Canadian multidisciplinary expert consensus on the use of biologics in upper airways: a Delphi study.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) often coexists with lower airway disease. With the overlap between upper and lower airway disease, optimal management of the upper airways is undertaken in conjunction with that of the lower airways. Biologic therapy with targeted activity within the Type 2 inflammatory pathway can improve the clinical signs and symptoms of both upper and lower airway diseases. Knowledge gaps nevertheless exist in how best to approach patient care as a whole. There have been sixteen randomized, double-blind, placebo-controlled trails performed for CRSwNP targeted components of the Type 2 inflammatory pathway, notably interleukin (IL)-4, IL-5 and IL-13, IL- 5R, IL-33, and immunoglobulin (Ig)E. This white paper considers the perspectives of experts in various disciplines such as rhinology, allergy, and respirology across Canada, all of whom have unique and valuable insights to contribute on how to best approach patients with upper airway disease from a multidisciplinary perspective. METHODS: A Delphi Method process was utilized involving three rounds of questionnaires in which the first two were completed individually online and the third was discussed on a virtual platform with all the panelists. A national multidisciplinary expert panel of 34 certified specialists was created, composed of 16 rhinologists, 7 allergists, and 11 respirologists who evaluated the 20 original statements on a scale of 1-9 and provided comments. All ratings were quantitively reviewed by mean, median, mode, range, standard deviation and inter-rater reliability. Consensus was defined by relative interrater reliability measures-kappa coefficient ([Formula: see text]) value > 0.61. RESULTS: After three rounds, a total of 22 statements achieved consensus. This white paper only contains the final agreed upon statements and clear rationale and support for the statements regarding the use of biologics in patients with upper airway disease. CONCLUSION: This white paper provides guidance to Canadian physicians on the use of biologic therapy for the management of upper airway disease from a multidisciplinary perspective, but the medical and surgical regimen should ultimately be individualized to the patient. As more biologics become available and additional trials are published we will provide updated versions of this white paper every few years.

Predictors of Asthma Control and Exacerbations: A Real-World Study.

BACKGROUND: Achieving optimal asthma control and minimizing the risk of exacerbation are the main goals of asthma treatment. OBJECTIVE: This study aimed to assess the predictors of poor asthma control and asthma exacerbations within a population of moderate to severe asthmatic patients treated in a tertiary-care center. METHODS: We conducted a cohort study assessing 738 patients enrolled in the Quebec registry in respiratory health (RESP) with a diagnosis of asthma confirmed by a respirologist and treated in a tertiary care center from April 2010 to March 2016. Sociodemographic and clinical data, including Asthma Control Questionnaire score, were collected at enrollment in the registry (ie, cohort entry) and patients were followed for a 2-year period thereafter. The information regarding exacerbations that occurred during follow-up was collected in administrative databases (Régie d l'assurance médicale du Québec [RAMQ], Maintenance et exploitation des données pour l'étude de la clientèle hospitalière [MED-ECHO], and medication data registry [reMed]). RESULTS: We assessed 738 subjects (64% women). Psychological distress (odds ratio [OR] 1.91; 95% confidence interval [95% CI] 1.21-3.02), smoking (OR 3.72; 95% CI 1.72-8.05]), and poor lung function, forced expiratory volume in 1 second less than 50% (OR 4.1; 95% CI 1.48-11.34]) appeared as significant factors associated with uncontrolled asthma. Occurrence of previous asthma exacerbations (hazard ratio [HR] 6.25; 95% CI 4.01-9.75]), poor asthma control (HR 1.60; 95% CI 1.07-2.38]), forced expiratory volume in 1 second between 50% and 80% (HR 2.25; 95% CI 1.58-3.34]), and older age (HR 2.26; 95% CI 1.37-3.74]) were associated with asthma exacerbations. Adherence to asthma treatment was very low in patients with (44.4% ± 34.4%) and without asthma exacerbations (37.5% ± 33.0%). CONCLUSIONS: Psychological distress and current smoking are modifiable factors that need to be addressed in tailored behavioral interventions to improve asthma control. Asthma exacerbations are mostly associated with the intrinsic severity of the disease.

Asthma and fixed airflow obstruction: Long-term trajectories suggest distinct endotypes.

BACKGROUND: Long-term trajectories of asthma with fixed airflow obstruction (FAO) may reveal links to inflammatory endotypes. OBJECTIVE: We investigated whether measures of asthma control and airway inflammation and remodelling differed by long-term FAO status in moderate-to-severe asthma. METHODS: Adults enrolled in the Difficult Asthma Study assessed initially using serial Asthma Control Questionnaire (ACQ), exacerbation history, spirometry and sputum cytology over 12 months, as well as endoscopic bronchial biopsy with airway smooth muscle (ASM) quantification, were revaluated three or more years later with questionnaires and spirometry. FAO was defined as a persistent post-bronchodilator forced expired volume in one second (FEV1 )-to-forced vital capacity ratio below 0.70. RESULTS: Sixty-two participants (mean ± SD age 48 ± 11 years; 50% female; 75% atopic; asthma duration 24 ± 14 years) returned for follow-up assessment (median interval 7.9 years; IQR: 5.4-8.8 years). Compared to participants without FAO (n = 28), those with FAO at baseline and long-term follow-up (n = 18) had higher baseline sputum neutrophil content and ASM, and a higher exacerbation frequency that persisted at long-term follow-up. Sputum eosinophils, ACQ and long-term FEV1 decline did not differ. Participants with incident FAO at long-term follow-up (n = 16) had higher baseline exacerbation frequency, sputum eosinophil content, higher ACQ scores and greater decline in FEV1 , whereas baseline ASM was similar to those without FAO. CONCLUSION: In moderate-to-severe asthma, long-term FAO is characterized by neutrophilic sputum inflammation and airway remodelling, but FEV1 decline is similar to those without FAO. Long-term incident FAO is preceded by higher exacerbation frequency, higher sputum eosinophil content and significant FEV1 decline.

Population-based case-finding to identify subjects with undiagnosed asthma or COPD.

BACKGROUND: ∼5-10% of adults may have undiagnosed airflow obstruction. The objective of this study was to develop a population-based case-finding strategy to assess the prevalence of undiagnosed airflow obstruction (asthma or COPD) amongst adults with respiratory symptoms in Canada. METHODS: Adults without a previous history of asthma, COPD or lung disease were recruited using random digit-dialling and asked if they had symptoms of dyspnoea, cough, sputum or wheeze within the past 6 months. Those who answered affirmatively completed the Asthma Screening Questionnaire (ASQ), COPD-Diagnostic Questionnaire (COPD-DQ) and COPD Assessment Test (CAT). Those with an ASQ score of ≥6 or a COPD-DQ score of ≥20 underwent pre- and post-bronchodilator spirometry to diagnose asthma or COPD. RESULTS: 12 117 individuals were contacted at home and assessed for study eligibility. Of the 1260 eligible individuals, 910 (72%) enrolled and underwent spirometry. Ultimately, 184 subjects (20% of those enrolled) had obstructive lung disease (73 asthma and 111 COPD). Individuals found to have undiagnosed asthma or COPD had more severe respiratory symptoms and impaired quality of life compared with those without airflow obstruction. The ASQ, COPD-DQ, and CAT had ROC areas for predicting undiagnosed asthma or COPD of 0.49, 0.64 and 0.56, respectively. Four descriptive variables (age, BMI, sex and pack-years smoked) produced better receiver operating characteristic (ROC) values than the questionnaires (ROC area=0.68). CONCLUSION: 20% of randomly selected individuals who report respiratory symptoms in Canada have undiagnosed airflow obstruction due to asthma or COPD. Questionnaires could exclude subjects at low risk but lack the ability to accurately find subjects with undiagnosed disease.

Novel clinical scores for occupational asthma due to exposure to high-molecular-weight agents.

OBJECTIVE: Specific inhalation challenge (SIC) as the reference diagnostic test for occupational asthma (OA) is not widely available worldwide. We aimed to develop non-SIC-based models for OA. METHODS: Of 427 workers who were exposed to high-molecular-weight agents and referred to OA clinic at Montréal Sacré-Cœur Hospital between 1983 and 2016, we analysed 160 workers who completed non-specific bronchial hyper-responsiveness (NSBHR) tests and still worked 1 month before SIC. OA was defined as positive SIC. Logistic regression models were developed. The accuracy of the models was quantified using calibration and discrimination measures. Their internal validity was evaluated with bootstrapping procedures. The final models were translated into clinical scores and stratified into probability groups. RESULTS: The final model, which included age ≤40 years, rhinoconjunctivitis, inhaled corticosteroid use, agent type, NSBHR, and work-specific sensitisation had a reasonable internal validity. The area under the receiver operating characteristics curve (AUC) was 0.91 (95% CI 0.86 to 0.95), statistically significantly higher than the combination of positive NSBHR and work-specific sensitisation (AUC=0.84). The top 70% of the clinical scores (ie, the high probability group) showed a significantly higher sensitivity (96.4%vs86.9%) and negative predictive value (93.6%vs84.1%) than the combination of positive NSBHR and work-specific sensitisation (p value <0.001). CONCLUSIONS: We developed novel scores for OA induced by high-molecular-weight agents with excellent discrimination. It could be helpful for secondary-care physicians who have access to pulmonary function test and allergy testing in identifying subjects at a high risk of having OA and in deciding on appropriate referral to a tertiary centre.

Clinical and inflammatory characteristics of Asthma-COPD overlap in workers with occupational asthma.

INTRODUCTION: Although Asthma-COPD Overlap (ACO) has been described among populations of subjects with COPD or asthma, ACO has never been described among a population of subjects with occupational asthma (OA). OBJECTIVES: The aims of this study were to: 1. identify ACO in a population of subjects with OA; and 2. compare the clinical characteristics between ACO and OA. METHODS: This retrospective study included all subjects diagnosed with OA between 2000 and 2017 in an OA referral center. Occupational Asthma-COPD Overlap (OACO) was defined as post-bronchodilator FEV1/FVC < 70% and smoking history ≥ 10 pack-years, along with a diagnosis of OA. RESULTS: Three hundred and four subjects were included, 262 (86.2%) were classified as OA and 42 (13.8%) as OACO. OA subjects presented higher sputum eosinophil counts after a specific-inhalation challenge than subjects with OACO (median [IQR]: 6.5 [17.0] vs 2.3 [3.5]). After adjusting for confounding factors, subjects with OACO were older (OR: 1.10 [1.05; 1.14]) and were taking higher doses of inhaled corticosteroids than OA subjects (OR, 5.20 [1.77; 16.48]). Subjects with OACO were less often atopic than OA subjects (OR, 0.19 [0.07; 0.62]). CONCLUSIONS: Subjects with OACO constitute a distinct clinical and inflammatory phenotype from subjects with OA.

Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study.

BACKGROUND: This phase 3 study further characterizes the efficacy and safety of reslizumab (a humanized anti-IL-5 monoclonal antibody) in patients aged 12 to 75 years with asthma inadequately controlled by at least a medium-dose inhaled corticosteroid and with a blood eosinophil count ≥ 400 cells/µL. METHODS: Patients were randomized to receive reslizumab 0.3 or 3.0 mg/kg or placebo administered once every 4 weeks for 16 weeks (total four doses). The primary end point was change from baseline in pre-bronchodilator FEV1 over 16 weeks. Secondary end points included FVC, forced expiratory flow at 25% to 75% of FVC (FEF25%-75%), patient-reported control of asthma symptoms, short-acting ß-agonist (SABA) use, blood eosinophil levels, and safety. RESULTS: Reslizumab significantly improved FEV1 (difference vs placebo [reslizumab 0.3 and 3.0 mg/kg], 115 mL [95% CI, 16-215; P = .0237] and 160 mL [95% CI, 60-259; P = .0018]). Clinically meaningful increases in FVC (130 mL) and FEF25%-75% (233 mL/s) were observed with reslizumab 3.0 mg/kg. Reslizumab improved scores on the Asthma Control Questionnaire (ACQ) and Asthma Quality of Life Questionnaire (AQLQ) vs placebo (greater effects seen with 3.0 mg/kg; P < .05). The minimally important difference was reached for the AQLQ (reslizumab 3.0 mg/kg) but not on the ACQ. Scores on the Asthma Symptom Utility Index and SABA use were improved with reslizumab. The most common adverse events were worsening of asthma, headache, and nasopharyngitis; most events were mild to moderate in severity. CONCLUSIONS: Reslizumab improved lung function, asthma control and symptoms, and quality of life. It was well tolerated in patients with inadequately controlled asthma (despite standard therapy) and elevated blood eosinophil levels. Overall, the 3.0-mg/kg dose of reslizumab provided greater improvements in asthma outcomes vs the 0.3-mg/kg dose, with comparable safety. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01270464; URL: www.clinicaltrials.gov.

Association between patterns of leisure time physical activity and asthma control in adult patients.

BACKGROUND: Physical activity has been shown to have various health benefits in patients with asthma, especially in children. However, there are still limited data on the nature of the association between physical activity and asthma control in adults. OBJECTIVE: The objective of the current study was to determine the nature of the association between physical activity and asthma control, with particular emphasis on the intensity of the activity and seasonal variations. METHODS: 643 adult patients with objectively confirmed asthma (mean age (SD)=53 (15) years, 60% women) were interviewed by telephone. Patients completed the asthma control questionnaire (ACQ), the asthma quality of life questionnaire, and a 1-year physical activity recall questionnaire to assess leisure time physical activity (LTPA). RESULTS: Total LTPA was related to control (ß (95% CI)=-0.013 (-0.030 to 0.006)), with those doing recommended levels of LTPA being nearly 2.5 times more likely to have good control compared with inactive patients. Analysis of seasonal exercise habits found that winter LTPA (ß=-0.027 (-0.048 to -0.006)) was more strongly associated with ACQ scores than summer LTPA (ß=-0.019 (-0.037 to -0.001)). Adjustment for age, sex, season of assessment, inhaled corticosteroid (ICS) dose, body mass index, and current smoking status reduced the strength of the relationships. CONCLUSIONS: Data indicate that higher levels of LTPA are associated with better levels of asthma control in adult patients with asthma, and that this seems to be more pronounced among asthmatics who do the recommended levels of exercise.

The development and test re-test reliability of a work-related asthma screening questionnaire.

OBJECTIVE: Work-related asthma (WRA) is under-recognized and delays in recognition contribute to long-term morbidity. The objective of the project was to develop a WRA screening questionnaire for use by primary care providers in the assessment of individuals with asthma, and to evaluate the respondent burden, test re-test reliability and face validity of the questionnaire. METHODS: A literature search was undertaken and an expert advisory committee was convened. A questionnaire was drafted and assessed for feasibility of use and content validity. The study enrolled patients with asthma attending outpatient clinics and an asthma education center. Participants were asked to respond to the questionnaire on two occasions, and comment on the content (face validity) and ease of completion (respondent burden). Ethics approval was obtained from an institutional review board. RESULTS: A 14-item self-administered screening questionnaire was created. Thirty-nine participants were recruited, and 26 participants completed a second administration of the questionnaire. The items on the relation of asthma symptoms to work demonstrated substantial agreement between testings. The workplace exposures items were found to have good reproducibility. The majority of participants denied that items were repetitive, not useful or difficult to understand. CONCLUSIONS: We have developed a WRA screening questionnaire designed to aid primary care providers in the recognition of possible WRA. The tool exhibited content and face validity, good test re-test reliability and low respondent burden. Participant feedback is being considered in revisions of the questionnaire.

Occupational asthma phenotypes identified by increased fractional exhaled nitric oxide after exposure to causal agents.

BACKGROUND: The added value of fractional exhaled nitric oxide (Feno) remains controversial in the investigation of occupational asthma (OA). OBJECTIVE: We sought to assess whether or not the increase of Feno levels following positive specific inhalation challenge (SIC) was restricted to phenotypes of subjects sharing common clinical characteristics by using a statistical cluster analysis. METHODS: Subjects were investigated for possible OA in a tertiary center using SICs from 2006 to 2012. Feno levels and sputum eosinophil counts were assessed at baseline and 24 hours after SIC. We performed a 2-step cluster analysis of the subgroup of subjects with OA. A multivariate logistic regression was performed in order to identify the variables associated with an increase in Feno in subjects with OA. RESULTS: One hundred and seventy-eight subjects underwent SIC; 98 had a positive test. The cluster analysis performed in the OA subgroup identified 3 clusters. Despite a positive SIC, there was no increase in the Feno levels after exposure to occupational agents in Cluster 3, in which subjects were only exposed to low-molecular-weight (LMW) agents. The molecular weight of the agent (high molecular weight vs LMW) was the only factor associated with an increase in Feno (OR: 4.2 [1.1-16.8]) in subjects with a positive SIC. CONCLUSION: An increase in Feno after exposure to agents causing OA seems to occur more consistently in subjects with OA caused by high molecular weight than in those with OA due to LMW.

The impact of body mass index on inpatient- versus outpatient-treated chronic obstructive pulmonary disease exacerbations.

BACKGROUND: Increased body weight has been associated with worse prognoses for many chronic diseases; however, this relationship is less clear in patients with chronic obstructive pulmonary disease (COPD), with underweight patients experiencing higher morbidity than normal or overweight patients. OBJECTIVE: To assess the impact of body mass index (BMI) on the risk for COPD exacerbations. METHODS: The present study included 115 patients with stable COPD (53% women; mean [± SD] age 67±8 years). Height and weight were measured to calculate BMI. Patients were followed for a mean of 1.8±0.8 years to assess the prospective risk of inpatient-treated exacerbations and outpatient-treated exacerbations, all of which were verified by chart review. RESULTS: Cox regression models revealed that underweight patients were at greater risk for inhospital-treated exacerbations (RR 2.93 [95% CI 1.27 to 6.76) relative to normal weight patients. However, overweight (RR 0.59 [95% CI 0.33 to 1.57) and obese (RR 0.99 [95% CI 0.53 to 1.86]) patients did not differ from normal weight patients. All analyses were adjusted for age, sex, length of diagnosis, smoking pack-years, forced expiratory volume in 1 s, and time between recruitment and last exacerbation. BMI did not influence the risk of out-of-hospital exacerbations. CONCLULSIONS: The present study showed that underweight patients were at greater risk for inhospital exacerbations. However, BMI did not appear to be a risk factor for out-of-hospital exacerbations. This suggests that the BMI-exacerbation link may differ according to the nature of the exacerbation, the mechanisms for which are not yet known.

Impact of maternal use of asthma-controller therapy on perinatal outcomes.

BACKGROUND: Asthma during pregnancy usually requires treatment with controller medications about which more safety information is needed. The objectives are to assess the impact of the use of long-acting ß2-agonists (LABAs) and the dose of inhaled corticosteroids (ICSs) during pregnancy on the prevalence of low birth weight (LBW), preterm birth (PB) and small for gestational age (SGA). METHODS: A cohort of women with asthma giving birth from 1998 to 2008 was constructed from Québec (Canada) administrative databases. LBW was defined as weight <2500 g, PB as delivery before 37 weeks' gestation and SGA as a birth weight below the 10th percentile. The impact of the use of LABAs and the dose of ICSs during pregnancy on the outcomes was determined with generalised-estimating-equation models. RESULTS: The cohort included 7376 pregnancies: 8.8% exposed to LABAs and 56.9% exposed to ICSs. All LABA users also received ICSs. The prevalence of LBW, PB and SGA was 7.7%, 9.5% and 13.5%, respectively. LABA use was not found to be associated with increased prevalence of LBW (OR 0.81; 95% CI 0.58 to 1.12), PB (OR 0.84; 95% CI 0.61 to 1.15) or SGA (OR 0.92; 95% CI 0.70 to 1.20). Mean ICSs doses >125 µg/day (fluticasone-equivalent) were associated with a non-significant trend of increased LBW, PB and SGA. CONCLUSIONS: Despite the possibility of residual confounding due to uncontrolled or more severe asthma or smoking status, the use of LABA and low to moderate doses of ICSs were not associated with increased prevalence of perinatal outcomes. Additional research on higher ICSs doses is required to better evaluate their safety during pregnancy.

Comparison of the adherence and persistence to inhaled corticosteroids among adult patients with public and private drug insurance plans.

BACKGROUND: Despite important differences in reimbursement procedures between private and public drug insurance plans in Quebec (Canada), no study has evaluated the impact of the type of drug insurance on the use of essential medications such as inhaled corticosteroids (ICS). The lack of data might be attributable, at least in part, to the absence of a provincial medication database for patients with private drug insurance. OBJECTIVES: To compare patient's adherence and persistence to ICS between Quebec residents (Canada) with private and public drug insurance. METHODS: A matched cohort design with patients selected from the database of the Régie de l'assurance maladie du Québec (RAMQ) and from reMed, a database that we have put in place for Quebec residents covered by a private drug insurance, was used. ICS users with private drug insurance were selected from reMed between 2008 and 2010 and matched to ICS users with public drug insurance selected from the RAMQ database. Patient's adherence, measured with the proportion of prescribed days covered (PPDC) and persistence over one year, was compared between patients privately and publicly insured using linear regression and Cox regression models. RESULTS: This study included 330 and 1,109 ICS users with private and public drug insurance, respectively. Patients privately insured were significantly less adherent than patients publicly insured (adjusted mean difference of PPDC: -9.7%; 95% CI: -13.2% to -6.5%). Moreover, patients privately insured were found to be 52% more likely to stop ICS during the first year than patients publicly insured (adjusted HR=1.5; 95% CI: 1.2 to 2.0). CONCLUSIONS: Although adherence and persistence were rather low in both groups, patients with public drug insurance appeared to have greater adherence and persistence to ICS than patients with private drug insurance. Differences in reimbursement policies might explain the observed differences.

Airway inflammatory responses following exposure to occupational agents.

BACKGROUND: Airway inflammatory responses to specific inhalation challenges (SICs) with low-molecular-weight (LMW) and high-molecular-weight (HMW) agents have not been studied thoroughly. We assessed the changes in airway inflammatory cells following SIC in sensitized workers, and looked at the influence of various factors on the pattern of inflammatory responses to SIC. METHODS: Induced sputum analysis was performed in workers sensitized to LMW (n = 41) or HMW agents (n = 41) after a control day and after a positive SIC. Cell counts were compared with lung function and various clinical parameters. RESULTS: In the LMW group, eosinophils were increased following late asthmatic responses (median [interquartile range], 0.02 [0.04] × 10(6) cells/g vs 0.30 [0.80] × 10(6) cells/g and 1.0% [3.5] vs 8.9% [8.0], P < .05), as were neutrophil numbers (0.8 [1.3] × 10(6) cells/g vs 2.3 [5.4] × 10(6) cells/g, P = .04). In the HMW group, eosinophil percentages increased both after early (1.0% [2.2] vs 5.5% [14.5], P = .003) and dual asthmatic responses (4.5% [3.7] vs 15.0% [13.7], P = .02). In the LMW group, the increases in neutrophils were higher in current smokers than in ex-smokers or nonsmokers. The length of exposure to the agent, tobacco use, and baseline percentage of eosinophils were independent predictors of the change in eosinophils, whereas age and baseline neutrophil percentage were predictors of the change in neutrophils. CONCLUSIONS: This study confirms that eosinophils and neutrophils are increased after SIC, whatever the causal agent. The type of agent is not predictive of the inflammatory response to SIC. Smoking is associated with a more neutrophilic response after SIC with an LMW agent.

Risk of perinatal mortality associated with inhaled corticosteroid use for the treatment of asthma during pregnancy.

BACKGROUND: Four studies investigating the association between inhaled corticosteroid (ICS) use during pregnancy and perinatal mortality reported no significantly increased risk. These studies must be interpreted with caution because they have insufficient statistical power and a lack of adjustment for potential confounders. OBJECTIVES: We sought to evaluate whether asthmatic women exposed to ICSs during pregnancy are more at risk of perinatal mortality than asthmatic women not exposed. We also sought to estimate the risk of perinatal mortality as a function of the daily ICS dose taken during pregnancy. METHODS: From the linkage of 3 administrative databases from Quebec, a cohort including 13,004 single pregnancies from asthmatic women was constructed. We used a 2-stage sampling cohort design to obtain information on cigarette smoking from the medical charts of 487 mothers. The final estimates of the odds ratios (ORs) of perinatal mortality were estimated with a logistic regression model. RESULTS: The cohort was formed of 4,140 women who used greater than 0 to 250 µg/d ICS, 1,140 women who used greater than 250 µg/d ICS, and 7,724 nonusers of ICSs during pregnancy. Women exposed to ICSs (any dose) had a nonsignificant increased risk of perinatal mortality (OR, 1.07; 95% CI, 0.70-1.61). The use of greater than 250 µg/d ICS was associated with a nonsignificant 52% increased risk of perinatal mortality (OR, 1.52; 95% CI, 0.62-3.76). CONCLUSION: The risk of perinatal mortality was not found to be significantly associated with ICS use during pregnancy. The result associated with higher doses of ICSs is limited due to a lack of statistical power and a possibility of residual confounding by asthma severity and control.

Protocol: influence of budesonide and budesonide/formoterol on asthma control in smoking asthmatic adults.

RATIONALE: A reduced response to inhaled corticosteroids (ICS) has been reported in smoking asthmatic patients but the effects of other medications remain to be evaluated in this population. SUBJECTS AND METHODS: We evaluated the effects of a combined therapy of budesonide 200 microg twice daily and formoterol 6 microg twice daily compared with budesonide 200 microg twice daily alone on asthma control questionnaire (ACQ), asthma quality of life questionnaire (AQLQ- Juniper), pulmonary function and airway inflammation, in a cross-over randomized double-blind study with treatment periods of two months separated by a one-month wash-out period. Seventeen smoking and 22 non-smoking patients not using inhaled corticosteroids with slightly uncontrolled mild asthma completed the study. RESULTS: ACQ and AQLQ scores were similar in both groups at baseline and improved similarly after treatments. beta2-agonist use was higher in smokers, regardless of the treatment received (p=0.03), as it was on baseline (p=0.003). Smokers treated with budesonide/formoterol showed an increase in the number of asthma episodes (intercurrent asthma symptoms, p=0.016) while non-smoking subjects had a significant decrease in these episodes (p=0.009). No difference was found between smokers and non-smokers in regard to post-treatment airway inflammatory parameters. CONCLUSIONS: No significant differences were found between smoking and non-smoking subjects with mild asthma in regard to clinical changes in asthma control, pulmonary function and airway inflammation following a 2-month treatment period with budesonide or the association of budesonide and formoterol for a period of 2 months. This should be further explored in larger groups of subjects.

Risk of perinatal mortality associated with asthma during pregnancy: a 2-stage sampling cohort study.

BACKGROUND: The association between maternal asthma during pregnancy and perinatal mortality has been investigated in 21 studies, and a significantly increased risk among asthmatic women was found in 4 studies. However, these studies have methodologic limitations, such as lack of adjustment for cigarette smoking, a major risk factor for perinatal mortality. OBJECTIVE: To evaluate whether maternal asthma during pregnancy increases the risk of perinatal mortality. METHODS: From the linkage of 3 administrative databases from Québec, Canada, a cohort including 13,100 asthmatic and 28,042 nonasthmatic women who had at least 1 pregnancy between 1990 and 2002 was constructed. We used a 2-stage sampling cohort design to obtain information on cigarette smoking and other potential confounders from the medical records of 1,247 selected mothers. RESULTS: In the cohort, 353 cases of perinatal mortality were identified, and we were able to retrieve the medical record of the mother for 304 cases. A significantly increased crude risk of perinatal mortality of 34% among asthmatic women compared with nonasthmatic women was found, but the odds ratio did not remain significant after adjustment for placental abruption and cigarette smoking (odds ratio, 1.12; 95% confidence interval, 0.87-1.45). CONCLUSION: The risk of perinatal mortality was not found to be significantly associated with maternal asthma after the effect of smoking was removed.

T Cells localize with proliferating smooth muscle alpha-actin+ cell compartments in asthma.

RATIONALE: Airway remodeling in asthma comprises increased airway smooth muscle (ASM), an alteration linked to airway hyperresponsiveness and disease severity. Experimental studies showed that T cells adhere to ASM through vascular cell adhesion molecule-1 (VCAM-1) and drive ASM growth through direct contact between the T cells and smooth muscle alpha-actin (alpha-SMA)(+) cells. OBJECTIVES: To support the hypothesis of a T-cell/alpha-SMA(+) cell contact mechanism of ASM remodeling in asthma, using bronchial biopsies. METHODS: We performed quantitative morphology on T cells, proliferating cell nuclear antigen (PCNA), alpha-SMA, and VCAM-1 on biopsies from subjects with moderate and severe asthma and healthy control subjects. MEASUREMENTS AND MAIN RESULTS: We demonstrate ASM cell proliferation and infiltration by T cells in proportion to severity in the subjects with asthma. T cells localized with alpha-SMA(+)PCNA(+) cells, suggesting direct intercellular contact and a relationship with alpha-SMA(+) cell proliferation. Furthermore, the subjects with asthma developed a proliferating compartment of subepithelial alpha-SMA(+), nonorganized airway contractile elements (NOACE), suggesting a phenotype gradient from undifferentiated cells to smooth muscle-like cells. T-cell juxtaposition events were also observed in this compartment and correlated to its mass. The subjects with asthma showed VCAM-1 expression in postcapillary venules and clusters of VCAM-1 immunoreactivity in ASM and NOACE, consistent with a role of VCAM-1 in T-cell/alpha-SMA(+) cell interaction. CONCLUSIONS: T cells may induce alpha-SMA(+) cell proliferation through direct intercellular contact. NOACE may in part contribute to ASM growth through differentiation and translocation of alpha-SMA(+) cells. The findings support the role of the T cell in ASM remodeling in asthma.

Outcome of occupational asthma after removal from exposure: A follow-up study.

BACKGROUND: Despite being removed from their workplace, the majority of workers with occupational asthma (OA) remain afflicted with asthma. OBJECTIVES: To assess the time course of clinical, functional and inflammatory parameters in subjects with OA over a four-year period, and whether the airway inflammation observed at the time of the diagnosis predicts the outcome of OA. METHODS: The present study was a four-year, prospective, longitudinal investigation of workers with OA. Spirometry, methacholine challenge and sputum induction were performed at two weeks, and followed up at six months, and one, two, three and four years after the performance of specific inhalation challenges. RESULTS: A total of 24 subjects were enrolled. Overall, clinical and functional characteristics remained stable during the four-year follow-up period. Sputum eosinophil (Eos) counts  decreased within two weeks after exposure. Two groups of subjects were identified according to low (less than 2%, Eos-) or high (2% or greater, Eos+) Eos counts after exposure to the offending agent. The Eos+ group decreased their dose of inhaled corticosteroids, had a trend toward an improvement of airway responsiveness as well as a stable forced expiratory volume in 1 s (FEV1), whereas the Eos- group showed a decrease in FEV1, without any improvement in their functional parameters. The Eos- group also had an increase in sputum neutrophils after exposure to the occupational agents as well as during the follow-up period. CONCLUSION: There was a rapid decrease in eosinophilic inflammation after removal from exposure. Subjects with a noneosinophilic asthmatic reaction during specific inhalation challenge seemed to have a poorer prognosis than subjects with eosinophilic airway  inflammation.