Issue 3-The occupational burden of respiratory diseases, an update.

INTRODUCTION AND AIMS: Workplace exposures are widely known to cause specific occupational diseases such as silicosis and asbestosis, but they also can contribute substantially to causation of common respiratory diseases. In 2019, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) published a joint statement on the occupational burden of respiratory diseases. Our aim on this narrative review is to summarise the most recent evidence published after the ATS/ERS statement as well as to provide information on traditional occupational lung diseases that can be useful for clinicians and researchers. RESULTS: Newer publications confirm the findings of the ATS/ERS statement on the role of workplace exposure in contributing to the aetiology of the respiratory diseases considered in this review (asthma, COPD, chronic bronchitis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, infectious pneumonia). Except for COPD, chronic bronchitis and infectious pneumonia, the number of publications in the last 5 years for the other diseases is limited. For traditional occupational lung diseases such as silicosis and asbestosis, there are old as well as novel sources of exposure and their burden continues to be relevant, especially in developing countries. CONCLUSIONS: Occupational exposure remains an important risk factor for airways and interstitial lung diseases, causing occupational lung diseases and contributing substantially in the aetiology of common respiratory diseases. This information is critical for public health professionals formulating effective preventive strategies but also for clinicians in patient care. Effective action requires shared knowledge among clinicians, researchers, public health professionals, and policy makers.

Sputum Inflammatory Patterns Are Associated With Distinct Clinical Characteristics in Patients with Occupational Asthma Independently of the Causal Agent

Background: Clinical heterogeneity in sensitizer-induced occupational asthma (OA) and its relationship to airway inflammatory profiles remain poorly elucidated. Objectives: To further characterize interactions between induced sputum inflammatory patterns, asthma-related outcomes, and the high- or low-molecular-weight category of causal agents in a large cohort of patients with OA. Methods: We conducted a multicenter, retrospective, cross-sectional study of 296 patients with OA confirmed by a positive specific inhalation challenge who completed induced sputum assessment before and 24 hours after challenge exposure. Results: Multivariate logistic regression analysis revealed that sputum eosinophilia ≥3% was significantly associated with a high dose of inhaled corticosteroid (OR [95%CI], 1.31 [1.11-1.55] for each 250-µg increment in daily dose), short-acting ß2-agonist use less than once a day (3.54 [1.82-7.00]), and the level of baseline nonspecific bronchial hyperresponsiveness (mild, 2.48 [1.21-5.08]; moderate/severe, 3.40 [1.44-8.29]). Sputum neutrophilia ≥76% was associated with age (1.06 [1.01-1.11]), male sex (3.34 [1.29-9.99]), absence of corticosteroid use (5.47 [2.09-15.16]), use of short-acting ß2-agonists once or more a day (4.09 [1.71-10.01]), ≥2 severe exacerbations during the previous 12 months at work (4.22 [1.14-14.99]), and isolated early reactions during the specific inhalation challenge (4.45 [1.85-11.59]). Conclusion: The findings indicate that sputum inflammatory patterns in patients with OA are associated with distinct phenotypic characteristics and further highlight the differential effects of neutrophils and eosinophils on asthma-related outcomes. These associations between inflammatory patterns and clinical characteristics share broad similarities with findings reported in nonoccupational asthma and are not related to the type of causal agent. (AU)

Antecedentes: La heterogeneidad clínica en el asma ocupacional (AO) inducida por agentes sensibilizantes y su relación con los perfiles inflamatorios de las vías respiratorias siguen siendo muy poco conocidas. Objetivos: Profundizar en la caracterización de las interrelaciones entre los patrones inflamatorios en esputo inducido, diversas variables relacionadas con el asma y la categoría de agentes causales de alto o bajo peso molecular, en una gran cohorte de sujetos con AO Métodos: Este estudio multicéntrico, retrospectivo y transversal se llevó a cabo en 296 sujetos con OA confirmada mediante una provocación bronquial específica (SIC) positiva, en los que se obtuvieron muestras de esputo inducido antes y 24 horas después de la SIC. Resultados: El análisis de regresión logística multivariable reveló que la presencia de eosinofilia en esputo ≥3 % se asoció significativamente con una dosis alta de corticosteroides inhalados (odds ratio [intervalo de confianza del 95 %], 1,31 [1,11-1,55] por cada incremento de 250 µg en la dosis diaria), el uso de agonistas ß2 de acción corta menos de una vez al día (3,54 [1,82-7,00]), y un nivel de hiperreactividad bronquial inespecífica inicial (leve: 2,48 [1,21-5,08]); moderado/grave: 3,40 [1,44-8,29]). La neutrofilia en esputo ≥76%, se asoció con la edad (1,06 [1,01-1,11]), el sexo masculino (3,34 [1,29-9,99]), la ausencia de uso de corticosteroides (5,47 [2,09-15,16]), el uso de agonistas ß2 de acción corta una vez o más al día (4,09 [1,71-10,01]), la presencia de ≥ 2 exacerbaciones graves en los últimos 12 meses en el trabajo (4,22 [1,14-14,99]) y reacciones inmediatas aisladas durante la SIC (4,45 [1,85-11,59])... (AU)

Exacerbations Among Patients With Asthma Are Largely Dependent on the Presence of Multimorbidity.

BACKGROUND AND OBJECTIVE: Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort. METHODS: The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient. RESULTS: The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC. CONCLUSION: Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.

Improvement in Olfaction in Patients With CRSwNP and Severe Asthma Taking Anti-IgE and Anti-IL-5 Biologics: A Real-Life Study.

BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP), which is characterized by partial loss of smell (hyposmia) or total loss of smell (anosmia), is commonly associated with asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). CRSwNP worsens disease severity and quality of life. The objective of this real-world study was to determine whether biological treatments prescribed for severe asthma can improve olfaction in patients with CRSwNP. A further objective was to compare the improvement in in olfaction in N-ERD and non-N-ERD subgroups. METHODS: We performed a multicenter, noninterventional, retrospective, observational study of 206 patients with severe asthma and CRSwNP undergoing biological treatment (omalizumab, mepolizumab, benralizumab, or reslizumab). RESULTS: Olfaction improved after treatment with all 4 monoclonal antibodies (omalizumab [35.8%], mepolizumab [35.4%], reslizumab [35.7%], and benralizumab [39.1%]), with no differences between the groups. Olfaction was more likely to improve in patients with atopy, more frequent use of short-course systemic corticosteroids, and larger polyp size. The proportion of patients whose olfaction improved was similar between the N-ERD (37%) and non-N-ERD (35.7%) groups. CONCLUSIONS: This is the first real-world study to compare improvement in olfaction among patients undergoing long-term treatment with omalizumab, mepolizumab, reslizumab, or benralizumab for severe asthma and associated CRSwNP. Approximately 4 out of 10 patients reported a subjective improvement in olfaction (with nonsignificant differences between biologic drugs). No differences were found for improved olfaction between the N-ERD and non-N-ERD groups.

Sputum Inflammatory Patterns are Associated with Distinct Clinical Characteristics in Subjects with Occupational Asthma Independently from the Causal Agent.

BACKGROUND AND OBJECTIVES: Clinical heterogeneity in sensitizer-induced occupational asthma (OA) and its relationship to airway inflammatory profiles remain poorly elucidated. To further characterize the interactions between induced sputum inflammatory patterns, asthma-related outcomes and the high- or low-molecular-weight category of causal agents in a large cohort of subjects with OA. METHODS: This multicenter, retrospective, cross-sectional study was conducted among 296 subjects with OA ascertained by a positive specific inhalation challenge who completed induced sputum assessment before and 24 hours after challenge exposure. RESULTS: Multivariate logistic regression analysis revealed that sputum eosinophilia ≥3% was significantly associated with a high dose of inhaled corticosteroid (odds ratio [95% confidence interval], 1.31 [1.11-1.55] for each 250-µg increment in daily dose), short-acting b2-agonist use less than once a day (3.54 [1.82-7.00]), and the level of baseline nonspecific bronchial hyperresponsiveness (mild: 2.48 [1.21-5.08]); moderate/severe: 3.40 [1.44-8.29]). Sputum neutrophilia ≥76% was associated with age (1.06 [1.01-1.11]), male gender (3.34 [1.29-9.99]), absence of corticosteroid use (5.47 [2.09-15.16]), short-acting b2-agonist use once or more a day (4.09 [1.71-10.01]), ≥2 severe exacerbations during the last 12 months at work (4.22 [1.14-14.99]), and isolated early reactions during the SIC (4.45 [1.85-11.59]). CONCLUSIONS: The findings indicate that sputum inflammatory patterns in subjects with OA are associated with distinct phenotypic characteristics and further highlight the differential effects of neutrophils and eosinophils on asthma-related outcomes. These associations between inflammatory patterns and clinical characteristics share broad similarities with what has been reported in nonoccupational asthma and are not related to the type of causal agent.

Role of diesel exhaust particles in the induction of allergic asthma to low doses of soybean.

INTRODUCTION: Exposure to environmental pollutants such as diesel exhaust particles (DEP) increases the risk of asthma and asthma exacerbation. However, the exact mechanisms inducing asthma to low doses of allergens remain poorly understood. The present study aimed to analyse the immunomodulatory effect of the inhalation of DEP in a mouse model exposed to non-asthmagenic doses of soybean hull extract (SHE). MATERIAL AND METHODS: BALB/c ByJ mice were randomly divided into four experimental groups. Two groups received nasal instillations of saline and the other two groups received 3 mg ml-1 SHE during 5 days per week for 3 weeks. One group in each pair also received 150 µg of DEP in the same instillations 3 days per week. SHE-specific IgE levels, oxidative stress, leukocyte pattern and optical projection tomography (OPT) imaging studies were assessed. RESULTS: Inhalation of SHE and/or DEP increased levels of H2O2 in BAL, while coexposure to SHE and DEP increased SHE-specific IgE levels in serum. Inhalation of SHE alone increased eosinophils, B cells, total and resident monocytes and decreased levels of NK cells, while inhalation of DEP increased neutrophils and decreased total monocytes. Regarding dendritic cells (DC), the inhalation of SHE and/or DEP increased the total population, while the inhalation of SHE alone increased Th2-related DCs (CD11b + Ly6C-) and decreased tolerogenic DCs (CD11b-Ly6C-). However, coexposure to SHE and DEP increased oxidative stress-sensitive DCs (CD11b-Ly6C+) and decreased Th1-related DCs (CD11b + Ly6C+). As regards macrophages, inhalation of SHE and DEP decreased total and alveolar populations. DEP deposition in lung tissue did not differ between groups. CONCLUSION: Coexposure to DEP activates the asthmatic response to low doses of soy by triggering the immune response and oxidative stress.

Immunomodulatory effect of pigeon serum in an acute and chronic murine model of bird fanciers lung.

INTRODUCTION: Since the immunopathological mechanisms of bird fancier's lung (BFL) are not well known, we created two models of the disease (acute and chronic BFL) to study and compare the pathways involved in its immunopathogenesis. MATERIALS AND METHODS: C57BL/6 mice were used. Two intraperitoneal injections of 100 µL of commercial pigeon serum (PS) or saline (SAL) were administered with an interval of 48 h in between. Subsequently, intranasal instillations of 40 µL of PS or SAL were performed three days a week, for three weeks in the acute model (AC/PS) and for twelve weeks in the chronic model (CR/PS). Total lung capacity (TLC) was assessed. Pulmonary inflammation was evaluated in bronchoalveolar lavage (BAL), and total serum immunoglobulin (Ig) G was measured in serum samples 24 h, 7 days and 14 days after the last exposure. Histological studies of lungs were assessed. RESULTS: A drop in TLC was observed in treated mice. This decrease was more marked in the CR/PS group (p < 0.001). Neutrophil and lymphocyte counts increased in both AC/PS and CR/PS groups (p < 0.01). The extent of airway inflammation was also examined in the histological analysis of the lungs, which showed predominant perivascular and peribronchiolar inflammation, with centrilobular oedema and subpleural inflammation in the AC/PS group. In the CR/PS group, the changes were greater, with increased levels of IL-5, IL-17F, IL-13 and IL-10 and decreased levels of IL-2. CONCLUSIONS: Bronchial inflammation is present in acute and chronic models of HP following exposure to PS. Our results support the role of neutrophils and IL-17 in the development of the disease and an evolution towards a Th-2 immune response in chronic HP. These models may serve as a tool for future studies of the pathogenesis of HP.

Diesel exhausts particles: Their role in increasing the incidence of asthma. Reviewing the evidence of a causal link.

Exposure to air pollutants has been correlated with an increase in the severity of asthma and in the exacerbation of pre-existing asthma. However, whether or not environmental pollution can cause asthma remains a controversial issue. The present review analyzes the current scientific evidence of the possible causal link between diesel exhaust particles (DEP), the solid fraction of the complex mixture of diesel exhaust, and asthma. The mechanisms that influence the expression and development of asthma are complex. In children prolonged exposure to pollutants such as DEPs may increase asthma prevalence. In adults, this causal relation is less clear, probably because of the heterogeneity of the studies carried out. There is also evidence of physiological mechanisms by which DEPs can cause asthma. The most frequently described interactions between cellular responses and DEP are the induction of pulmonary oxidative stress and inflammation and the activation of receptors of the bronchial epithelium such as toll-like receptors or increases in Th2 and Th17 cytokines, which generally orchestrate the asthmatic response. Others support indirect mechanisms through epigenetic changes, pulmonary microbiome modifications, or the interaction of DEP with environmental antigens to enhance their activity. However, in spite of this evidence, more studies are needed to assess the harmful effects of pollution - not only in the short term in the form of increases in the rate of exacerbations, but in the medium and long term as well, as a possible trigger of the disease.

Identification of Pen m 4 as a potential cause of occupational asthma to Gammarus shrimp.

We present the case of a 34-year-old male patient employed for 8 years in a company manufacturing and packaging animal feed. The patient developed occupational asthma to dry Gammarus powder. The diagnosis was confirmed by specific bronchial provocation test. The determination of specific IgE antibodies was positive for Pen m 4, a sarcoplasmic calcium binding protein, with a level of 6.7 ISU-E. The sensitization to Pen m 4 described here may identify a new allergen causing occupational asthma in these workers.

Asthma exacerbations: risk factors for hospital readmissions.

OBJECTIVE: The aim of our study is to analyse hospital readmissions due to asthma, as well as the factors associated with their increase. STUDY DESIGN: We carried out a retrospective study including all admissions of patients over 18 years old due to exacerbation of asthma occurring in our hospital between the years 2000 and 2010. METHODS: The data were gathered by two members of the research team, by reviewing the clinical records. The first hospital admission of each patient was included for this study. An early readmission (ER) was defined as that which occurred in the following 15 days after hospital discharge and late readmission (LR) to that occurring from 16 days after discharge. RESULTS: This study included 2166 hospital admissions and 1316 patients, with a mean age of 62.6 years. Of the 1316 patients analysed, 36 (2.7%) had one ER and 313 (23.8%) one LR. The only factor independently associated with a higher probability of an ER was poor lung function. A higher probability of LR was associated with a greater severity of the asthma (OR: 17.8, for severe asthma versus intermittent asthma), to have had any hospital admission in the previous year (OR: 3.5) and the use of a combination of ICS-LABA as maintenance treatment. CONCLUSIONS: About 25% of the patients in our area admitted to hospital due to asthma exacerbation had repeat episodes of hospitalisation.

Effect of anti-IgE in occupational asthma caused by exposure to low molecular weight agents.

BACKGROUND: The role of immunoglobulin (Ig)-E in occupational asthma (OA) due to low molecular weight (LMW) agents is not well established compared to classical atopic asthma. In this study, we evaluate whether anti-IgE monoclonal antibody (mAb) has an effect in a mouse model of OA, using persulfate salts. METHODS: On days 1 and 8, BALB/C mice were dermally sensitized with 5% ammonium persulfate (AP) or dimethyl sulfoxide (DMSO). On days 15, 18, and 21, animals were injected intraperitoneally with anti-IgE mAb or PBS 6 hours before challenge with AP or saline. Airway hyper-responsiveness (AHR) using a methacholine test, airway inflammation in bronchoalveolar lavage (BAL) and lung tissue, and total free IgE in serum samples were analyzed 24, 48, and 96 hours after the last challenge. RESULTS: Anti-IgE mAb treatment almost completely neutralized free serum IgE. In AP-sensitized and challenged mice, anti-IgE mAb treatment abolished AHR 24 hour and 48 hour after the last challenge and significantly reduced the total number of eosinophils and neutrophils 48 hour and 96 hour after the last AP challenge compared with nontreated mice. Levels of interleukin (IL)-13 in BAL were also significantly decreased after anti-IgE administration 24 hour and 48 hour after the last AP challenge. Histological analysis of the lung sections from anti-IgE-treated mice revealed normal inflammatory patterns similar to control groups 48 hour after the last challenge. CONCLUSIONS: Anti-IgE-treated mice showed a significant improvement in asthma features related to the AHR and airway inflammation. Anti-IgE mAb has positive effects in OA induced by persulfate salts.

Late mandibular fracture occurring in the postoperative period after third molar removal: systematic review and analysis of 124 cases.

Factors associated with the diagnosis, aetiology, and treatment of mandibular fractures occurring during the postoperative period following the removal of a lower third molar are discussed. The following databases were searched using specific key words: PubMed/MEDLINE, LILACS, Embase, and Scopus. The search yielded 124 cases. Sex, age, side, tooth position and angulation, bone impaction, relationship between the tooth and the inferior alveolar nerve, local pathological conditions, aetiology of the fracture, symptomatology, and time between surgery and fracture, as well as any displacement of the fracture and the treatment of the fracture, were evaluated. Data were tabulated and the χ2 statistical test was applied (P<0.05). Male patients aged >35 years, with teeth in positions II/III and B/C, complete bony impaction, and local bone-like alterations, were found to have a higher frequency of fracture and pericoronitis (P<0.05). Late fractures generally occurred between the second and fourth postoperative weeks (P<0.05). They were generally not displaced and the typical treatment was the non-surgical approach (P<0.05). It is concluded that the risk of mandibular fracture after extraction is associated with excessive ostectomy and/or local alterations. At-risk patients should be thoroughly briefed on the importance of a proper postoperative diet.

Persistence of respiratory and inflammatory responses after dermal sensitization to persulfate salts in a mouse model of non-atopic asthma.

BACKGROUND: Exposure to ammonium persulfate (AP) has been reported to be the main cause of occupational asthma in hairdressers. The aim of this study is to assess how long the asthmatic response to AP can be induced after dermal sensitization in a mouse model. METHODS: BALB/c mice received dermal applications of AP or dimethylsulfoxide (DMSO) (control) on days 1 and 8. They then received a single nasal instillation (challenge) of AP or saline on days 15, 22, 29, 36, 45, 60 and 90. Respiratory responsiveness to methacholine was measured 24 h after the challenge using a non-specific methacholine provocation test. Pulmonary inflammation was analysed in bronchoalveolar lavage (BAL), and total serum immunoglobulin (Ig) E, IgG1 and IgG2a were measured in serum samples. Histological analysis of lung slides was performed. RESULTS: Mice dermally sensitized and intranasally challenged with AP showed respiratory responsiveness to methacholine as long as 45 days after initial sensitization, as well as increased percentage of neutrophils in BAL compared with the control group. At day 60, dermally sensitized mice still presented bronchial hyperresponsiveness, while the percentage of neutrophils returned to baseline levels similar to those of controls. Total serum IgE increased significantly on day 22 after dermal sensitization. Total serum IgG1 and IgG2a increased from 45 days after dermal sensitization and remained high at 90 days. CONCLUSIONS: Both respiratory responsiveness to methacholine and airway inflammation responses decrease with increasing time between sensitization and challenge. Respiratory responsiveness to methacholine tends to persist longer than inflammation.

Utility of Exhaled Nitric Oxide Fraction for the Diagnosis of Hypersensitivity Pneumonitis.

BACKGROUND: There is very little evidence of the utility of the exhaled fraction of NO (FeNO) for the diagnosis of interstitial lung disease and nearly all of it is related with connective tissue disease. Some authors have suggested that in patients with hypersensitivity pneumonitis (HP), evolution to pulmonary fibrosis may be mediated by a Th2 mechanism, which could redound in a potential utility of FeNO. The aim of this study was to investigate the values of FeNO before and after antigenic exposure with the specific inhalation challenge (SIC) and to analyze its potential utility for the diagnosis of HP. METHODS: It was a prospective, cross-sectional study of all patients older than 18 years referred to our center for suspected chronic HP between May 2012 and May 2014 and who underwent a SIC. FeNO was collected before and after SIC. RESULTS: The study sample comprised 25 patients. Eleven were diagnosed with chronic HP; six had been exposed to avian proteins and five to fungal agents. Of these 11 patients, seven had positive SICs. In the 14 patients with diagnoses other than HP, all the SICs were negative. No significant differences in baseline characteristics were observed according to HP diagnosis, except in the BAL lymphocyte count. No differences were found after the test in patients diagnosed with HP; nor were there differences in baseline FeNO in patients diagnosed with HP and those who received alternative diagnoses. CONCLUSIONS: The results suggest that FeNO measurement is not useful for the diagnosis of chronic HP.