High-dose nedocromil sodium as an addition to inhaled corticosteroids in the treatment of asthma.

In a double-blind placebo-controlled trial nedocromil sodium in a dose of 8 mg four times daily or matching placebo was added to the treatment of 29 asthmatic patients. All patients were taking inhaled corticosteroids in a dose of up to 1000 micrograms daily. The trial agents were given for 6 weeks after a 2-week run-in period. Twenty-four patients completed the study, three withdrew because of adverse effects, two on placebo. Daytime asthma symptoms were significantly reduced on nedocromil compared to placebo (-0.46 vs. +0.09, P = 0.03). Night-time asthma and morning tightness were not changed significantly. Bronchodilator use in the night and day were lower on nedocromil but the differences were not significant. Morning peak flow rates were higher on nedocromil (+22.2 vs. +0.08, P = 0.06) and physicians opinions of overall effectiveness favoured nedocromil (U = 35.0, P = 0.04). These results confirm that nedocromil sodium may be a useful addition in asthma to low to medium doses of inhaled corticosteroids. The effects of 32 mg nedocromil daily were comparable to previous reports with lower doses.

Unusual spinal tuberculosis after adequate chemotherapy for lymph node tuberculosis in an immunocompetent man.

A 35 year old man developed paraplegia due to an epidural mass 15 months after completion of a full chemotherapy course for pulmonary and lymph node Mycobacterium bovis infection. His cellular immune function was normal after treatment. It is suggested that the lesion was a granulomatous healing response rather than bacteriological recurrence.

Airway responsiveness to histamine and leukotriene E4 in subjects with aspirin-induced asthma.

Airway responsiveness to histamine and leukotriene E4 (LTE4) has been compared between five subjects with aspirin-induced asthma (AIA) and 15 asthmatic subjects without aspirin sensitivity (non-AIA). In the AIA group, the geometric mean doses of histamine and LTE4 causing a 35% fall in specific airway conductance (PD35) were 0.31 mumol and 0.17 nmol, respectively, and LTE4 was 1,870 times more potent than histamine. In the non-AIA group, the histamine and LTE4 PD35 doses were 0.40 mumol (non-AIA versus AIA, NS) and 2.8 nmol (non-AIA versus AIA, p = 0.002), respectively, and LTE4 was 145 times more potent than histamine in eliciting bronchoconstriction (non-AIA versus AIA, p = 0.001). After desensitization to aspirin the geometric mean histamine and LTE4 PD 35 in the AIA group changed to 0.19 mumol (NS) and 3.3 nmol (p = 0.007), respectively, and there was an average 33-fold reduction in the responsiveness of the airways to LTE4 relative to histamine (p less than 0.001). In five non-AIA subjects. Ingestion of 600 mg of aspirin daily did not lead to any significant change in airway responsiveness to histamine or to LTE4. These results demonstrate a selective and marked increase in airway responsiveness to LTE4 in subjects with AIA. The efficacy of desensitization may relate in part to a selective down-regulation of LTE4 receptors within the airways.

Role of histamine release in hypertonic saline induced bronchoconstriction.

In a study designed to determine the protective effect of the specific histamine H1 antagonist terfenadine on hypertonic saline induced bronchoconstriction, 10 asthmatic subjects underwent hypertonic saline challenge (3.6%) after premedication with placebo or terfenadine (120 mg) 12 and two hours before the challenge. Hypertonic saline was administered in a dose dependent manner and the response determined as the dose of hypertonic saline that induced a 20% fall in FEV1 (PD20 FEV1). FEV1 was on average 11% greater with terfenadine than with placebo given before the challenge with hypertonic saline. PD20 FEV1 was attenuated by a mean of 2.5 fold after terfenadine (geometric mean PD20 FEV1 was 22 litres after placebo and 56 l after terfenadine). There was substantial intersubject variation in the inhibitory effect of terfenadine on hypertonic saline induced bronchoconstriction: the ratio of the PD20 hypertonic saline after terfenadine to that after placebo ranged from 0.9 to 10.0. Terfenadine inhibited histamine induced bronchoconstriction in the eight subjects in whom it was tested, by 13 to 160 fold compared with placebo in four subjects and by greater than 2 to greater than 9 fold in the four who showed no response to the highest dose of histamine given (16 mg/ml). These results suggest that histamine release has a role in hypertonic saline induced bronchoconstriction in some individuals; other mediators or mechanisms may have a more prominent role in others.

Airway responsiveness to adenosine 5' monophosphate following inhalation of hypertonic saline.

We wished to determine whether the refractory period after hypertonic saline (HS) challenge is due to mast cell mediator depletion. Therefore, the airway responsiveness to adenosine 5' monophosphate (AMP), which induces bronchoconstriction via mast cell histamine release, was determined after the inhalation of HS aerosol. Nine asthmatic subjects attended the laboratory on three occasions. On day 1 HS challenge was performed followed one hour later by a second HS challenge. On day 2 an AMP challenge was performed. On day 3 an HS challenge was performed followed one hour later by an AMP challenge. Airway responsiveness (PD35 sGaw) to an initial HS challenge ranged from 12 to 315 l of aerosol (mean 47 l). Airway responsiveness to a second HS challenge ranged from 8 to 800 l (mean 102 l p = 0.035, n = 9). Airway responsiveness to AMP increased from 0.44 to 14.0 mumol (mean 2.37 mumol) at baseline to 0.3 to 15.5 (mean 1.3 mumol) (p = 0.05) after HS challenge. There was a linear correlation between baseline AMP responsiveness and baseline HS responsiveness (r = 0.911, p = 0.001). There was no correlation between the degree of refractoriness and the change in AMP responsiveness (r = 0.1, p = 0.9). Thus airway responsiveness to AMP increased significantly after inhalation of HS aerosol and this increase was independent of refractory behaviour. Our results suggest that the refractory period to HS is not due to mediator depletion.

The effects of indomethacin on the refractory period to hypertonic saline-induced bronchoconstriction.

The purpose of this study was to determine the effect of pretreatment with indomethacin on the refractory period to hypertonic saline-induced bronchoconstriction. In a double-blind, placebo-controlled, randomized trial nine asthmatic subjects underwent two hypertonic saline challenges, 60 min apart, on a control day and after premedication with indomethacin 50 mg or matching placebo, twice daily for three days. Premedication with indomethacin did not change airway responsiveness to the initial hypertonic saline challenge. The mean maximal % fall in specific airway conductance (sGaw) was 40.3, 44.1 and 47.6% on the control, placebo and indomethacin days, respectively. Subjects were significantly less responsive to the second hypertonic challenge as compared to the initial challenge on all three study days. There was a variable effect of indomethacin pretreatment on the refractory period. Five subjects lost their refractory period after indomethacin, when the variability of the test was taken into account. This suggests that there may be contributory mechanisms to the refractory period other than the release of protective prostanoid metabolites.

Occupational asthma due to glutaraldehyde and formaldehyde in endoscopy and x ray departments.

BACKGROUND: Glutaraldehyde is the best disinfectant for fibreoptic endoscopes. It is also used in the processing of x ray films. A number of studies have reported eye, nose, and respiratory symptoms in exposed workers. Three individual case reports of occupational asthma in endoscopy workers and a radiographer have also been published. We describe a further seven cases of occupational asthma due to glutaraldehyde in endoscopy and x ray departments, together with exposure levels measured during the challenge tests and in 19 endoscopy and x ray departments in the region. METHODS: Eight workers were referred for investigation of suspected occupational asthma following direct or indirect exposure to glutaraldehyde at work. They were investigated by serial measurements of peak expiratory flow (PEF) and specific bronchial provocation tests. Glutaraldehyde levels were measured using personal and static short and longer term air samples during the challenge tests and in 13 endoscopy units and six x ray darkrooms in the region where concern about glutaraldehyde exposure had been expressed. Three of the workers investigated with occupational asthma came from departments where glutaraldehyde air measurements had been made; the others came from other hospitals or departments. RESULTS: The diagnosis of occupational asthma was confirmed in seven workers, all of whom had PEF records suggestive of occupational asthma and positive specific bronchial challenge tests to glutaraldehyde. Bronchial provocation testing was negative in one worker who was no longer exposed and who had a less clearcut history of occupational asthma. Three workers also had a positive specific bronchial challenge to formaldehyde. The mean level of glutaraldehyde in air during the challenge tests was 0.068 mg/m3, about one tenth of the short term occupational exposure standard of 0.7 mg/m3. The levels obtained in the challenge chamber were similar to those measured in 13 endoscopy suites and six x ray darkrooms where median short term levels were 0.16 mg/m3 during decantation in endoscopy suites and < 0.009 mg/m3 in darkrooms. CONCLUSIONS: Glutaraldehyde can cause occupational asthma. The exposure levels measured in the workplace suggest that sensitisation may occur at levels below the current occupational exposure standard.

Manchester air disaster.

On 22 August 1985 a fire occurred on a Boeing 737 jet airliner at take off at Manchester Airport. One hundred and thirty seven passengers and crew were on board. Fifty two passengers died on the aircraft, 85 escaped. Most survivors had minor physical injuries, but 15 required admission to hospital because of smoke inhalation and two of these had severe burns. At presentation only one survivor required ventilation but within 12 hours a further five required ventilation. Although initially patients suffering from smoke inhalation may seem relatively well, lung function may deteriorate rapidly in the first 24 hours. Careful organisation and regular practice of procedures to deal with a major accident are essential to be able to respond adequately to such an event.

Airway responsiveness to methacholine after inhalation of nebulized hypertonic saline in bronchial asthma.

To assess whether the changes in airway methacholine (Meth) responsiveness induced by an initial hypertonic challenge determine the response to a subsequent hypertonic provocation, 11 subjects with asthma had bronchial challenges with 3.6% hypertonic saline (HS) and Meth in a dose-dependent manner and in random order. Challenges consisted of (1) an HS challenge (HS1) followed 1 hour later by a second HS challenge (HS2), (2) a Meth challenge alone (Meth1), and (3) an HS challenge followed 1 hour later by a Meth challenge (Meth2). The dose of HS that produced a 35% fall in SGaw (PD35) in HS1 was 69 L (geometric mean), and the PD35 in HS2 was 107 L (p = 0.02). Refractory index (PD35 HS2/PD35 HS1) ranged from 0.7 to 5.0. After HS challenge, airway responsiveness to Meth increased, and the Meth PD35 fell from 0.26 mumol to 0.11 mumol (geometric mean, p = 0.004). There was an inverse linear correlation between the refractory index and increases in Meth sensitivity (PD35 Meth1/PD35 Meth2) (r = -0.66; p = 0.027). After an initial HS challenge, the ratio of PD35 HS to PD35 Meth increased in all subjects, indicating that all subjects had become less responsive to HS compared to Meth, irrespective of their refractory index. We suggest that an initial HS challenge induces protective mechanisms toward a subsequent HS challenge in all individuals. The degree of increase in Meth responsiveness elicited by the initial provocation is a major factor in determining the airway response to a subsequent HS challenge.

Does single dose salmeterol affect exercise capacity in asthmatic men?

The aim of this study was to investigate whether the long-acting beta-agonist salmeterol affects athletic performance in patients with asthma. The effect of 50 micrograms salmeterol on the cardiorespiratory responses to a progressive maximal cycle exercise test and on endurance capacity (defined as the exercise duration at 70% maximum oxygen uptake), was compared with 200 micrograms salbutamol and a matched placebo in eight asthmatic men. Both salmeterol and salbutamol improved pre- and postexercise forced expiratory volume in one second (FEV1) for maximal and endurance exercise. Following active treatment, patients exercised from a significantly high baseline FEV1, with both salmeterol (3.58(1.16)l) (mean (SD)) and salbutamol (3.55(1.24)l) compared with placebo (3.29(1.35)l). Similar improvements preceded endurance exercise. Cardiorespiratory, haemodynamic or subjective responses to the progressive maximum exercise tests were not different with salmeterol, salbutamol or placebo, nor did endurance capacity change with any treatment modality. Blood lactate levels, after 15 min exercise, were significantly higher with salbutamol (3.64 (1.83) mM), but not with salmeterol (3.03 (1.64) mM), compared with placebo (2.95 (1.69) mM). These results demonstrate the absence of significant cardiorespiratory or metabolic effects during exercise after a single dose of salmeterol, together with a lack-of ergogenic effect, as measured by maximal or endurance exercise performance, in patients with asthma.

The relative responsiveness to inhaled leukotriene E4, methacholine and histamine in normal and asthmatic subjects.

The relative bronchoconstricting potencies of leukotriene E4 (LTE4) methacholine and histamine have been compared in asthmatic and normal subjects. LTE4 responsiveness in asthmatic subjects, as measured by the dose which produced a 35% fall in specific airways conductance (PD35), ranged from 0.06-24.4 nmol (geom mean 4.1 nmol, n = 20). This was significantly less than the PD35 in normal subjects (range 39.0-370 nmol, geom mean 105 nmol, n= 6; p less than 0.001). There was a correlation between LTE4 and methacholine responsiveness (r = 0.84, p less than 0.001) and between LTE4 and histamine responsiveness (r = 0.79, p less than 0.001). LTE4 was 73 times more potent than methacholine and 112 times more potent than histamine in asthmatic subjects. LTE4 was 20 times more potent than methacholine and 58 times more potent than histamine in normal subjects. LTE4 is a potent bronchoconstrictor agent, and LTE4 responsiveness correlates with both histamine and methacholine responsiveness.

Occupational asthma due to chrome and nickel electroplating.

BACKGROUND: Exposure to chromium during electroplating is a recognised though poorly characterised cause of occupational asthma. The first series of such patients referred to a specialist occupational lung disease clinic is reported. METHODS: The diagnosis of occupational asthma was made from a history of asthma with rest day improvement and confirmed by specific bronchial provocation testing with potassium dichromate and nickel chloride. RESULTS: Seven workers had been exposed to chrome and nickel fumes from electroplating for eight months to six years before asthma developed. One subject, although exposed for 11 years without symptoms, developed asthma after a single severe exposure during a ventilation failure. This was the only subject who had never smoked. The diagnosis was confirmed by specific bronchial challenges. Two workers had isolated immediate reactions, one a late asthmatic reaction, and four a dual response following exposure to nebulised potassium dichromate at 1-10 mg/ml. Two of the four subjects were also challenged with nebulised nickel chloride at 0.1-10 mg/ml. Two showed isolated late asthmatic reactions, in one at 0.1 mg/ml, where nickel was probably the primary sensitising agent. Four workers carried out two hourly measurements of peak expiratory flow over days at and away from work. All were scored as having occupational asthma using OASYS-2. Breathing zone air monitoring was carried out in 60 workers from four decorative and two hard chrome plating shops from workers with similar jobs to those sensitised. No measurement exceeded the current occupational exposure standard for chromate or nickel, the mean levels of chromate exposure for jobs similar to those of the affected workers were 9-15 micrograms/m3. CONCLUSION: Chrome used in electroplating is a potential cause of occupational asthma. Sensitivity to chrome in electroplaters may occur in situations where exposure levels are likely to be within the current exposure standards. There may be cross reactivity with nickel. Inhalation challenge with nebulised potassium dichromate solution is helpful in making the specific diagnosis where doubt exists.

Asthmatic airways have a disproportionate hyperresponsiveness to LTE4, as compared with normal airways, but not to LTC4, LTD4, methacholine, and histamine.

Airways responsiveness to leukotriene (LT) C4, LTD4, LTE4, histamine, and methacholine have been studied in eight asthmatic and six normal subjects. Airways responsiveness to each bronchoconstrictor agonist was assessed by constructing cumulative dose-response curves, and the dose that produced a 35% decrease in specific airways conductance (PD35) was obtained by linear interpolation. Airways of subjects with asthma were approximately 14-, 15-, 6-, 9-, and 219-fold more responsive to histamine, methacholine, LTC4, LTD4, and LTE4, respectively, than were normal subjects. Thus, there was a substantially augmented level of hyperresponsiveness to LTE4 in bronchial asthma, which was not observed for the other bronchoconstrictor agents, when compared to normal subjects. In contrast to LTC4 and LTD4, as histamine and methacholine responsiveness increase, the dose ratio of histamine to LTE4 (PD35 histamine/PD35 LTE4) and the dose ratio of methacholine to LTE4 also tended to increase. This suggests that as the nonspecific airways responsiveness increases, the relative potency of LTE4 also increases, whereas potency of LTC4 and LTD4 decrease. These results suggest that the mechanism of the bronchoconstriction induced by LTE4 may be distinct from that produced by LTC4 or LTD4 in subjects with asthma. This may reflect leukotriene subtype receptor heterogeneity in asthmatic airways.

Sulphidopeptide leukotrienes in asthma.

Bronchial asthma is characterized by airways inflammation and airways hyperresponsiveness. It is unlikely that the pathophysiology of asthma and bronchial hyperresponsiveness can be explained on the basis of a single cell or a single class of mediators. Nevertheless, the possibility that leukotrienes may contribute to the pathogenesis of the inflammatory, vasoactive ans spasmogenic components of bronchial asthma is suggested by the properties of these lipid mediators, the preferential capacity of inflammatory cells to generate leukotrienes and the presence of leukotrienes in the airways of asthmatic subjects. The sulphidopeptide leukotrienes are potent bronchoconstrictor agonists when inhaled. The airways of asthmatic subjects are hyperresponsive to leukotrienes as to other bronchoconstrictor agonists. Nevertheless, the airways responsiveness of asthmatic subjects to these agonists demonstrate several unusual properties. While the airways of asthmatic subjects are relatively less responsive to LTC4 and LTD4, compared to agents such as histamine or methacholine, they demonstrate a marked and selective hyperresponsiveness to LTE4, suggesting a possibly unique role for this mediator in the pathogenesis of airways hyperresponsiveness. In addition an increased sensitivity of the airways to LTE4 may contribute to the mechanism of aspirin-induced asthma. The capacity of the sulphidopeptide leukotrienes to increase the airways responsiveness of normal subjects to methacholine and of asthmatic subjects to histamine is further evidence for a role for these substances in the pathogenesis of bronchial asthma.

Leukotrienes C4, D4, and E4 enhance histamine responsiveness in asthmatic airways.

The effects of prior inhalation of each of the sulfidopeptide leukotrienes (LT), LTC4, LTD4, and LTE4 on airway responsiveness to histamine have been compared in seven asthmatic and six normal subjects. Each subject underwent histamine inhalation challenge at 1, 4, and 7 h after inhalation of phosphate-buffered saline and bronchoconstricting doses of LTC4, LTD4, LTE4, and methacholine, which produced a greater than 30% fall in specific airway conductance. In asthmatic subjects, prior inhalation of LTC4, LTD4, and LTE4 enhanced airway responsiveness to histamine when compared with saline inhalation, on average by a maximum of 3.9-, 2.8-, and 3.1-fold, respectively, at 4 h after inhalation. Methacholine inhalation did not significantly after histamine responsiveness throughout the time course studied. In normal subjects, inhalation of LTC4, LTD4, LTE4, and methacholine did not change airway responsiveness to histamine. Thus, LTC4 and LTD4 were similar to LTE4 in their capacity to enhance airway responsiveness to histamine in asthmatic subjects, and, in common with LTE4, they failed to elicit a change in airway responsiveness to histamine in normal subjects.

Pulmonary function and respiratory symptoms in a population of airport workers.

OBJECTIVES: To assess the prevalence of respiratory symptoms and to measure spirometry in a sample of employees of Birmingham International Airport, United Kingdom, to examine whether occupational exposure to aircraft fuel or jet stream exhaust might be associated with respiratory symptoms or abnormalities of lung function. METHODS: Cross sectional survey by questionnaire and on site measurement of lung function, skin prick tests, and exhaled carbon monoxide concentrations. Occupational exposure was assigned by job title, between group comparison were made by logistic regression analysis. RESULTS: 222/680 full time employees were studied (mean age 38.6 y, 63% male, 28% current smokers, 6% self reported asthma, 19% self reported hay fever). Upper and lower respiratory tract symptoms were common and 51% had one or more positive skin tests. There were no significant differences in lung function tests between exposure groups. Between group comparisons of respiratory symptoms were restricted to male members of the medium and high exposure groups. The adjusted odds ratio (OR) for cough with phlegm and runny nose were found to be significantly associated with high exposure (OR 3.5, 95% confidence interval (95% CI) 1.23 to 9.74 and 2.9, 1.32 to 6.40 respectively) when the measured confounding effects of age and smoking, and in the case of runny nose, self reported hay fever had been taken into account. There was no obvious association between high exposure and the presence of shortness of breath or wheeze, or for the symptoms of watering eyes or stuffy nose. CONCLUSIONS: These findings support an association in male airport workers, between high occupational exposures to aviation fuel or jet stream exhaust and excess upper and lower respiratory tract symptoms, in keeping with a respiratory irritant. It is more likely that these effects reflect exposure to exhaust rather than fuel, although the effects of an unmeasured agent cannot be discounted.