Exosomal miR-17-5p, miR-146a-3p, and miR-223-3p Correlate with Radiologic Sequelae in Survivors of COVID-19-Related Acute Respiratory Distress Syndrome.

We investigated the association between circulating microRNAs (miRNAs) potentially involved in the lung inflammatory process and fibrosis development among COVID-19-related acute respiratory distress syndrome (ARDS) survivors. At 4 ± 2 months from clinical recovery, COVID-19-related ARDS survivors matched for age, sex, and clinical characteristics underwent chest high-resolution computerized tomography (HRCT) and were selected based on imaging pattern evolution into fully recovered (N = normal), pulmonary opacities (PO) and fibrosis-like lesions (FL). Based on the previous literature, we performed plasma miRNA profiling of exosomal miRNAs belonging to the NLRP3-inflammasome platform with validated (miR-17-5p, miR-223-3p) and putative targets (miR-146a-5p), miRNAs involved in the post-transcriptional regulation of acute phase cytokines (miR128-3p, miR3168, miR125b-2-3p, miR106a-5p), miRNAs belonging to the NLRP4-inflammasome platform (miR-141-3p) and miRNAs related to post-transcriptional regulation of the fibrosis process (miR-21-5p). miR-17-5p, miR-223-3p, and miR-146a-5p were significantly down-regulated in patients with FL when compared to patients with PO. miR-146a-5p was also down-regulated in patients with FL than in N. The expression of the remaining miRNAs did not differ by group. In patients with long-term pulmonary radiological sequelae following COVID-19-related ARDS, a down-regulation of miR-17-5p, miR-146a-3p, and miR-223-3p correlated to fibrosis development in patients showing persistent hyper-reactivity to inflammatory stimulation. Our results support the hypothesis that NLRP3-Inflammasome could be implicated in the process of fibrotic evolution of COVID-19-associated ARDS.

Mild/Moderate Asthma Network in Italy (MANI): a long-term observational study.

OBJECTIVE: The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences. METHODS: This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844). RESULTS AND CONCLUSION: Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease. ABBREVIATIONS: MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting ß2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

Mepolizumab Effectiveness and Allergic Status in Real Life.

BACKGROUND: It is not clear whether mepolizumab is differently effective in allergic and nonallergic severe eosinophilic asthmatics (SEA) in real life. OBJECTIVE: We tested mepolizumab effectiveness in allergic/nonallergic SEA in real life. A strict criterion to identify the 2 phenotypes was used. METHOD: We retrospectively considered 134 consecutive patients divided into allergic, with a positivity to at least 1 allergen to prick tests and/or IgE values ≥100 UI/mL (severe allergic eosinophilic asthma [SAEA]; n: 97-72.4%), and nonallergic, with no prick test results and normal IgE levels <100 UI/mL (severe nonallergic eosinophilic asthma [SNAEA]; n: 37-27.6%). They had taken mepolizumab for at least 6 months. RESULTS: After 10.9 ± 3.7 months, improvements in FEV1%, FEF25-75%, exacerbation numbers, blood eosinophil (BE) counts, fractional exhaled nitric oxide (FENO) (ppb), percentages of patients that stopped/reduced short-acting ß2-agonists (SABAs) or oral corticosteroid (OC), observed after treatment, were similar in both groups. Only Asthma Control Test (ACT) increases were higher in SNAEA (8 [5-9]) than in SAEA (5 [2.5-8.5]; p = 0.016). However, no differences were found after treatment in percentages of subjects with ACT ≥20, as well as with FEV1 >80%, FEF25-75 >65%, exacerbations ≤2, BE <300 cells/µL, and FENO <25 ppb between SAEA and SNAEA. Besides, no significant relationships were found, comparing SNAEA with SAEA, for FEV1% (ß = -0.110; p = 0.266), FEF25-75% (ß = -0.228; p = 0.06), BE counts (ß = -0.012; p = 0.918), FENO (ß = 0.234; p = 0.085), ACT (ß = 0.046; p = 0.660), and exacerbations (ß = -0.070; p = 0.437). No different associations between lung function and SNAEA occurrence when compared to SAEA condition (FEV1 >80%: OR = 1.04 [95% CI: 0.43-2.55], p = 0.923; FEF25-75 >65%: OR = 0.41 [95% CI: 0.08-2.03], p = 0.272) were detected. Neither all other parameters, such as ACT >20 (OR = 0.73 [95% CI: 0.32-1.63], p = 0.440), presence of exacerbations (OR = 1.35 [95% CI: 0.55-3.27], p = 0.512), SABA discontinuation (OR = 1.16 [95% CI: 0.40-3.39], p = 0.790), and OC cessation/reduction (OR = 3.44 [95% CI: 0.40-29.27], p = 0.258), were differently associated with 1 or the other phenotype. CONCLUSION: Mepolizumab can be considered as a valid therapeutic choice for either allergic or nonallergic SEA in real life.

Exposure to additives or multigrain flour is associated with high risk of work-related allergic symptoms among bakers.

OBJECTIVES: Wheat flour exposure in bakers can elicit respiratory and skin symptoms. Scarce data are available on the prevalence of such conditions in bakers. We investigated the prevalence of work-related rhinitis, asthma-like symptoms and dermatitis in bakers according to job task and type of allergens involved. METHODS: Of the 229 traditional bakeries in Verona area who were invited to participate in a cross-sectional survey, 211 (92%) accepted; 727 employees in these bakeries answered a modified version of a questionnaire on job tasks; allergen exposure within the bakery; and work-related nasal, asthma-like and skin symptoms during 2010-2014. Determinants of work-related nasal, asthma-like or skin disorders were separately evaluated using different logistic models. RESULTS: The prevalence of work-related nasal and asthma-like symptoms was, respectively, 15.1% and 4.2% in bakery shop assistants, increasing to 25.7% and 9.5% in bakers using only wheat flour, and further to 31.8% and 13.6% in bakers using flour and additives, and then to 34.1% and 18.2% in bakers using flour with additives and multigrain (p<0.001). The risk of work-related asthma-like symptoms was more than doubled in bakers using additives without or with multigrain than in shop assistants (OR 2.3, 95% CI 1.0 to 5.5 and OR 3.4, 95% CI 1.1 to 10.8, respectively). Making bread with additives alone or with multigrain significantly increased the risk of work-related nasal symptoms in shop assistants, while the risk of skin symptoms was not significantly affected. CONCLUSIONS: Bakers using additives alone or with multigrain are at a high risk of experiencing nasal and asthma-like symptoms.

Impact of the COVID-19 pandemic and work-related stress in Umbrian healthcare workers during Phase 1 in Italy.

BACKGROUND: Depression, anxiety, psychological distress, and poor sleep quality increased in healthcare workers (HCWs) during the COVID-19 pandemic. The aim of the study was to assess levels of psychological distress in Umbrian HCWs during the COVID-19 Phase 1 lockdown along with exploring the relationship between sociodemographic/occupational factors. METHODS: Data on sociodemographic and occupational characteristics, change of job description, economic losses and emergency involvement and SARS-CoV2 infections in the workplace were collected using an anonymous online survey sent by healthcare professional associations. Data concerning psychological healthcare distress, were collected anonymously using BIAS 20 (stress balance) and Depression Anxiety Stress Scales (DASS-21). RESULTS: One thousand and one healthcare workers responded to the questionnaire. Biological risk at work was perceived by all HCWs, less so from psychologists and more so from those working in hospitals. Stress symptoms (DASS21 >14) were associated with a younger age group (OR 0.98; 95% CI 0.97-0.99) and less work experience (OR 0.98; 95% CI 0.96-0.99). Younger age was also associated with anxiety symptoms (DASS 21 >7) (OR 0.98; 95% CI 0.97-0.99), as well as graduate/post graduate education level (OR 2.04; 95% CI 1.14-3.63). Working as an independent contractor was a risk factor for high stress health impact (OR 2.00; CI 1.40-2.86) and stress (OR 1.87; CI 1.20-2.92), anxiety (OR 1.89; CI 1.22-2.92) and depression (OR 1.57; CI 1.10-2.22) symptoms. CONCLUSIONS: Our study showed a possible relationship between healthcare type of employment and distress symptoms during Covid19 pandemic phase 1. Results of our study should be confirmed in other Italian healthcare settings and could serve as a preliminarily baseline for multidisciplinary Italian collaboration.

Mepolizumab effectiveness on small airway obstruction, corticosteroid sparing and maintenance therapy step-down in real life.

BACKGROUND: Mepolizumab (MEP) has been recently introduced to treat severe eosinophilic asthma. Trials have demonstrated a significant effectiveness in this asthma phenotype. We evaluated MEP efficacy on lung function, symptoms, asthma exacerbations, biologic markers, steroid dependence and controller treatment level in real-life. METHODS: We retrospectively analyzed 134 severe asthmatics (61 males; mean age 58.3 ± 11; mean FEV1%:72 ± 21), treated with MEP for at least 6 months (mean duration:10.9 ± 3.7 months). RESULTS: FEV1% improved significantly after MEP. Mean FEF25-75 also increased from 37.4 ± 25.4% to 47.2 ± 27.2% (p < 0.0001). Mean baseline blood eosinophil level was 712 ± 731/µL (8.4 ± 5.2%) decreasing to 151 ± 384/µL (1.6 ± 1.6%) (p < 0.0001), FENO levels decreased likewise. MEP treatment also led to a significant ACT improvement (mean pre:14.2 ± 4.4; mean post:20.5 ± 28) and exacerbations significantly fell from 3.8 ± 1.9 to 0.8 ± 1.1 (p < 0.0001). 74% of patients were steroid-dependent before MEP. 45.4% and 46.4% of them showed a suspension and dose reduction respectively (p < 0.0001). A significant number reduced also ICS doses. Only 67% of subjects used SABA as needed before MEP, falling to 20% after MEP. About 40% of patients highlighted a maintenance therapy step-down. Subjects showing an omalizumab treatment failure before MEP had a similar positive response when compared with omalizumab untreated patients. CONCLUSION: In real-life, MEP improved significantly all outcomes even small airway obstruction, suggesting its possible role also in distal lung region treatment. Furthermore, it demonstrated its high effectiveness in OC/ICS-sparing, in reducing SABA as needed and in stepping-down maintenance therapy. MEP is a valid alternative for patients with previous omalizumab treatment failure.

Food processing and occupational respiratory allergy- An EAACI position paper.

Occupational exposure to foods is responsible for up to 25% of cases of occupational asthma and rhinitis. Animal and vegetable high-molecular-weight proteins present in aerosolized foods during food processing, additives, preservatives, antioxidants, and food contaminants are the main inhalant allergen sources. Most agents typically cause IgE-mediated allergic reactions, causing a distinct form of food allergy (Class 3 food allergy). The allergenicity of a food protein, allergen exposure levels, and atopy are important risk factors. Diagnosis relies on a thorough medical and occupational history, functional assessment, assessment of sensitization, including component-resolved diagnostics where appropriate, and in selected cases specific inhalation tests. Exposure assessment, including allergen determination, is a cornerstone for establishing preventive measures. Management includes allergen exposure avoidance or reduction (second best option), pharmacological treatment, assessment of impairment, and worker's compensation. Further studies are needed to identify and characterize major food allergens and define occupational exposure limits, evaluate the relative contribution of respiratory versus cutaneous sensitization to food antigens, evaluate the role of raw versus cooked food in influencing risk, and define the absolute or relative contraindication of patients with ingestion-related food allergy, pollinosis, or oral allergy syndrome continuing to work with exposure to aerosolized food allergens.

Occupational risk factors for idiopathic pulmonary fibrosis in Southern Europe: a case-control study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown cause associated with the histopathologic and/or radiologic pattern of usual interstitial pneumonia (UIP). Occupational risk factors have been proposed to be associated with UIP. The aim of this case-control study is to evaluate the relationship between UIP pattern and occupational exposure in Southern Europe. METHODS: Sixty nine cases with a UIP radiological pattern at CT-scan were selected from a clinical database of the University Hospital of Perugia, Umbria, between January 2010 and December 2013. Controls (n = 277) not reporting doctor diagnosed pulmonary fibrosis, were ascertained casually among general population from the same catching area of cases. Data were collected by a questionnaire used previously in a similar study. Logistic regression models, adjusted for gender, age and smoking, were performed to evaluate the association between UIP and occupational exposure. RESULTS: Farmers, veterinarians and gardeners (OR = 2.73, 95%CI = 1.47-5.10), metallurgical and steel industry workers (OR = 4.80, 95%CI = 1.50-15.33) were occupations associated with UIP. Metal dust and fumes and organic dust were risk factors for UIP. Increasing the length of occupational exposure in jobs at risk of pulmonary fibrosis, increased the risk of having UIP. CONCLUSIONS: This case control study confirm partially the results from previous similar studies. Some discrepancies could be explained by the different geographical origins of the population under study, reflecting also different occupational exposures.

Upper airway and eye involvement in polyurethane shoe sole production workers.

OBJECTIVES: This cross-sectional study was aimed to investigate the prevalence of work-related upper and lower airway and eye symptoms in 118 workers in polyurethane shoe soles (PSS) production. METHODS: Workplace monitoring of methylene diphenyl diisocyanate (MDI) and solvents was performed. Subjects completed a study-specific questionnaire and underwent anterior rhinoscopy, skin prick tests for common aeroallergens, spirometry, nasal peak inspiratory (NPIF) and expiratory flow (NPEF). RESULTS: MDI and solvent levels were below threshold limit value-time-weighted average (TLW-TWA) except for two measures of dichloromethane and tetrachloroethylene, respectively, and in one measure of acetonitrile, which were higher then TLW-TWA. In exposed workers the prevalence of cough (p < 0.05) and nasal congestion at rhinoscopy (p = 0.05) was more frequent than in non-exposed workers. Occupational exposure (OR 4.5, 95% CI 1.2-16.5) and a low FEV1 (OR 2.6, 95% CI 1.1-6.3) were significant predictors of cough. CONCLUSIONS: In workers exposed to low levels of MDI and solvents in polyurethane shoe sole production there was a high prevalence of cough and nasal congestion. An improvement in the exhaust ventilation system and other preventive measures were needed.

Asthma and rhinitis in cleaning workers: a systematic review of epidemiological studies.

OBJECTIVE: This article presents a systematic review of epidemiological studies linking cleaning work and risk of asthma and rhinitis. METHODS: Published reports were identified from PubMed covering the years from 1976 through June 30, 2012. In total, we identified 24 papers for inclusion in the review. The quality of studies was evaluated using the Strengthening of the Reporting of Observational Studies in Epidemiology (STROBE) statement checklist of 22 items for cross-sectional, cohort and case-control studies. RESULTS: Increased risk of asthma or rhinitis has been shown in 79% of included epidemiological studies. In four studies the increased risk of asthma in cleaning workers was confirmed by objective tests, such as bronchial hyper-reactivity or airflow obstruction. Level of exposure to cleaning products, cleaning sprays, bleach, ammonia, mixing products and specific job tasks has been identified as specific causes of asthma and rhinitis. CONCLUSIONS: Possible preventive measures encompass the substitution of cleaning sprays, bleach and ammonia, avoidance of mixing products, the use of respiratory protective devices, worker education and medical surveillance.

Chronic use of Datura stramonium cigarettes and late diagnosis of bullous emphysema in a smoker of marijuana and tobacco.

Unconventional inhaled therapy as a treatment for respiratory diseases became very common during the 19th century. Here, we present the case of a 52-year-old patient who smoked Datura stramonium cigarettes, tobacco cigarettes, and cannabis, with only an early diagnosis of asthma. The patient was admitted to our hospital with acute respiratory syndrome, characterized by worsening dyspnea, cough, and an acute episode of dyspnea and chest tightness. The combined chronic use of both D. stramonium cigarettes and cannabis masks the progression of chronic obstructive lung damage due to tobacco cigarette smoking because of the lack of clinical signs and symptoms.

Industrial Air Pollution and Respiratory Health Status among Residents in an Industrial Area in Central Italy.

The area of Civitavecchia (Lazio region, Central Italy) has been a reason of concern in the past because of environmental air contamination. The aim of this study was to evaluate the association between air pollution from different sources and respiratory symptoms and lung function in the population. A sample of 1177 residents underwent medical examination and lung function tests. Information on individual characteristics, histories of exposure and medical history were collected through a validated questionnaire. Long-term exposure to industrial, harbour, biomass combustion emissions (PM10) and urban traffic (NOx) at residential address was assessed using a Lagrangian dispersion model. The associations between exposure and wheezing and dyspnea were assessed using logistic regression models, while modified Poisson regression models were used to evaluate cough with phlegm. Relationships between exposure and lung function were analysed using linear mixed-effects models and cross-correlation. PM10 emissions from the harbour were associated with lower lung function parameters (FEV1: ß = -0.12, 95% CI -0.21 -0.03; p = 0.02; FEV1/FVC: ß = -1.67, (-3.10 -0.23); p = 0.02. This association was observed also in healthy subjects, but not in females. We found, even if at low exposure level, an effect of environmental PM10 exposure from harbour on lung function.

EAACI position paper on occupational rhinitis.

The present document is the result of a consensus reached by a panel of experts from European and non-European countries on Occupational Rhinitis (OR), a disease of emerging relevance which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored on that of occupational asthma, as well as a diagnostic algorithm based on steps allowing for different levels of diagnostic evidence are proposed. The needs for future research are pointed out. Key messages are issued for each item.

Severe Occupational Asthma: Insights From a Multicenter European Cohort.

BACKGROUND: Although sensitizer-induced occupational asthma (OA) accounts for an appreciable fraction of adult asthma, the severity of OA has received little attention. OBJECTIVE: The aim of this study was to characterize the burden and determinants of severe OA in a large multicenter cohort of subjects with OA. METHODS: This retrospective study included 997 subjects with OA ascertained by a positive specific inhalation challenge completed in 20 tertiary centers in 11 European countries during the period 2006 to 2015. Severe asthma was defined by a high level of treatment and any 1 of the following criteria: (1) daily need for a reliever medication, (2) 2 or more severe exacerbations in the previous year, or (3) airflow obstruction. RESULTS: Overall, 162 (16.2%; 95% CI, 14.0%-18.7%) subjects were classified as having severe OA. Multivariable logistic regression analysis revealed that severe OA was associated with persistent (vs reduced) exposure to the causal agent at work (odds ratio [OR], 2.78; 95% CI, 1.50-5.60); a longer duration of the disease (OR, 1.04; 95% CI, 1.00-1.07); a low level of education (OR, 2.69; 95% CI, 1.73-4.18); childhood asthma (OR, 2.92; 95% CI, 1.13-7.36); and sputum production (OR, 2.86; 95% CI, 1.87-4.38). In subjects removed from exposure, severe OA was associated only with sputum production (OR, 3.68; 95% CI, 1.87-7.40); a low education level (OR, 3.41; 95% CI, 1.72-6.80); and obesity (OR, 1.98; 95% CI, 0.97-3.97). CONCLUSIONS: This study indicates that a substantial proportion of subjects with OA experience severe asthma and identifies potentially modifiable risk factors for severe OA that should be targeted to reduce the adverse impacts of the disease.

Riflessioni medico-legali su un caso giudizario di mobbing.

Lo stress e le violenze morali nei luoghi di lavoro, come indicato dai dati epidemiologici, sono in costante aumento e rappresentano una causa di alterazione dello stato di salute dei lavoratori, con importanti ricadute negative sui soggetti, sulle aziende e sulla società. Nel caso descritto qui di seguito, le violenze morali e la disfunzionalità organizzativa, una delle principali fonti di stress correlato al lavoro, sono state intenzionalmente impiegate quale mezzo mobbizzante nei confronti di un lavoratore da parte dei suoi superiori (mobbing verticale). Attraverso il procedimento giudiziario, intrapreso dal lavoratore per vedersi riconosciuto vittima di mobbing, è stato possibile ripercorrere e identificare le ragioni e le modalità dell'azione mobbizzante, l'eziopatogenesi della conseguente psicopatologia, la sua strutturazione e la manifestazione sintomatologica. L'esame del caso permette di formulare delle considerazioni riguardo la necessità che i casi di mobbing siano trattati all'interno di un team multidisciplinare (medico di famiglia, medico del lavoro, psichiatra e medico legale) al fine di garantire un efficace trattamento terapeutico e la tutela del lavoratore nei diversi ambiti previsti dalla legge.

Update on asthma and cleaning agents.

PURPOSE OF REVIEW: Asthma due to cleaning products has been known for 20 years, and the interest in this topic is still large because of the number of cleaning workers with respiratory problems. In this review, we sought to highlight the most recent findings on the relationship between exposure to cleaning products and asthma and to summarize the specific literature published between 2013 and 2016. RECENT FINDINGS: Women are confirmed as most of workers exposed to cleaning products and have a higher frequency than men of work-related respiratory symptoms and diseases. Many cases of asthma due to cleaning products occur in healthcare occupations. The increased risk of asthma has been shown to be related to the number of years in the job and to early life disadvantage. Recent evidence suggests that predisposition to adult-onset asthma may be related to interaction between genes and occupational exposure to low-molecular weight agents/irritants. There is some evidence that an irritant mechanism is more common, although several case reports showed animmunologic mechanism (e.g. disinfectants, amine compounds, aldehydes and fragrances). SUMMARY: The review updated recent findings on epidemiology, cleaning agents and their mechanism, and prevention of asthma due to cleaning agents. This article provides new information on the level of exposure, which is still high in professional cleaners and even more in domestic cleaners, and on the frequency of asthma in professional and domestic cleaners. An irritant mechanism is more common, although an immunological mechanism is possible, especially in healthcare workers exposed to disinfectants.

Occupational rhinitis affects occupational asthma severity.

BACKGROUND: The strong interactions between asthma and rhinitis, and the influence of rhinitis in the severity and/or control of asthma, have clearly been demonstrated. Nevertheless, no specific study has been conducted in the occupational setting. OBJECTIVE: The aim of the study was to assess the severity of occupational asthma and rhinitis and evaluate whether rhinitis is a predictor for increased asthma severity. METHODS: We retrospectively reviewed the clinical charts of 72 patients who received a diagnosis of allergic occupational asthma, with or without associated occupational rhinitis. RESULTS: Our findings suggested that persistent asthma tended to be more common in subjects with associated occupational asthma and rhinitis, and occupational asthma severity was associated with occupational rhinitis severity. Moderate-severe persistent occupational rhinitis is a risk factor for persistent occupational asthma. CONCLUSIONS: We demonstrated, for the first time in the occupational setting, a significant association between occupational rhinitis and asthma severity.

Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study.

OBJECTIVE: To examine whether deviation from the standard intention to treat analysis has an influence on treatment effect estimates of randomised trials. DESIGN: Meta-epidemiological study. DATA SOURCES: Medline, via PubMed, searched between 2006 and 2010; 43 systematic reviews of interventions and 310 randomised trials were included. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: From each year searched, random selection of 5% of intervention reviews with a meta-analysis that included at least one trial that deviated from the standard intention to treat approach. Basic characteristics of the systematic reviews and randomised trials were extracted. Information on the reporting of intention to treat analysis, outcome data, risk of bias items, post-randomisation exclusions, and funding were extracted from each trial. Trials were classified as: ITT (reporting the standard intention to treat approach), mITT (reporting a deviation from the standard approach), and no ITT (reporting no approach). Within each meta-analysis, treatment effects were compared between mITT and ITT trials, and between mITT and no ITT trials. The ratio of odds ratios was calculated (value <1 indicated larger treatment effects in mITT trials than in other trial categories). RESULTS: 50 meta-analyses and 322 comparisons of randomised trials (from 84 ITT trials, 118 mITT trials, and 108 no ITT trials; 12 trials contributed twice to the analysis) were examined. Compared with ITT trials, mITT trials showed a larger intervention effect (pooled ratio of odds ratios 0.83 (95% confidence interval 0.71 to 0.96), P=0.01; between meta-analyses variance τ(2)=0.13). Adjustments for sample size, type of centre, funding, items of risk of bias, post-randomisation exclusions, and variance of log odds ratio yielded consistent results (0.80 (0.69 to 0.94), P=0.005; τ(2)=0.08). After exclusion of five influential studies, results remained consistent (0.85 (0.75 to 0.98); τ(2)=0.08). The comparison between mITT trials and no ITT trials showed no statistical difference between the two groups (adjusted ratio of odds ratios 0.92 (0.70 to 1.23); τ(2)=0.57). CONCLUSIONS: Trials that deviated from the intention to treat analysis showed larger intervention effects than trials that reported the standard approach. Where an intention to treat analysis is impossible to perform, authors should clearly report who is included in the analysis and attempt to perform multiple imputations.

Regular versus as-needed budesonide and formoterol combination treatment for moderate asthma: a non-inferiority, randomised, double-blind clinical trial.

BACKGROUND: Treatment guidelines for patients with moderate persistent asthma recommend regular therapy with a combination of an inhaled corticosteroid and a longacting ß2 agonist plus as-needed rapid-acting bronchodilators. We investigated whether symptom-driven budesonide and formoterol combination therapy administered as needed would be as effective as regular treatment with this combination plus as-needed symptom-driven terbutaline for patients with moderate asthma. METHODS: In this non-inferiority randomised clinical trial, we recruited adult patients (18-65 years of age) with stable moderate persistent asthma, according to 2006 Global Initiative for Asthma guidelines. Patients were recruited from outpatient clinics of secondary and tertiary referral hospitals and university centres. After a 6-week run-in period of inhaled regular budesonide and formoterol plus as-needed terbutaline, the patients were randomly assigned in a 1:1 ratio to receive placebo twice daily plus as-needed treatment with inhaled 160 µg budesonide and 4·5 µg formoterol (as-needed budesonide and formoterol therapy) or twice-daily 160 µg budesonide and 4·5 µg formoterol combination plus symptom-driven 500 µg terbutaline (regular budesonide/formoterol therapy) for 1 year. Randomisation was done according to a list prepared with the use of a random number generator and a balanced-block design stratified by centre. Patients and investigators were masked to treatment assignment. The primary outcome was time to first treatment failure measured after 1 year of treatment using Kaplan-Meier estimates, and the power of the study was calculated based on the rate of treatment failure. Analyses were done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00849095. FINDINGS: Between April 20, 2009, and March 31, 2012, we screened 1010 patients with moderate asthma and randomly assigned 866 eligible patients to the two treatment groups (424 to as-needed budesonide and formoterol therapy and 442 to regular budenoside and formoterol therapy). Compared with regular budesonide and formoterol therapy, as-needed budesonide and formoterol treatment was associated with a lower probability of patients having no treatment failure at 1 year (Kaplan-Meier estimates 53·6% for as-needed treatment vs 64·0% for regular treatment; difference 10·3% [95% CI 3·2-17·4], at a predefined non-inferiority limit of 9%). Patients in the as-needed budesonide and formoterol group had shorter time to first treatment failure than those in the regular therapy group (11·86 weeks vs 28·00 weeks for the first quartile [ie, the time until the first 25% of patients experienced treatment failure]). The difference in treatment failures was largely attributable to nocturnal awakenings (82 patients in the as-needed treatment group vs 44 in the regular treatment group). Both treatment regimens were well tolerated. INTERPRETATION: In patients with moderate stable asthma, as-needed budesonide and formoterol therapy is less effective than is the guideline-recommended regular budesonide and formoterol treatment, even though the differences are small. FUNDING: Italian Medicines Agency.

[Occupational asthma: role of airway inflammation and remodelling in persistent respiratory symptoms and bronchial hyper-responsiveness]. / Asma professionale: il ruolo dell'infiammazione e del rimodellamento delle vie aeree sulla persistenza dei sintomi e dell'iperresponsività bronchiale.

BACKGROUND: Until the late 1970's occupational asthma (OA) was considered reversible once patients were removed from exposure. Unfortunately, respiratory symptoms and non-specific bronchial hyper-responsiveness (NSBH) persist in about two-thirds of patients for years after removal from the offending agent. OBJECTIVES AND METHODS: This review focuses on the role of airways inflammation and remodelling in persistent respiratory symptoms and NSBH after cessation of occupational exposure. RESULTS: Even though cessation of exposure does not always result in remission of OA, symptoms, airways calibre and NSBH do improve in many patients. Although improvements in FEV1 and NSBH tend to reach a plateau 1-2 years after workers leave exposure, reversing NSBH may take much longer and respiratory symptoms and NSBH can persist in subjects removed from exposurefor >10 yrs. Long-term treatment with inhaled corticosteroids (ICS) induces a small but significant improvement in respiratory symptoms and in quality of life and a decrease in NSBH. Prolonged exposure and respiratory symptoms, marked airway obstruction and NSBH, high total cell, eosinophil and neutrophil counts in bronchoalveolar lavage fluid, a strong reaction during specific inhalation challenge, and delayed treatment with ICS have been identified as prognostic factors of unfavourable outcome. If exposure persists, OA tends to deteriorate in many patients but regular long-term treatment with ICS and long-acting beta2-agonists seems to stabilize the outcome. Soon after the last exposure inflammatory cell infiltrates, including eosinophils, and increased thickness of sub-epithelial collagen have been observed. When time since removal from exposure was longer, persistence of respiratory symptoms and NSBH was associated with airway inflammation, remodelling and hypersensitivity to the offending agent. Thickness of sub-epithelial collagen and specific airway sensitivity were reduced after prolonged non-exposure to isocyanates, although NSBH and airway inflammation persisted. CONCLUSIONS: Pathologic features are similar in OA and non-occupational asthma. The main factors of favourable outcome are early removal from exposure and a mild airway obstruction and NSBH at diagnosis. Persistence of airway inflammation years after removal from exposure suggests this process may become independent of the offending agent. The role of remodelling on persistence of OA needs to be clarified further.