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.

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.

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.

An entomological and seroepidemiological study of the vectorial-transmission risk of Chagas disease in the coast of northern Chile.

Four species of triatomines are known from Chile: Triatoma infestans Klug, Mepraia spinolai Porter, M. gajardoi Frías, Henry & González, and M. parapatrica Frías (Hemiptera: Reduviidae), the last three are endemic. The geographical distribution of M. gajardoi includes the coastal areas in the north of Chile between 18° and 21°S, an area with both a resident workforce and summer-season visitors. A study was developed to assess the risk of vectorial transmission of Chagas disease by M. gajardoi in hut settlements on the coast of the Tarapacá Region, in particular in Caleta San Marcos and Caleta Río Seco. The study comprised fingerstick sampling of 95 persons, venous samples from 29 domestic dogs and capture of 52 triatomines, from both fishing coves. The samples were analysed by enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) techniques. The results show that, of the total number of persons studied, 100% were negative for Trypanosoma cruzi Chagas (Trypanosomatida: Trypanosomatidae) antibodies, 10.34% of canids were positive for the antibody and 5.8% of M. gajardoi were infected to the PCR technique. The presence of this species in areas close to human settlements constitutes a risk to human populations established on the coast of northern Chile.

Changes in PH in exhaled breath condensate after specific bronchial challenge test in patients with chronic hypersensitivity pneumonitis: a prospective study.

BACKGROUND: The aim of this study was to investigate the influence of the specific inhalation challenge (SIC) on changes of pH values in exhaled breath condensate (EBC) in patients with hypersensitivity pneumonitis (HP). METHODS: A prospective study of 85 patients with suspected HP, of whom 63 were diagnosed with HP due to exposure to avian or fungal antigens. In all cases, EBC samples were collected before and after completion of the SIC and pH values were determined. RESULTS: Taken as a whole, patients with HP did not present changes in EBC pH after SIC. However, considering only patients with exposure to molds, those diagnosed with HP had a significantly more acid pH post-SIC than those with another diagnosis (p = 0.011). This fact is not observed in patients exposed to bird's antigens. A ROC curve showed that a reduction in EBC pH of 0.3 units or more after SIC in patients diagnosed with HP due to exposure to molds had a sensitivity of 30 % (CI: 12.8 to 54.3 %) and a specificity of 100 % (CI: 65.5 to 100 %). CONCLUSION: EBC pH may be useful in interpreting SIC results in patients with HP, especially in those patients exposed to molds. Further studies are now required to test the validity of these proposals.

Work-related asthma: diagnosis and prognosis of immunological occupational asthma and work-exacerbated asthma.

The incidence and prevalence of asthma are increasing. One reason for this trend is the rise in adult-onset asthma, especially occupational asthma, which is 1 of the 2 forms of work-related asthma. Occupational asthma is defined as asthma caused by agents that are present exclusively in the workplace. The presence of pre-existing asthma does not rule out the possibility of developing occupational asthma. A distinction has traditionally been made between immunological occupational asthma (whether IgE-mediated or not) and nonimmunological occupational asthma caused by irritants, the most characteristic example of which is reactive airway dysfunction syndrome. The other form of work-related asthma is known as work-exacerbated asthma, which affects persons with pre-existing or concurrent asthma that is worsened by work-related factors. It is important to differentiate between the 2 entities because their treatment, prognosis, and medical and social repercussions can differ widely. In this review, we discuss diagnostic methods, treatment, and avoidance/nonavoidance of the antigen in immunological occupational asthma and work-exacerbated asthma. Key words: Specific inhalation challenge. Peak expiratory flow. Workplace. Irritants.

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.

Soy aeroallergens in thoracic fraction particles (PM10).

BACKGROUND: The aerodynamic diameter of biological particles determines their ability to penetrate the human respiratory system. OBJECTIVE: To assess the content of allergens less than 10 pm in diameter in the particle fraction of airborne dust in order to improve control of exposure to harmful soybean aeroallergens. METHODS: In this study, 98 pairs of particulate matter measuring less than 10 microm in diameter (PM10) and total suspended particulate (TSP) filters were collected in parallel and analyzed for soy aeroallergens by the inhibition enzyme-linked immunosorbent assay. RESULTS: The median levels found were 6 and 22.5 U/m3 for PM10 and TSP filters, respectively. A good correlation was found between soy aeroallergen content in PM10 and TSP filters. The median proportion of soy aeroallergen content in PM10 filters versusTSP filters was 28.6%, and varied widely across different days. CONCLUSIONS: Due to this wide variation between days, it seems that soy aeroallergen content in TSP filters is not a good surrogate of soy allergen content in PM10 filters. Further clinical studies should be conducted to assess differences in the health impact of soy allergen content in PM10 filters and TSP filters.

Bronchial inflammation and hyperresponsiveness in well controlled asthma.

BACKGROUND: Little research has been devoted to the characteristics of bronchial inflammation in patients with stable, well controlled asthma. OBJECTIVE: The aim of this study was to assess the degree and type of airway inflammation and to investigate the relationship between inflammation and bronchial hyperresponsiveness in patients with well controlled asthma. METHODS: A cross-sectional study was conducted in 84 adult patients (43 men, mean age 43 years) with documented well controlled asthma. Induced sputum samples were obtained and cell types determined by differential cell count. Spirometry and methacholine challenge testing were performed. Asthma Control Questionnaire (ACQ) was used to assess symptoms. Patients were included if their ACQ score was < 0.75. RESULTS: A total of 59 patients had persistent bronchial inflammation: 28 cases were considered eosinophilic, 28 neutrophilic, and 3 mixed. Median (range) percentage of eosinophils was 4% (0-64) in patients testing positive to methacholine challenge (n = 66) and 1% (0-3) in those testing negative (n = 18) (P = 0.003). A positive correlation was found between eosinophil percentage and the methacholine dose/response ratio (r = 0.477, P = 0.0001). The geometric mean (95% CI) of the methacholine PC20 was 1.74 mg/mL (1.04-2.93) in patients with eosinophilic inflammation and 4.14 mg/mL (2.5-6.84) in those with neutrophilic inflammation (P = 0.03). CONCLUSIONS: Inflammation and bronchial hyperresponsiveness persist in most patients with well controlled asthma. CLINICAL RELEVANCE: The study demonstrates that eosinophilic or neutrophilic inflammation persisted in most well controlled asthma patients despite the fact that their condition was controlled and therefore, measurement of bronchial inflammation seems essential to achieve proper asthma control.

Utility of exhaled breath condensate pH for diagnosing occupational asthma.

INTRODUCTION: The current reference standard method for diagnosing occupational asthma (OA) is specific inhalation challenge (SIC) with the suspected agent. The alternative method is serial peak expiratory flow (PEF) monitoring. Nevertheless, PEF does not have optimal sensitivity and specificity for this purpose. The aim of this study was to evaluate the utility of exhaled breath condensate (EBC) pH for the diagnosis of OA. MATERIAL AND METHODS: A prospective study was performed in 37 subjects with suspected OA. Serial PEF monitoring was carried out for 2 weeks at work and for 2 weeks off work. At the end of each period, the EBC pH and the methacholine concentration resulting in a 20% FEV(1) decrease (PC20) were measured. SIC was subsequently performed. PEF graphs were interpreted visually by 3 experienced independent readers. RESULTS: Seventeen patients tested positive with SIC. Receiver-operating characteristic curves showed that a decrease in EBC pH greater than 0.4 units during the period at work compared to the off-work period achieved the most satisfactory sensitivity (40%, CI 19.4-66.5) and specificity (90%, CI 66.9-98.2) for diagnosing OA. When EBC pH findings were added to PEF results, the diagnostic yield of PEF generally increased. Other test combinations (e.g. EBC pH plus PC20 or EBC pH plus PC20 plus PEF) did not improve diagnostic performance. CONCLUSIONS: Acidification of EBC pH at work and adding the EBC pH measurement to PEF monitoring during periods at work and off work may be useful for improving the diagnosis of OA.

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.