Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans.

OBJECTIVES: Characterise inhalational exposures during deployment to Afghanistan and Southwest Asia and associations with postdeployment respiratory symptoms. METHODS: Participants (n=1960) in this cross-sectional study of US Veterans (Veterans Affairs Cooperative Study 'Service and Health Among Deployed Veterans') completed an interviewer-administered questionnaire regarding 32 deployment exposures, grouped a priori into six categories: burn pit smoke; other combustion sources; engine exhaust; mechanical and desert dusts; toxicants; and military job-related vapours gas, dusts or fumes (VGDF). Responses were scored ordinally (0, 1, 2) according to exposure frequency. Factor analysis supported item reduction and category consolidation yielding 28 exposure items in 5 categories. Generalised linear models with a logit link tested associations with symptoms (by respiratory health questionnaire) adjusting for other covariates. OR were scaled per 20-point score increment (normalised maximum=100). RESULTS: The cohort mean age was 40.7 years with a median deployment duration of 11.7 months. Heavy exposures to multiple inhalational exposures were commonly reported, including burn pit smoke (72.7%) and VGDF (72.0%). The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively. Burn pit smoke exposure was associated with dyspnoea (OR 1.22; 95% CI 1.06 to 1.47) and chronic bronchitis (OR 1.22; 95% CI 1.13 to 1.44). Exposure to VGDF was associated with dyspnoea (OR 1.29; 95% CI 1.14 to 1.58) and wheeze (OR 1.18; 95% CI 1.02 to 1.35). CONCLUSION: Exposures to burn pit smoke and military occupational VGDF during deployment were associated with an increased odds of chronic respiratory symptoms among US Veterans.

Thrombocytopenia Associated with Elemental Mercury Poisoning in Two Siblings - Connecticut, July 2022.

Two siblings aged 5 and 15 years from Connecticut were hospitalized with petechial rash, oral mucositis, and severe thrombocytopenia approximately 10 days after they played with a jar of elemental mercury they found in their home. Before the mercury exposure was disclosed, the siblings were treated with platelet transfusions, intravenous immune globulin (IVIG) for possible immune thrombocytopenic purpura, and antibiotics for possible infectious causes. When their conditions did not improve after 6 days, poison control facilitated further questioning about toxic exposures including mercury, testing for mercury, and chelation with dimercaptosuccinic acid. The older sibling soon recovered, but the younger child required a prolonged hospitalization for severe thrombocytopenia, ultimately receiving repeated doses of IVIG, steroids, and romiplostim, a thrombopoietin receptor agonist. Close collaboration among multiple agencies was required to identify the extent of mercury contamination, evaluate and treat the other family members, and decontaminate the home. These cases demonstrate the importance of ongoing public health outreach to promote early detection of elemental mercury toxicity, and the need to evaluate for environmental exposures when multiple close contacts experience similar signs and symptoms.

Reducing asthma exacerbations in vulnerable children through a medical-legal partnership.

BACKGROUND: Asthma health disparities are widely recognized, with worse outcomes in children from low income families. In a Medical-Legal Partnership (MLP), an attorney is embedded in a healthcare setting to address social determinants of health. We studied whether an MLP could impact asthma exacerbation rates in a vulnerable urban population at an academic children's hospital. METHODS: The study population comprised children with asthma who were referred to the MLP between 2013 and 2017. We compared healthcare utilization for asthma exacerbations managed in primary care, emergency department and inpatient settings in the year before and year after MLP intervention. RESULTS: 98 children with asthma were included in the study. The mean total encounters per person per year decreased from 1.16 to 0.66 (relative reduction 44.2%, p < 0.01). The largest effect was on hospitalizations, with a reduction from 0.33 to 0.10 hospitalizations per patient per year (relative reduction 69.7%, p < 0.01). Encounters for asthma exacerbations in the primary care office and emergency department also decreased but these changes did not meet statistical significance. CONCLUSION: In a pediatric population with asthma, an MLP intervention was associated with a significant reduction in asthma exacerbation encounters and hospitalizations comparing the year before and after MLP intervention. Further studies are needed to better understand which interventions are most effective, and for which patient groups MLP referral would be particularly useful. MLPs may be an important way to reduce health disparities in patients with asthma and other chronic illnesses.

Severe asthma and death in a worker using methylene diphenyl diisocyanate MDI asthma death.

Diisocyanates are well-recognized to cause occupational asthma, yet diisocyanate asthma can be challenging to diagnose and differentiate from asthma induced by other allergens. The present study assesses the potential contribution of methylene diphenyl diisocyanate (MDI) to a workplace fatality. Examination of medical records, tissue, and blood from the deceased worker were undertaken. Formalin-fixed paraffin-embedded lung tissue sections were assessed through histologic and immunochemical stains. Serum MDI-specific IgE and IgG, and total IgE, were measured by enzyme-linked immunosorbent assays and/or Western blot. Information about potential chemical exposures and industrial processes in the workplace were provided by the employer and through interviews with co-workers. Review of the worker's medical records, occupational history, and autopsy findings were consistent with severe asthma as the cause of death, and ruled out cardiac disease, pulmonary embolism, or stroke. Lung pathology revealed hallmarks of asthma including smooth muscle hypertrophy, eosinophilia, basement membrane thickening, and mucus plugging of bronchioles. Immunochemical staining for MDI was positive in the thickened basement membrane of inflamed airways. MDI-specific serum IgE and IgG were significantly elevated and demonstrated specificity for MDI versus other diisocyanates, however, total serum IgE was normal (24 IU/ml). The workplace had recently introduced MDI into the foundry as part of a new process, but MDI air levels had not been measured. Respirators were not required. In summary, post-mortem findings support the diagnosis of diisocyanate asthma and a severe asthma attack at work as the cause of death in a foundry worker.

Assessment of personal inhalation and skin exposures to polymeric methylene diphenyl diisocyanate during polyurethane fabric coating.

Methylene diphenyl diisocyanate (MDI) monomers and polymeric MDI (pMDI) are aromatic isocyanates widely used in the production of polyurethanes. These isocyanates can cause occupational asthma, hypersensitivity pneumonitis, as well as contact dermatitis. Skin exposure likely contributes toward initial sensitization but is challenging to monitor and quantitate. In this work, we characterized workers' personal inhalation and skin exposures to pMDI in a polyurethane fabric coating factory for subsequent health effect studies. Full-shift personal and area air samples were collected from eleven workers in representative job areas daily for 1-2 weeks. Skin exposure to hands was evaluated concomitantly with a newly developed reagent-impregnated cotton glove dosimeter. Samples were analyzed for pMDI by liquid chromatography-tandem mass spectrometry. In personal airborne samples, the concentration of 4,4'-MDI isomer, expressed as total NCO, had a geometric mean (GM) and geometric standard deviation (GSD) of 5.1 and 3.3 ng NCO/m3, respectively (range: 0.5-1862 ng NCO/m3). Other MDI isomers were found at much lower concentrations. Analysis of 4,4'-MDI in the glove dosimeters exhibited much greater exposures (GM: 10 ng/cm2) and substantial variability (GSD: 20 ng NCO/cm2; range: 0-295 ng NCO/cm2). MDI inhalation exposure was well below occupational limits for MDI for all the job areas. However, MDI skin exposure to hands was substantial. These findings demonstrated the potential for substantial isocyanate skin exposure in work settings with very low airborne levels. This exposure characterization should inform future studies that aim to assess the health effects of work exposures to MDI and the effectiveness of protective measures.

Analysis of Lung Gene Expression Reveals a Role for Cl- Channels in Diisocyanate-induced Airway Eosinophilia in a Mouse Model of Asthma Pathology.

Diisocyanates are well-recognized causes of asthma. However, sensitized workers frequently lack diisocyanate-specific IgE, which complicates diagnosis and suggests the disease involves IgE-independent mechanisms. We used a mouse model of methylene diphenyl diisocyanate (MDI) asthma to identify biological pathways that may contribute to asthma pathogenesis. MDI sensitization and respiratory tract exposure were performed in Balb/c, transgenic B-cell (e.g., IgE)-deficient mice and a genetic background (C57BL/6)-matched strain. Eosinophils in airway fluid were quantitated by flow cytometry. Lung tissue gene expression was assessed using whole-genome mRNA microarrays. Informatic software was used to identify biological pathways affected by respiratory tract exposure and potential targets for disease intervention. Airway eosinophilia and changes (>1.5-fold; P value < 0.05) in expression of 192 genes occurred in all three mouse strains tested, with enrichment in chemokines and a pattern associated with alternatively activated monocytes/macrophages. CLCA1 (calcium-activated chloride channel regulator 1) was the most upregulated gene transcript (>100-fold) in all exposed mouse lungs versus controls, followed closely by SLC26A4, another transcript involved in Cl- conductance. Crofelemer, a U.S. Food and Drug Administration-approved Cl- channel inhibitor, reduced MDI exposure induction of airway eosinophilia, mucus, CLCA1, and other asthma-associated gene transcripts. Expression changes in a core set of genes occurs independent of IgE in a mouse model of chemical-induced airway eosinophilia. In addition to chemokines and alternatively activated monocytes/macrophages, the data suggest a crucial role for Cl- channels in diisocyanate asthma pathology and as a possible target for intervention.

Occupational lung diseases in the 21st century: the changing landscape and future challenges.

PURPOSE OF REVIEW: Occupational exposures remain an underrecognized and preventable cause of lung disease in high-income countries. The present review highlights the emergence of cleaning-related respiratory disease and the re-emergence of silicosis as examples of trends in occupational lung diseases in the 21st century. RECENT FINDINGS: Employment trends, such as the shift from large-scale manufacturing to a service economy, the growth of the healthcare sector, and changing consumer products have changed the spectrum of work-related lung diseases. Following decades of progress in reducing traditional hazards such as silica in U.S. workplaces, cases of advanced silicosis have recently re-emerged with the production of engineered stone countertops. With growth in the healthcare and service sectors in the United States, cleaning products have become an important cause of work-related asthma and have recently been associated with an increased risk of chronic obstructive pulmonary disease (COPD) in women. However, these occupational lung diseases largely go unrecognized by practicing clinicians. SUMMARY: The present article highlights how changes in the economy and work structure can lead to new patterns of inhalational workplace hazards and respiratory disease, including cleaning-related respiratory disease and silicosis. Pulmonary clinicians need to be able to recognize and diagnose these occupational lung diseases, which requires a high index of suspicion and a careful occupational history.

The Occupational Burden of Nonmalignant Respiratory Diseases. An Official American Thoracic Society and European Respiratory Society Statement.

Rationale: Workplace inhalational hazards remain common worldwide, even though they are ameliorable. Previous American Thoracic Society documents have assessed the contribution of workplace exposures to asthma and chronic obstructive pulmonary disease on a population level, but not to other chronic respiratory diseases. The goal of this document is to report an in-depth literature review and data synthesis of the occupational contribution to the burden of the major nonmalignant respiratory diseases, including airway diseases; interstitial fibrosis; hypersensitivity pneumonitis; other noninfectious granulomatous lung diseases, including sarcoidosis; and selected respiratory infections. Methods: Relevant literature was identified for each respiratory condition. The occupational population attributable fraction (PAF) was estimated for those conditions for which there were sufficient population-based studies to allow pooled estimates. For the other conditions, the occupational burden of disease was estimated on the basis of attribution in case series, incidence rate ratios, or attributable fraction within an exposed group. Results: Workplace exposures contribute substantially to the burden of multiple chronic respiratory diseases, including asthma (PAF, 16%); chronic obstructive pulmonary disease (PAF, 14%); chronic bronchitis (PAF, 13%); idiopathic pulmonary fibrosis (PAF, 26%); hypersensitivity pneumonitis (occupational burden, 19%); other granulomatous diseases, including sarcoidosis (occupational burden, 30%); pulmonary alveolar proteinosis (occupational burden, 29%); tuberculosis (occupational burden, 2.3% in silica-exposed workers and 1% in healthcare workers); and community-acquired pneumonia in working-age adults (PAF, 10%). Conclusions: Workplace exposures contribute to the burden of disease across a range of nonmalignant lung conditions in adults (in addition to the 100% burden for the classic occupational pneumoconioses). This burden has important clinical, research, and policy implications. There is a pressing need to improve clinical recognition and public health awareness of the contribution of occupational factors across a range of nonmalignant respiratory diseases.

Polymerization of hexamethylene diisocyanate in solution and a 260.23 m/z [M+H]+ ion in exposed human cells.

Hexamethylene diisocyanate (HDI) is an important industrial chemical that can cause asthma, however pathogenic mechanisms remain unclear. Upon entry into the respiratory tract, HDI's N=C=O groups may undergo nucleophilic addition (conjugate) to host molecules (e.g. proteins), or instead react with water (hydrolyze), releasing CO2 and leaving a primary amine in place of the original N=C=O. We hypothesized that (primary amine groups present on) hydrolyzed or partially hydrolyzed HDI may compete with proteins and water as a reaction target for HDI in solution, resulting in polymers that could be identified and characterized using LC-MS and LC-MS/MS. Analysis of the reaction products formed when HDI was mixed with a pH buffered, isotonic, protein containing solution identified multiple [M+H]+ ions with m/z's and collision-induced dissociation (CID) fragmentation patterns consistent with those expected for dimers (259.25/285.23 m/z), and trimers (401.36/427.35 m/z) of partially hydrolyzed HDI (e.g. ureas/oligoureas). Human peripheral blood mononuclear cells (PBMCs) and monocyte-like U937, but not airway epithelial NCI-H292 cell lines cultured with these HDI ureas contained a novel 260.23 m/z [M+H]+ ion. LC-MS/MS analysis of the 260.23 m/z [M+H]+ ion suggest the formula C13H29N3O2 and a structure containing partially hydrolyzed HDI, however definitive characterization will require further orthogonal analyses.

Improving the asthma disparity gap with legal advocacy? A qualitative study of patient-identified challenges to improve social and environmental factors that contribute to poorly controlled asthma.

OBJECTIVE: To identify challenges that disadvantaged adults with asthma face in mitigating social and environmental factors associated with poor symptom control. METHODS: Using a community-engaged approach, we partnered with a community health center in New Haven, CT to conduct in-person interviews and a written survey of asthmatic adults with poor symptom control. Using the constant comparative method, we analyzed participant interviews to establish emerging themes and identify common barriers to improved outcomes. Through a written survey utilizing clinically validated questions, we assessed information on access to medical care, asthma control, and selected social and environmental risk factors. RESULTS: Twenty-one patients (mean age 47, 62% female, 71% Black, 95% insured by Medicaid) participated. The average Asthma Control Test (ACT) score was 11.6. Seventy-six percent of participants were currently employed and of those, 75% reported work-related symptoms. Among participants currently in housing, 59% reported exposure to domiciliary mice and 47% to mold. We identified three themes that summarize the challenges the study participants face: 1) Lack of knowledge about home and workplace asthma triggers; 2) Lack of awareness of legal rights or resources available to mitigate adverse conditions in the home or work environment; and 3) Fear of retaliation from landlords or employers, including threats of eviction, sexual assault, and job loss. CONCLUSION: Patients with poorly controlled asthma in a disadvantaged urban northeast community identified common barriers in both the domestic and work environments that impeded attainment of symptom control. These challenges may be best addressed through legal advocacy for those most at risk.

Reaction products of hexamethylene diisocyanate vapors with "self" molecules in the airways of rabbits exposed via tracheostomy.

1. Hexamethylenediisocyanate (HDI) is a widely used aliphatic diisocyanate and a well-recognized cause of occupational asthma. 2. "Self" molecules (peptides/proteins) in the lower airways, susceptible to chemical reactivity with HDI, have been hypothesized to play a role in asthma pathogenesis and/or chemical metabolism, but remain poorly characterized. 3. This study employed unique approaches to identify and characterize "self" targets of HDI reactivity in the lower airways. Anesthetized rabbits free breathed through a tracheostomy tube connected to chambers containing either, O2, or O2 plus ∼200 ppb HDI vapors. Following 60 minutes of exposure, the airways were lavaged and the fluid was analyzed by LC-MS and LC-MS/MS. 4. The low-molecular weight (<3 kDa) fraction of HDI exposed, but not control rabbit bronchoalveolar lavage (BAL) fluid identified 783.26 and 476.18 m/z [M+H]+ ions with high energy collision-induced dissociation (HCD) fragmentation patterns consistent with bis glutathione (GSH)-HDI and mono(GSH)-HDI. Proteomic analyses of the high molecular weight (>3 kDa) fraction of exposed rabbit BAL fluid identified HDI modification of specific lysines in uteroglobin (aka clara cell protein) and albumin. 5. In summary, this study utilized a unique approach to chemical vapor exposure in rabbits, to identify HDI reaction products with "self" molecules in the lower airways.

Injury, illness, and disability risk in American seafarers.

BACKGROUND: Seafarers are an understudied and essential workforce, isolated from medical care. This study describes injuries, illness, and risk factors for resultant disability in one shipping company with a majority of American seafarers. METHODS: The study used a telemedicine database of injury and illness incidence in seafarers, and applied descriptive statistical methods and logistic regression modeling. RESULTS: Illnesses were more frequently reported than injuries (860 vs 479). The overall injury rate was 113 per 1000 person-years, and the overall illness rate was 211 per 1000 person-years. Seafarer ratings had higher risk for disability compared to officers (OR = 1.60; 95%CI 1.17, 2.18), and incidents on dry cargo ships (OR = 2.70; 95%CI 1.49, 4.91) and articulated tug-barges (ATBs) (OR = 2.21; 95%CI 1.26, 3.86) had higher disability risk compared to container vessels. CONCLUSION: Additional research in this vital American workforce may be useful to confirm these findings forming a basis for preventive interventions.

National Institute of Environmental Health Sciences: 50 Years of Advancing Science and Improving Lung Health.

The American Thoracic Society celebrates the 50th anniversary of the National Institute of Environmental Health Sciences (NIEHS). The NIEHS has had enormous impact through its focus on research, training, and translational science on lung health. It has been an advocate for clean air both in the United States and across the world. The cutting-edge science funded by the NIEHS has led to major discoveries that have broadened our understanding of the pathogenesis and treatment for lung disease. Importantly, the NIEHS has developed and fostered mechanisms that require cross-cutting science across the spectrum of areas of inquiry, bringing together environmental and social scientists with clinicians to bring their expertise on specific areas of investigation. The intramural program of the NIEHS nurtures cutting-edge science, and the extramural program encourages investigator-initiated research while at the same time providing broader direction through important initiatives. Under the umbrella of the NIEHS and guided by Dr. Linda Birnbaum, the director of the NIEHS, important collaborative programs, such as the Superfund Program and the National Toxicology Program, work to discover mechanisms to protect from environmental toxins. The American Thoracic Society has overlapping goals with the NIEHS, and the strategic plans of both august bodies converge to synergize on population lung health. These bonds must be tightened and highlighted as we work toward our common goals.

Asbestosis and environmental causes of usual interstitial pneumonia.

PURPOSE OF REVIEW: Recent epidemiologic investigations suggest that occupational and environmental exposures contribute to the overall burden of idiopathic pulmonary fibrosis (IPF). This article explores the epidemiologic and clinical challenges to establishing exposure associations, the current literature regarding exposure disease relationships and the diagnostic work-up of IPF and asbestosis patients. RECENT FINDINGS: IPF patients demonstrate a histopathologic pattern of usual interstitial pneumonia. In the absence of a known cause or association, a usual interstitial pneumonia pattern leads to an IPF diagnosis, which is a progressive and often terminal fibrotic lung disease. It has long been recognized that asbestos exposure can cause pathologic and radiographic changes indistinguishable from IPF. Several epidemiologic studies, primarily case control in design, have found that a number of other exposures that can increase risk of developing IPF include cigarette smoke, wood dust, metal dust, sand/silica and agricultural exposures. Lung mineralogic analyses have provided additional support to causal associations. Genetic variation may explain differences in disease susceptibility among the population. SUMMARY: An accumulating body of literature suggests that occupational and environmental exposure can contribute to the development of IPF. The impact of exposure on the pathogenesis and clinical course of disease requires further study.

Official American Thoracic Society technical standards: spirometry in the occupational setting.

PURPOSE: This document addresses aspects of the performance and interpretation of spirometry that are particularly important in the workplace, where inhalation exposures can affect lung function and cause or exacerbate lung diseases, such as asthma, chronic obstructive pulmonary disease, or fibrosis. METHODS: Issues that previous American Thoracic Society spirometry statements did not adequately address with respect to the workplace were identified for systematic review. Medline 1950-2012 and Embase 1980-2012 were searched for evidence related to the following: training for spirometry technicians; testing posture; appropriate reference values to use for Asians in North America; and interpretative strategies for analyzing longitudinal change in lung function. The evidence was reviewed and technical recommendations were developed. RESULTS: Spirometry performed in the work setting should be part of a comprehensive workplace respiratory health program. Effective technician training and feedback can improve the quality of spirometry testing. Posture-related changes in FEV1 and FVC, although small, may impact interpretation, so testing posture should be kept consistent and documented on repeat testing. Until North American Asian-specific equations are developed, applying a correction factor of 0.88 to white reference values is considered reasonable when testing Asian American individuals in North America. Current spirometry should be compared with previous tests. Excessive loss in FEV1 over time should be evaluated using either a percentage decline (15% plus loss expected due to aging) or one of the other approaches discussed, taking into consideration testing variability, worker exposures, symptoms, and other clinical information. CONCLUSIONS: Important aspects of workplace spirometry are discussed and recommendations are provided for the performance and interpretation of workplace spirometry.