate well with clinical and spirometric features of airway obstruction. The amount of wheezing in early adolescence seemed to be a guide for severity in later life with 73% of those with few symptoms at 14 continuing to have little or no asthma at 28 years. Similarly 68% of those with frequent wheezing at 14 still suffered from recurrent asthma at 28 years. Most subjects with frequent wheezing at 21 continued to have comparable asthma at 28 years. Of those with infrequent wheezing at 21, 44% had worsened at 28 years. Women fared better than men between 21 and 28 with 19% having worse symptoms compared with 28% of men. Treatment at all ages was generally inadequate. The number of smokers among those with asthma was of concern.

A 4-week Australian multicentre study of nedocromil sodium in asthmatic patients.

The use of nedocromil sodium 4 mg q.i.d. in asthmatics with mildly unstable asthma induced by a reduction of their inhaled beclomethasone dipropionate dose was investigated in a double-blind, parallel group, placebo-controlled study. Compared with placebo, nedocromil sodium improved night-time and daytime asthma score, night-time and daytime bronchodilator use, and evening PEFR at some stage during the 4-week treatment. It is concluded that nedocromil sodium exerts a beneficial effect in chronic asthma.

The potential bronchodilator action of verapamil.

Although calcium antagonists such as verapamil are used primarily in cardiovascular disease, they appear to relax smooth muscle generally. Therefore, the possibility that verapamil might have bronchodilator properties was explored using the guinea-pig tracheal ring technique. Verapamil was found to produce considerable tracheal smooth muscle relaxation from a threshold concentration of 2 X 10(-7) M and with maximum effect at 10(-3) M. The responses to the contractile agonists histamine and prostaglandin F2 alpha and especially methacholine and serotonin were substantially reduced by prior administration of verapamil. Verapamil 2 X 10(-4) M was equally effective as isoprenaline 10(-8) M in producing 50% maximum direct relaxation but was more effective than isoprenaline as an antagonist of the contractile agonists, methacholine, histamine and serotonin, but not prostaglandin F2 alpha. Verapamil abolished the contractile responses to barium chloride. It is concluded that, although verapamil was not very potent as a direct bronchodilator, it could potentially be of prophylactic benefit in asthma because of its efficacy as an antagonist of common contractile agonists.

Respiratory disability in workers' compensation claimants.

This study was designed to examine whether claimants for compensation for work-related respiratory impairment due to chronic airflow obstruction exhibited greater symptoms of disablement than other patients with similar obstruction. It also sought evidence of bias, either towards or against the claimants, by the medical examiners. One hundred and twenty-eight subjects (68 claimants) with chronic asthma, chronic bronchitis, and emphysema were studied. There was a reasonable concordance of subjective judgements between patients and medical examiners in 81% of the disabled workers, and in 90% of the other medical group. Similarly, impairment of lung function (FEV1/VC ratio) in both groups was comparable at most levels of subjective disability. It was concluded that, in contrast to some previous reports, claimants for compensation for work-related chronic obstructive airway diseases did not tend to exaggerate their disabilities. This does not imply that the claimants' ailments were necessarily occupation-related.

Hypercapnic ventilatory control in patients with chronic airflow obstruction: a follow-up study.

A four year follow-up study of ventilatory control has been performed in 50 patients with chronic airflow obstruction. Hypercapnia was induced by rebreathing, and both the ventilation and the mouth pressures produced during transient airway conclusion during inspiration were obtained. Both the chemoreceptor sensitivity to hypercapnia (delta P/delta PCO2) and the ventilatory response (delta V/delta PCO2) measured during the initial study were shown to be unrelated to prognosis when the outcome of these patients was determined four years later. A relationship between initial hypercapnia and survival was found. Twenty of the patients were restudied. No significant change occurred in the chemosensitivity to hypercapnia over the four year period. In the initial study and the follow-up study hypercapnia was also found to be associated with a reduced chemoreceptor sensitivity. Although both chemosensitivity to hypercapnia and survival were found to be separately related to arterial CO2 tension, there was no direct relationship between them. These results suggest that any possible influence of chemosensitivity on survival is likely to be overshadowed by other factors.