Nonspecific Bronchial Responsiveness Research Articles

Does Exhaled Nitric oxide predict non-specific bronchial responsiveness in childhood asthma?

Does Exhaled Nitric oxide predict non-specific bronchial responsiveness in childhood asthma?

Review of Diagnostic Challenges in Occupational Asthma.

Occupational asthma (OA) is one of the most frequent occupational diseases and its diagnosis is often difficult. This review summarizes its current diagnostic challenges. OA is associated with significant health and socio-economic burden. It is underdiagnosed and physicians need to adopt a stepwise approach to confirm the diagnosis. Although early removal from exposure to the offending agent is associated with a better prognosis, physicians should try to confirm the diagnosis of work-related asthma before taking a worker off work. A proper occupational and medical history is very important but is not enough to make the diagnosis of OA. Objective evidence of work-related asthma is required and this represents a serious challenge to most physicians. Measurement of non-specific bronchial responsiveness (NSBR) and spirometry may confirm the diagnosis of asthma but do not confirm the diagnosis of OA. Serial monitoring of peak expiratory flows (PEF), NSBR, and airway inflammation at and off work may confirm the diagnosis of OA but are often difficult to perform. Confirming sensitization by skin prick tests or specific IgE may help to support the diagnosis of OA. Specific inhalation challenges (SIC) in the lab or at work are considered the reference standard but are of limited access. Medical surveillance programs along with primary prevention (reducing exposure) may help to reduce the burden of OA, but the ideal program has yet to be defined. The diagnostic workup of OA remains a challenge and needs a rigorous stepwise evaluation.

Bronchial lability in children with bronchial asthma depending on blood inflammatory patterns

Comprehensive clinical and paraclinical examination of 120 children with bronchial asthma has revealed that the most significant nonspecific reactivity of airways to indirect bronchial stimuli was associated with hypergranulocytic blood inflammatory pattern where the chances of bronchial hyperreactivity (index of bronchial lability > 30 %) increased by 14.2 times. Neutrophilic inflammatory pattern was predominantly accompanied by excessive airways’ constriction: the chances of presence of index of bronchial spasm > 20 % increased from 3 to 21,3 times. In one out of five patients with eosinophilic blood inflammatory pattern there were signs of significant induced bronchial obstruction, but hyporgranulocytic inflammatory pattern was associated with the lowest indices of non-specific bronchial reactivity.

Predictive value of nonspecific bronchial responsiveness in occupational asthma

The diagnosis of occupational asthma (OA) can be challenging and needs a stepwise approach. However, the predictive value of the methacholine challenge has never been addressed specifically in this context. We sought to evaluate the sensitivity, specificity, and positive and negative predictive values of the methacholine challenge in OA. A Canadian database was used to review 1012 cases of workers referred for a suspicion of OA between 1983 and 2011 and having had a specific inhalation challenge. We calculated the sensitivity, specificity, and positive and negative predictive values of methacholine challenges at baseline of the specific inhalation challenge, at the workplace, and outside work. At baseline, the methacholine challenge showed an overall sensitivity of 80.2% and a specificity of 47.1%, with positive and negative predictive values of 36.5% and 86.3%, respectively. Among the 430 subjects who were still working, the baseline measures displayed a sensitivity of 95.4%, a specificity of 40.1%, and positive and negative predictive values of 41.1% and 95.2%, respectively. Among the 582 subjects tested outside work, the baseline measures demonstrated a sensitivity and specificity of 66.7% and 52%, respectively, and positive and negative predictive values of 31.9% and 82.2%, respectively. When considering all subjects tested by a methacholine challenge at least once while at work (479), the sensitivity, specificity, and positive and negative predictive values were 98.1%, 39.1%, and 44.0% and 97.7%, respectively. A negative methacholine challenge in a patient still exposed to the causative agent at work makes the diagnosis of OA very unlikely.

Nonspecific bronchial hyperreactivity after exposure to Western Red Cedar.

A 55-year-old nonatopic man presented with a 2-year history of progressively severe conjunctivitis, rhinitis, and asthma related to exposure to freshly cut red cedar. Chest roentgenogram, lung volumes, diffusing capacity for carbon monoxide, and expiratory flow rates were normal. A histamine inhalation test demonstrated mild, nonspecific bronchial hyperreactivity. After a 35-min cumulative exposure to Western Red Cedar sawdust in the laboratory, the patient developed a late asthmatic response. Bronchial reactivity to inhaled histamine increased significantly after exposure to red cedar in the laboraotry and again after natural exposure to red cedar at work. However, on both occasions forced expiraotry volume in one sec was decreased when compared to control values. Exposure to red cedar sawdust for 15 min was repeated in the laboratory, and histamine inhalation tests were performed the day before, for 4 consecutive days after, and 11 days after exposure. Before each test, one-sec forced expiratory volume, lung volumes, specific conductance, maximal expiratory flow rates at 25 and 50 per cent of vital capacity, closing capacity, and the slope of phase III from the single-breath O2 test were measured. Six hours after exposure to cedar, all measurements documented significant airway obstruction that persisted until the second day. Bronchial responsiveness to inhaled histamine also increased on the first 2 days after exposure to cedar, but this increase persisted on the third and fourth day when all other pulmonary function tests had returned to control values. Eleven days later, the bronchial hyperreactivity to inhaled histamine had also returned to control values. In a sensitized subject, exposure to Western Red Cedar induced a transient increase in nonspecific bronchial reactivity that was present in the absence of airflow obstruction. Factors other than decreased airway caliber are probably important in this phenomenon.

Challenge inhalation tests in the diagnosis of occupational asthma: the guidelines of European Respiratory Society

This consensus statement provides practical recommendations for specific inhalation challenge (SIC) in the diagnosis of occupational asthma. They are derived from a systematic literature search, a census of active European centres, a Delphi conference and expert consensus. This article details each step of a SIC, including safety requirements, techniques for delivering agents, and methods for assessing and interpreting bronchial responses. The limitations of the procedure are also discussed. Testing should only be carried out in hospitals where physicians and healthcare professionals have appropriate expertise. Tests should always include a control challenge, a gradual increase of exposure to the suspected agent, and close monitoring of the patient during the challenge and for at least 6 hours afterwards. In expert centres, excessive reactions provoked by SIC are rare. A positive response is defined by a fall in forced expiratory volume in 1 so15 % from baseline. Equivocal reactions can sometimes be clarified by finding changes in nonspecific bronchial responsiveness, sputum eosinophils or exhaled nitric oxide. The sensitivity and specificity of SIC are high but not easily quantified, as the method is usually used as the reference standard for the diagnosis of occupational asthma.

Specific inhalation challenge in the diagnosis of occupational asthma: consensus statement

This consensus statement provides practical recommendations for specific inhalation challenge (SIC) in the diagnosis of occupational asthma. They are derived from a systematic literature search, a census of active European centres, a Delphi conference and expert consensus. This article details each step of a SIC, including safety requirements, techniques for delivering agents, and methods for assessing and interpreting bronchial responses. The limitations of the procedure are also discussed. Testing should only be carried out in hospitals where physicians and healthcare professionals have appropriate expertise. Tests should always include a control challenge, a gradual increase of exposure to the suspected agent, and close monitoring of the patient during the challenge and for at least 6 h afterwards. In expert centres, excessive reactions provoked by SIC are rare. A positive response is defined by a fall in forced expiratory volume in 1 s ≥ 15% from baseline. Equivocal reactions can sometimes be clarified by finding changes in nonspecific bronchial responsiveness, sputum eosinophils or exhaled nitric oxide. The sensitivity and specificity of SIC are high but not easily quantified, as the method is usually used as the reference standard for the diagnosis of occupational asthma.

Predictive Value of Normal Non-Specific Bronchial Responsiveness (NSBR) in the Investigation of Occupational Asthma (OA)

Although guidelines emphasize that the absence of increased NSBR virtually rules out the diagnosis of OA in a worker symptomatic while at work, the level of evidence supporting this statement is low. We thus aimed to assess the predictive value of NSBR in diagnosing OA.

Diagnostic approach in cases with suspected work-related asthma

BackgroundWork-related asthma (WRA) is a major cause of respiratory disease in modern societies. The diagnosis and consequently an opportunity for prevention are often missed in practice.MethodsBased on recent studies and systematic reviews of the literature methods for detection of WRA and identification of specific causes of allergic WRA are discussed.Results and ConclusionsAll workers should be asked whether symptoms improve on days away from work or on holidays. Positive answers should lead to further investigation. Spirometry and non-specific bronchial responsiveness should be measured, but carefully performed and validly analysed serial peak expiratory flow or forced expiratory volume in one second (FEV1) measurements are more specific and confirm occupational asthma in about 82% of those still exposed to the causative agent. Skin prick testing or specific immunoglobulin E assays are useful to document allergy to high molecular weight allergens. Specific inhalational challenge tests come closest to a gold standard test, but lack standardisation, availability and sensitivity. Supervised workplace challenges can be used when specific challenges are unavailable or the results non-diagnostic, but methodology lacks standardisation. Finally, if the diagnosis remains unclear a follow-up with serial measurements of FEV1 and non-specific bronchial hyperresponsiveness should detect those likely to develop permanent impairment from their occupational exposures.

Distinct temporal patterns of immediate asthmatic reactions due to high‐ and low‐molecular‐weight agents

Exposure to occupational agents can cause immediate asthmatic reactions. It can be hypothesized that the pattern of immediate reactions is different for high (HMW)- and low-molecular-weight (LMW) agents. To test this, we studied the temporal features of reactions in workers who underwent specific inhalation challenges for possible occupational asthma. We examined 467 immediate reactions due to HMW (n = 248, 53%) and LWW (n = 219, 47%) agents in regards to timing of the maximum reaction and recovery. The median duration of exposure to elicit significant immediate reactions was comparable for HMW and LMW agents (15 min). The median maximum fall in FEV (1) occurred after 20 min for LMW by comparison with 10 min for HMW agents (P < 0.001). The median timing of recovery of FEV (1) to 10% baseline was shorter for HMW (60 min) than for LMW (90 min) agents (P < 0.01), and significantly more subjects recovered to 10% baseline (89.5%) for HMW than for LMW agents (72.6%) (P < 0.001). Confounding variables such as age, atopy, baseline airway calibre and the maximum fall in FEV (1) at the time of the immediate reaction did not alter the significant effect of the nature of the agent per se. Immediate reactions were followed by a late asthmatic reaction more often in the case of LMW (37.3%) than HMW (26.2%) agents (P < 0.05). Significant changes in non-specific bronchial responsiveness were significantly (P = 0.02) more frequent after reactions to LMW (31.9%) than to HMW (21.4%) agents. We found similar trends by comparing reactions to flour (n = 113), the principal cause of reactions to HMW agents, and diisocyanates (n = 111), the principal LMW agent. This study shows distinct patterns for immediate reactions due to occupational agents. These results can provide useful guidelines for performing specific inhalation challenges and improve the safety of the procedure.

Sensitization and irritant-induced occupational asthma with latency are clinically indistinguishable

Acute irritant exposures at work are well-recognized causes of asthma. In the occupational setting, low-dose exposure to the same agent does not provoke asthma. Occupational asthma (OA) with latency due to irritants is not widely accepted. To compare workers with OA with latency likely to be due to irritant exposures with workers with the more usual sensitization-induced OA. Following identification of a worker who fulfils all the criteria for irritant-induced OA with latency whose investigation documented lime dust as a cause for his OA, we searched the Shield reporting scheme database between 1989 and 2010 for entries where the OA was more likely to be due to irritant than allergic mechanisms and compared these with the remainder where allergic mechanisms were likely. Outcome measures were latent interval from first exposure to first work-related symptom, non-specific bronchial reactivity, smoking, atopy and the presence of pre-existing asthma. A previously fit lecturer teaching bricklaying had irritant-induced OA with latency without unusual exposures with an immediate asthmatic reaction following exposure to a sand/lime mixture (pH 8). The Shield database identified 127 workers with likely irritant-induced asthma with latency and 1646 with hypersensitivity-induced OA. The two groups were indistinguishable in terms of pre-existing asthma, atopy, age, latent interval, non-specific reactivity and smoking. Irritant exposure is a cause of OA with latency currently clinically indistinguishable from OA due to sensitization.

Upper respiratory impairment in restorers of cultural heritage

There is a paucity of data regarding respiratory health in restorers of cultural heritage or similar occupations, such as visual artists or museum workers, although they are exposed to a complex mixture of various respiratory hazards. To evaluate atopy and respiratory health parameters, including bronchial and nasal non-specific reactivity, in restorers and conservators of cultural heritage (restorers). Fifty-six restorers and 62 controls provided general data and data on ever experienced rhinitic or asthma-like symptoms, spirometry, non-specific bronchial and nasal responsiveness to histamine, skin prick testing to common inhalational allergens and serum total IgE levels. Spirometry values were in the range of normal values in 55 of 56 restorers and did not differ significantly from those in control subjects. However, restorers had more than two times higher prevalence of nasal hyper-responsiveness (NHR), with 2.3 times higher risk of NHR compared to controls [95% confidence interval (CI): 1.4-3.6, P < 0.001]. The risk of NHR was slightly reduced by increasing age (odds ratio 0.95, 95% CI: 0.91-0.99, P < 0.05). NHR was not associated with gender, smoking status, bronchial hyperresponsiveness (BHR), upper or lower respiratory symptoms or atopy status. Compared with controls, the studied group of workers occupationally exposed to respiratory hazards during restoration/conservation activities had no deterioration of lung function but had an increased non-specific nasal responsiveness that was not correlated with upper and lower respiratory symptoms, BHR or atopy. The relationship of this finding to future clinical outcome should be investigated in a longitudinal study.

Allergen immunotherapy

Specific immunotherapy (SIT) involves the administration of allergen extracts to achieve clinical tolerance of those allergens that cause symptoms in patients with allergic conditions. Immunotherapy is effective in patients with mild forms of allergic disease and also in those who do not respond well to standard drug therapy. Most SIT is given by means of injection, but there is increasing interest in performing SIT through the sublingual route. SIT remains the treatment of choice for patients with systemic allergic reactions to wasp and bee stings and should be considered as an option in patients with allergic rhinitis, asthma, or both. SIT can modify the course of allergic disease by reducing the risk of new allergic sensitizations and inhibiting the development of clinical asthma in children treated for allergic rhinitis. The precise mechanisms responsible for the beneficial effects of SIT remain a matter of research and debate. An effect on regulatory T cells seems most probable and is associated with switching of allergen-specific B cells toward IgG4 production. Few direct comparisons of SIT and drug therapy have been made. Existing data suggest that the effects of SIT take longer to develop, but once established, SIT achieves long-lasting relief of allergic symptoms, whereas the benefits of drugs only last as long as they are continued.

The frequency of self-reported allergic diseases in patients with crimean-congo haemorrhagic fever

Background Crimean-Congo haemorrhagic fever (CCHF) is an acute, tick-borne viral disease. In temperate areas, CCHF cases occur between spring and early autumn when tick activity is high. This period is also the pollen season during which symptoms of allergic diseases are exacerbated. Viruses induce inflammatory and antiviral responses by binding to specific receptors on the surface of airway epithelial cells, resulting in activation of innate immune responses; release of mediators such as cytokines and chemokines; and recruitment of neutrophils and mononuclear cells to the area. Aim We aimed to evaluate the frequency of self-reported allergic diseases and the effect on CCHF severity. Method Between June and August 2008, a questionnaire was applied to 114 CCHF (+) patients and 122 healthy control subjects, 16 to 88 years old who attended the Infectious Diseases clinic and were hospitalised with CCHF suspected, by face to face interview including history of allergic rhinitis (AR), asthma symptoms and nonspecific bronchial reactivity, doctor diagnosed AR and/or asthma, and familial allergic diseases history. Results According to PCR and/or enzyme-linked immunoassay (ELISA) results, 51.7% of patients (n=114) had CCHF. There was no significant relation between CCHF and history of AR, asthma symptoms and nonspecific bronchial reactivity, doctor diagnosed AR and/or asthma, and familial allergic diseases history. The severity of CCHF has not affected these parameters (p>.05). Of patients with positive CCHF test, 2.6% (n=3) and 3.5% (n=4) had doctor diagnosed AR and asthma, respectively. Conclusion Self-reported allergic diseases and CCHF are not related with each other.

Asthma, airway inflammation and epithelial damage in elite athletes

In recent years there has been special focus on the increased occurrence of asthma and bronchial responsiveness among top athletes within endurance sports. As early as 1989, an increase in nonspecific bronchial responsiveness after heavy endurance training was found in young competitive swimmers 1. Later, reports were made concerning increased prevalence of asthma and bronchial hyperresponsiveness to metacholine among top cross-country skiers 2, 3. Reports came from Trondheim (Norway) regarding inflammatory changes in bronchial biopsies appearing during a winter season in young competitive cross-country skiers 4, 5. These studies confirmed that both bronchial responsiveness and airway inflammation increased through heavy endurance training 1–5. In the Olympic arena, such reports were confirmed by Voy 6, who reported a prevalence of exercise-induced asthma of 11% among the American summer Olympic athletes of 1984; this increased to >20% among the American participants in the 1996 summer Olympic Games, and was especially high among cyclists and mountain bikers 7. K. Fitch (who supplied some of the data presented in 8) reported that the use of asthma drugs and, in particular, inhaled β2-agonists, was highest in cross-country skiing and speed-skating followed by cycling, Nordic combined (both cross-country skiing and ski jumping) …

A Primer in Longitudinal Data Analysis

Longitudinal data, comprising repeated measurements of the same individuals over time, arise frequently in cardiology and the biomedical sciences in general. For example, Frison and Pocock1 used repeated measurements of the liver enzyme creatine kinase in serum of cardiac patients to study changes in liver function over a 12-month study period. The main goal, indeed the raison d’etre , of a longitudinal study is characterization of changes in the response of interest over time. Ordinarily, changes in the response are also related to selected covariates. For example, Frison and Pocock1 compared changes in creatine kinase between patients randomized to active drug and placebo. The past 25 years have witnessed remarkable developments in statistical methods for the analysis of longitudinal data. Despite these important advances, researchers in the biomedical sciences have been somewhat slow to adopt these methods and often rely on statistical techniques that fail to adequately account for longitudinal study designs. The goal of the present report is to provide an overview of some recently developed methods for longitudinal analyses that are more appropriate, with a focus on 2 methods for continuous responses: the analysis of response profiles and linear mixed-effects models. The analysis of response profiles is better suited to settings with a relatively small number of repeated measurements, obtained on a common set of occasions, whereas linear mixed-effects models are suitable in more general settings. Before describing these methods, we review some of the defining features of longitudinal studies and highlight the main aspects of longitudinal data that complicate their analysis. ### Covariance Structure A common feature of repeated measurements on an individual is correlation; that is, knowledge of the value of the response on one occasion provides information about the likely value of the response on a future occasion. Another common feature of longitudinal data is heterogeneous …

Normal Variation of Bronchial Reactivity in Nonasthmatics is Associated with the Level of Mite-Specific IgE

Objective. To investigate association between non-specific bronchial reactivity (NBR) and level of mite specific IgE amongst mite-sensitized non-asthmatic subjects. Methods. Subjects attending occupational check-up were assessed for: respiratory symptoms, atopic status (skin prick testing [SPT], total and specific IgE), spirometry and NBR. Individuals without history of respiratory disease (N = 234) were included into analysis. Results. All subjects had normal spirometry and 99% had normal NBR while 41.8% had detectable specific IgE to mites. Lung function parameters and NBR were significantly lower in mite sensitized subjects. Multiple regression analysis controlling for age, gender, smoking, family history, SPT, IgE, and lung function showed that NBR was significantly associated only with mite specific IgE level (ß = 0.26; 95% CI, 0.05–0.47; p = 0.018). Conclusion. Even in subjects without allergic symptoms, IgE-mediated sensitization does not appear to be all or nothing phenomenon influencing the normal variability of underlying airway reactivity.

Association of toxic and essential metals with atopy markers and ventilatory lung function in women and men

The association of age, smoking, alcohol, superoxide dismutase (SOD), glutathione peroxidase (GPx), blood lead (BPb) and cadmium (BCd) levels, and serum levels of copper (SCu), zinc (SZn) and selenium (SSe) with atopic status and ventilatory function was examined in the groups of 166 women and 50 men with no occupational exposure to metals or other xenobiotics. Markers of atopy included serum total IgE, skin prick test (SPT) to common inhalatory allergens, non-specific nasal reactivity (NNR) and non-specific bronchial reactivity (NBR). Parameters of ventilatory function included forced vital capacity (FVC) and forced expiratory volume in the first second (FEV 1). Significantly higher BPb, SZn, IgE and prevalence of positive SPT, and lower SCu and NNR was found in men than in women. Fifteen women taking female sex hormones (HT) had significantly higher SCu than women without HT. Regression models showed significant inverse associations between IgE and SCu ( P = 0.021) and NNR and SCu ( P = 0.044) in women. When excluding women with HT, the association of SCu and total IgE became of borderline significance ( P = 0.051), association between SCu and NNR disappeared, and significant positive association between total IgE and BPb emerged ( P = 0.046). In men, significant inverse association was found between positive SPT and SSe, and between NBR and SSe. A decrease in FVC% and FEV 1% was associated with an increase in smoking intensity ( P < 0.001) and a decrease in SZn ( P = 0.043 and P = 0.053, respectively). These results were observed at the levels of the metals comparable to those in general populations worldwide. The observed differences between men and women may partly be explained by different levels of relevant toxic and essential metals, and their combination. The role of female HT in associations of atopy markers and SCu should be further investigated.

Nonspecific Bronchial Hyperresponsiveness Caused by T. canis 2nd Stage Larval Infestation

Whether parasite infestations stimulate or inhibit bronchial asthma is debated. In epidemiologic studies, occurrence of asthma/recurrent bronchitis were associated with Toxocara seroprevalence in children. The aim of this study was to evaluate the nonspecific bronchial responsiveness in patients with toxocariasis. Seventy-one patients (mean 52.7 yr, M: F = 48: 23) with eosinophilia caused by toxocara larval infection were evaluated from September 1, 2003 through March 30, 2006.

Bronchial responsiveness to bakery‐derived allergens is strongly dependent on specific skin sensitivity

Quantitative relationships between immunological reactivity, non-specific bronchial responsiveness and bronchial responsiveness to allergens have scarcely been investigated in occupational asthma. We assessed the above relationships in 24 subjects with baker's asthma. The skin endpoint titration to bakery allergens as a measure of immunological reactivity, together with the methacholine PC20 and allergen PC20 during early asthmatic reaction were determined. All patients had positive skin tests to some bakery allergens (wheat and rye flour, soybean flour, fungal enzymes and egg white proteins) and bronchial hyperresponsiveness to methacholine. Specific inhalation challenge (SIC) tests were performed with aqueous allergen extracts of cereal flour (n = 14), soybean (n = 8), baking enzymes (n = 12), and egg white proteins (n = 8) in sensitized workers. A positive asthmatic reaction was observed in 84% of the inhalation challenges. SIC elicited isolated early asthmatic reactions in 62%, dual reactions in 32% and isolated late reactions in 5%. Multiple linear regression analysis showed allergen PC20 as a function of skin sensitivity to allergen and methacholine PC20, yielding the following highly significant regression formula: log-allergen PC20 = 0.18 + 0.99 log(skin sensitivity) + 0.343 log(methacholine PC20) (r = 0.89, P < 0.001). This formula predicted allergen PC20 to within one double concentration in 67%, to within two double concentrations in 85% and within three double concentrations in 97%. The main determinant of bronchial responsiveness to allergen in patients with baker's asthma is the degree of sensitization to occupational allergens as determined by skin reactivity, modulated to a lesser extent by non-specific bronchial hyperresponsiveness.