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The frequency with which disagreement occurs between the clinician's diagnosis of asthma and the objective measurement of methacholine airway responsiveness is not known. We have examined this in 51 consecutive new adult patients presenting with symptoms consistent with asthma but with normal spirometry. Disagreement between the physician's assessment and the result of the methacholine test occurred in 20 patients (39%). Of these, 13 had a clinical diagnosis of asthma but normal responsiveness and 7 had an unexpected increase in methacholine responsiveness. There was no difference in the type of symptoms experienced whether or not there was agreement between the test and the physician's assessment. Thus, an objective measurement like a methacholine inhalation test is clinically useful when spirometry is normal. A normal methacholine test in the presence of symptoms suggestive of asthma should alert the physician to the need for further investigation.

Treatment with beclomethasone dipropionate aerosol (BDA), 50 mug four times daily in each nostril, was compared with placebo therapy in a double-blind non-crossover trial of 30 matched patients with allergic rhinitis induced by ragweed pollen. The trial was started at the beginning of the ragweed season and continued for 42 days. Response to treatment was assessed from information on daily diary cards, weekly objective measurements of nasal patency and measurement of total eosinophil count (TEC) before treatment and at week 4. Patients in the BDA group had significantly less (P less than 0.05) sneezing, rhinorrhea and nasal stuffiness at 36 days, cough at 10 days and antihistamine consumption at 17 days. There was no significant difference between the groups in eye symptoms, nasal airway inspiratory resistance, maximum inspiratory nasal flow or TEC. Overall comparison with previous pollen seasons by the patients indicated moderate to great improvement in 86% of the BDA group and in 13% of the placebo group (P less than 0.01). Minor side effects were noted by two patients in each group.

A knowledge of the atmospheric pollen and fungal spores is necessary for the diagnosis and management of extrinsic rhinitis and asthma. The Hirst automatic volumetric spore trap has been used for the first time in Canada to identify the quantitative and seasonal incidence of these particles. The trap is easy to operate and has several advantages over the previously used gravity samplers. Tree, grass and ragweed pollens occurred in short, well-defined seasons. Fungal spores greatly outnumbered pollen by 120 to one, and occurred in long, ill-defined seasons. They included large numbers of small basidiospores and ascospores which have previously not been detected in Canada. The latter have not been considered as potential allergens; their clinical importance requires investigation.

Leukotrienes C4 and D4 may serve as chemical mediators in asthma. Although patients with asthma are known to be hyperresponsive to the bronchoconstrictive effects of histamine and methacholine, whether the same is true for the leukotrienes is controversial. We compared the airway responses to methacholine and to leukotrienes C4 and D4 in 12 asthmatic patients and 6 controls. We found that the patients were more responsive to the leukotrienes than the controls, and we observed a linear correlation between airway response to methacholine and that to leukotriene C4 (r = 0.68, P less than 0.01) and D4 (r = 0.79, P less than 0.001). However, relative to the airway response to methacholine, the response to the leukotrienes was much greater in the controls than in the patients. Furthermore, the asthmatic subjects who were most responsive to methacholine had the lowest relative airway response to both leukotrienes. Thus, the patients with the greatest airway responsiveness to methacholine paradoxically showed the lowest relative airway response to the leukotrienes. In contrast, this difference in relative airway responses has not been observed between methacholine and other bronchoconstrictor mediators, such as histamine. Although no adequate explanation for these observations has yet emerged, our data suggest that leukotrienes C4 and D4 are unique bronchoconstrictors with a possible role in the pathogenesis of asthma.

Isocapnic hyperpnea (ISH) of cold air induces bronchoconstriction in many asthmatic subjects. Although this response is well described, it is unclear whether this bronchoconstriction is related to the release of bronchoactive mediators. We examined whether pretreatment with LY171883, a competitive antagonist of leukotriene D4 activity via LTD4 receptors, reduced the bronchospastic response to cold air ISH in asthmatics using a randomized, double-blind, two-phase crossover design. In 20 subjects, 2 wk of treatment with either LY171883 600 mg twice a day or placebo did not result in a change in FEV1 (3.45 +/- 0.21 L placebo versus 3.59 +/- 0.20 L LY171883; p greater than 0.05). Nineteen subjects underwent cold-air ISH; LY171883 increased the geometric mean respiratory heat loss required to reduce the FEV1 by 20% (PD20RHE) from 1.00 kcal/min with placebo to 1.24 kcal/min with LY171883 (p less than 0.05). A similar difference was noted when responses were expressed as a function of minute ventilation. LY171883 produced greater shifts in the PD20RHE in more reactive subjects (r = 0.69, p less than 0.002). Among 11 different symptom scores recorded by 18 subjects, there was a significant decrease in daytime chest tightness with LY171883 (p less than 0.03). The increase in PD20RHE while the subjects received LY171883 is consistent with the hypothesis that LTD4 becomes available during cold-air ISH and may mediate bronchoconstriction. The small magnitude of the effect on the PD20RHE may be due to the role of other mediators in cold-air-induced bronchoconstriction or, alternatively, to an inadequate blockade of LTD4 effects.

Controlled standardised histamine inhalation tests were carried out in 21 asthmatics to determine the degree of non-specific bronchial hyperreactivity with and without prior treatment with several anti-asthmatic drugs. A significant protective effect was produced by inhaled salbutamol, 200 microgram, ingested salbutamol, 4 mg, inhaled Sch1000, 40 microgram inhaled atropine sulphate, 290 microgram, and ingested choline theophylinate (200 or 400 mg) producing serum theophylline levels over 10 mg/l. Inhaled salbutamol was consistently the most effective and was significantly better than the other drugs. The protective effect between the other four was not significantly different. Drug side-effects occurred only with the ingested drugs. No significant protection was detected after ingested choline theophyllinate producing serum theophylline levels of less than 10 mg/l, inhaled sodium cromoglycate, 20 mg given once or six-hourly for one week, or ingested ascorbic acid, 1 gram.

Observations in two subjects undergoing three allergen challenges for a drug study suggested 'priming' of the late sequelae, namely allergen-induced increase in airway responsiveness. Both subjects had rhinitis and asthma limited to the ragweed season, near normal out-of-season histamine PC20, and extreme IgE sensitivity to ragweed. Both had an isolated early response with no change in histamine PC20 after the first allergen challenge. Significant (3.5- to 5.8-fold) reductions in histamine PC20 occurred after the second and third allergen challenge in Subject 1, and after the third challenge in Subject 2; this was associated with equivocal 5-8% late responses. Such a 'priming' effect, the prevalence of which is not known, may be important in the pathogenesis of naturally occurring allergic asthma, and in the design of clinical trials involving repeated allergen inhalations.

Non-allergic bronchial hyper-reactivity is a feature of most patients with asthma. We have measured non-allergic bronchial reactivity to inhaled histamine and methacholine in thirteen asthmatic subjects before and after allergen inhalation in the laboratory. The allergen inhalation produced mild early asthmatic responses (19-40% FEV1 fall) in all thirteen, additional definite late asthmatic responses (17-29% FEV1 fall) in four, and equivocal late asthmatic responses (5-11% FEV1 fall) in five. Following allergen inhalation, non-allergic bronchial reactivity increased in seven for up to 7 days. The seven included all four with definite late asthmatic responses and three of the five with equivocal late asthmatic responses. We conclude that allergens make asthma worse, partly through non-allergic mechanisms, and that avoidance of allergens is important in reducing non-allergic bronchial hyper-reactivity.

The protective effect was examined of three doses (2, 10, and 20 mg) of sodium cromoglycate inhaled from a pressurised metered dose inhaler on the response to isocapnic hyperventilation of cold dry air in 10 asthmatic subjects. This was compared with the effect of cromoglycate powder (20 mg) inhaled from a Spincap and with placebo given on two occasions. The medications were inhaled on separate days, in random order and with the use of a double blind double dummy technique, 20 minutes before isocapnic hyperventilation of two fold increasing volumes of air (-15 degrees C, 0% humidity) to produce a 20% fall in the post-treatment FEV1. The response was expressed as the provocative dose of respiratory heat loss required to cause a fall in FEV1 of 15% (PD15, kcal/min). The mean baseline spirometric indices exceeded 85% of predicted normal values on each test day; both placebo treatments reduced the baseline FEV1 by comparison with all active treatments (p less than 0.0001). Comparison of the PD15 on the two placebo days confirmed excellent reproducibility. All doses of cromoglycate shifted the respiratory heat loss dose-response curve to the right of the placebo curve; PD15 after all active treatments exceeded PD15 after placebo (p less than 0.0001). There was no cromoglycate dose-response relationship between the three doses of aerosol (p greater than 0.05), or between any dose of aerosol and powder (p greater than 0.05). It is concluded that cromoglycate aerosol inhaled from a pressurised inhaler in a dose of 2 mg gives the same magnitude of protection against bronchoconstriction stimulated by airway cooling as 20 mg of pressurised aerosol or powder from a Spincap.

In order to test the possibility that airway dilation following lung inflation (ADFLI) could exhibit habituation, partial and complete maximum expiratory flow-volume curves were obtained in 12 healthy individuals before and after inhaling methacholine aerosol in a dose that reduced in each individual the partial expiratory flows to approximately 50% of baseline values. Following methacholine inhalation, the difference in flows between complete and partial flow-volume curves at 40% VC was 64 +/- 22% (mean +/- SD) of partial curves after a single full lung inflation and 79 +/- 36% after 12 consecutive full inflations (p = NS). The absence of demonstrable habituation (tachyphylaxis) of ADFLI makes it unlike that ADFLI is due to a release of mediators and supports the view that it may be due to the intrinsic properties of the airway smooth muscle.

The relationship between transnasal pressure and nasal flow is markedly curvilinear during tidal breathing in man, and there is poor agreement among the results of various methods used to define this characteristic with a single number. We used Rohrer's equation (P = K1 V + K2 V2), where P = pressure and V = flow, and calculated values for K1 and K2 from 474 nasal inspiratory pressure/flow curves obtained from 34 human subjects by a standard method of posterior rhinometry. Nasal airway inspiratory resistance at an air flow of 0.4 liter per sec (NAIR0.4) was also calculated. Rohrer's equation was found by regression analysis to fit each curve well (0.86 less than r less than 0.9999; mean, 0.983). There was a strong correlation between NAIR0.4 and K2: NAIR 0.4 = 0.91 K2 + 0.39 (r = 0.97). Nasal congestion induced in 7 normal subjects with histamine resulted in larger changes in K2 and NAIR0.4 than K1. Patients given an intranasal corticosteroid aerosol (beclomethasone dipropionate) in a double blind crossover trial showed symptomatic improvement in nasal congestion (P less than 0.01) and significant decreases in K2 (P less than 0.02) and NAIR 0.4 (P less than 0.05), but no change in K1 (P greater than 0.2).

Immediate asthmatic responses have been regarded as the characteristic type of asthmatic response to follow exposure to inhaled allergens in patients with extrinsic asthma. They begin within minutes, clear within one to three hours and are inhibited by disodium cromoglycate but not by corticosteroids. They involve the reaction of antigen with antibodies usually of the IgE class. In recent years allergen inhalation tests have demonstrated the frequent occurrence of late asthmatic responses, either following immediate responses (dual responses) or occurring in isolation. The late asthmatic responses begin two to six hours after the allergen challenge, are prolonged and often severe, and are inhibited by both disodium cromoglycate and corticosteroids. The mechanisms involved in their provocation are not clearly understood but from the allergic viewpoint they may involve the participation of IgG +/- IgM antibodies and/or IgE antibodies. Late asthmatic responses explain the frequent occurrence of allergen-induced prolonged asthma. Their features suggest that they are more important than immediate responses in the pathophysiology of asthma.

An easy and safe dose-response histamine-inhalation test is described, to measure the level of non-specific bronchial reactivity. The test was performed in 307 subject. Non-specific bronchial reactivity was increased in 3% of presumed normal subjects, in 100% of active asthmatics and in 69% of asymptomatic asthmatics with previous symptoms only at times of exposure to clinically relevant allergens. It was also increased in 47% of patients with cough and no other chest symptoms, in 40% of patients with rhinitis and vague chest symptoms not by themselves diagnostic of asthma, and in 22% of patients with rhinitis and no chest symptoms. The patients with asthma were studied when their asthma was well controlled and when their minimum drug requirements had been established. The mean level of bronchial reactivity increased with increasing minimum drug requirements. The level of bronchial reactivity also showed a strong negative correlation with the forced expiratory volume in 1 sec (FEV1). Atopic subjects, with or without asthma, showed a significant positive correlation between the level of bronchial reactivity and atopic status as indicated by the number of positive allergy skin tests.

The pattern of asthmatic response after inhalation of atropine and methacholine was studied in six adult asthmatics. After pretreatment with atropine, the provocation concentration of methacholine to cause a fall in FEV1 of 20% was increased from 0.66 +/- 2.09 to 94.90 +/- 1.78 mg/ml. In the subsequent 7 hr, four subjects developed prolonged asthmatic responses. These occurred after concentrations of methacholine higher than those used clinically but did not directly relate to the dose of methacholine or to the increase in dose after atropine. In one subject the prolonged response was not accompanied by increased methacholine responsiveness and was not prevented by pretreatment with cromolyn sodium (40 mg). These results show that high doses of methacholine inhaled after pretreatment with atropine can induce prolonged asthmatic responses but the mechanism is unclear.

In the myometrium and gut, smooth muscle becomes less contractile during pregnancy, probably because of the effect of progesterone and estrogen. It is not known whether these hormones cause similar changes in airway smooth muscle, and therefore, this study examined airway responsiveness during the large hormonal changes of pregnancy and evaluated whether changes in responsiveness are associated with changes in (1) progesterone and estrogen and (2) the clinical severity of asthma. Twenty nonpregnant asthmatic women were assessed every 3 months until conception. In the 16 who conceived, assessments were repeated once during the second and third trimesters and 1 month after delivery. Data collected preconception and from those who did not conceive within 1 yr were used for control subjects. There was a 2-fold improvement in airway responsiveness during pregnancy from a preconception mean PC20 0.35 to 0.72 mg/ml during the second trimester and 0.58 mg/ml during the third (p = 0.03). Post-delivery responsiveness (0.48 mg/ml) was not significantly different from preconception. The improvements during pregnancy were greater than the 3 monthly fluctuations when not pregnant (p = 0.04) and were greatest in those who were most hyperresponsive initially (p = 0.01). There was an associated improvement in clinical asthma severity as indicated by a reduction in minimum medication requirements (p = 0.03) and this was not at the expense of good symptoms control; both symptoms and spirometry remained unchanged during pregnancy. Changes in responsiveness were not closely related to progesterone or estriol, suggesting that other nonhormonal factors may also contribute to the improvement during pregnancy and that the control of asthmatic airway smooth muscle may not be exactly the same as that of the myometrium and gut.

In the treatment of asthma salbutamol can be administered as an aerosol with a metered-dose inhaler or as a powder with a breath-actuated device (Rotahaler). The two forms of the drug were compared in a double-blind placebo-controlled study involving 10 asthmatic adults who were known to respond to salbutamol. The bronchodilating effect of the aerosol and the powder at doses of 200 micrograms and of the powder at doses of 200 and 400 micrograms was compared, bronchodilation being measured in terms of forced expiratory volume and vital capacity. The response was far greater to salbutamol than to placebo, but there was no significant difference between the two forms of the drug or between the lower and higher doses of powder. No side effects were observed.

Programs designed for the control of asthma are complex. Implementation of a number of modalities may be necessary, and the mean and level of treatment may need to be varied from time to time. Medical treatment is a primary concern but preventive measures and education of the family are essential as well.

Exacerbations of symptoms have been reported in some women with asthma just prior to and during menstruation. We examined changes in airway responsiveness to methacholine during 2 consecutive menstrual cycles in 17 well-controlled asthmatics with a wide range of airway responsiveness. In 10 women with regular natural cycles, measurements were made 1 wk before and 1 wk after the start of menstruation to coincide with the highest and lowest progesterone levels. The mean concentration of methacholine to cause a fall in FEV1 of 20% (PC20) premenstruation was 1.49 mg/ml, which was not significantly different from the mean postmenstruation PC20 of 1.34 mg/ml (p = 0.45). Although there were only 10 subjects, the power was 96%, indicating little likelihood of any difference between the 2 phases. In 7 women taking oral contraceptives, the mean PC20, measured within 1 wk of completing a 21-day course, was 1.19 mg/ml, which was not different from the mean PC20 of 0.97 mg/ml measured after the start of menstruation but before restarting medication (p = 0.17). The power was 98%. In both groups, there was no difference in FEV1 or medication use during the cycle, but symptoms were worse during menstruation. The results suggest that the fluctuations in serum progesterone levels that occur during natural menstrual cycles are insufficient to alter airway responsiveness in an unselected sample of asthmatic women. They also demonstrate that changes in symptoms occur during the cycle both in women with natural cycles and those using contraceptives and that these changes are not related to serum progesterone levels or airway responsiveness.

A series of workers with exposure to and respiratory symptoms from toluene diisocyanate (TDI) was compared with a group of exposed, asymptomatic workers and with normal controls using immunologic and clinical evaluations. Improved understanding of TDI-induced respiratory disease may best be achieved by categorizing the symptomatic workers into at least 3 and possibly 4 groups: immunologic TDI asthma; pre-existing chronic respiratory disease exacerbated or unaffected by TDI; asthma coincidental with TDI exposure, and possibly TDI respiratory disease secondary to toxic or inflammatory mechanisms.

Recent advances in the use of inhalation provocation tests in the clinical evaluation of asthma have been made with methacholine and histamine tests. The tests can be better standardized and the results more accurately interpreted. The ease of stimulation of bronchoconstriction by methacholine and histamine (bronchial responsiveness) relates closely to the presence and the degree of variable airflow obstruction that occurs spontaneously or is triggered by natural stimuli. Responsiveness can be heightened by bronchial infection and by exposure to allergens or sensitizing chemicals, such as toluene diisocyanate, and can be reduced by treatment. These observations indicate three uses of the tests in clinical practice. First, they can be used to validate the presence of hyperresponsiveness which, when spirometric study is normal, is synonymous with the presence of asthma. Second, they can be used to quantify the severity of hyperresponsiveness which relates closely to the amount of bronchodilator required to treat asthma. Finally, they can be used to measure a change in responsiveness, which is useful to document occupational asthma (defined as hyperresponsiveness caused by materials at work), and to optimize the treatment required to reverse or reduce hyperresponsiveness as much as possible.

Extrinsic allergic alveolitis is caused by the inhalation of small organic allergen particles by non-atopic subjects which provoke an allergic reaction, thought to be chiefly due to a type III mechanism, in the peripheral respiratory tissues. The clinical features are determined by the nature of exposure, the immunopathological mechanism(s) involved and the site of reaction in the lung. When the exposure is intermittent and intensive, febrile episodes with respiratory symptoms beginning after four to six hours are prominent, but when it is more continuous and less intensive they are not and the features are those of a chronic fibrosing lung disease. The diagnosis is important to make because management by the avoidance of exposure is followed by improvement. It is made by recognizing the clinical presentation, by identifying the source of allergen exposure and by obtaining supportive evidence from precipitin and skin tests, or from allergen inhalation tests or lung biopsy.