Small airways function declines after allogeneic haematopoietic stem cell transplantation.

Bronchiolitis obliterans (BO) following allogeneic haematopoietic stem cell transplantation (HSCT) affects peripheral airways. Detection of BO is presently delayed by the low sensitivity of spirometry. We examined the relationship between peripheral airway function and time since HSCT, and compared it with spirometry and clinical indices in 33 clinically stable allogeneic HSCT recipients. The following measurements were performed: lung function, exhaled nitric oxide, forced oscillatory respiratory system resistance and reactance, acinar (S(acin)) and conductive airways ventilation heterogeneity and lung clearance index (LCI) measured by multiple breath nitrogen washout. 22 patients underwent repeat visits from which short-term changes were examined. Median time post HSCT was 12 months. Eight patients were clinically diagnosed as having BO. In multivariate analysis, time since HSCT was predicted by S(acin) and forced expiratory volume in 1 s % predicted. 20 patients had abnormal S(acin) with normal spirometry, whereas none had airflow obstruction with normal S(acin). S(acin) and LCI were the only measures to change significantly between two visits, with both worsening. Change in S(acin) was the only parameter to correlate with change in chronic graft-versus-host disease grade. In conclusion, peripheral airways ventilation heterogeneity worsens with time after HSCT. S(acin) may be more sensitive than spirometry in detecting BO at an early stage, which needs confirmation in a prospective study.

Prevalence of bronchial hyperresponsiveness and asthma in a rural adult population.

The prevalence of bronchial hyperresponsiveness in adult populations is not known. To document its prevalence and distribution and to determine the factors associated with it, a random sample of the adult population of Busselton, Western Australia, was studied. Spirometric function, bronchial responsiveness to histamine, and atopic responses to skin prick tests were measured. Respiratory symptoms were determined by questionnaire. Data were obtained from 916 subjects. Of these, 876 underwent a histamine inhalation test and bronchial hyperresponsiveness to histamine (defined as a dose of histamine provoking a 20% fall in FEV1 equal to or less than 3.9 mumol) was found in 10.5%. Another 40 subjects with poor lung function were tested with a bronchodilator and 12 were found to have bronchial hyperresponsiveness (defined as a greater than 15% increase in FEV1), making the total prevalence of bronchial hyperresponsiveness 11.4%. The prevalence of current asthma, defined as bronchial hyperresponsiveness plus symptoms consistent with asthma in the last 12 months, was 5.9%. The distribution of bronchial hyperresponsiveness in the studied population was continuous. There was a significant association between it and respiratory symptoms, atopy, smoking, and abnormal lung function (p less than 0.001 for all associations). There was no association with age, sex, or recent respiratory tract infection.

Airway cooling as the stimulus to exercise-induced asthma--a re-evaluation.

Exercise-induced asthma (EIA) was recorded in 20 of 22 asthmatic children who cycled for 8 min while inspiring hot (32-40 degrees C) dry (3-10 mg H2O L-1) air. The mean +/- 1SD reduction in forced expiratory volume in one second was 39.8% +/- 22.3 of the pre-exercise value. To determine the relationship between respiratory heat loss (RHL) and retrotracheal temperature (RTT) under these inspired air conditions we studied 11 non-asthmatic adults who performed steady-state and incremental bicycle exercise. Exercise tests were also carried out while inspiring cold dry air. At the equivalent RHL, RTT was reduced by only 0.1 +/- 0.35 degrees C breathing hot air compared with 1.0 +/- 0.81 degrees C when cold air was inhaled. These data suggest that abnormal cooling of the airways is not occurring during the inhalation of hot dry air. Thus an additional stimulus to airway cooling must have been acting to induce asthma in the children. We propose that water loss and not heat loss is the stimulus to EIA under these inspired air conditions.

Increased responsiveness to methacholine and histamine after challenge with ultrasonically nebulised water in asthmatic subjects.

Responsiveness to inhaled methacholine was compared before and 40-60 minutes after a challenge with ultrasonically nebulised water (UNH2O) in 16 asthmatic patients. The sensitivity to methacholine increased after UNH2O challenge (p less than 0.001). The mean dose of methacholine producing a 20% fall in forced expiratory volume in one second was 0.4 (95% confidence limits 0.2, 0.8) mumol, compared with 0.9 (95% confidence limits 0.5, 1.6) mumol in the first methacholine challenge. When the study was repeated in six asthmatic patients with histamine substituted for methacholine, five of the patients were significantly more sensitive to histamine after UNH2O challenge. It is concluded that challenge with UNH2O produces an increase in airway responsiveness.

Mediators of hypersensitivity and "fog"-induced asthma.

Seven asthmatic and five normal subjects inhaled increasing amounts of nebulized water ("fog"). Neutrophil chemotactic activity (NCA), histamine and FEV1 measurements were undertaken before and at time intervals after challenge. In asthmatics, the mean maximal reduction in FEV1 (+/- 1 SD) was 46.6% +/- 11.5; whereas, in normal subjects, the reductions were less than 20% of pre-challenge values after the inhalation of 33 ml of water. There were no significant differences in the pre-challenge values for NCA between the asthmatics and the normal controls. When the highest values for NCA during the 30 min after challenge in the asthmatics were compared with controls there was a significant increase (P less than 0.02). The percentage change in NCA was also significantly greater in the asthmatics compared with the controls at 10 min after challenge (P less than 0.05). Fog-induced NCA was shown to be associated with proteins with approximate molecular weight of 600,000 daltons (as assessed by gel filtration chromatography on Sephacryl-S400). There was an increase in plasma histamine in the asthmatics after challenge but this was not significantly greater than the controls. These findings support the view that mediators might be involved in fog-induced asthma, possibly as a result of mast cell degranulation by "osmotic shock".

Effect of aerosol fenoterol on the severity of bronchial hyperreactivity in patients with asthma.

Beta adrenergic agents given by aerosol decrease the responsiveness of the airways to histamine and methacholine in subjects with asthma, causing a shift of the dose response curve to the right. To find out whether the shift is related to the dose of beta adrenergic agent given and to determine the duration of the reduced responsiveness, eight subjects with asthma were given histamine inhalation tests after inhaled saline and after increasing doses of inhaled fenoterol on different days. The histamine inhalation tests were repeated at hourly intervals for five hours after a selected dose of fenoterol. Fenoterol caused a dose related shift to the right of the histamine dose response curve in each subject and in some the dose response relationship reached the "non-symptomatic range." The shift in the dose response curve was short lived and had returned towards the control position within three hours in all subjects. There was no change in shape of the curves at the time of maximal shift. The results show that inhaled fenoterol greatly reduces the airway responsiveness to histamine, but up to 400 micrograms of fenoterol every four to five hours may be needed to keep the responsiveness of the airways in the non-symptomatic range.

Sodium cromoglycate as a pressurised aerosol (vicrom) in exercise-induced asthma.

We investigated the effect of sodium cromoglycate (SCG), delivered as a pressurised aerosol, in a dose of 2 or 4 mg in 15 patients known to have exercise-induced asthma (EIA). All patients had a fall in peak expiratory flow rate (PEFR) greater than 20% of the pre-exercise level following placebo (Range 21.1 to 74.7%). When an identical exercise test was performed after 2 mg of SCG aerosol, nine of the 15 patients had falls in PEFR less than 50% of the value observed on placebo. Of the remaining six patients, four had greater than 50% protection afforded by 4 mg of SCG. Of the 15 patients, 12 had falls in PEFR less than 11% after either 2 or 4 mg of SCG aerosol. The dose of aerosol SCG required to inhibit EIA is only 10 to 20% of that delivered by conventional spinhaler. The apparent superiority of the pressurised aerosol may be due to its site of deposition in the airways.

Evaluation of ultrasonically nebulised solutions for provocation testing in patients with asthma.

The airway response to the inhalation of ultrasonically nebulised distilled water was determined in 55 asthmatic patients and 16 normal subjects. We calculated the dose of water required to induce a 20% reduction (PD20) in forced expiratory volume in one second (FEV1) by measuring the output of the nebuliser and the volume ventilated by each subject. Forty-eight of the asthmatic patients had a PD20 of 9 ml or less but three patients required as much as 24 ml. A PD20 was not recorded in the normal subjects and the challenge was stopped after 33 ml. In 12 patients the challenge was repeated within six months and the airway response was shown to be reproducible at equivalent doses of water. In a separate group of 11 patients there was, however, a highly significant reduction in the percentage fall in FEV1 when equivalent doses of water were given on two occasions 40 minutes apart. When the temperature of the inhaled water was increased from 22 degrees C to 36 degrees C eight of 10 patients had a similar change in FEV1 with equivalent doses of water. The airways obstruction induced by the inhalation of water was readily reversed with salbutamol administered by aerosol. In some patients a challenge with water or 3.6% saline was repeated after pretreatment with sodium cromoglycate, atropine methonitrate, and verapamil hydrochloride, all given as aerosols. The airway response to the equivalent dose of water or saline was significantly reduced after treatment with sodium cromoglycate but not atropine or verapamil.

Sensitivity to heat and water loss at rest and during exercise in asthmatic patients.

We investigated the respiratory heat and water loss in 24 asthmatic patients who performed bicycle exercise while inspiring air conditioned to varying temperatures and water contents. Measurements of peak expiratory flow and forced expiratory volume in 1 s were made at rest, during and after exercise to determine changes in airways resistance. Respiratory heat and water loss were measured using rapid thermistors and a mass spectrometer to measure inspired and expired temperature and water vapour pressure. Exercise-induced asthma (EIA) was enhanced as the inspired water content of the air was reduced. However, there was a wide variation in sensitivity to the loss of heat and water between individual patients. This variability could not be accounted for by differences in body size. When patients inspired air conditioned to body temperature and fully saturated with water vapour, EIA was significantly reduced; however, half the patients still had an attack of asthma following exercise which had induced no significant loss of heat or water. It is suggested that the bronchoconstriction induced by water loss from the airways during exercise may be due to a change in osmolarity in the respiratory tract fluid.

Respiratory heat and water loss during exercise in patients with asthma. Effect of repeated exercise challenge.

A study was performed to investigate the loss of heat and water from the airways during repeated exercise challenge. Twenty-six asthmatic patients performed 6-8 min exercise on a bicycle ergometer at a workload equivalent to 57-85% of their predicted maximum working capacity. Sixteen patients performed two exercise tests separated by 40-52 min. Exercise-induced asthma (EIA) occurred in all patients after initial challenge but eight had significant protection from EIA following a second challenge. This protection was not associated with a reduction in heat and water loss from the airways during exercise. A further 10 patients performed two exercise tests 2-3 h apart. The second test was preceded by the administration of 200 microgram salbutamol aerosol. There was no significant difference between the two tests in loss of heat and water from the airways during exercise. Exercise-induced asthma occurred in all patients after the initial challenge but was inhibited by the salbutamol after the second challenge. Thus the reduction in EIA as a result of a refractory period or in response to aerosol salbutamol is not due to changes in heat and water loss from the airways during exercise.

Pattern and time course of ventilation-perfusion inequality in exercise-induced asthma.

The relation between exercise-induced airway obstruction and changes in the gas exchange function of the lung was studied in 6 subjects with asthma. Continuous distributions of ventilation perfusion (VA/Q) ratios and spirometry were measured before and at intervals after an exercise challenge that caused a greater than 20% decrease in FEV1 or in peak expiratory flow rate (PEFR). Before exercise, all subjects had unimodal VA/Q distributions that were broader than normal (mean log SD of blood flow, 0.54) and all developed wider distributions 15 to 28 min after the start of the 8-min exercise challenge (mean log SD of blood flow, 1.02). Two subjects developed bimodal VA/Q distributions, but all distributions returned to baseline configuration within 58 min, usually before FEV1 and PEFR had returned to baseline values. There was no relation between the decrease in FEV1 or PEFR and the degree of VA/Q inequality. Aerosolized salbutamol resulted in improved spirometry and further narrowing of the VA/Q distributions in 3 subjects tested.

Bronchial hyperreactivity in response to inhalation of ultrasonically nebulised solutions of distilled water and saline.

To assess non-specific bronchial reactivity the effect of inhaling ultrasonically nebulised solutions of distilled water and hypotonic (0.3%), isotonic (0.9%), and hypertonic (2.7%, 3.6%) saline was investigated in 10 asthmatic patients and nine normal subjects. Expired ventilation and the maximum percentage fall in forced expiratory volume in one second (FEV1) were recorded. The sensitivity to the inhaled solutions was determined by measuring the ventilation required to induce a fall in FEV1 of 20% from the prechallenge value. Hypotonic and hypertonic but not isotonic solutions caused a significant fall in FEV1 in the asthmatic subjects. Normal subjects showed no response to either distilled water or 3.6% saline, the only solutions with which they were challenged. The method used for this challenge is rapid, simple, and inexpensive and provides a new means of diagnosing non-immunologically mediated bronchial hyperreactivity.

Effect of aerosol and oral fenoterol on histamine and methacholine challenge in asthmatic subjects.

In order to determine the effect of drugs on bronchial hyperreactivity in subjects with asthma, 12 atopic asthmatic volunteers underwent bronchial challenge with either histamine or methacholine on three separate days. Before the challenges no medication was given on the first day, on the second 400 microgram of aerosol fenoterol and on the third 5 mg of oral fenoterol were administered. The aerosol fenoterol caused the dose response curves to both histamine and methacholine to be shifted to the right in all subjects. The oral dose produced no significant change from the control values. The slope of the dose response curves was not altered by either the oral or the aerosol drug. It is concluded that aerosol but not oral fenoterol in the clinical dosage, causes a change in the sensitivity but not in the reactivity of the airway of patients with atopic asthma.

The protective effect and duration of action of metaproterenol aerosol on exercise-induced asthma.

Ten asthmatic subjects performed two exercise tests two hours apart on two separate days after inhalation of metaproterenol metered dose aerosol (1.5 mg) or placebo. Metaproterenol was effective in preventing exercise-induced asthma when administered 15 minutes before exercise but the duration of this protective effect was less than two hours in most subjects.

Arterial plasma histamine levels at rest, and during and after exercise in patients with asthma: effects of terbutaline aerosol.

Eight asthmatic patients and two normal subjects performed two identical exercise tests 140 minutes apart (first test preceded by inhalation of saline and the second by terbutaline sulphate). A ninth asthmatic patient exercised twice after placebo 40 minutes apart. Arterial plasma levels of histamine and cyclic AMP, expiratory flow rates and volumes were measured at rest and during and after exercise. After the first test the mean +/- SEM fall in PEFR was 45.2 +/- 2.6%. In five asthmatics there was an increase in plasma histamine (mean +/- SEM 14.8 +/- 3.3 pmol ml-1) coinciding with exercise-induced asthma (EIA). Histamine levels returned to pre-exercise values within 30 minutes. After terbutaline these five patients had histamine levels greater than those observed before, during, or after the first test. This effect may have been the result of changes in pulmonary microcirculation. After the second test the levels decreased indicating no further release of histamine in response to exercise. No EIA occurred in these patients after terbutaline. The other patients and the two normal subjects had little or no change in histamine throughout the study. The one patient in whom exercise was repeated after placebo demonstrated less histamine release and less EIA after the second test.

Comparison of bronchial reactivity to histamine and methacholine in asthmatics.

Eight subjects with asthma underwent bronchial challenge with histamine and methacholine. Dose-response curves were drawn on a scale which made the dosage equivalent in molecular weight. The results were analysed in terms of both the slope of the dose-response curve and the dose required to elicit a 20% fall in FEV1. No significant difference between methacholine and histamine was found in either measurement. Because of the similarity of the responses we conclude that the two agents are similar in action and may be used with equal effectiveness in bronchial challenges.

The importance of suspecting sleep apnoea as a common cause of excessive daytime sleepiness: further experience from the diagnosis and management of 19 patients.

Over an 18 month period, 19 patients were referred for assessment of excessive daytime sleepiness and/or loud snoring. Respiratory studies during sleep were performed in 14 of these patients with additional features such as disturbed sleep, observed apnoea during sleep, morning headache, mental and personality changes, hypertension and cardiac failure. Nocturnal respiratory studies undertaken for periods of 4-8 hours confirmed a diagnosis of the Sleep Apnoea Syndrome in eight patients. In these patients apnoeas, lasting from 30-144 seconds, occurred frequently during sleep (from 35-291 episodes per patient). In one severely affected patient, tracheostomy abolished all symptoms. The use of conservative therapy such as weight loss, protriptyline or a neck collar, highlighted the inadequacies of current medical treatment. Awareness of the symptom complex and potential complications of the Sleep Apnoea Syndrome is important because the diagnosis may easily be missed if the patient presents with one or two isolated complaints.