Asthma can be difficult to diagnose, but bronchial provocation with methacholine, exercise or mannitol is helpful when used to identify bronchial hyperresponsiveness (BHR), a key feature of the disease. The utility of these tests in subjects with signs and symptoms of asthma but without a clear diagnosis has not been investigated. We investigated the sensitivity and specificity of mannitol to identify exercise-induced bronchoconstriction (EIB) as a manifestation of BHR; compared this with methacholine; and compared the sensitivity and specificity of mannitol and methacholine for a clinician diagnosis of asthma.
509 people (6–50 yr) were enrolled, 78% were atopic, median FEV1 92.5% predicted, and a low NAEPPII asthma score of 1.2. Subjects with symptoms of seasonal allergy were excluded. BHR to exercise was defined as a ≥ 10% fall in FEV1 on at least one of two tests, to methacholine a PC20 ≤ 16 mg/ml and to mannitol a 15% fall in FEV1 at ≤ 635 mg or a 10% fall between doses. The clinician diagnosis of asthma was made on examination, history, skin tests, questionnaire and response to exercise but they were blind to the mannitol and methacholine results.
Mannitol and methacholine were therapeutically equivalent to identify EIB, a clinician diagnosis of asthma, and prevalence of BHR. The sensitivity/specificity of mannitol to identify EIB was 59%/65% and for methacholine it was 56%/69%. The BHR was mild. Mean EIB % fall in FEV1 in subjects positive to exercise was 19%, (SD 9.2), mannitol PD15 158 (CI:129,193) mg, and methacholine PC20 2.1(CI:1.7, 2.6)mg/ml. The prevalence of BHR was the same: for exercise (43.5%), mannitol (44.8%), and methacholine (41.6%) with a test agreement between 62 & 69%. The sensitivity and specificity for a clinician diagnosis of asthma was 56%/73% for mannitol and 51%/75% for methacholine. The sensitivity increased to 73% and 72% for mannitol and methacholine when two exercise tests were positive.
In this group with normal FEV1, mild symptoms, and mild BHR, the sensitivity and specificity for both mannitol and methacholine to identify EIB and a clinician diagnosis of asthma were equivalent, but lower than previously documented in well-defined populations.
This was a multi-center trial comprising 25 sites across the United States of America. (NCT0025229).
The prevalence of asthma has increased in recent decades globally. The objective of the present study is to elucidate whether hospitalization for bronchiolitis in infancy and low socioeconomic status interact for bronchial hyperreactivity during teenage years.
We studied 522 children age 13-14 years attending schools in rural and urban areas to investigate the risk factors for bronchial hyperreactivity (BHR), defined as a provocation concentration of methacholine that causes a decrease of 20% (PC20) in forced expiratory volume within 1 second. Clinical examination, skin prick test, spirometry, and methacholine challenge were performed on all study subjects, who provided written consent. We used multivariate logistic regression to investigate the risk factors for BHR, and analyze the interaction between hospitalization for bronchiolitis in infancy and low socioeconomic status.
Forty-six (10.3%) positive BHR cases were identified. In the multivariate logistic analysis, as independent predictors of BHR, adjusted odds ratio of bronchiolitis diagnosed before 2 years of age in low income families was 13.7 (95% confidence interval, 1.4 to 135.0), compared to reference group, controlling for age, gender, parental allergy history, skin prick test, and environmental tobacco smoke (ETS) exposure. Interaction was observed between bronchiolitis before 2 years old and low socioeconomic status on children's bronchial hyperreactivity (p-interaction=0.025).
This study showed that bronchiolitis diagnosed before 2 years of age and low socioeconomic status interacted on children's bronchial hyperreactivity. Prevention of acute respiratory infection in early childhood in low socioeconomic status is important to prevent BHR as a precursor of asthma.
Asthma; Bronchial hyperreactivity (BHR); Bronchiolitis; Children; Socioeconomic status
We previously demonstrated in a group of patients with perennial allergic rhinitis alone impairment of spirometric parameters and high percentage of subjects with bronchial hyperreactivity (BHR). The present study aimed at evaluating a group of polysensitized subjects suffering from allergic rhinitis alone to investigate the presence of spirometric impairment and BHR during the pollen season.
One hundred rhinitics sensitized both to pollen and perennial allergens were evaluated during the pollen season. Spirometry and methacholine bronchial challenge were performed.
Six rhinitics showed impaired values of FEV1 without referred symptoms of asthma. FEF 25–75 values were impaired in 28 rhinitics. Sixty-six patients showed positive methacholine bronchial challenge. FEF 25–75 values were impaired only in BHR positive patients (p < 0.001). A significant difference was observed both for FEV1 (p < 0.05) and FEF 25–75 (p < 0.001) considering BHR severity.
This study evidences that an impairment of spirometric parameters may be observed in polysensitized patients with allergic rhinitis alone during the pollen season. A high percentage of these patients had BHR. A close relationship between upper and lower airways is confirmed.
allergic rhinitis; polysensitization; bronchial hyperreactivity; methacholine challenge; FEF 25–75
OBJECTIVES--22 workers, exposed to potassium aluminium tetrafluoride used as flux for soldering aluminium, were studied as clinical outpatients for symptoms of irritation of the nose, eye, skin, and airways. METHODS--16 volunteered for spirometry with methacholine provocation test including a test for small airways function by volume of trapped gas (VTG). RESULTS--Median (range) latency time before respiratory symptoms developed was 6 (1-60) months. Symptoms of airways irritation diminished in all subjects after flux exposure ended. The FEV1 was within the normal range in 16 of 17 subjects before the methacholine provocation test. The FEV1 decreased by > or = 20% in two out of 16 subjects after the 0.1% methacholine provocation. Four out of the 17 subjects had a high VTG before methacholine provocation. After inhalation of 0.1% methacholine eight out of 16 subjects (50%) had an abnormal increase of VTG indicating hyperreactivity in small airways. DISCUSSION--Potassium aluminium tetrafluoride flux seems to induce an increase of bronchial reactivity in small airways. A setting of an occupational standard for potassium aluminium tetrafluoride is proposed.
The regulations for doping control prohibit the use of β2 agonist bronchodilators (salbutamol, salmeterol, formoterol, and terbutaline) unless the subject follows the procedure known as abbreviated therapeutic use exemption (ATUE).
To highlight how the interest in discovering possible cheats may result in damage to athletes who really need bronchodilator treatment.
Thirty one high level athletes (18 men and 13 women) with a previous diagnosis of asthma were examined in our laboratory in order to obtain an ATUE for β2 agonists. All the subjects underwent spirometry at rest. If the results were normal, the subjects underwent an effort test and, if negative, a methacholine test inhaling progressive doses of methacholine until a fall of 20% in forced expiratory volume in one second (FEV1) was achieved. The international anti‐doping regulations require that the fall in FEV1 occurs with a concentration of methacholine (PC20) lower than 2 mg/ml (4 mg/ml for Torino 2006). In clinical practice, a test is positive if the response occurs with a PC20 lower than 8 mg/ml.
Only one subject met the criterion for the bronchodilation test at rest. The remaining 30 athletes underwent an effort test, which was positive in nine of them. In 21 cases (13 men and 8 women) the effort test was negative so a methacholine test was carried out. Seven (33%) were negative for ATUE with a PC20 higher than 8 mg/ml, seven (33%) were positive for ATUE with a PC20 less than 2 mg/ml, in four (19%) the PC20 was 2–4 mg/ml, and in three (14%) it was 4–8 mg/ml.
Strict vigilance of fair play should be pursued, but excessive control can lead to situations of inequality for asthmatic athletes such that a third of athletes cannot be treated with β2 agonists. Therefore under current regulations, asthmatic athletes are often denied the most effective therapeutic option.
asthma; β2 agonists; bronchial hyper‐responsiveness; doping
Exercise-induced cough is common among athletes. Athletes training in cold air often report an increasingly troublesome cough during the winter season. Chronic airway irritation or inflammation may increase the sensory response of cough receptors. The aim of this study was to evaluate the seasonal variability of cough reflex sensitivity to capsaicin in elite athletes.
Fifty-three elite winter athletes and 33 sedentary subjects completed a respiratory questionnaire and a capsaicin provocation test during the summer, fall, and winter. Allergy skin prick tests, spirometry, eucapnic voluntary hyperpnea test (EVH), methacholine inhalation test (MIT), and induced sputum analysis were also performed.
In athletes, the prevalence of cough immediately after exercise was high, particularly during winter. Athletes often showed a late occurrence of cough between 2-8 h after exercise. The cough reflex sensitivity to capsaicin was unchanged through the seasons in both athletes and non-athlete subjects. No significant correlations were found in groups between cough reflex sensitivity to capsaicin and the number of years in sport training, the number of hours of training per week, EVH response (% fall in FEV1), airway responsiveness to methacholine (PC20), airway inflammation or atopy.
The prevalence of cough immediately and a few hours after exercise is high in athletes and more frequently reported during winter. However, cough does not seem to be associated with cough reflex hypersensitivity to capsaicin, bronchoconstriction, or airway inflammation in the majority of athletes.
Cough; athletes; cold air
There are increasing evidences that allergic rhinitis (AR) may influence the clinical course of asthma. We conducted methacholine challenge test and nasal eosinophils on nasal smear to patients with allergic rhinitis in order to investigate the mechanism of connecting upper and lower airway inflammation in 35 patients with AR during exacerbation. The methacholine concentration causing a 20% fall in FEV1 (PC20) was used as thresholds of bronchial hyperresponsiveness (BHR). Thresholds of 25 mg/dL or less were assumed to indicate BHR. All patients had normal pulmonary function. Significant differences in BHR were detected in the comparison of patients with cough or postnasal drip and without cough or postnasal drip. There were significant differences of PC20 between patients with cough or postnasal drip and those without cough or postnasal drip (3.41+/-3.59 mg/mL vs 10.2+/-1.2 mg/mL, p=0.001). The levels of total IgE were higher in patients with seasonal AR than in patients with perennial AR with exacerbation (472.5+/-132.5 IU/L vs. 389.0+/-70.9 IU/L, p<0.05). Nasal eosinophils were closely related to log PC20 (r=-0.65, p<0.01). These findings demonstrated that nasal eosinophilic inflammation might contribute to BHR in patients with AR.
Identification of the risk factors for bronchial hyperresponsiveness (BHR) would increase the understanding of the causes of asthma. The relationship between physical activity and BHR in men and women aged 28.0–56.5 years randomly selected from 24 centres in 11 countries participating in the European Community Respiratory Health Survey II was investigated.
5158 subjects answered questionnaires about physical activity and performed BHR tests. Participants were asked about the frequency and duration of usual weekly exercise resulting in breathlessness or sweating. BHR was defined as a decrease in forced expiratory volume in 1 s of at least 20% of its post‐saline value for a maximum methacholine dose of 2 mg.
Both frequency and duration of physical activity were inversely related to BHR. The prevalence of BHR in subjects exercising ⩽1, 2–3 and ⩾4 times a week was 14.5%, 11.6% and 10.9%, respectively (p<0.001). The corresponding odds ratios were 1.00, 0.78 (95% CI 0.62 to 0.99) and 0.69 (95% CI 0.50 to 0.94) after controlling for potential confounding factors. The frequency of BHR in subjects exercising <1 h, 1–3 h and ⩾4 h a week was 15.9%, 10.9% and 10.7%, respectively (p<0.001). The corresponding adjusted odds ratios were 1.00, 0.70 (95% CI 0.57 to 0.87) and 0.67 (95% CI 0.50 to 0.90). Physical activity was associated with BHR in all studied subgroups.
These results suggest that BHR is strongly and independently associated with decreased physical activity. Further studies are needed to determine the mechanisms underlying this association.
Bronchial hyperresponsiveness (BHR) is typically measured by bronchial challenge tests that employ direct stimulation by methacholine or indirect stimulation by adenosine 5'-monophosphate (AMP). Some studies have shown that the AMP challenge test provides a better reflection of airway inflammation, but few studies have examined the relationship between the AMP and methacholine challenge tests in children with asthma. We investigated the relationship between AMP and methacholine testing in children and adolescents with atopic asthma.
The medical records of 130 children with atopic asthma (mean age, 10.63 years) were reviewed retrospectively. Methacholine and AMP test results, spirometry, skin prick test results, and blood tests for inflammatory markers (total IgE, eosinophils [total count, percent of white blood cells]) were analyzed.
The concentration of AMP that induces a 20% decline in forced expiratory volume in 1 second [FEV1] (PC20) of methacholine correlated with the PC20 of AMP (r2=0.189, P<0.001). No significant differences were observed in the levels of inflammatory markers (total eosinophil count, eosinophil percentage, and total IgE) between groups that were positive and negative for BHR to methacholine. However, significant differences in inflammatory markers were observed in groups that were positive and negative for BHR to AMP (log total eosinophil count, P=0.023; log total IgE, P=0.020, eosinophil percentage, P<0.001). In contrast, body mass index (BMI) was significantly different in the methacholine positive and negative groups (P=0.027), but not in the AMP positive and negative groups (P=0.62). The PC20 of methacholine correlated with FEV1, FEV1/forced vital capacity (FVC), and maximum mid-expiratory flow (MMEF) (P=0.001, 0.011, 0.001, respectively), and the PC20 of AMP correlated with FEV1, FEV1/FVC, and MMEF (P=0.008, 0.046, 0.001, respectively).
Our results suggest that the AMP and methacholine challenge test results correlated well with respect to determining BHR. The BHR to AMP more likely implicated airway inflammation in children with atopic asthma. In contrast, the BHR to methacholine was related to BMI.
AMP; atopic asthma; bronchial hyper-responsiveness; methacholine
The prevalence of bronchial hyperresponsiveness (BHR) to methacholine inhalation in a consecutive series of 21 patients with primary Sjögren's syndrome was studied prospectively. Slight to severe BHR was seen in 12/20 (60%) of the patients. Ten of 12 patients with BHR (83%) had a non-productive cough, wheezing, or intermittent breathlessness. Bronchial hyperresponsiveness was more common in patients with extraglandular symptoms (10/14, 71%) than in those with only glandular symptoms (29%). Spirometrically 29% (6/21) of the patients had 'small airways' disease', and all those had BHR. Of 6/21 (29%) who had diffuse interstitial lung disease, two had BHR. Three of the four patients with obstructive lung function were challenged with methacholine and two of them had BHR. Only two patients with BHR had normal spirometry findings. The data showed that respiratory disease--mostly mild or moderate but even severe bronchial hyperresponsiveness--is commonly seen in patients with primary Sjögren's syndrome.
The relationship between sensitisation to helminths and atopy, bronchial-hyperresponsiveness and allergic diseases may differ depending on many factors, including the genes of the population studied. We sought to examine this relationship in an African cohort.
Urban Xhosa children were tested for ascaris IgE levels, bronchial hyper-responsiveness (BHR) by methacholine challenge, atopic sensitisation (skin tests to aeroallergens) and allergic disease (asthma, eczema and rhinitis) assessed by questionnaire.
Ascaris sensitisation was strongly associated with BHR but not with asthma, eczema or rhinitis. There was a dose-response relationship between increasing class of ascaris IgE and increased BHR (Prevalence ratio (PR) 1.75; CI 1.09-2.82). Higher levels of ascaris IgE were seen in those with BHR. Ascaris IgE was associated with atopic sensitisation to aeroallergens. There was a dose-response relationship between increasing class of ascaris IgE and sensitisation to one or more allergen (PR 1.65; CI, 1.27-2.13), sensitisation to house dust mites (HDM) (PR 1.79; CI, 1.29-2.46) and grass (PR 2.66; CI, 1.24-5.71) and number of positive skin prick tests (PR 1.78; CI, 1.27-2.49). Presence of any sensitisation to ascaris was associated with more than doubling the prevalence of HDM sensitisation (41.5 vs 18.5%) and almost quadrupling the prevalence of grass sensitisation (10.8 vs 2.8%).
Ascaris sensitisation was strongly associated with BHR and with atopy, but not with allergic diseases. Possible explanations might be that the type of ascaris infection that causes high levels of ascaris IgE in this genetic population may also favour the development of atopy or that atopics in Africa have upregulation of their defence system against parasitic infection. These hypotheses are not mutually exclusive.
To measure the levels of exposure to nitrogen trichloride (NCl3) and aldehydes among cleaning and disinfecting workers in the atmosphere of food industry plants during cleaning and disinfecting operations, and to examine how they relate to irritant and chronic respiratory symptoms—which are indices of pulmonary function—and bronchial hyperresponsiveness (BHR) to methacholine.
175 exposed workers (M = 149; F = 26) recruited from 17 enterprises of the food industry (8 cattle, pig, and ovine slaughterhouses, 8 fowl slaughterhouses, and 1 catering firm) and 70 non‐exposed workers (M = 52; F = 18) were examined. Concentration levels of NCl3 and aldhehydes were measured by personal sampling. Symptoms were assessed by means of a questionnaire and the methacholine bronchial challenge (MBC) test using an abbreviated method. Subjects were labelled MBC+ if forced expiratory volume in one second (FEV1) fell by 20% or more. The linear dose‐response slope (DRS) was calculated as the percentage fall in FEV1 at last dose divided by the total dose administered.
277 air samples were taken in the 17 food industry plants. For a given plant and in a given workshop, the actual concentrations of chloramines, aldehydes, and quaternary ammonium compounds were measured with personal samplers during the different steps of the procedures. For each cleaner, a total exposure index Σ was calculated. A statistically significant concentration‐response relationship was found between eye, nasal, and throat symptoms of irritation—but not chronic respiratory symptoms—and exposure levels or exposure duration. No relation was found between BHR and exposure.
These data show that cleaning and disinfecting workers in the food industry are at risk of developing eye, nasal, and throat irritation symptoms. Although NCl3 exposure does not seem to carry a risk of developing permanent BHR, the possibility of transient BHR cannot be ruled out entirely.
OBJECTIVES: To study the role of individual and occupational risk factors for asthma in furniture workers. METHODS: 296 workers were examined (258 men, 38 women) with a questionnaire of respiratory symptoms and diseases, baseline spirometry, bronchial provocative test with methacholine, and skin prick tests. Non-specific bronchial hyperreactivity was defined as when a provocative dose with a fall of 20% in forced expiratory volume in 1 second (PD20FEV1) was < 0.8 mg and atopy in the presence of at least one positive response to skin prick tests. Workers were subdivided into spray painters (exposed to low concentrations of diisocyanates and solvents), woodworkers (exposed to wood dusts), and assemblers (control group). RESULTS: The prevalences of attacks of shortness of breath with wheezing and dyspnoea were higher in spray painters (13.5% and 11.5% respectively) than in woodworkers (7.7% and 6.3%) or in assemblers (1.6% and 1.6%); prevalences of chronic cough, asthma, and rhinitis were also slightly but not significantly higher in spray painters and in woodworkers than in assemblers. The difference in the prevalence of respiratory symptoms among the job titles was due to the atopic subjects, who showed a higher prevalence of chronic cough, wheeze, shortness of breath with wheeze, dyspnoea, and asthma in spray painters than in the other groups. The prevalence of non-specific bronchial hyperreactivity in subjects who performed bronchial provocative tests was 17.7%, with no significant difference among groups. Asthma symptoms were significantly associated with non-specific bronchial hyperreactivity. Asthma-like symptoms plus non-specific bronchial hyperreactivity was found in 4% of assemblers, 10% of woodworkers, and 13.3% of spray painters (chi 2 = 2.6, NS). Multiple logistic analysis taking into account individual (smoke, atopy, age) and occupational (job titles) risk factors confirmed that spray painters had higher prevalence of chronic cough than assemblers, and a trend in increasing the prevalence of shortness of breath with wheeze, dyspnoea, and asthma. CONCLUSIONS: Painters in the furniture industry, particularly atopic subjects, are at higher risk of asthma-like symptoms than other job titles. In these workers asthma-like symptoms are more sensitive than non-specific bronchial hyperreactivity in detecting a negative effect of the occupational exposure.
Methacholine hyperresponsiveness is prevalent in elite athletes. Comparative studies have hitherto been limited to methacholine, eucapnic voluntary hyperpnoea and exercise. This study investigated airway responsiveness to these stimuli as well as to adenosine 5′-monophosphate (AMP) and mannitol, in 58 cross-country ski athletes.
Exhaled nitric oxide concentration (FENO), spirometry and bronchial challenge in random order with methacholine, AMP and mannitol were consecutively performed on three study days in the autumn. Specific IgE to eight aeroallergens and a self-completed questionnaire about respiratory symptoms, allergy and asthmatic medication were also performed on day 1. Eucapnic voluntary hyperventilation (EVH) and field exercise tests were randomly performed in 33 of the skiers on two study days in the following winter.
Of 25 (43%) skiers with airway hyperresponsiveness (AHR), 23, five and three skiers were hyperresponsive to methacholine, AMP and mannitol, respectively. Methacholine hyperresponsiveness was more prevalent in subjects without asthma-like symptoms. The FENO was not significantly different in skiers with and without methacholine hyperresponsiveness. Four of 14 skiers with and four of 19 skiers without methacholine hyperresponsiveness were hyperresponsive to EVH or exercise challenge. AHR to any stimulus was present in 16 asymptomatic and nine symptomatic skiers. Asthma-like symptoms were not correlated with AHR to any stimulus.
Methacholine hyperresponsiveness is more common in asymptomatic skiers and is a poor predictor of hyperresponsiveness to mannitol and hyperpnoea. The low prevalence of hyperresponsiveness to indirect stimuli may suggest differences in the pathogenesis of methacholine hyperresponsiveness in elite skiers and non-athletes.
Bronchial hyperresponsiveness (BHR) is an important pathophysiological feature of asthma. In addition to the diagnostic significance, BHR is associated with the severity of airway inflammation and BHR- based treatment approaches has been shown to be effective. Nevertheless, challenge tests are time consuming, inconvenient to patients, and are not accessible in every primary care physicians. We aimed to develop a questionnaire for the assessment of BHR in Korean subjects.
From the 24 University-affiliated hospitals, we recruited 149 adults between age 20 and 40 years with more than one asthmatic symptom (cough, sputum or dyspnea) and who had bronchial provocation test. A list of 33 symptoms, past history of allergy or smoking and 10 provoking stimuli were selected for the BHR questionnaire. After a methacholine challenge test patients were asked to complete each questionnaire. For each item of questionnaire, diagnostic odds ratios for the presence of BHR were calculated and multiple logistic regression analysis was performed to select final questionnaire items. Receiver operating characteristic (ROC) curve analysis was used to evaluate the sensitivity and specificity of the selected questionnaire items.
Methacholine challenge test was positive in 36 patients (24.2%). Eleven symptoms and 2 provoking stimuli items were statistically significant by the results of diagnostic odds ratio. According to the result of multiple logistic regression analysis, 4 items were finally selected for the significant BHR questionnaire: the presence of wheezing episode, past history of physician-diagnosed asthma, family history of asthma. The psychiatric stress was negatively associated provoking stimuli item for the presence of BHR. The area under the ROC curve was 0.80 (95% CI, 0.72-0.86). Sensitivity was 84.9% (95% CI, 68.1-94.9) and specificity was 65.5% (95% CI, 55.8-74.3).
Four BHR questionnaire items including wheezing episode, past history of physician-diagnosed asthma, family history of asthma and psyachiatric stress stimuli were able to assess the presence of BHR in Korean adults.
Exercise-induced bronchoconstriction (EIB) in patients with asthma occurs more frequently in winter than in summer. The concentration of house dust mite (HDM) allergens in beds also shows seasonal variation. This study examined the relationship between seasonal differences in the prevalence of EIB and sensitization to HDMs in patients with asthma.
The medical records of 74 young adult male patients with asthma-like symptoms who underwent bronchial challenge with methacholine, 4.5% saline and exercise, and allergen skin prick tests, were reviewed. The subjects were divided into summer (n=27), spring/fall (n=26) and winter (n=21) groups according to the season during which they underwent testing.
The positive responses to exercise differed according to season (48.1% in summer, 73.1% in spring/fall, and 90.5% in winter; P<0.01). In addition, the prevalence of positive responses to HDM (70.4%, 88.5%, and 95.2%, respectively; P<0.05) and pollen skin tests (37.0%, 19.2%, and 0%, respectively; P<0.01) also showed significant seasonal differences. Severe responses to 4.5% saline showed a similar trend, although it was not statistically significant (44.4%, 50.0%, and 71.4%, respectively; P=0.07). Skin test reactivity to HDMs was significantly related to maximal fall in forced expiratory volume in one second (FEV1) following exercise (r=0.302, P<0.01) and the index of airway hyperresponsiveness (AHR) to 4.5% saline (r=-0.232, P<0.05), but not methacholine (r=-0.125, P>0.05).
Positive skin test reactions to HDMs and EIB occurred in winter, spring/fall, and summer in decreasing order of frequency. Seasonal variation in the prevalence of EIB may be related to seasonal variation in sensitization to HDMs, accompanied by differences in indirect, but not direct, AHR.
Asthma; bronchoconstriction; exercise; house dust mite; season
The airway muscles from allergen-sensitized animals in vitro show a heightened response to histamine, but not to carbachol. This study investigated whether the airway responsiveness to histamine in vivo is comparable to that of methacholine in human subjects with varying degrees of atopy.
One-hundred-and-sixty-eight consecutive adult asthma patients or volunteers underwent bronchoprovocation tests to both histamine and methacholine after determining their blood eosinophil counts, serum total IgE levels and skin test reactivity to 10 common aeroallergens.
The responsiveness to histamine was significantly related to that to methacholine (r=0.609, p<0.001), but many individuals with a negative methacholine test response showed a positive response to histamine. The histamine-bronchial reactivity index (BRindex) was significantly higher than the methacholine-BRindex in subjects with a positive response to none (n=69, p<0.01) or only one (n=42, p<0.001) of histamine and methacholine, while there was no significant difference in the subjects with positive responses to both of them (n=57). The histamine-BRindex was significantly higher than the methacholine-BRindex in the subjects with mild histamine hyperresponsiveness (n=58, 1.28±0.01 vs. 1.20±0.02, respectively, p<0.001). Both histamine and methacholine responsiveness was significantly related to the atopy markers. However, the histamine-BRindex/methacholine-BRindex ratio of the atopics was not significantly different from that of the non-atopics.
The airway responsiveness to histamine is comparable to that of methacholine in the subjects with positive responses to both histamine and methacholine, but the airway responsiveness to histamine is greater than that to methacholine in those subjects with mild airway hyperresponsiveness, regardless of atopy.
Asthma; Atopy; Histamine; Methacholine
The frequency of adults reporting a history of asthma is rising. However, it is unclear whether this increased prevalence accurately demonstrates a rising trend or if it reflects an overall increase in asthma awareness.
To determine the frequency of negative methacholine bronchoprovocation tests in adults who report physician-diagnosed asthma and to explore the clinical characteristics of subjects with negative tests.
Data from methacholine challenge, spirometry, and physician assessment were analysed from 304 adults who reported physician-diagnosed asthma and responded to community based advertising for asthma research studies. The clinical characteristics of methacholine-positive and -negative subjects were compared and a predictive model was tested to identify those characteristics associated with a negative test.
Of the 304 subjects tested, 83 (27%) had a negative methacholine test. A negative test was positively associated with adult-onset of symptoms (p<0.001), normal FEV1 (p<0.001), and having no history of exacerbation requiring oral steroids (p=0.03). Over half (60%) of those with a negative test reported weekly asthma-like symptoms (cough, dyspnea, chest tightness or wheeze), while 39% reported emergency department visits for asthma-like symptoms.
Conclusions and Clinical Relevance
A sizeable percentage of subjects who report physician diagnosed asthma have a negative methacholine challenge test. These subjects are characterized by diagnosis of asthma as an adult and by normal or near normal spirometry. Caution should be exercised in the assessment and diagnosis of adults presenting with asthma-like symptoms, because they may not have asthma. Further diagnostic studies, including bronchoprovocation testing, are warranted in this patient group, especially if their spirometry is normal. (ClinicalTrials.gov - NCT00201266).
Asthma; Diagnosis and Assessment; Brochoprovocation Testing
Increased volume of trapped gas (VTG), indicating small airways dysfunction, was found among 14 never smoking non-atopic welders who had worked for 10-31 (mean 22) years in their occupation. Spirometry and nitrogen wash out data were compared with those from a reference group of 14 never smoking men not exposed to welding. A methacholine provocation test was carried out. The effect was measured by change in forced expiratory volume in one second (FEV1) and VTG. The maximum decrease in FEV1 after inhalation of methacholine was 6% in welders and 2% among referents. Before provocation VTG and VTG total lung capacity (TLC) was higher among welders (127 ml v 98 ml and 1.76% v 1.38%). The increase in VTG and VTG/TLC was higher in welders after inhalation of methacholine at concentrations of 0.001% to 2% and remained increased after inhalation of salbutamol. The differences indicate small airways disease among shipyard welders.
We hypothesized that hyperresponsiveness in asthma is caused by an impairment in the ability of inspiration to stretch airway smooth muscle. If the hypothesis was correct, we reasoned that the sensitivity to inhaled methacholine in normal and asthmatic subjects should be the same if the challenge was carried out under conditions where deep inspirations were prohibited. 10 asthmatic and 10 normal subjects received increasing concentrations of inhaled methacholine under conditions where forced expirations from a normal end-tidal inspiration were performed. When no deep inspirations were allowed, the response to methacholine was similar in the normal and asthmatic subjects, compatible with the hypothesis we propose. Completely contrary to our expectations, however, was the marked responsivity to methacholine that remained in the normal subjects after deep breaths were initiated. 6 of the 10 normal subjects had > 20% reduction in forced expiratory volume in one second (FEV 1) at doses of methacholine < 8 mg/ml, whereas there was < 15% reduction with 75 mg/ml during routine challenge. The ability of normal subjects to develop asthmatic responses when the modulating effects of increases in lung volume was voluntarily suppressed suggests that an intrinsic impairment of the ability of inspiration to stretch airway smooth muscle is a major feature of asthma.
A number of subjects, especially the very young and the elderly, are unable to cooperate and to perform forced expiratory manoeuvres in the evaluation of bronchial hyperresponsiveness (BHR). The objective of our study was to investigate the use of the interrupter technique as a method to measure the response to provocation and to compare it with the conventional PD20 FEV1.
We studied 170 normal subjects, 100 male and 70 female (mean ± SD age, 38 ± 8.5 and 35 ± 7.5 years, respectively), non-smoking from healthy families. These subjects had no respiratory symptoms, rhinitis or atopic history. A dosimetric cumulative inhalation of methacholine was used and the response was measured by the dose which increases baseline end interruption resistance by 100% (PD100Rint, EI) as well as by percent dose response ratio (DRR).
BHR at a cut-off level of 0.8 mg methacholine exhibited 31 (18%) of the subjects (specificity 81.2%), 21 male and 10 female, while 3% showed a response in the asthmatic range. The method was reproducible and showed good correlation with PD20FEV1 (r = 0.76, p < 0.005), with relatively narrow limits of agreement at -1.39 μmol and 1.27 μmol methacholine, respectively, but the interrupter methodology proved more sensitive than FEV1 in terms of reactivity (DRR).
Interrupter methodology is clinically useful and may be used to evaluate bronchial responsiveness in normal subjects and in situations when forced expirations cannot be performed.
To investigate whether the effects of nifedipine on methacholine induced broncho-constriction could impair pulmonary gas exchange in bronchial asthma a randomised, double blind, crossover study in 13 symptom free asthmatic subjects was designed. Each patient underwent a methacholine bronchial challenge test on two separate days one week apart, after having either oral nifedipine (20 mg thrice daily) or placebo for three days. Arterial blood gases were measured before and after methacholine challenge in nine subjects. Prechallenge values of forced expiratory volume in one second (FEV1) and arterial oxygen tension (Pao2) were similar after nifedipine and after placebo. After challenge, the cumulative doses of methacholine required to produce a 20% fall in FEV1 (PD20 FEV1) were significantly larger after nifedipine (280 (SD 347)) cumulative breath units (CBU) than after placebo (120 (183) CBU; p less than 0.01). After challenge the fall in Pao2 values (17.1 (1.6) mm Hg; (2.28 (0.21) kPa)) was significantly greater than after placebo (11.7 (2.4) mm Hg; (1.56 (0.32) kPa) p less than 0.03). Our data show that although oral nifedipine significantly reduces airway reactivity in patients with mild bronchial asthma, it also adversely affects pulmonary gas exchange, resulting in a lowered postchallenge Pao2, probably because of worsening ventilation-perfusion relationships.
Airway inflammation and airway hyperresponsiveness (AHR) are two characteristic features of asthma. Fractional exhaled nitric oxide (FENO) has shown good correlation with AHR in asthmatics. Less information is available about FENO as a marker of inflammation from work exposures. We thus examined the relation between FENO and AHR in lifeguards undergoing exposure to chloramines in indoor pools.
39 lifeguards at six indoor pools were given a respiratory health questionnaire, FENO measurements, spirometry, and a methacholine bronchial challenge (MBC) test. Subjects were labeled MBC+ if the forced expiratory volume (FEV1) fell by 20% or more. The normalized linear dose-response slope (NDRS) was calculated as the percentage fall in FEV1 at the last dose divided by the total dose given. The relation between MBC and FENO was assessed using logistic regression adjusting on confounding factors. The association between NDRS and log-transformed values of FENO was tested in a multiple linear regression model.
The prevalence of lifeguards MBC+ was 37.5%. In reactors, the median FENO was 18.9 ppb (90% of the predicted value) vs. 12.5 ppb (73% predicted) in non-reactors. FENO values ≥ 60% of predicted values were 80% sensitive and 42% specific to identify subjects MBC+. In the logistic regression model no other factor had an effect on MBC after adjusting for FENO. In the linear regression model, NDRS was significantly predicted by log FENO.
In lifeguards working in indoor swimming pools, elevated FENO levels are associated with increased airway responsiveness.
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.
Bronchial hyperresponsiveness (BHR) is a common feature of asthma. However, BHR is also present in asymptomatic individuals and its clinical and prognostic significance is unclear. We hypothesised that BHR might play a role in the development of chronic obstructive pulmonary disease (COPD) as well as asthma.
In 1991 respiratory symptoms and BHR to methacholine were evaluated in 7126 of the 9651 participants in the SAPALDIA cohort study. Eleven years later 5825 of these participants were re‐evaluated, of whom 4852 performed spirometric tests. COPD was defined as an FEV1/FVC ratio of <0.70.
In 1991 17% of participants had BHR, of whom 51% were asymptomatic. Eleven years later the prevalence of asthma, wheeze, and shortness of breath in formerly asymptomatic subjects with or without BHR was, respectively, 5.7% v 2.0%, 8.3% v 3.4%, and 19.1% v 11.9% (all p<0.001). Similar differences were observed for chronic cough (5.9% v 2.3%; p = 0.002) and COPD (37.9% v 14.3%; p<0.001). BHR conferred an adjusted odds ratio (OR) of 2.9 (95% CI 1.8 to 4.5) for wheezing at follow up among asymptomatic participants. The adjusted OR for COPD was 4.5 (95% CI 3.3 to 6.0). Silent BHR was associated with a significantly accelerated decline in FEV1 by 12 (5–18), 11 (5–16), and 4 (2–8) ml/year in current smokers, former smokers and never smokers, respectively, at SAPALDIA 2.
BHR is a risk factor for an accelerated decline in FEV1 and the development of asthma and COPD, irrespective of atopic status. Current smokers with BHR have a particularly high loss of FEV1.
bronchial hyperresponsiveness; asthma; chronic obstructive pulmonary disease; smoking; epidemiological study