Effects of diurnal variation and prolonged refractoriness on repeated measurements of airways responsiveness to methacholine.

BACKGROUND--A number of studies have suggested that diurnal variation in airways responsiveness underlies the circadian rhythm of ventilatory function in asthma. Measurements of airways responsiveness are therefore often performed at standardised times in order to avoid this possible effect, but this is not practical for epidemiological studies. Refractoriness to methacholine has also been reported and this, too, could confound the results of methacholine tests repeated over short intervals. This investigation was carried out to evaluate the possible magnitude of diurnal variation and refractoriness in repeated measures of airways responsiveness to methacholine. METHODS--To investigate diurnal variation in airways responsiveness, 24 asthmatic subjects aged 18-45 underwent five methacholine tests over three days which were not necessarily consecutive: day 1 at 08:00 hours; day 2 at 08:00 hours, 14:00 hours, 20:00 hours; day 3 at 20:00 hours. To investigate refractoriness a retrospective analysis was undertaken of all paired methacholine tests performed in individuals within our unit between 1984 and 1990 where there had been no intervention likely to affect the results. RESULTS--The first investigation revealed no diurnal change in airways responsiveness although there was a change in FEV1. Mean PD20 did, however, increase 1.57 fold from 08:00 hours on day 1 to 08:00 hours on day 2 for subjects studied on consecutive days. The second investigation confirmed that a test interval of up to 24 hours (but not of 48 or more hours) was associated with a refractory index (PD20 test 2/PD20 test 1) of > 1. CONCLUSIONS--No diurnal variation in airways responsiveness was detected for measurements made between 08:00 hours and 20:00 hours, but an interval between successive tests of up to 24 hours was associated with refractoriness. Diurnal variation is not likely to exert an important confounding effect on methacholine tests carried out between 08:00 hours and 20:00 hours, but confounding could result from refractoriness if tests are repeated at intervals up to 24 hours.     

Beta-blockers in bronchial asthma: effect of propranolol and pindolol on large and small airways.

In 11 asthmatic subjects the relative magnitude and the site of airway bronchoconstriction were compared after the oral administration of 40 mg of propranolol and 2.5 mg of pindolol and the magnitude and site of bronchodilation produced by 0.5 mg subcutaneous terbutaline were tested after pretreatment with propranolol and pindolol. Specific airway conductance (sGaw) and peak expiratory flow rate (PEFR), both believed to reflect changes in large airways, and capacity isoflow (Ciso-v) and delta Vmax50, both believed to reflect changes in small airways, were determined before and after administration of placebo, pindolol, and propranolol. Treatments were given double blind and in random order. After the administration of propranolol we noted a significant bronchoconstrictive effect in the large airways (mean values of PEFR and sGaw, expressed as percentages of control values, decreased by 87.4% +/- 13.2% and 43.3% +/- 8.9%) and in the small airways (mean value of Ciso-v increased by 20.6% +/- 4.7% and that of delta Vmax50 decreased by 50% +/- 11.9% of control). By contrast, pindolol produced no significant effect on sGaw or PEFR but the tests of small airway function showed significant bronchoconstriction (mean values of Ciso-v increased by 12.9% +/- 2.6% and those of delta Vmax50 decreased by 47.2% +/- 9.2%). This action makes pindolol potentially dangerous in asthmatic patients. The bronchodilator action of terbutaline on large airways is diminished after the use of both propranolol and pindolol.     

Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects.

Short term variability in FEV1 and responsiveness to inhaled bronchodilator were measured in 150 patients with obstructive ventilatory defects. The range of initial FEV1 was 0.5-4.71 and the natural variability over a 20 minute period when expressed in absolute terms was similar over the entire range, and differed insignificantly from that found in normal subjects. The increase in FEV1 and vital capacity (VC) required to exclude natural variability with 95% confidence in these patients was 160 ml and 330 ml respectively. Natural variability when expressed in percentage terms was negatively correlated with the level of FEV1 recorded. The analysis of changes in FEV1 and VC after administration of bronchodilator used absolute and percentage criteria for response. The number of responders differed considerably according to the criterion used. In those defined by the absolute criterion as responders there was no evidence that size of response was related to level of FEV1. Percentage criteria have traditionally been used to identify responses to bronchodilator that may be clinically useful, while absolute criteria, although statistically valid, have not been favoured. Reappraisal of the criteria used and their limitations and implications is required.     

Characterisation of bronchoconstrictor responses to sodium metabisulphite aerosol in atopic subjects with and without asthma.

Inhalation of sodium metabisulphite is thought to induce bronchoconstriction by release of sulphur dioxide. We sought to establish the reproducibility of the airway response to inhaled sodium metabisulphite given in increasing doubling concentrations (0.3 to 160 mg/ml) to 13 asthmatic and five atopic non-asthmatic subjects and the contribution of cholinergic mechanisms to this response. In 15 of the 18 subjects bronchoconstriction was sufficient to allow calculation of the dose of metabisulphite causing a 20% reduction in the forced expiratory volume in one second (FEV1) from baseline values (PD20 metabisulphite). The 95% confidence limit for the difference between this and a second PD20 metabisulphite determined 2-14 days later was 2.5 doubling doses. The difference between repeat PD20 metabisulphite measurements was unrelated to the number of days between challenges or change in baseline FEV1. Ten subjects returned for a third study 3-120 days after the second challenge; variability in PD20 metabisulphite did not differ from that seen between the first and second challenges. PD20 methacholine was determined between the two metabisulphite challenges and found to correlate with PD20 metabisulphite (r = 0.71). Inhaled ipratropium bromide 200 micrograms given in a randomised, placebo controlled, crossover study to 10 subjects increased PD20 methacholine 42 fold but had no significant effect on the response to metabisulphite. A single inhalation of the PD20 metabisulphite in five subjects induced maximal bronchoconstriction 2-3 minutes after inhalation, with a plateau in FEV1 lasting a further four minutes before recovery. A further single inhalation of the same PD20 dose 43 minutes later produced a 27% (SEM 4%) smaller fall in FEV1 than the first inhalation. These results show that metabisulphite PD20 values measured over days and weeks show similar reproducibility to those reported for histamine inhalation and that PD20 metabisulphite correlates with methacholine responsiveness. Most of the bronchoconstriction is not inhibited by antimuscarinic agents; the underlying mechanisms require further investigation.     

Ketotifen in atopic asthma and exercise-induced asthma.

The efficacy of ketotifen, a tricyclic benzocycloheptathiophene derivative, was assessed in an outpatient clinical trial and in a group of 12 asthmatic subjects with exercise-induced asthma. Subjects in the outpatient trial had mild asthma and consisted of two groups: a group of 24 atopic asthmatics with at least one positive skin test reaction and with an associated history of bronchial reactivity to at least one allergen; and a group of eight asthmatics with one or more positive skin prick tests but not bronchial reactivity to an allergen. Both groups took four weeks medication of ketotifen 1 mg bd and placebo in a randomised double-blind crossover study. There was no difference between ketotifen and placebo for any measurement made during the study and consequently no evidence of drug efficacy. The exercise study followed a standardised protocol and each subject took in random double-blind order, placebo, 1 mg, 2 mg, and 4 mg ketotifen two hours before exercise. There was no difference in the mean decreases in lung function from pre-exercise baseline values after three doses of ketotifen than with placebo. Drug levels suggested ketotifen was well absorbed. It would appear that if given for a period of only four weeks ketotifen had no beneficial effects in the management of mild asthma, and that a single dose before exercise does not modify exercise-induced asthma.     

Effects of air pollution on symptoms and peak expiratory flow measurements in subjects with obstructive airways disease.

BACKGROUND--Evidence from laboratory studies suggests that air pollution can produce bronchoconstriction and respiratory symptoms in selected subjects, but the relevance of these findings to exposure to natural pollution is unclear. This study was performed to determine whether air pollution at typical levels found in the UK has demonstrable effects on respiratory function and symptoms in subjects with airways disease. METHODS--Seventy five adult patients with diagnoses of asthma or chronic obstructive pulmonary disease (COPD) were studied for a period of four weeks during which they kept records of their peak expiratory flow (PEF) rates, symptoms (wheeze, dyspnoea, cough, throat and eye irritation), and bronchodilator use. Thirty six patients in whom the provocative dose of methacholine causing a 20% fall in FEV1 was below 12.25 mumol were classified as reactors. Ambient air pollution was measured with absorption spectroscopy. RESULTS--There were modest but significant increases in PEF variability, bronchodilator use, and wheeze with increasing sulphur dioxide levels; bronchodilator use, dyspnoea, eye irritation, and minimum PEF readings were related to ozone levels. In the subgroup of reactors falls in mean and minimum peak flow and increases in wheeze, dyspnoea, and bronchodilator use were associated with increases in levels of both sulphur dioxide and ozone. Some associations were seen with pollution levels on the same day, but for others the pollution effects appeared to be delayed by 24 or 48 hours. Pollution levels did not breach the WHO guide levels during the course of the study. CONCLUSIONS--Increases in environmental levels of ozone and sulphur dioxide are associated with adverse changes in peak flow measurements and both ocular and respiratory symptoms in subjects with obstructive airways disease. Although the peak flow and symptom changes were modest, they occurred at pollution levels below current WHO guide levels.     

Effect of dietary sodium on airways responsiveness and its importance in the epidemiology of asthma: an evaluation in three areas of northern England.

BACKGROUND--Although several investigations have shown a relationship between asthma (or its surrogate, airways responsiveness) and dietary or urinary sodium, others have not, and the matter remains controversial. This "salt effect" has been investigated during two recent epidemiological surveys of men in northern England. The first assessed the possible effect on airways responsiveness of occupational exposure to welding fumes, and the second characterised airways responsiveness in two geographically distinct residential areas. Thus, three separate study areas/populations were involved. METHODS--Investigation 1 involved 1059 shipyard workers aged 16-27 years who were exposed variously to welding fumes, and Investigation 2 involved 587 men aged 20-44 years who lived in rural West Cumbria or in urban Newcastle upon Tyne. In Investigation 1, a 24 hour urine specimen was requested from each subject with quantifiable airways responsiveness (PD20 < or = 6400 micrograms methacholine) and from an equal number of subjects without measurable airways responsiveness from the same occupational subgroup. In Investigation 2, every subject was asked to provide a 24 hour urine specimen. RESULTS--Of the men undergoing methacholine tests, satisfactory 24 hour urine specimens were obtained from 234 (22.1%) in Investigation 1 and 232 (39.5%) in Investigation 2. Analysis using multiple linear regression, multiple linear logistic regression, and multiple regression for censored data produced consistent results within each study population but conflicting results between them, such that there was no hint of a relationship between airways responsiveness and 24 hour urinary sodium excretion in the shipyard workers of Investigation 1 nor in the rural West Cumbrian population of Investigation 2, but an association was found in the urban Newcastle population of Investigation 2. All study populations were sufficiently large to demonstrate anticipated relationships between airways responsiveness and atopy, baseline FEV1, and (Newcastle only) age. CONCLUSIONS--If airways responsiveness is related to dietary sodium the relationship is not likely to be strong.     

Relation of the hypertonic saline responsiveness of the airways to exercise induced asthma symptom severity and to histamine or methacholine reactivity.

BACKGROUND: Conflicting views exist over whether responsiveness of the airways to hypertonic saline relates to non-specific bronchial hyperresponsiveness measured by histamine or methacholine challenge. The bronchoconstrictor responses to exercise and hypertonic saline are reported to be closely related, but the relationship between the symptoms of exercise induced asthma and airway responsiveness to hypertonic saline is not known. METHODS: In 29 asthmatic patients with a history of exercise induced asthma, the response to an ultrasonically nebulised hypertonic saline (3.6% sodium chloride) aerosol, measured as the volume of hypertonic saline laden air required to produce a fall in forced expiratory volume in one second (FEV1) of > or = 20% (PD20), was compared with the concentration of histamine (PC20; group 1) and methacholine (PC20; group 2) producing a 20% fall in baseline FEV1 and exercise induced asthma symptom severity score (groups 1 and 2). The hypertonic responsiveness was determined in a dose-response manner to a maximum dose of 310 1 and the exercise induced asthma symptom severity was scored on a scale of 0-5. RESULTS: Of the 29 patients, 23 (79%) were responsive to the hypertonic saline, with PD20 values ranging from 9 to 310 1. A significant correlation was found between the PD20 hypertonic saline and the exercise induced asthma symptom score. There was no significant correlation between the PD20 response to hypertonic saline and the histamine PC20 or methacholine PC20. The exclusion of those subjects who failed to respond to hypertonic saline improved the relationship between hypertonic saline and methacholine PC20. No significant correlation was found between the exercise induced asthma symptom score and histamine PC20 or methacholine PC20. CONCLUSION: These findings suggest that hypertonic saline responsiveness bears a closer relationship to the severity of exercise induced asthma symptoms than to the non-specific bronchial hyperresponsiveness measured by histamine or methacholine reactivity.     

Activated memory T helper cells in bronchoalveolar lavage fluid from patients with atopic asthma: relation to asthma symptoms, lung function, and bronchial responsiveness.

BACKGROUND: Bronchial mucosal inflammation and epithelial damage are characteristic features of asthma. Activation of T helper lymphocytes may contribute to this process by mechanisms including the release of cytokines promoting eosinophil infiltration and activation. METHODS: Bronchial washings and bronchoalveolar lavage fluid were obtained from 29 atopic asthmatic patients (19 with current symptoms and 10 symptom free) and 13 normal volunteers. Flow cytometry was used to assess T cell phenotype and activation status in bronchoalveolar lavage fluid and peripheral blood, and differential cell counts were made on bronchial washings and bronchoalveolar lavage fluid. Findings were related to severity of disease as reflected by symptom scores, baseline lung function, and airway responsiveness. RESULTS: CD4 T lymphocytes in bronchoalveolar lavage fluid and blood from asthmatic patients were activated by comparison with controls (CD4 CD25, median 16.8% v 8.7% for bronchoalveolar lavage fluid, and 15.3% v 8.7% in blood). Bronchoalveolar lavage fluid CD4 T cells from both asthmatic patients and controls were of memory phenotype (95.8% and 96.8% CD45RO and 1.7% and 0.4% CD45RA respectively), whereas both CD45RO and CD45RA T cells were present in blood. Patients with asthma and current symptoms showed increased bronchoalveolar T cell activation compared with patients without symptoms (CD4 CD25 18.7% v 12.3%). Within the asthmatic group there was a significant association between CD4 CD25 lymphocytes and asthma symptom scores (rs = 0.75), airway methacholine responsiveness (log PC20, rs = -0.43) and baseline FEV1 (rs = -0.39). A correlation was also found between CD4 CD25 lymphocytes and eosinophils in bronchoalveolar lavage fluid (rs = 0.48). Eosinophils in bronchoalveolar lavage fluid were increased in asthmatic patients compared with controls and the percentage of eosinophils in bronchoalveolar lavage fluid correlated with asthma symptom score. A relation was found between percentage of epithelial cells in bronchoalveolar lavage fluid and FEV1 and methacholine PC20. CONCLUSION: These results support the hypothesis that selective activation of memory CD4 T cells contributes to eosinophil accumulation, bronchial hyperresponsiveness, and symptoms in asthma.     

Beta-adrenergic function in airways of healthy and asthmatic subjects.

We measured the short-term effects of beta-adrenergic blockade with propranolol (0.2 mg/kg iv), followed by stimulation with salbutamol (200 mug inhaled), on specific airway conductance (SGaw) heart rate, and systemic blood pressure (BP) in 11 healthy subjects, and 11 symptom-free asthmatics with normal lung function values. Propranolol induced a significant bronchoconstrictor effect in both groups, stronger in asthmatics than in normals: mean SGaw decreased 34.6 +/- 25% against 9.4 +/- 9% (p less than 0.01). Six of the 11 asthmatics exhibited a more pronounced bronchoconstriction than the most responsive healthy subject. Large individual variations were seen in both groups although they were greater in the asthmatics. A similar rise in SGaw was produced by salbutamol in both groups. The decrease of heart rate provoked by propranolol was similar in the two groups, averaging 18.6%, with no further change after salbutamol. The blood pressure was slightly decreased by propranolol in both groups. The results indicate that normal subjects have a weak and variable bronchodilator beta-adrenergic activity. In most asthmatics beta-adrenergic tone appeared more pronounced. The individual differences in response to propranolol observed in both groups suggest that asthmatic patients differ quantitatively rather than qualitatively from healthy subjects with respect to beta-adrenergic receptor function. There was no association between clinical findings and the degree of bronchomotor effect of propranolol in the patients with asthma. This study does not support the view that airways of asthmatic patients have a decreased beta-adrengeric receptor function.     

Characteristics of wheeze during histamine-induced airways obstruction in children with asthma.

BACKGROUND--An automated system has been developed for the detection of sound patterns suggestive of airways obstruction in long term recordings. The first step, presented here, was tracheal sound recording during histamine-induced airways obstruction. METHODS--The tracheal sounds of 29 children aged 8-19 years with asthma were recorded during airways obstruction caused by histamine inhalation using a system for continuous respiratory telemetry and computer analysis. Sound patterns were analysed, classified, and related to airways obstruction measured by lung function tests based on the forced expiratory volume in one second (FEV1). RESULTS--Five sound patterns were identified, one dominant sensitive and four specific to a fall in FEV1 of > 20%. The presence of at least one of three specific sound patterns during unforced respiration predicted a fall in FEV1 of > 20% in 87.5% of the subjects. The inspiratory and expiratory sound patterns were almost equally informative of airways obstruction. CONCLUSIONS--Wheezes can be differentiated with more precision than is currently accepted. Tracheal sound patterns are sensitive and specific predictors of histamine-induced airways obstruction. These patterns are neither invariably nor proportionally related to the results of lung function testing. However, they can be used for detection of airways obstruction on the basis of their presence or absence.     

Evaluation of asymptomatic subjects with low forced expiratory ratios (FEV1/VC).

BACKGROUND--Heightened bronchial hyperreactivity is frequently associated with airflow limitation, atopy, or cigarette smoking. The purpose of this study was to evaluate healthy subjects with significantly low values of forced expiratory volume in one second/vital capacity % (FEV1/VC%) by measuring their airway response to exercise and methacholine challenge, compared with a control group with normal spirometric values. METHODS--Eighty four healthy subjects with significantly low flow rates (group A, FEV1/VC% < 2 SD% predicted) were evaluated and compared with 37 subjects with normal flow rates (group B). Static lung volumes, spirometric tests, exercise, and methacholine challenges were performed. RESULTS--Lung volumes were normal for both groups. Mean FEV1/VC% was 69% for group A and 82% for the control group. Salbutamol improved baseline FEV1 in eight subjects in group A (mean 15%), while methacholine induced a drop in FEV1 in 12 subjects. The dose-response curve to methacholine reached a plateau in all the responders. None of the subjects in the control group improved their baseline FEV1/VC% to salbutamol, but three showed bronchial hyperreactivity similar to those in group A. CONCLUSIONS--Bronchial hyperreactivity does not occur more often in asymptomatic subjects with mildly low FEV1/VC% so these subjects do not require special investigations for airway disease.     

Comparison of circadian variations using FEV1 and peak expiratory flow rates among normal and asthmatic subjects.

BACKGROUND--Most studies that describe circadian variations in asthma have used maximum rate of peak expiratory flow (PEF) rather than forced expiratory volume in one second (FEV1) to assess airway calibre. This study was designed to assess circadian variations in PEF and FEV1 measured simultaneously and to compare variations in these measurements in normal and asthmatic subjects in a stable clinical state. METHODS--Twenty nine subjects (nine asthmatic subjects on bronchodilators, 10 on inhaled steroids, and 10 normal controls) were asked to record their PEF and FEV1 with a new portable instrument every two hours during the day and once on waking at night for two weeks. Circadian variations were examined in different ways using arithmetical indices and cosinor analysis. RESULTS--78% of PEF values and 75% of FEV1 values were considered to be reproducible and were included in the analysis. Variations obtained using PEF did not differ from those obtained using FEV1. Significant cosinor variations were found in at least 50% of recording days for most of the subjects and showed the same features as for arithmetical indices. Daily variations in PEF and FEV1 were significantly correlated with airway calibre and PC20 methacholine (r approximately 0.5 to approximately 0.6). CONCLUSIONS--PEF is as satisfactory as FEV1 for describing circadian variations among normal subjects and stable asthmatic subjects.     

Measurement of responsiveness to inhaled histamine using FEV1: comparison of PC20 and threshold

Two methods of interpreting histamine inhalation dose-response curves were compared in 27 normal and 41 asthmatic subjects. The histamine provocation concentration producing a 20% fall (PC20) in forced expiratory volume in one second (FEV1) was calculated on the basis of the lowest FEV1 after inhalation of saline and the lowest value after inhalation of histamine. The histamine threshold was determined as the first histamine concentration causing the FEV1 to fall more than 2 SD below the mean of five pre-histamine (three pre-saline, two post-saline) FEV1 determinations. The PC20 was on average one doubling concentration larger than the threshold. The PC20 provided better discrimination between asthmatic and normal subjects than did the histamine threshold and was significantly more reproducible. These findings suggest that the histamine threshold may prove useful for studies on populations, particularly those with a low degree of responsiveness to histamine, because of the possibility of measuring a response at a lower histamine concentration. On the other hand, the PC20 is preferable for clinical use in individuals because of its better discriminating power and better reproducibility.     

Mid-expiratory flow versus FEV1 measurements in the diagnosis of exercise induced asthma in elite athletes

BACKGROUND: A fall in FEV(1) of > or =10% following bronchoprovocation (eucapnic voluntary hyperventilation (EVH) or exercise) is regarded as the gold standard criterion for diagnosing exercise induced asthma (EIA) in athletes. Previous studies have suggested that mid-expiratory flow (FEF(50)) might be used to supplement FEV(1) to improve the sensitivity and specificity of the diagnosis. A study was undertaken to investigate the response of FEF(50) following EVH or exercise challenges in elite athletes as an adjunct to FEV(1). METHODS: Sixty six male (36 asthmatic, 30 non-asthmatic) and 50 female (24 asthmatic, 26 non-asthmatic) elite athletes volunteered for the study. Maximal voluntary flow-volume loops were measured before and 3, 5, 10, and 15 minutes after stopping EVH or exercise. A fall in FEV(1) of > or =10% and a fall in FEF(50) of > or =26% were used as the cut off criteria for identification of EIA. RESULTS: There was a strong correlation between DeltaFEV(1) and DeltaFEF(50) following bronchoprovocation (r = 0.94, p = 0.000). Sixty athletes had a fall in FEV(1) of > or =10% leading to the diagnosis of EIA. Using the FEF(50) criterion alone led to 21 (35%) of these asthmatic athletes receiving a false negative diagnosis. The lowest fall in FEF(50) in an athlete with a > or =10% fall in FEV(1) was 14.3%. Reducing the FEF(50) criteria to > or =14% led to 13 athletes receiving a false positive diagnosis. Only one athlete had a fall in FEF(50) of > or =26% in the absence of a fall in FEV(1) of > or =10% (DeltaFEV(1) = 8.9%). CONCLUSION: The inclusion of FEF(50) in the diagnosis of EIA in elite athletes reduces the sensitivity and does not enhance the sensitivity or specificity of the diagnosis. The use of FEF(50) alone is insufficiently sensitive to diagnose EIA reliably in elite athletes.     

Effects of inhaled tumour necrosis factor alpha in subjects with mild asthma

BACKGROUND: Inhaled tumour necrosis factor alpha (TNF alpha) has previously been shown to induce airway neutrophilia and increased airway reactivity in normal subjects. It was hypothesised that a similar challenge would increase airway reactivity in those with mild asthma, but that the inflammatory profile may differ. METHODS: Ten mild asthmatic subjects were recruited on the basis of clinical asthma and either a sensitivity to methacholine within the range defined for asthma or a 20% improvement in forced expiratory volume (FEV(1)) after 200 micro g salbutamol. Subjects inhaled either vehicle control or 60 ng recombinant human (rh)TNF alpha and were studied at baseline, 6, 24, and 48 hours later. Variables included spirometric parameters, methacholine provocative concentration causing a 20% fall in FEV(1) (PC(20)), induced sputum differential cell count, relative sputum level of mRNA of interleukins (IL)-4, IL-5, IL-9, IL-14, IL-15 and TNF alpha, and the exhaled gaseous markers of inflammation, nitric oxide and carbon monoxide. RESULTS: PC(20) showed an increase in sensitivity after TNF alpha compared with control (p<0.01). The mean percentage of neutrophils increased at 24-48 hours (24 hour control: 1.1 (95% CI 0.4 to 2.7) v 9.2 (95% CI 3.5 to 14.9), p<0.05), and there was also a rise in eosinophils (p=0.05). Relative levels of sputum mRNA suggested a rise in expression of TNF alpha, IL-14, and IL-15, but no change in IL-4 and IL-5. Spirometric parameters and exhaled gases showed no significant change. CONCLUSION: The increase in airway responsiveness and sputum inflammatory cell influx in response to rhTNF alpha indicates that TNF alpha may contribute to the airway inflammation that characterises asthma.