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.

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.

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.

[Determining asthma treatment in children by monitoring fractional exhaled nitric oxide, sputum eosinophils and leukotriene B4]. / Monitorización del tratamiento en el asma bronquial mediante determinación de fracción exhalada de óxido nítrico, eosinófilos y leucotrieno B4 en esputo inducido de población infantil.

Sputum eosinophils and exhaled fractional nitric oxide (FENO) are markers of airway inflammation in asthma. Cytokines, cysteinyl-leukotrienes and leukotriene B4 (LTB4) are responsible for this inflammation. The aim of this study is to determine the usefulness of these markers in monitoring asthma treatment in children. FENO, sputum eosinophils, and LTB4 in induced sputum were performed in 10 children (9-15 years old). These determinations were repeated four months later, after the beginning or an increase in the treatment. FENO values tended to decrease (P=.15), pulmonary function tended to improve (P=.10), and sputum eosinophils decreased (P=.003) compared to the first determination. There were no differences in LTB4 concentrations (P=.88). Sputum eosinophils seem to be more precise than FENO in the monitoring of inflammation in asthmatic children.

Evolution of occupational asthma: does cessation of exposure really improve prognosis?

AIM: To assess the evolution of occupational asthma (OA) depending on whether the patient avoids or continues with exposure to the offending agent. METHODS: Study in patients diagnosed with OA using a specific inhalation challenge. Patients underwent the following examinations on the same day: clinical interview, physical examination, forced spirometry, methacholine test and determination of total IgE. Clinical improvement, deterioration or no change were defined according to the changes seen on the GINA severity scale at the time of diagnosis. RESULTS: Of the 73 patients finally included, 55 had totally ended exposure and 18 continued to be exposed at work. Clinical improvement was observed in 47% of those who had terminated exposure and in 22% of those who remained exposed; clinical deterioration was observed in 14% and 17% respectively (p = 0.805). Logistical regression analysis, including the type of agent and the persistence or avoidance of exposure among the variables, did not show any predictive factors of clinical evolution. Similarly, the changes in FEV1 and in bronchial hyperresponsiveness were not associated with the avoidance or continuation of exposure to the causative agent. CONCLUSIONS: Avoiding exposure to the causative agent in patients with OA does not seem to improve prognosis in this disease. Despite these findings, there is insufficient evidence to recommend a change in current management guidelines.

Expression of the vitamin K-dependent proteins GAS6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques.

The GAS6/ProS-TAM system is composed of two vitamin K-dependent ligands (GAS6 and protein S) and their three protein tyrosine kinase receptors TYRO3, AXL and MERTK, known as the TAM receptors. The system plays a prominent role in conditions of injury, inflammation and repair. In murine models of atherosclerotic plaque formation, mutations in its components affect atherosclerosis severity. Here we used Taqman low-density arrays and immunoblotting to study mRNA and protein expression of GAS6, ProS and the TAM receptors in human carotid arteries with different degrees of atherosclerosis. The results show a clear down-regulation of the expression of AXL in atheroma plaques with respect to normal carotids that is matched by decreased abundance of AXL in protein extracts detected by immunoblotting. A similar decrease was observed in PROS1 mRNA expression in atherosclerotic carotids compared to the normal ones, but in this case protein S (ProS) was clearly increased in protein extracts of carotid arteries with increasing grade of atherosclerosis, suggesting that ProS is carried into the plaque. MERTK was also increased in atherosclerotic carotid arteries with respect to the normal ones, suggesting that the ProS-MERTK axis is functional in advanced human atherosclerotic plaques. MERTK was expressed in macrophages, frequently in association with ProS, while ProS was abundant also in the necrotic core. Our data suggest that the ProS-MERTK ligand-receptor pair was active in advanced stages of atherosclerosis, while AXL signalling is probably down-regulated.

TNF-α system and lung function impairment in obesity.

A potential interaction between pulmonary function, abnormal adipose tissue activity, and systemic inflammation has been suggested. This study explores the relationship between circulating soluble TNF-α receptors (sTNF-R1 and sTNF-R2) and respiratory function parameters in obese subjects. Thirty-one non-diabetic morbidly obese women with a history of non-smoking and without prior cardiovascular or respiratory disease were prospectively recruited in the outpatient Obesity Unit of a referral center. Pulmonary function test included a forced spirometry, static pulmonary volume measurements, non-attended respiratory polygraphy, and arterial gas blood sampling. Circulating levels of sTNFR-R1, sTNF-R2, interleukine 6 and adiponectin were determined using ELISA. Statistical analysis included a multivariate regression analysis taking into account the potential confounders. sTNF-R1 positively correlated with BMI (r=0.571, p=0.001) and arterial carbon dioxide pressure (PaCO(2), r=0.381, p=0.038), but negatively with forced expiratory volume in 1s (FEV(1), r=-0.437, p=0.012), maximum midexpiratory flow (FEF(25-75), r=-0.370, p=0.040) and forced vital capacity (FVC, r=-0.483, p=0.005). However, no correlation between sTNF-R2 and BMI and either pulmonary function tests or arterial blood samples was observed. Multiple linear regression analysis showed that sTNF-R1 independently predicted FEV(1) (beta=-0.437, p=0.012) and FVC (beta=-0.483, p=0.005). Thus, circulating levels of sTNF-R1, but not sTNF-R2, are related to reduced lung volumes and airflow limitation in morbidly obese patients prior to the development of a clinically recognized respiratory disease. Therefore, studies addressed to evaluating the potential beneficial effect of anti-TNF-α agents on pulmonary function tests in obese subjects seem warranted.

Type 2 diabetes impairs pulmonary function in morbidly obese women: a case-control study.

AIMS/HYPOTHESIS: To determine whether the presence of type 2 diabetes and the degree of metabolic control are related to reduced pulmonary function in obese individuals. METHODS: Seventy-five morbidly obese women (25 with type 2 diabetes [cases]--and 50 without diabetes [controls]) with a history of non-smoking and without prior cardiovascular or respiratory disease were prospective recruited for a case-control study in the outpatient obesity unit of a referral centre. Both groups were closely matched by age, BMI and waist circumference. Pulmonary function test included forced spirometry and static pulmonary volume measurements. RESULTS: Type 2 diabetic patients showed lower forced expiratory volume at 1 s (FEV1) (mean difference -11.6% of predicted [95% CI -20.4 to -2.8]; p = 0.011), and FEV1/forced vital capacity (FEV1/FVC) ratio (mean difference -4.4% [95% CI -8.1 to -0.7]; p = 0.049), but a greater residual volume (RV) (mean difference 19.5% of predicted [95% CI 10.8-28.3]; p < 0.001). In addition, an obstructive ventilatory pattern was more frequent in diabetic patients. Significant negative correlations between FEV1 and fasting glucose, HbA1c and HOMA insulin resistance (HOMA-IR) were detected. By contrast, RV was positively correlated with fasting glucose, HbA1c and HOMA-IR. Multiple linear regression analyses showed that fasting glucose and HbA1c independently predicted FEV1 and RV. CONCLUSIONS/INTERPRETATION: The presence of diabetes and the degree of glycaemic control are related to respiratory function impairment in morbidly obese women. Therefore, the impact of type 2 diabetes on pulmonary function should be taken into consideration by those providing care for obese people.

Occupational asthma caused by metal arc welding of iron.

Epidemiological studies have shown that exposure to welding fumes can be a cause of occupational asthma (OA), although the mechanisms implicated are unknown. We describe 3 patients (all men, mean age 42 years) with OA secondary to exposure to welding fumes generated during metal arc welding on iron. The exposure time ranged from 7 to 43 years and the time of the onset of symptoms following the start of exposure was 2-12 years. Patients were diagnosed by specific inhalation challenge (SIC). Environmental levels of Fe, Cd, Cu, Cr, Ni, NO2, NO, CO, and O3 produced during the SIC did not exceed threshold limit values. Samples of induced sputum were obtained before and after the SIC and showed an increase in neutrophils and concentrations of IL-8, TNF-α and TNF-ß after the SIC. This study presents the first clinical findings reported in welders with OA, mainly working with iron. Neutrophilic inflammation seems to play a role in this disease.

Occupational asthma related to mouse allergen exposure and rhinoconjunctivitis due to collagenase inhalation in a laboratory technician.

We describe the case of a 27-year-old patient working in a research laboratory, who developed occupational asthma to mouse proteins and presented symptoms of rhinoconjunctivitis caused by manipulation of collagenase. Specific inhalation challenge confirmed the diagnosis of occupational asthma to mouse proteins, whereas specific challenge with collagenase only evoked symptoms of rhinitis and conjunctivitis. SDS-PAGE and Western blot analysis for collagenase showed that the patient's IgE antibodies bound specifically to a protein with a molecular weight of 92 kDa. Hence, this was an unusual case of double sensitization. The sensitization to collagenase presented in this report may represent a new occupational disease in technicians working in medical or research laboratories.

Mortality in severe sleep apnoea/hypopnoea syndrome patients: impact of treatment.

The aim of this study was to determine mortality in patients with sleep apnoea/hypopnoea syndrome (SAHS) according to the treatments employed and comorbidity. An historical cohort of patients with SAHS diagnosed at a university hospital between 1982 and 1992 and followed until 1996 was studied. From a total of 475 SAHS patients, 444 (94%), with a mean+/-SD apnoea/hypopnoea index at diagnosis of 55+/-27, were located and included in the study. SAHS treatments employed were: surgery (88), weight loss (134), continuous positive airway pressure (124) and 98 patients were not treated. By the end of follow-up, 49 patients had died. According to Cox regression analysis, mortality in treated patients was lower than in those not treated, but higher in those with a history of severe chronic obstructive pulmonary disease. Mortality in nontreated patients compared with that of the general population, adjusted for age and sex, showed excessive mortality, which decreased in treated patients. Stratification by age showed a greater mortality rate ratio in patients <50 yrs. These findings were maintained when mortality from cardiovascular causes was compared. In conclusion, a rise in mortality was found in nontreated sleep apnoea/hypopnoea syndrome patients compared with the general population, whereas mortality in those treated for sleep apnoea/hypopnoea syndrome did not differ significantly from that of the general population.

Ventilatory insufficiency due to asbestos-related diffuse pleural fibrosis successfully treated with noninvasive home mechanical ventilation.

A 54-year-old man with diffuse pleural fibrosis due to previous asbestos exposure developed hypercapnic respiratory failure. Noninvasive mechanical ventilation (NIMV) was started at the hospital and maintained at the patient's home, achieving reversal of the respiratory failure. During a 2-year follow-up, NIMV has been well tolerated by the patient and no relapse in ventilatory failure has occurred. Home NIMV can be considered as an alternative to pleural decortication in asbestos-related diffuse pleural fibrosis with ventilatory insufficiency.

Evolution of idiopathic pleural effusion: a prospective, long-term follow-up study.

UNLABELLED: The management of idiopathic pleural effusion remains controversial. Because the long-term evolution of this entity is not well known, two different approaches, aggressive and conservative, have been proposed. We conducted a 10-year study of the evolution of idiopathic pleural effusion. METHODS: Between 1984 and 1994, we prospectively studied 40 consecutive patients (30 men and 10 women; mean [+/- SD] age, 53.8 +/- 19.4 years) with exudative pleural effusion undiagnosed after exhaustive evaluation. The pleural fluid adenosine deaminase level was below 43 IU/L in all; periodic chest radiographs and clinical evaluation were carried out in all patients for a mean of 62 months (range, 36 to 108 months). Further diagnostic procedures were performed whenever the effusion recurred or when indicated by the clinical picture. RESULTS: Effusions resolved in a mean time of 5.6 months (range, 7 days to 48 months). Five patients (12.5%) had one or more relapses of their pleural effusion, and in a further 5 (12.5%), the effusion persisted unchanged for more than 1 month. In 32 cases (80%), no potential cause of the effusion was detected. The diagnoses in the remaining eight cases were asbestos pleural effusion in three, pulmonary adenocarcinoma in one, mesothelioma in one, congestive heart failure in one, liver cirrhosis in one, and rheumatoid arthritis in one. Tuberculosis was not detected in any of the cases, although 19 patients initially had positive tuberculin tests. CONCLUSIONS: Most idiopathic pleural effusions follow a benign course. Our results support conservative treatment of patients with idiopathic pleural effusion. Antituberculous treatment does not appear to he warranted, regardless of tuberculin test results, if the pleural fluid adenosine deaminase level is not elevated.

Cocaine-induced Churg-Strauss vasculitis.

A freebase cocaine-smoking woman developed relapsing fever, bronchoconstriction, arthralgias and weight loss. Pulmonary infiltrates, arthritis, microhaematuria, pruriginous skin rash and mononeuritis multiplex were later added to the clinical picture. Both skin and muscle biopsies showed eosinophilic angiitis. Improvement or worsening of her clinical picture repeatedly coincided with avoidance or use of smoked cocaine, respectively. We suggest that Churg-Strauss vasculitis may be a complication of smoking freebase cocaine.

Cáncer de las glándulas salivales: estudio de sobrevida / Salivary glands cancer: survival study

Se presentan los resultados del estudio de sobrevida en 84 pacientes con cáncer de las glándulas salivales mayores y menores, tratados primariamente con cirugía. La tasa de sobrevida acumulada a 5 años de toda la serie fue de 70,3%. La tasa de sobrevida acumulada a 5 años para los enfermos tratados en el "período inicial" fue menor que para los del grupo "período reciente" y esta diferencia fue estadísticamente significativa (p=<0.01). La tasa de sobrevida acumulada a 5 años para los enfermos con cánceres "poco agresivos" fue mayor que para los portadores de cánceres "altamente agresivos". La diferencia fue estadísticamente significativa (p=<0,001). El porcentaje de sobrevida acumulada a 5 años para los enfermos de carcinoma agrupados por estadio clínico fue mejor para los estadios menos avanzados (Z=3,3;p=<0,01). En este grupo, el período de observación mínima fue de 3 años. El rendimiento del seguimiento de toda la serie fue de 91,7%