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Background Data on the outcome of occupational asthma (OA) are heterogeneous. Objective To assess the impact of being part of a specific cluster at diagnosis on the long-term outcome of diisocyanate-induced OA. Methods We collected data from 56 patients who had a diagnosis of OA confirmed by a positive specific inhalation challenge. Patients sensitized to toluene diisocyanate were allocated to cluster 1 or 2 based on a tree analysis, using the 3 variables relevant for cluster segregation identified in a previous study: age, body mass index, and forced expiratory volume in 1 second/forced vital capacity at diagnosis. Patients sensitized to methylene diisocyanate were allocated to cluster 3, as in previous study. We defined OA remission when a patient had met a total of 3 criteria: no asthma symptoms and no antiasthma therapy for the last year, as well as having normal lung function. Results At follow-up, 16 patients showed OA remission. They exhibited better lung function, less bronchial hyperreactivity, as well as younger age at diagnosis. Twenty-eight patients were allocated to cluster 1, 10 to cluster 2, and 18 to cluster 3. The percentage of patients with OA remission was higher in cluster 2 (50% vs 25% in cluster 1 and 22.5% in cluster 3), although the difference was not statistically significant (P = .2789). Conclusions Age at diagnosis was a strong predictor of OA remission. The outcome of diisocyanate OA tended to be more favorable for patients with toluene diisocyanate OA allocated in cluster 2, but this finding needs to be validated by further data.

The battle against the new coronavirus that continues to kill millions of people will be still long. Novel strategies are demanded to control infection, mitigate symptoms and treatment of COVID-19. This is even more imperative given the long sequels that the disease has on the health of the infected. The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection. In this review, we explore the role of the TRPV-1 channel in the infection, susceptibility, pathogenesis, and treatment of COVID-19, with the aim of looking at novel strategies to control infection and mitigate symptoms, and trying to translate this knowledge into new preventive and therapeutic interventions.

Aging is the predominant risk factor for most degenerative diseases, including chronic obstructive pulmonary disease (COPD). This process is however very heterogeneous. Defining the biological aging of individual tissues may contribute to better assess this risky process. In this study, we examined the biological age of induced sputum (IS) cells, and peripheral blood leukocytes in the same subject, and compared these to assess whether biological aging of blood leukocytes mirrors that of IS cells. Biological aging was assessed in 18 COPD patients (72.4 ± 7.7 years; 50% males). We explored mitotic and non-mitotic aging pathways, using telomere length (TL) and DNA methylation-based age prediction (DNAmAge) and age acceleration (AgeAcc) (i.e., difference between DNAmAge and chronological age). Data on demographics, life style and occupational exposure, lung function, and clinical and blood parameters were collected. DNAmAge (67.4 ± 5.80 vs. 61.6 ± 5.40 years; p = 0.0003), AgeAcc (−4.5 ± 5.02 vs. −10.8 ± 3.50 years; p = 0.0003), and TL attrition (1.05 ± 0.35 vs. 1.48 ± 0.21 T/S; p = 0.0341) are higher in IS cells than in blood leukocytes in the same patients. Blood leukocytes DNAmAge (r = 0.927245; p = 0.0026) and AgeAcc (r = 0.916445; p = 0.0037), but not TL, highly correlate with that of IS cells. Multiple regression analysis shows that both blood leukocytes DNAmAge and AgeAcc decrease (i.e., younger) in patients with FEV1% enhancement (p = 0.0254 and p = 0.0296) and combined inhaled corticosteroid (ICS) therapy (p = 0.0494 and p = 0.0553). In conclusion, new findings from our work reveal a differential aging in the context of COPD, by a direct quantitative comparison of cell aging in the airway with that in the more accessible peripheral blood leukocytes, providing additional knowledge which could offer a potential translation into the disease management.

Background: A neurogenic pathway, involving TRPV1 expressed in the airways, has been hypothesized to be implicated in acute cardiovascular events occurring after peaks of air pollution. Aims: To test whether inhaled prostaglandin E2 (PGE2) and bradykinin (BK) modulate TRPV1 activity in vivo by changing cough response to capsaicin (CPS) and whether sensitization of TRPV1 by PGE2 and BK affects heart rate variability (HRV). Methods: 17 healthy volunteers (median age 35 IQR, 29.5-47) inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge. The results were expressed as n° of coughs caused by 30 μM of CPS. HRV, expressed by low (0.04–0.15 Hz) and high (0.15–0.40 Hz) normalized frequency components (nLF, sympathetic component, and nHF, vagal component), as well as nLF/nHF ratio (sympathovagal balance), was evaluated after inhalation of diluent, PGE2 and BK. Results: Inhalations of PGE2 and BK were associated with a highly significant increase in cough response induced by CPS: PGE2 (n° cough=4.20±0.42; p Conclusion: Inhalation of PGE2 and BK sensitizes TRPV1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.

A neurogenic pathway, involving airway TRPV-1, has been implicated in acute cardiovascular events occurring after peaks of air pollution. We tested whether inhaled prostaglandin-E2 (PGE2) and bradykinin (BK) regulate TRPV-1 activity in vivo by changing cough response to capsaicin (CPS) and affecting heart rate variability (HRV), while also taking into account the influence of TRPV-1 polymorphisms (SNPs). Moreover, we assessed the molecular mechanism of TRPV-1 modulation in vitro. Seventeen healthy volunteers inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge and the sympathetic activity by HRV, expressed by low (nLF) and high (nHF) normalized frequency components, as well as nLF/nHF ratio. Intracellular [Ca2+] was measured in HeLa cells, transfected with wild-type TRPV-1, pre-treated with increasing doses of PGE2, BK or diesel exhaust particulate (DEP), after CPS stimulation. Six functional TRPV-1 SNPs were characterized in DNA from each subject. Inhalation of PGE2 and BK was associated with significant increases in cough response induced by 30 μM of CPS (cough number after PGE2 = 4.20 ± 0.42; p p 2 = 6.1; p p 2 and BK, DEP directly activated TRPV-1. Inhalation of PGE2 and BK sensitizes TRPV-1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.

We describe a 47-year-old non-atopic woman, working as a spray painter in a tannery for 23 years, with a 16-year history of cutaneous symptoms and a subsequent 2-year history of asthmatic symptoms after exposure to aerosol and vapour of polyfunctional aziridine (PFA) at work. To confirm the occupational origin of the dermatitis and asthma we performed a skin prick test with PFA and a specific inhalation challenge (SIC) with PFA. Prick test with PFA elicited an immediate positive skin reaction. She developed an immediate asthmatic reaction upon SIC with PFA. The onset of occupational dermatitis before asthma is consistent with the hypothesis that the sensitization to PFA was triggered in the skin. The observation that the reactions elicited in skin and airways upon exposure to PFA exhibited the same time course, suggests a similar mechanism at both sites. Thus, the avoidance of both skin and airway exposure to PFA should be recommended in workplace hygiene practice.

Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, shows striking clinical aging-associated features of lung. We tested the hypothesis that lung biological aging in COPD is accelerated. Biological aging was assessed by mitotic telomere length (TL) and non-mitotic age-dependent methylation changes in specific CpGs (DNAmAge) of lung cells, obtained from induced sputum, and peripheral blood leucocytes in 18 COPD patients (72.4±7.7 years; 50% males), clinically appraised by lung function and blood parameters. DNAmAge (67.4±5.80 vs 61.6±5.40 years; p=0.0003), AgeAcc (-4.5±5.02 vs -10.8±3.50 years; p=0.0003) and TL attrition (1.05±0.35 vs 1.48±0.21 T/S; p=0.0341) are higher in lung than blood in the same patients. Blood DNAmAge (r=0.927245; p=0.0026) and AgeAcc (r=0.916445; p=0.0037), but not TL, highly correlate with that of lung. Therefore, blood can be a proxy indicator of lung biological age. Multiple regression analyses show that both blood DNAmAge and AgeAcc decrease (i.e., younger) in patients with combined inhaled corticosteroids (ICS) therapy (p=0.0494 and p=0.0553) and FEV1% enhancement (p=0.0254; p=0.0296). In conclusion, the new finding, that lung of COPD patients is remarkably biologically older than blood, opens new research challenge on novel therapeutic approaches to counteract this key aspect of the disease.

Work-related asthma (WRA) comprises occupational asthma (OA) and work-exacerbated asthma (WEA). It is unknown whether the inflammatory pathways activated in WRA are mostly of type 2 (T2) or non-type 2 (non-T2). The aim of the study was to determine whether OA and WEA differ at diagnosis in terms of inflammatory endotype based on T2 or non-T2 circulating biomarkers. We collected clinical data of 40 asthmatics with a diagnosis of OA (n=25) or WEA (n=15) due to various agents (80% isocyanates) confirmed by a positive or negative Specific Inhalation Challenge (SIC) between 2008 and 2018. All the patients had been free from corticosteroid treatment for the last 2 weeks. Blood samples were collected before SIC and sera were stored at -80°C until used. Serum periostin, IL-2, IL-3, IL-5, IL-8, IL-9, IL12p70, IL-17, IL-33, TNFα, IFNγ levels were assessed by ELISA (periostin) and Luminex xMAP Technologies. At diagnosis OA and WEA patients did not differ in terms of age, gender, atopy, eosinophil and neutrophil count in blood, latency and months of symptomatic exposure. OA patients exhibited higher bronchial hyperreactivity (PD20FEV1: median 431 vs 865 mcg), higher levels of fractional exhaled NO (50 vs 29 ppb) and of total IgE (95.9 vs 45.5 kUa/L) than WEA patients. All cytokines were detected in sera. OA patients exhibited higher levels of periostin (31.87 vs 21.98 pg/ml) and IL-33 (4.4 vs 0.7 pg/ml), than WEA subjects. No differences between OA and WEA subjects were found in the expression profiles of the other cytokines. At diagnosis OA is characterized by a more pronounced T2 endotype than WEA. Higher serum IgE, periostin and IL-33 levels might represent potential serologic markers of OA.

Introduction: Clusters of silicosis related to fabrication of quartz conglomerates have been recently reported. The prognosis of this form of silicosis has not been established. Aim: To evaluate the progression of silicosis in workers exposed to quartz conglomerate. Methods: A short-term follow-up of workers with silicosis was performed. Lung function tests, high resolution computed tomography (HRCT) and levels of airborne crystalline silica during activity in the finishing lines were assessed at diagnosis and after 12 months. Results: We studied 18 cases of silicosis (age at diagnosis: range 25-53 yr; duration of exposure to quartz conglomerate dust: 3.5-10 yr, and average workplace silica dust levels: 0.260-0.744 mg/m3). At diagnosis, 50% of subjects exhibited an impairment of DLco (75.7±15% predicted). The most common spirometric alteration (38% of cases) was a restrictive pattern based on TLC (5.73±1.02L and 85.5±13% pred.). HRCTs showed well-defined rounded opacities and enlarged mediastinal lymph-nodes. During follow-up period, wet or automatic finishing was introduced and all workers were supplied with Filtering Face Piece-3 masks. At follow-up, the levels of airborne silica had been drastically reduced (0.009-0.013 mg/m3). We observed a significant decline of TLC (-0.41±0.7L and -6±10% pred., p=0.008), while DLco was stable. A slight increase of HRCT opacities was detected in 6 subjects. No significant relationship between HRCT and TLC worsening was observed. Conclusions: Silicosis due to quartz conglomerates seems characterized by an accelerated lung function decline, despite a reduction of exposure to silica dust. Spirometry appears the most sensitive tool to monitor the progression of the disease.

Background Cough is a common symptom in several respiratory diseases and may occur in healthy subjects as a defense mechanism against noxious inhalants. Cough response is mediated by transient receptor potential vanilloid-1 (TRPV1) expressed by C-fibers in the airways. Capsaicin (CPS) activates TRPV1 and is regularly used as a tool to study cough response. Although single nucleotide polymorphisms (SNPs) of TRPV1 are implicated in CPS binding, their role in cough response is not fully elucidated. Aims In this study we investigated the relationship between capsaicin cough challenge sensitivity and multiple TRPV1 polymorphisms. Methods The dose-response of cough induced by CPS inhalation was determined in 20 unselected healthy volunteers and the concentration of CPS causing two coughs (C2) was calculated. The SNPs I585V(rs8065080), T505A(rs17633288), T469I(rs224534), I315 M(rs222747), P91S(rs222749), and K2N(rs9894618) were characterized in blood DNA from each subject. The association between combinations of TRPV1 SNPs and CPS sensitivity of each subject was assessed by linear regression . Results All subjects were wild type for T505A and K2N, while they exhibited two to six SNPs with high capsaicin responsiveness. The major contribution to CPS sensitivity in vivo (C2) was due to four combined SNPs: 315 M, 585I, 469I and 91S (p = 0.015). We found, however, that the presence of a minimum of two polymorphisms, such as 91S combined with 315 M (p = 0.032) or 91S with 585I (p = 0.025), was sufficient to detect an effect on C2. Conclusion Capsaicin cough challenge sensitivity in healthy subjects is dependent on multiple TRPV1 polymorphisms.

Introduction: Diagnosis of silicosis is a resurgent issue since clusters of this occupational disease have been reported in relation to fabrication of quartz conglomerates. Aim: To evaluate the sensitivity of different diagnostic tools in the detection of silicosis. Methods: Active search of pneumoconiosis was performed in 4 companies of North-Eastern Italy involved in the fabrication of benchtops made of artificial quartz conglomerates. Occupational history, silica cumulative exposure, chest x-ray, spirometry, carbon monoxide lung diffusion (DLco) and chest HRCT (classified according to International Classification of HRCT for Occupational and Environmental Respiratory Diseases) were obtained. In selected cases, trans-bronchial biopsies were taken for histological evaluation and identification of silica crystals in the tissue by Electron Microscopy. Results: Twenty-two cases of silicosis were diagnosed. Mean age at diagnosis was 43 years and duration of exposure to quartz conglomerate dust was 3.5 to 20 years. The range of silica cumulative exposure was 1.74-5.40 mg/m3/years. Abnormal findings were detected in 41% of chest x-ray, in 38% of spirometry (restrictive pattern) and 57% of DLco. HRCTs were abnormal in all cases showing well-defined rounded opacities (size p), irregular/linear intralobular opacities and bilateral enlarged mediastinal lymph-nodes. Histological findings consistent with silicosis were observed in 18 cases. Numerous silica particles (diameter 0.1-5 μm) were identified in lung tissue. Conclusions: Chest HRCT is the most sensitive diagnostic tool for the detection of silicosis, while reduction in DLco is the most frequent functional abnormality. The results suggest that chest HRCT is indicated for screening of workers with high cumulative exposure to silica.

IntroductionClusters of silicosis cases have been reported in the fabrication of quartz conglomerate, a new high-silica-content artificial stone for kitchen and bathroom benchtops (countertops).AimWe describe two cases of accelerated-type silicosis with hepatic granulomas arising in workers exposed to artificial quartz conglomerates.MethodsA confident diagnosis of multiorgan silicosis was based on high level of respirable silica in the workplace, typical radiological alterations in chest high-resolution CT, histological findings in the lung and liver, and detection of silica crystals in both tissues by phase-contrast polarising light microscopy and scanning electron microscopy and energy dispersive spectroscopy.ResultsThe development of the disease 3, that is, much higher than the threshold limit value according to American Conference of Governmental Industrial Hygienists (0.025 mg/m3). Moreover, liver granulomas were associated with accumulation of crystalline silica particles in the hepatic tissue.ConclusionsQuartz conglomerate fabrication is a potentially dangerous occupation. General practitioners and physicians should have awareness of this newly described occupational hazard. Accurate occupational history is critical in avoiding misdiagnosis, as silicosis caused by inhalation of dust from artificial quartz conglomerates may exhibit atypical presentation. These features seem to be related to the extremely high level of silica exposure and, possibly, to an increased toxicity of the dust generated in this process.

Background: Interstitial lung diseases with usual interstitial pneumonia (UIP) pattern include Idiopathic Pulmonary Fibrosis (IPF) and asbestosis. Despite the label of ‘idiopathic’ there is epidemiological evidence that IPF is associated to occupational exposures to dust. Aims: To test the hypothesis that IPF in individuals with past occupational exposure to dust may have a slower progression of the disease as it occurs in UIP pattern due to asbestos exposure. Methods: We collected occupational history of 44 patients with proven diagnosis of IPF. All patients had been under pirfenidone therapy for at least one year. Occupational exposure was defined when a subject had at least 10 yr of cumulative work exposure to inorganic or organic dusts. Annual decline of Forced Vital Capacity (FVC) was used to assess functional progression during therapy. The duration of symptoms before diagnosis was determined ( 1yr slow onset, S). Results: Sixteen/44 IPF patients (36%) had occupational exposure to inorganic (n=11) or organic (n=5) dusts. IPF patients with dust exposure tended to show slower onset of symptoms (S=64%) compared with non-exposed group (S=37%) [Χ2=2.75; p= 0.09]. Independently from smoking habit, IPF patients with dust exposure exhibited a reduced decline in lung function compared to IPF patients without exposure, although not statistically significant (FVC-120+58 ml/yr vs -209+86 ml/yr). Conclusions: IPF patients with occupational exposure to dusts tended to have a slower onset of symptoms and less functional decline during therapy than non-exposed IPF patients. The results suggest a possible role of dust exposure in the heterogeneity of IPF progression.