Methacholine Inhalation Research Articles

Infección por el virus respiratorio sincitial y asma

Presentation of bronchial asthma, in the years following the first outbreak of bronchiolitis due to respiratory syncytial virus (RSV) was first described by McIntosh, who postulated a common pathogenesis that was confirmed by the greater frequency (50%) of wheezing bronchiolitis and asthma during the more than 5 year follow up of these children. More recently, Hibbert and Schroechkenstein have again confirmed this phenomenon. These authors report that the percentage of asthma was increased by up to 71% in a group of children who contracted bronchiolitis during the first year of life and who were closely followed-up for 5 years after the outbreak. Other authors report figures between 25% and 57%. Stein et al. followed-up 888 children with RSV bronchiolitis until the age of 13 years and observed that at the age of 3-5 years 69% had asthma, at 4-5 years 55% did so and at 6-8 years 31% were asthmatic. In our experience of children who developed RSV bronchiolitis before the age of 6 months, 58 of 75 developed infantile asthma in following 3 years. Seventeen infants were aged more than 6 months at onset of bronchiolitis and of these 5 had bronchiolitis. We carried out a prospective study of 50 children aged 3-7 months with RSV bronchiolitis from December 1997 to February 1998. Follow-up was until the year 2000. Of these children, 22 (44%) had asthma and the remaining 28 (56%) had isolated episodes of cough and wheezing, which did not fulfill the criteria for asthma. Of the 22 children with asthma, all presented elevated total IgE by the second year of follow-up but only one of the children presented hypersensitivity to egg. The breathing difficulties that appeared in the initial outbreak of bronchiolitis is well explained by the cytopathic effect of the virus on the airways of infants. RSV virus produces inflammation of the bronchial mucosa, the effects of which may persist for 6-7 weeks, even after recovery from the first episode. The damaged and denuded epithelium provides fertile ground for future viral reinfections which, although less severe, produce dyspnea due to irritation of the exposed vagal receptors. Irrespective of the mechanism involved (RSV, histamine, methacholine or ozone inhalation) inflammation alters the intercellular junctions of the bronchial mucosal epithelium which, even in the absence of significant necrotic lesions, leads to increased penetration of irritants and stimulates the vagal receptors, leading to bronchospasm. In conclusion, it can currently be stated that RSV bronchiolitis constitutes a risk factor for the development of infantile asthma. The risk is increased in children with familial or personal antecedents of atopy. Serious forms of bronchiolitis due to RSV are more frequent in atopic individuals. The appearance of extrinsic asthma is more frequent in children who have previously had RSV bronchiolitis than in those who have not.

Asma relacionada con la inhalación de Plantago ovata

Psyllium is the seed of the plant Plantago ovata, which is widely used in nonprescription laxatives. It has been reported that psyllium powder may act as an inhalant allergen, especially in the workplace. A patient with asthma due to inhalation of P. ovata seed powder is described, being highlighted the allergenic potential of this substance frequently used as a laxative. We report a 31 year-old atopic woman, who handled and prepared at home, twice daily, a laxative containing P. ovata seeds (Plantaben) prescribed to her paralytic mother. Skin prick test to psyllium powder extract was positive. Specific IgE antibodies to psyllium were positive as determined by ELISA. Methacholine inhalation test revealed mild bronchial hyperresponsiveness (PC20 = 1.5 mg/ml). Specific bronchial challenge to psyllium powder elicited an isolated early asthmatic response. The allergens in psyllium were investigated by SDS-PAGE and immunoblotting, being identified several allergenic components with an apparent molecular weight of 66, 60, 36-20 and 14 kDa. No cross-reactivity was found between P. ovata seed and P. lanceolata pollen, as determined by ELISA-inhibition. Psyllium may act as a potent inhalant allergen capable of eliciting asthma symptoms, not only in an occupational context, but also in a domestic environment, affecting consumers of this laxative or relatives who handle it.

Effect of interferon-α on pulmonary function and airway responsiveness in patients with chronic hepatitis C

ABSTRACT Background Interferon (IFN)-α is the only approved treatment for chronic hepatitis C. Interstitial pneumonia and, rarely, exacerbation of bronchial asthma have been reported as adverse pulmonary effects of IFN-α treatment. The purpose of the present study was to clarify whether IFN-α treatment affects pulmonary function and airway responsiveness in patients with chronic hepatitis C. Methods We studied 17 patients (nine males and eight females; mean age 46 years; range 30–62 years) with chronic active hepatitis C diagnosed by serum tests and liver biopsy. Pulmonary function tests included vital capacity (VC), forced expiratory volume in 1 s (FEV 1 ), forced expiratory flow in the middle half of the forced vital capacity (FVC 25–75% ), total lung capacity and carbon monoxide diffusing capacity of the lung (D LCO ), which was adjusted for hemoglobin concentration. Airway responsiveness was measured by methacholine inhalation challenge and determination of the provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 ). These tests were performed before and 3 months after initiation of IFN-α therapy. Results No patient developed interstitial pneumonia, although there was a tendency for the hemoglobin-adjusted D LCO to decrease. Other pulmonary function test parameters were not affected. Overall, there was no significant change in PC 20 (from 15.0 to 11.4 mg/mL). In three patients whose initial PC 20 was within the normal range, airway hyperresponsiveness was induced and one patient developed bronchial asthma after IFN-α therapy. Conclusions These findings suggest that IFN-α induces airway hyperresponsiveness to methacholine in a few patients with chronic hepatitis C.

Methacholine inhalation challenge: a shorter, cheaper and safe approach.

Increased nonspecific bronchial hyperresponsiveness to pharmacological agents such as histamine or methacholine (MCh) is a hallmark of asthma. The measurement of airway reactivity is quite sensitive but testing is tedious, and time and money consuming. The present aim was, therefore, to design the shortest possible, yet safe inhalation challenge protocol applicable for a lung function referral centre. All records of studies performed in our institution during 1996 were analyzed retrospectively with a baseline ratio (bl) of forced expiratory volume in one second/forced vital capacity (FEV1/FVC) > or = 0.7 (n=449). It was questioned what the initial dose should be, and whether some inhalation steps could have been skipped without losing pertinent information and/or causing an adverse response (a fall in FEV1 >40%). When unavailable, provocative dose causing a 20% fall in FEV1 (PD20) values were obtained by linear inter- or extrapolation of the existing data. The present study showed that three-fold concentration steps could have been employed with minimal change in outcome. Only 151449 patients (3.3%) would have experienced a severe response. Five subjects (of 169, 3.0%) with FEV1/FVCbl 0.7-0.8 reacted to inhalation up to 0.073 micromol. Four subjects (of 280, 1.4%) with FEV1/ FVCbl> or =0.8 reacted to inhalation up to 0.219 micromol. The authors suggest that: 1) an initial dose of 0.219 micromol (initial concentration= 0.21 mg.mL(-1)) may be used when the baseline ratio of forced expiratory volume in one second to forced vital capacity > or =0.8 and 0.073 micromol (initial concentration=0.07 mg.mL(-1)) when the baseline ratio is <0.8; 2) a tripling dose protocol is easier to perform, cheaper and 30.2%, faster, yet just as safe; and 3) other abbreviated protocols used in epidemiologic settings may not be applicable in a referral centre setting.

Effects of Esophageal Acid Perfusion on Airway Hyperresponsiveness in Patients With Bronchial Asthma

The effects of gastroesophageal reflux on airway hyperresponsiveness in patients with bronchial asthma have yet to be studied in significant detail. The purpose of the present study was to determine how esophageal acid perfusion could change airway responsiveness in patients with bronchial asthma. In seven patients with bronchial asthma (mean +/- SD age, 55.1 +/- 6.4 years; four women and three men), esophageal pH was monitored by a pH meter and airway responsiveness was evaluated by aerosol inhalation of methacholine, during esophageal perfusion through an esophageal tube filled with either saline solution or 0. 1N hydrochloric acid (HCl), the order of which was selected at random, in 1-week intervals. Spirometry was also performed during esophageal pH monitoring. A significant decrease in the geometric mean of airway sensitivity or the concentration of methacholine causing a 35% fall in respiratory conductance was observed during esophageal HCl perfusion compared with that of saline solution perfusion (p < 0.01 or p < 0.003), although no significant changes were observed in vital capacity, FEV(1), peak expiratory flow, respiratory resistance, or slope of respiratory conductance during the periods of saline solution and HCl perfusion. We concluded that an increase in airway hyperresponsiveness was induced when HCl stimulated the esophagus in patients with bronchial asthma. These results suggest that esophageal reflux is one of the important factors that aggravate asthmatic status.

Exhaled nitric oxide following leukotriene E(4) and methacholine inhalation in patients with asthma.

Nitric oxide (NO) is a molecular gas that can be recovered in higher levels from the exhaled gas of subjects with asthma than from subjects without asthma. However, the precise mechanisms responsible of promoting increased fraction of expired nitric oxide (FE(NO)) in asthma are unknown. As leukotriene antagonism has been shown to reduce FE(NO) in patients with asthma, we hypothesized that leukotrienes mediate the increased FE(NO) encountered in this condition. Furthermore, because leukotriene antagonism stabilizes serum eosinophil markers during reductions in inhaled corticosteroid doses, and FE(NO) has been shown to correlate with sputum eosinophils in asthma, we reasoned that the effect of leukotrienes on FE(NO) might be mediated by eosinophils recruited to the airway by leukotrienes. To test this hypothesis, we performed methacholine and leukotriene (LT) E(4) bronchoprovocation challenges in 16 subjects with atopic asthma and measured FE(NO) and sputum differential counts before and after bronchoprovocation. We then compared FE(NO) in the seven subjects who developed increased sputum eosinophils following LTE(4) inhalation with values measured after methacholine inhalation in these seven subjects. Following LTE(4) inhalation, eosinophils rose from 4.01 +/- 0.89% pre-LTE(4) to 8.33 +/- 1.52% post-LTE(4). The mean change in sputum eosinophils from baseline after LTE(4) inhalation was larger than that after methacholine inhalation (+4.31 +/- 1.25% versus -1.14 +/- 0.93%). After LTE(4) inhalation, FE(NO) levels did not differ from prechallenge baseline or from levels following methacholine inhalation (ANOVA p > 0.05). These data indicate that neither LTE(4) nor recruitment of eosinophils into the airway by LTE(4) is a sufficient stimulus to acutely increase FE(NO) in subjects with asthma.

Airway hyperresponsiveness, inflammation, and subepithelial collagen deposition in recently diagnosed versus long-standing mild asthma. Influence of inhaled corticosteroids.

This study aimed at documenting airway inflammation and subepithelial collagen deposition in patients using only inhaled beta(2)-agonists with either recently diagnosed asthma (RDA: </= 2 yr, n = 16) or long-standing asthma (LSA: >/= 13 yr, n = 16) and at the influence of an intense inhaled corticosteroid (ICS) treatment on these parameters, in relation to changes in airway responsiveness. Patients had a methacholine inhalation test and a bronchoscopy with bronchial biopsies before and after an 8-wk treatment with inhaled fluticasone propionate (FP), 1,000 microgram/day. Baseline FEV(1) (mean +/- SEM) was normal and similar in both groups (RDA: 98.1 +/- 2.7, LSA: 94.5 +/- 4.6%). Geometric mean methacholine PC(20) was lower in LSA than in RDA (0.44 versus 3.37 mg/ml) at baseline and improved similarly by 1.85 and 1.86 double concentrations with FP treatment. PC(20) normalized (>/= 16 mg/ml) in five patients with RDA and two patients with LSA. Baseline mean bronchial cell counts (per mm(2) connective tissue surface) for CD3(+), CD4(+), CD8(+), CD25(+), EG1(+), CD45ro(+), and AA1(+) cells were similar in both groups. With FP, EG1(+) (p < 0.001), EG2(+) (p = 0.018), and AA1(+) counts (p = 0.009) decreased significantly in both groups while CD45ro(+) (p = 0.02) counts decreased only in LSA. Baseline type 1 and type 3 collagen deposition underneath the basement membrane was similar in RDA and LSA and did not change significantly after FP. This study shows that recent compared to long-standing mild asthma is associated with a similar degree of airway inflammation and subepithelial fibrosis, and a similar improvement in airway hyperresponsiveness after 8 wk on high-dose ICS. It also indicates that once asthma becomes symptomatic, airway responsiveness cannot normalize in most subjects over such a time period, even with a high dose of ICS.

Timing of administration of anti-VLA-4 differentiates airway hyperresponsiveness in the central and peripheral airways in mice.

The development of airway hyperresponsiveness (AHR) is correlated with the infiltration into the lungs of activated eosinophils and T lymphocytes. In large part, influx of eosinophils into the lung is dependent on very late activating antigen-4 (VLA-4) expression. However, the kinetics of eosinophil recruitment and the development of AHR are not fully delineated. Airway function was monitored by changes in lung resistance (RL) and dynamic compliance (Cdyn) to methacholine (MCh) inhalation after anti-VLA-4. After ovalbumin (OVA) sensitization and airway challenge of BALB/c mice, AHR increased as did the number of lung inflammatory cells. Administration of anti-VLA-4 to sensitized mice 2 h before the first (of three) OVA airway challenges significantly prevented changes in RL. Moreover, injection of the antibody from 2 h before the first challenge to 42 h after the last challenge significantly prevented the increases in RL, as well as eosinophil and lymphocyte numbers in the bronchoalveolar lavage fluid (BALF); interleukin-5 (IL-5) and leukotriene concentrations in BALF were also significantly inhibited. Interestingly, treatment with anti-VLA-4 only prevented changes in Cdyn and goblet cell hyperplasia when administered 2 h before the first challenge. These studies demonstrate that the timing of anti-VLA-4 administration can selectively affect pathologic processes that contribute to altered airway function in the central and peripheral airways after allergen challenge.

Frequency and determinants of exaggerated bronchoconstriction during shortened methacholine challenge tests in epidemiological and clinical set-ups.

The European Respiratory Society guidelines on bronchial provocation testing have proposed time-saving procedures, which may lead to unwanted exaggerated responses. The frequency and determinants of exaggerated bronchoconstriction in response to methacholine inhalation testing in clinical and epidemiological settings have not been assessed. The authors evaluated: 1) the prevalence of exaggerated bronchoconstriction, 2) its relation to time-saving measures (starting methacholine concentration and skipping concentrations); and 3) associations between such reactions and risk factors, respiratory symptoms and/or lung function parameters. Clinical (n=408) and epidemiological (n=711) groups were included. Exaggerated bronchoconstriction was defined as either a fall > or =20% following saline or a > or =30% fall in forced expiratory volume in one second (FEV1) after methacholine inhalations. Cases were compared with two groups of subjects: 1) with measurable bronchial responsiveness (MBR); and 2) without MBR. In the epidemiological group, 84 subjects (12%) presented exaggerated bronchoconstriction. Skipped concentrations accounted for an exaggerated bronchoconstriction in 18 of these. In the clinical group, 41 subjects (10%) experienced exaggerated reactions. Skipped concentrations accounted for an exaggerated bronchoconstriction in five of these. The provocative concentration of methacholine causing a 20% fall in FEV1 values were marginally lower in subjects with exaggerated bronchoconstriction. Questionnaire analysis in epidemiological subjects showed some symptoms of asthma and rhinitis to be more prevalent in cases than in subjects without MBR. In conclusion, methacholine inhalation tests with time-saving measures result in a 10% risk of exaggerated bronchoconstriction as defined in this study and bronchial responsiveness is more prominent in subjects with exaggerated bronchoconstriction.

Clarithromycin suppresses bronchial hyperresponsiveness associated with eosinophilic inflammation in patients with asthma

Although long-term administration of 14-membered macrolide antibiotics is a therapeutic alternative in asthma, both its pharmacologic mechanism of action and association with the pathogenesis of asthma remain obscure. This study investigated the suppressive effect of clarithromycin on airway responsiveness to methacholine provocation testing and examined whether chrarithromycin's antiasthmatic activity is associated with a reduction in eosinophilic inflammation. For 8 weeks, patients received 200 mg of clarithromycin or identical-appearing placebo twice daily. We assessed the effects of treatment with clarithromycin on bronchoconstriction precipitated by inhalation of methacholine in 17 adults with mild or moderate bronchial asthma who were in stable clinical condition. A double-blind, randomized, crossover design was used. Eosinophil counts and eosinophilic cationic protein (ECP) levels were determined in blood and sputum samples obtained on the morning of the methacholine provocation testing day. After 8 weeks of treatment with clarithromycin, patients' symptoms, blood and sputum eosinophils counts and sputum ECP levels were significantly decreased compared with both placebo and baseline. Furthermore, values of PC20 methacholine improved in all patients after clarithromycin treatment. Clarithromycin has a bronchial anti-inflammatory effect associated with decreased eosinophilic infiltration. This study suggests interesting therapeutic possibilities for bronchial asthma that warrant further trials.

Respiratory and upper airways impedance responses to methacholine inhalation in spontaneously breathing cats.

The upper airways may contribute to the increase in respiratory resistance induced by methacholine (Mch). The aim of this study was to simultaneously assess the Mch response of upper airways and lower respiratory resistances (Rua, Rrs,lo) and reactances (Xua, Xrs,lo), and to test whether the change of total respiratory resistance and reactance after Mch were affected by upper airways mechanisms. Seven cats breathing spontaneously were studied under chloralose, urethane anaesthesia. Forced oscillations were generated at 20 Hz by a loud-speaker connected to the pharyngeal cavity. A pneumotachograph was placed between rostral and caudal extremities of the severed cervical trachea. Pressure drops were measured across the upper airways and across the lower respiratory system. Rua, Xua, Rrs,lo and Xrs,lo were obtained after nebulized normal saline and Mch administered directly through the tracheostomy. The analysis focused on Mch tests showing clear positive upper airways response. Volume and flow dependence of Rrs,lo and Rua were assessed during tidal inspiration using multiple linear regression analysis. After Mch, Rrs,lo increased and became negatively volume dependent, while the increase in Rua was associated with no significant change in volume dependence; Xrs,lo became negative while Xua did not change. The upper airways response to methacholine may thus contribute to the increase in total respiratory resistance but may not account for either its negative volume dependence or the decrease in total resistance. It is surmised that these features more specifically reflect alterations in respiratory mechanics occurring at the level of the intrathoracic airways.

Prevalence of pulmonary disorders in patients with newly diagnosed rheumatoid arthritis.

Our objective was to determine the prevalence of airway hyperreactivity (AHR) in patients with newly diagnosed rheumatoid arthritis (RA) who had received no disease-modifying antirheumatic drugs (DMARDs) and to characterise the spectrum of lung diseases identifiable in these patients at the time of presentation. Eighteen consecutive patients with newly diagnosed RA referred to our medical centre's rheumatology clinic over 2 years underwent pulmonary evaluation with arterial blood gas analysis, chest radiographs, spirometry before and after bronchodilator medication, and body plethysmography. They returned on subsequent days in random order for methacholine inhalation challenge (MIC) and eucapnic voluntary hyperventilation (EVH) as bronchoprovocation techniques. One patient had severe obstructive disease at presentation and therefore did not undergo bronchoprovocation. We found a wide variety of pulmonary abnormalities, including two patients with hypoxia (12%), two with obstruction (12%), three with restriction (18%) and four with AHR (23%). The data also suggest a strong association between pulmonary diseases in RA and cigarette smoking. Although no single characteristic lung disease such as AHR was identified in patients presenting with RA, the association between lung disease and cigarette smoking is striking and underscores the need to emphasise smoking cessation in this patient population.

The salt output of a nebulizer—a comparison between two nebulizer types

The output of a nebulizer is generally defined as its weight loss during 1 min of nebulization. This mass output includes the weight loss due to evaporation of the solution required to moisten the dry air that is fed through the nebulizer. In order to compare results obtained from studies using different nebulizers we introduce the salt output as the amount of the solution that actually leaves the liquid phase as droplets and not by evaporation.The performance characteristics of a standard jet nebulizer (MA2) and a Sidestream jet neublizer were compared. Mass output was determined at different methacholine concentrations. Salt output was assessed by analysing the remaining salt in the nebulizers after 1 min of nebulization. Overall system performance in terms of forced expiratory volume in 1 sec (FEV1) reduction after 1 min of exposure to individually selected concentrations of methacholine were studied in 15 healthy, non-smoking subjects.Both nebulizer types showed a moderate linear increase of mass output with methacholine concentration. The efficiency coefficient, the quotient between salt output and mass output, was found to be 0·93 and 0·75 for the MA2 and Sidestream nebulizer respectively. These findings were explained by differences in airflow through, and temperature inside, the nebulizers. The salt output of the nebulizers proved to be better correlated to the FEV1-reduction following methacholine inhalation than did the mass output. The relative amount of the salt output that adhered to the acrylic walls of the Sidestream nebulizer drying tower was found to be 9%.We conclude that it is more appropriate to use salt output than mass output as a nebulizer performance descriptor. The study also shows the importance of determining nebulizer system performance under conditions as similar to true provocations as possible.

Influence of alpha-adrenoceptor blockade on antigen- and propranolol-induced bronchoconstriction in guinea-pigs in vivo.

1. Beta-adrenoceptor antagonists, such as propranolol, can provoke severe bronchoconstriction only in asthmatic subjects. Recently, we developed a guinea-pig model of propranolol-induced bronchoconstriction (PIB) and the purpose of this study was to investigate the role of alpha-adrenergic nerve pathways in this reaction. 2. Phentolamine administered after an antigen challenge did not inhibit PIB; however, its administration before the antigen challenge significantly inhibited the antigen-induced bronchoconstriction and also bronchoconstriction induced by methacholine inhalation. 3. We conclude that the alpha-adrenergic nerve system is not involved in the development of PIB following allergic reaction in our guinea-pig model.

The Effect of Regular Salbutamol on Lung Function and Bronchial Responsiveness in Patients with Primary Ciliary Dyskinesia

There is growing evidence that regular beta(2)-agonist use in patients with asthma is associated with decreased airway caliber and increased bronchial responsiveness. The aim of this study was to determine whether regular treatment with beta(2)-agonists induces changes in lung function and bronchial responsiveness in patients with primary ciliary dyskinesia. A randomized, double-blind, placebo-controlled, crossover study. Nineteen children with primary ciliary dyskinesia. Subjects received inhaled salbutamol or identical placebo (2 x 100 microg qid) for periods of 6 weeks with a wash-out period of 4 weeks. FEV(1) was measured before and 3 weeks and 6 weeks after salbutamol or placebo treatment. High-dose methacholine inhalation tests were performed before and 6 weeks after each treatment. The provocative concentration of methacholine producing a 20% fall in FEV(1) (PC(20)) and maximal airway narrowing (MDeltaFFEV(1)) was measured. No significant change in FEV(1) was observed during the salbutamol or placebo periods. No significant differences in the parameters of bronchial responsiveness (PC(20) and MDeltaFFEV(1)) were noted as the result of either salbutamol or placebo treatment. Our data have shown that salbutamol, inhaled regularly for 6 weeks, did not cause either a decline in lung function or an increase in bronchial responsiveness in subjects with primary ciliary dyskinesia.

Comparison of two standardized methods of methacholine inhalation challenge in young adults

In the European Community Respiratory Health Study (ECRHS), airway responsiveness to methacholine was determined using the Mefar dosimeter protocol. Elsewhere, the 2-min tidal breathing method has become the preferred standardized method. The relationship between measurements of responsiveness by these two methods is not well established. This study measured airway responsiveness to methacholine by dosimeter and tidal breathing methods in 47 healthy asthmatic subjects aged 20-44 yrs. Tests were performed within 1 week and in random order. Baseline forced expiratory volume in one second (FEV1) varied by &lt;10% between tests in 42/47 subjects. There was a close association between responsiveness determined by the two methods. A provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) value of &lt; or =8.0 mg x mL(-1) (tidal method) used to categorize airway hyperresponsiveness agreed most closely with a provocative dose of methacholine causing a 20% fall in FEV1 (PD20) value of &lt; or =0.5 mg (dosimeter method) (kappa statistic 0.78). Each doubling or halving of PC20 to define a level of hyperresponsiveness agreed closely with a doubling or halving of PD20. Assessment of airway responsiveness as provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second by the Mefar dosimeter protocol gave a close and predictable relationship with provocative concentration of methacholine causing a 20% fall in expiratory volume in one second assessed using the tidal breathing method. Airway hyperresponsiveness as determined by the accepted criterion of provocative concentration of methacholine causing a 20% fall in expiratory volume in one second &lt; or =8 mg x mL(-1) was best correlated with provocative dose of methacholine causing a 20% fall in forced expiratory volume in one second &lt;0.5 mg by Mefar dosimeter.

Irritant-Induced Asthma: Clinical and Functional Aspects

We report on three patients who experienced persistent asthma symptoms after repetitive irritant exposure which took place over a period from several days to months. Airway inflammation was assessed by induction of sputum and functional follow-up information was obtained from serial lung function tests. All patients had bronchial hyperresponsiveness to methacholine at the time of diagnosis. However, induced sputum samples did not show increased differential count of eosinophils. Treatment with inhaled corticosteroids was started in all of the patients and two of them were removed from work. In the two patients who left the workplace, methacholine inhalation test became negative when symptoms disappeared, whereas the patient who continued working had persistent asthma symptoms and a deterioration of bronchial hyperresponsiveness.

Role of microbial burden in aetiology of allergy and asthma

Recent decades have seen a significant shift in the main causes of illness among infants and young children. Until the 1950s and 196Os, acute infectious diseases affecting the gastrointestinal tract were the most common conditions requiring medical attention. This pattern of morbidity persists to this day in the poorest regions of the world and still claims the lives of millions of children. In developed countries, however, and also in developing countries where successful programmes of vaccination and prevention have been established, chronic, recurrent illnesses of the respiratory tract have taken the place of acute diarrhoea. A very high proportion of children (up to half in populations of northern European origin) are affected by allergies, and the prevalence of asthma and other forms of recurrent airway obstruction is rising.’ Paradoxically, the increases seem most striking in areas where the quality of outdoor air has significantly improved’ and where good sanitation and nutrition prevail. Some years ago we separately proposed3,* similar hypotheses to explain these findings. This so-called “hygiene hypothesis” was an immunological extension of a concept introduced by Strachan.5 Its cornerstone is that changes in the type and level of stimulation from the microbial environment associated with improvements in public health and hygiene may have indirectly influenced the postnatal development of immune function(s), so as to increase predisposition to chronic allergic conditions during childhood. These changes involve both a general decrease in infectious burden during early life (in particular, respiratory infections) and variations in gastrointestinal flora. In this paper, we review how recent advances in understanding of the way immune responses develop in early life support the hygiene hypothesis.

Muscarinic blockade of methacholine induced airway and parenchymal lung responses in anaesthetised rats

BACKGROUNDIt has previously been shown that M1 cholinergic receptors are involved in the parenchymal response to inhaled methacholine in puppies using the M1 selective antagonist pirenzepine. Although M3 receptors are...

Bronchial eosinophilic infiltration in Crohn's disease in the absence of pulmonary disease.

Immunological and functional bronchopulmonary abnormalities may be present in up to two-thirds of patients with Crohn's disease. Having recently described a mild increase in methacholine airways responsiveness in these patients, we investigated whether this physiological abnormality is associated with bronchial inflammation since it has previously been described in asthma. Eighteen patients with Crohn's disease and 15 healthy controls matched for age, atopy and smoking habit, were studied. All the subjects underwent a bronchial methacholine challenge (1, 4 and 16 mg/mL) and a sputum induction by inhalation of hypertonic saline (NaCl 4.5%). The sputum samples were analysed for their cellular composition as well as for the levels of several mediators and proteins in the fluid phase, including eosinophil cationic protein (ECP), myeloperoxydase, albumin, alpha2-macroglobulin, interleukin-8 (IL-8), IgA and IL-8/immunoglobulin A complexes. When compared to control subjects, patients with Crohn's disease had significantly higher sputum eosinophil counts (14.5% [0-79.9%] vs 0.2% [0-2.3%]; P < 0. 001) and ECP levels (26.2 microg/L [4-124.2 microg/L] vs 9.8 microg/L [0-94.2 microg/L]; P < 0.05). However, patients with Crohn's disease had no sign of increased plasma exudation as reflected by sputum levels of albumin and alpha2-macroglobulin similar to those seen in control subjects. Furthermore the sputum levels of IL-8, IgA and IL-8/IgA complexes were not significantly different between the two groups. The magnitude of the fall in forced expiratory volume in 1 s after methacholine inhalation was significantly increased in Crohn's disease patients although it did not correlate with the extent of sputum eosinophilia or with the sputum ECP levels. Crohn's disease patients without any clinical respiratory involvement have airway eosinophilia without local increased plasma exudation. However, bronchial eosinophilia in Crohn's disease per se is not sufficient to induce clinically significant airway hyperresponsiveness, suggesting that other factors than bronchial eosinophilic infiltration are required for the clinical expression of an airway instability.