Respiratory Diseases Associated with Organic Dust Exposure

Abstract

Organic dusts are complex bioaerosol mixtures comprised of dust and particulate matter of organic origin. These include components from bacteria, fungi, pollen, and viruses to fragments of animals and plants commonplace to several environmental/occupational settings encompassing agriculture/farming, grain processing, waste/recycling, textile, cotton, woodworking, bird breeding, and more. Organic dust exposures are linked to development of chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, asthma-like syndrome, byssinosis, hypersensitivity pneumonitis (HP), and idiopathic pulmonary fibrosis (IPF). Risk factors of disease development include cumulative dust exposure, smoking, atopy, timing/duration, and nutritional factors. The immunopathogenesis predominately involves Toll-like receptor signaling cascade, Th1/Th17 lymphocyte responses, neutrophil influx, and potentiation of manifestations associated with allergy. The true prevalence of airway disease directly attributed to organic dust, especially in a workplace setting, remains challenging. Diagnostic confirmation can be difficult and complicated by hesitancy from workers to seek medical care, driven by fears of potential labor-related consequence. Clinical respiratory and systemic presentations coupled with allergy testing, lung function patterns of obstructive versus restrictive disease, and radiological characteristics are typically utilized to delineate these various organic dust-associated respiratory diseases. Prevention, risk reduction, and management primarily focus on reducing exposure to the offending dust, managing symptoms, and preventing disease progression.

INTRODUCTION

Organic dusts refer to a complex mixture of dust and particulate matter of organic origin including components from bacteria, fungi, pollen, and viruses to fragments of animals and plants (1). Organic dust exposures have been linked to development of chronic occupational airway diseases such as chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, asthma-like syndrome, byssinosis, hypersensitivity pneumonitis (HP), and idiopathic pulmonary fibrosis (IPF). Establishing the true prevalence of airway disease directly attributed to organic dust, especially in a workplace setting, remains challenging. The diagnostic confirmation of occupational respiratory diseases can be difficult and complicated by hesitancy from workers to seek medical care, driven by fears of potential labor-related consequences (2). Workers with worsening symptoms tend to leave their jobs, and those without immediate symptoms remain in the workplace, which has been referred to as “the healthy worker effect” (3). This review will address risk factors contributing to disease development, immunopathogenesis, disease entities, diagnostic approaches, and management strategies.

EPIDEMIOLOGY

Industries commonly affected by organic dusts include agriculture and food production with high variability in concentration exposure typically related to tasks performed rather than herd size (3). In the dairy industry, milking and animal handling activities provided a higher risk of concentration exposure (3). In the avian industry, hatchery workers experience an increased prevalence of respiratory symptoms including cough and/or phlegm (4). Furthermore, workers assigned to avian sorting rooms also had a decrease of 11% in forced vital capacity (FVC) compared to those working in incubation rooms (4). Moreover, in a Norwegian study of farmers, livestock farmers had increased risk of chronic bronchitis (adjusted odds ratio (aOR) (95% confidence interval, CI): 1.9 (1.4–2.6) and COPD (aOR: 1.4 (1.1–1.7)) when compared to crop farmers after adjustment for potential confounders including age, gender, and smoking status (5). A meta-analysis by Guillien et al. demonstrated a positive association between farming exposure and airflow limitation or chronic bronchitis in 10 of 22 studies (OR: 1.77 (1.50–2.08)) with cattle, swine, poultry, and crop farming associated with either airflow limitation or chronic bronchitis (6).

In the waste and recycling sector, organic dusts and volatile organic compounds were the highest during the sorting of materials in compost stations (7). In the textile industry, recognized to have high endotoxin exposure, byssinosis is an occupational respiratory disease due to exposure to cotton, hemp, or flax. Hinson et al. reported a prevalence of byssinosis of 44% amongst workers directly exposed to cotton dust in a textile company in Benin, West Africa (8). In the wood processing sector, Neghab et al. observed that 35% of Iranian sawmill workers experienced a 5% cross-work shift decrease in forced expiratory volume in one second (FEV₁). This occurred despite the existence of recommended occupational exposure limits and precautions offered by occupational safety organizations (9).

IMMUNOPATHOGENESIS

Organic dusts are bioaerosols comprised of a diverse and wide array of organic particles, encompassing fragments from both animal and plant sources, alongside pro-inflammatory mediators such as gram-negative endotoxins or lipopolysaccharides (LPS), gram-positive peptidoglycans, and fungal (1–3) b-D-glucans, amongst others (10, 11). These exposures induce release of pro-inflammatory cytokines/chemokines that typically drive the recruitment and activation of neutrophils, induce airway hyperresponsiveness, generate free radicals, and promote lymphocyte activation (12, 13). With repetitive exposures, airway remodeling and chronic disease develops (14). Whereas LPS is a notable element within organic dust, it is the “whole” composition (as opposed to one isolated agent) of organic dust mixtures that drive pathogenesis. For example, individuals exposed to pig barn dust had a more pronounced inflammatory response as evidenced by elevated levels of interleukin (IL)-6, IL-8, and total cell counts in sputum samples as compared to exposure to LPS alone, despite the concentration of LPS being several fold higher than what is encountered in pig barns (15).

Organic dust engages innate signaling pathways, mainly through the recognition of pathogen-associated molecular pattern molecules typically by Toll-like receptors (TLRs). TLR2, TLR4, TLR9, and the common adaptor protein myeloid differentiation factor 88 (MyD88) have been implicated in the acute inflammatory response to agricultural-related organic dust exposures (16–21). In murine studies, swine confinement facility organic dust extract-induced acute airway inflammatory responses (i.e., neutrophil influx, release of tumor necrosis factor (TNF)-α, IL-6 and neutrophil chemoattractants, and airway hyper-responsiveness) were nearly completely abrogated in MyD88-deficient mice (18). Furthermore, striking reduction in airway inflammatory responses remained after daily exposure for one week in MyD88-deficient mice (22), but there was enhanced airway mucous cell metaplasia (23). Correspondingly, acute organic dust exposure in humans is also associated with cellular infiltration and increased cytokine production ascribed to TLR signaling. Namely, Hedelin et al. demonstrated increases in nasal lavage total and blood neutrophils, monocytes, and basophils following a 3-hour exposure to swine dust with associated increases in monocyte expression of TLR2 and TLR4 (24). This response was reduced following the installment of fine particle separators (24).

Highlighting the importance of TLR signaling pathways, a missense mutation in TLR4 (Asp299Gly) have been associated with hypo-responsiveness to inhalant LPS exposure with decreased NF-κB activity, decreased IL-1⍺ production, and decreased airway epithelial TLR4 receptor (25). Single nucleotide polymorphisms in the TLR10-TLR1-TLR6 gene cluster have also been associated with ex vivo whole blood IL-6 (but not TNF-⍺) hyper-responsiveness to organic dust and gram-positive components in agricultural workers (26). CD14 is a receptor for LPS, and the CD14/−159 T allele polymorphism has been associated with increased circulating levels of CD14 and increased prevalence of wheezing without association in lung function in farmers (27). In this same study, there was no association between TLR4/Asp299Gly and lung function or wheeze in farmers (27). Otherwise, there is a paucity of data understanding the role of genetic susceptibility in organic dust associated respiratory diseases.

As compared to the robust acute inflammatory response to a one-time organic dust exposure, repetitive exposures result in a comparative reduction in pro-inflammatory cytokines/chemokines levels but persistence of lung neutrophils, lymphocytes, and recruited monocyte/macrophages in animals studies, which has been termed the chronic inflammatory adaptation response (22, 28). Similarly, a one-time organic dust exposure induces an increase in airway hyper-responsiveness in mice, and this response is lost with repetitive exposures (29), consistent with the adaptation response but differs from experimental allergy asthma murine models. Correspondingly, pig farmers demonstrated an attenuation of symptoms, lung function, bronchial responsiveness, and markers of airway inflammation as compared to first-time exposed naïve individuals (15). Nevertheless, these pig farmers had markers of low grade, persistent inflammation as compared to never-exposed individuals (15).

Organic dust exposures can induce the recruitment of CD4⁺ T helper (Th) 1 cells, Th2 cells, Th17 cells, innate lymphoid cells (ILCs), airway epithelial cells, and monocyte/macrophage activation responses (30–32). In animal models, organic dust extract exposure induces lung alarmin IL-33 release, Th1/Th17 responses, and increased serum IgE levels without evidence for a Th2-mediated response or airway eosinophil influx (22, 33). Th17 cells and IL-17 are recognized to induce the recruitment of neutrophils and monocytes/macrophages, contributing to the pathogenesis of asthma and COPD (34, 35). In Severe Equine Asthma Syndrome, a naturally occurring chronic organic dust airway disease in horses that shares similarities with asthma in humans, a similar Th17 response has also been demonstrated (36).

Regulators of organic dust-associated airway inflammatory response include the anti-inflammatory cytokine IL-10. In a cross-sectional study of 625 veterans with farming experience, higher baseline blood concentrations of IL-10 were associated with higher FEV₁/FVC and inversely associated with whole blood stimulated ΔTNF-α and ΔIL-6 (37). In IL-10 deficient mice, organic dust extract-induced airway inflammation, neutrophil influx, and lung pathology were elevated, and this response was reversed with IL-10 supplementation (38). Furthermore, short-term, lung-delivered recombinant IL-10 favorably hastened airway inflammatory recovery processes following acute, high dose inhalant LPS exposure in mice (39). In addition, airway cathelicidin (LL-37), an antimicrobial and LPS neutralizing peptide implicated in tissue repair (40), was increased in farmers with and without COPD versus healthy urban persons (41). In advanced stages of COPD, LL-37 levels have been found to decrease, possibly highlighting the role of this peptide in antimicrobial protection (42).

RISK FACTORS

Cumulative exposure to organic dust represents an important factor in disease development. In a cross-sectional study in Ethiopia, there was a high incidence of chronic respiratory symptoms in flour mill workers (43). The presence of chronic respiratory symptoms was associated with working in the mixing department (aOR (CI): 5.3 (1.68–16.56)), work experience of 6–9 years (aOR: 5.1 (2.05–12.48)), work experience ≥10 years (aOR: 2.5, (1.01–6.11)), and working ≥8 hours per day (aOR: 2.4 (1.16–5.10)) (43). The degree of exposure is also important. Andersson et al. demonstrated that each year of high exposure to soft paper dust (defined as >5mg/m³) was associated with a 0.87% predicted decrease in FEV₁ (CI: −1.39 to −0.35) and a 0.54% decrease in FVC (CI: −1.00 to −0.08) (44). In contrast, a Danish register-based cohort study did not find an association between the cumulative organic dust exposure and COPD in the farming or wood industry despite lagging their variables 10 years to consider the period of disease development of COPD and the healthy worker survivor effect (45). Instead, they noted a decreased risk of COPD in the highest exposed group (adjusted rate ratio:0.63 (0.56–0.70)) (45). However, it was suggested that tobacco smoke may have confounded the results to suggest need for additional longitudinal studies (45). Indeed, the co-influence of tobacco smoking is important. Guillam et al. demonstrated lower forced expiratory flow between 25–75% of vital capacity and forced expiratory flow at 50% of vital capacity in duck hatchery workers who smoked compared to non-smoking workers (4).

The role of atopy as a risk factor is less clear. Dairy farmers who had persistent airflow limitation were more likely to have at least 3 positive tests for allergen-specific IgE when compared to dairy farmers without persistent airflow limitation (46). House dust endotoxin has been associated with atopic and non-atopic asthma in farming populations across the United States (U.S). In a large case-control study involving a cohort of farmers and their spouses, Carnes et al. demonstrated that increasing endotoxin levels was associated with higher odds of current asthma (unadjusted OR: 1.30 (1.14–1.47)), and moreover, endotoxin was associated with atopic asthma (aOR: 1.38 (1.09–1.74)) and non-atopic asthma (aOR: 1.24 (1.07–1.43)) after adjustment for sex, smoking status, race, and season (47).

Timing of exposure may also be important. Exposing mice to Amish organic dust extracts prior to the onset of experimental allergen-induced asthma sensitization and challenge resulted in reduced airway inflammatory outcomes (48). In contrast, when mice were exposed to swine confinement organic dust extracts after allergen-induced asthma sensitization and challenge phase, there was potentiation of airway inflammatory outcomes (49). Amongst U.S. farmers, a non-linear relationship between endotoxin and asthma was described, with higher endotoxin levels associated with current asthma (OR: 1.30 (1.14–1.47)) and modifiable by early-life farm exposure (47). Notably, the association between dust endotoxin and asthma was higher in individuals not born on a farm (OR: 1.67 (1.26–2.20)) compared to those who were (OR: 1.18 (1.02–1.37)). This highlights that the “protective effect” of early-life farming exposure may be linked to endotoxin exposure (47, 48).

The impact of age as a risk factor for the development of organic dust airway disease has been difficult to establish. Earlier studies (1990’s) demonstrated that a relative excess of respiratory symptoms and reduced lung function were higher among swine producers aged 26–35 years, which may have reflected more intense exposures (50). It has also been demonstrated that “young (7–9 week)” mice had a more robust inflammatory response to swine confinement organic dust exposures as compared to “older (12–14 month)” mice (51).

Micronutrient deficiencies represent global health concerns (52) and may represent an additional risk factor. Nutritional zinc insufficiency has been associated with lower pulmonary function (FEV₁/FVC, p=0.03; trends for FEV₁, p=0.056) among veterans with history of farm exposure in COPD individuals (53). In animal studies, dietary vitamin D (54) and docosahexaenoic acid (DHA, omega-3 fatty acid) (55) supplementation demonstrated reduced airway inflammatory indices following exposure to organic dust extracts. Thus, nutritional approaches may potentially reduce organic dust-associated airway inflammation, but future studies in humans are necessary. A summary of the risk factors and respiratory disease(s) associated with organic dust exposure is shown in Table I.

Table I.

Risk factors associated with development of organic dust associated respiratory diseases.

Risk factor	Respiratory disease
Cumulative exposure	COPD/Chronic bronchitis Hypersensitivity pneumonitis Idiopathic pulmonary fibrosis
Very high concentration, one-time exposure	Organic dust toxic syndrome Hypersensitivity pneumonitis
Tobacco smoking	COPD/Chronic bronchitis Byssinosis
Composition of organic dust (e.g., endotoxin)	Atopic and non-atopic asthma COPD/chronic bronchitis Byssinosis
Age* (e.g., young adults)	Obstructive lung disease
Atopy*	Asthma
Timing of exposure (e.g., late- vs. early-life exposure)	Atopic and non-atopic asthma COPD/Chronic bronchitis
Micronutrient deficiencies* (e.g., Zinc deficiency)	COPD/Chronic bronchitis

^*Additional studies are needed to fully understand its impact in the development of respiratory diseases.

RESPIRATORY DISEASES ASSOCIATED WITH ORGANIC DUST EXPOSURES

ORGANIC DUST TOXIC SYNDROME

Organic dust toxic syndrome (ODTS) is a complex disease entity that can develop acutely, usually occurring within hours of exposure to very high dust concentrations, also referred to as acute febrile syndrome or grain fever. The risk of its development increases with concentration and duration of exposure. Symptoms include fever with generalized malaise, myalgias, dyspnea, non-productive cough, chest tightness, and nausea (56). Laboratory testing typically reveals leukocytosis with neutrophilia. Chest imaging, oxygen saturation, and pulmonary function test may be unremarkable (57). Most cases of ODTS are mild, with symptoms usually resolving within 24 hours, but can persist for 2–5 days (56). In contrast to HP, ODTS lacks prior sensitization to antigens driving its pathogenesis. Furthermore, the role of corticosteroid therapy remains uncertain in ODTS (58).

ASTHMA

Adult exposure to organic dusts in industries such as farming, soft paper, and cotton are associated with an increased risk of developing asthma (59). A comprehensive meta-analysis revealed that exposure to dust from paper/wood, flour/grain, and textiles can raise the risk of asthma by 48% (60), but information regarding pre-existing asthma was not included. Reducing exposure also decreases the frequency of asthma exacerbations (61). The term “asthma-like syndrome” refers to acute, nonallergic airway responses commonly seen in agricultural settings, characterized by chest tightness, wheezing, and/or shortness of breath. This syndrome may also manifest as a cross-shift decline in FEV₁, often linked to acute neutrophilic airway inflammation. Unlike classic asthma, this syndrome can occur upon first exposure, suggesting an inflammatory rather than an allergic reaction.

BYSSINOSIS

Byssinosis refers to a specific respiratory disease directly caused by cotton dust (textile industry). Breathlessness, cough, and chest tightness are more severe at the start of the workweek but may evolve to include productive cough and exertional dyspnea with repeated exposures (62). Tobacco smoking is an additional risk factor (63). Ocular and nasal irritation may also be present (64). Disease progression has been categorized into distinct stages. Initially, there is a stage of irritation (0–5 years), which often improves upon cessation of exposure. The next phase is temporary incapacity, usually occurring after 10+ years. The final stage involves complete disability, characterized by chronic bronchitis and emphysema (65). Diagnosis is based on the World Health Organization grading system and Schilling criteria that includes symptoms and the weekday affected (8). The severity of byssinosis correlates with a more rapid decline in pulmonary function (66, 67). Note, swine confinement workers also report worsening respiratory symptoms with weekday exposure and improvement when away from work (68) and these symptoms are rarely related to allergy to porcine proteins (69–71).

COPD/Chronic Bronchitis

The prevalence of COPD/chronic bronchitis among nonsmokers varies between 2 and 4.2% (72) with a systematic review demonstrating associations between farming exposure (i.e., cattle, swine, poultry and crop farming) and airflow limitation or chronic bronchitis (73). Livestock farmers were more likely to have chronic bronchitis (OR: 1.9 (1.4–2.6)) and COPD (OR: 1.4 (1.1 to 1.7)) as compared to crop farmers (74). Farmers with allergy have significantly lower FEV₁, and the effects of farming and specific agents on COPD were substantially greater in farmers with atopy (74). Despite modernization efforts in the dairy industry that have reduced COPD prevalence (75, 76), traditional dairy farming remains a risk factor for COPD with additive smoking effects observed (77). In poultry work, prevalence rates of COPD were higher in individuals with longer exposure regardless of smoking status (78). In cotton work, particularly those exposed to both jute and hemp dust, the frequency of chronic bronchitis in retired workers who previously smoked was higher (20%) as compared to currently smoking workers (17%) (79). Working in dense dust areas, active smoking, being older than 40 years of age, being an ex-smoker, and working in the factory for a period exceeding 15 years were significantly associated with bronchitis and emphysema development (79).

ASTHMA-COPD OVERLAP

Asthma and COPD are prevalent respiratory conditions that can overlap in 15%−20% of patients (80), referred to as Asthma-COPD Overlap (ACO). Individuals with COPD displaying asthmatic characteristics, as well as asthma patients with a history of smoking who develop non-fully reversible airflow obstruction, fall into this ACO category (81). Diagnosis of ACO in COPD patients typically reflects presence of reversible airflow obstruction, type 2 inflammation with airway or peripheral blood eosinophilia, or a previous physician’s diagnosis of asthma (82).

The association of ACO with work-related asthma (WRA) or organic dust exposure is not well-established. A U.S. Behavioral Risk Factor Surveillance Survey found that 51.9% of adults with WRA and 25.6% of those with non-WRA had also been diagnosed with COPD (83). Those with concurrent WRA and COPD experienced more severe asthma exacerbations and outcomes compared to those with non-WRA and no COPD. In a study identifying ACO in an OA cohort of 304 subjects by Ojanguren et al. in Montreal (84), 86% were diagnosed with OA alone and 14% with occupational ACO. The occupational ACO group was older, required higher doses of inhaled corticosteroids, had longer exposure to offending agents, was more frequently exposed to low molecular weight agents, and showed less atopy compared to the OA group (84). In Finland, a study highlighted the significant association between the risk of ACO and the presence of mold odor in the workplace (85). A Finnish study demonstrated that asthma patients exposed to vapors, gases, dust, or fumes in their occupation were more likely to develop ACO compared to those without such exposures (86).

HYPERSENSITIVITY PNEUMONITIS

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a complex syndrome caused by a non-IgE-mediated allergic reaction to organic particles or low molecular weight agents involving type III (immune complex-mediated) and type IV (delayed-type hypersensitivity) reactions (87). Symptoms can vary widely depending on the duration and intensity of exposure and typically include cough, fever, chills, dyspnea, and fatigue. These symptoms can appear acutely, often 4–8 hours after exposure, or develop insidiously, particularly if the exposure to the antigen persists. Lung inflammation is characterized by lymphocytic and frequently granulomatous features that can result in lung fibrosis (87). The occupational causes of HP have been recently described in a systematic review (88), which includes farmers (farmer’s lung) and bird breeders or pet bird owners (bird fancier’s lung) as well as woodworking, cheese manufacturing, and textiles. Diagnosing HP involves a combination of clinical evaluation, lung imaging, lung function tests, and sometimes lung biopsies (89). The primary treatment for HP is avoidance of the offending antigen. Corticosteroids are often used. In advanced fibrotic stages, management is more complex, requiring additional intervention including possible lung transplantation.

IDIOPATHIC PULMONARY FIBROSIS

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia of unknown cause, primarily occurring in older adults. It is defined by the presence of radiological and/or histological usual interstitial pneumonia and has a poor prognosis with a median survival of 2.5–4 years (90). Although organic dust exposures have been proposed in the development and/or exacerbation of IPF, its direct link to IPF remains unclear (91). An international collaborative review and meta-analysis assigned an attributable fraction for occupational exposures to the burden of IPF of 26%, calculated from 11 studies (92). In this study, several exposure categories (vapors/gases/dust/fumes, metal dust, wood dust, silica dust) but not agricultural dust were significantly associated with IPF (92). However, a U.S. multicenter, case-control study identified several occupations which were associated with IPF that included farming, livestock, hairdressing, raising birds, stone cutting/polishing, and jobs with exposure to metal dust and vegetable/animal dust (93). Awadalla et al., in a multicenter, case-control study in Egypt, demonstrated that the risk of IPF was higher in females working in farming, raising birds, and with occupational exposures to animal feeds, dust, and pesticides (94). Moreover, a case-control study in Italy found that farmers, veterinarians, and gardeners had a particularly high risk of developing IPF, and the risk increased with increased lengths of exposure (95).

The issue of incorrectly diagnosing chronic HP as IPF has been raised. A 2013 study revealed that out of 46 patients initially diagnosed with IPF following established guidelines, 20 were later found to have HP (96). Many of these cases were associated with bird-related antigens, particularly from feather bedding (96). De Sadeleer et al. segmented 244 patients with IPF to demonstrate that IPF patients with a history of exposure to mold or birds had improved survival rates compared to those without such exposure, although survival was less than that of HP (97).

DIAGNOSTIC STRATEGIES

Presentation

Organic dust exposure generally triggers symptoms of cough, chest tightness, wheezing, mucus production, and shortness of breath, even in healthy individuals. In asthma and COPD, exposure can further exacerbate symptoms, reduce lung function, and increase in airway hyperresponsiveness (98). Flu-like symptoms can be found in ODTS and HP, and progression to irreversible pulmonary fibrosis, restriction, and diminished diffusing capacity of the lungs for carbon monoxide (DLCO) can be seen in HP and IPF (87, 90). Clinical, functional, and radiological characteristics of organic dust-associated respiratory disease are summarized (Table II) (99).

Table II.

Characteristics and diagnostic features associated with various organic dust-associated respiratory diseases

Organic dust-associated disease	Clinical Symptoms	Causative Agents	Diagnostic procedures	Lung function testing	Imaging
Asthma	Respiratory	Livestock & crop dusts, wood dust, cotton dust, mold, pollens, bacteria, chemicals	Possible eosinophilia ± Specific allergen sensitivity	Variable obstructive pattern Cross-shift ↓ in FEV1 >10%	Normal, bronchial wall thickening, air trapping
Asthma-like syndrome	Respiratory	Grain and farming dust, mold, bacteria, chemicals	Allergen skin testing is typically negative ±airway neutrophils	Variable obstructive pattern Cross-shift ↓ FEV1, <10%	Normal, bronchial wall thickening, air trapping
Byssinosis	Respiratory	Cotton dust	Allergen skin testing is typically negative	Variable airflow limitation Across workday variability	Normal, bronchial wall thickening to opacities
Organic dust toxic syndrome	Respiratory & systemic	High concentrations of organic dust	Leukocytosis, specific IgE and IgG testing is typically negative	Normal with possible obstructive or restrictive pattern	Normal, ground-glass opacities possible
COPD, chronic bronchitis	Respiratory & systemic	Livestock & crop dust, wood dust, cotton dust, mold, bacteria, chemicals	± Skin testing, may be positive in ACO	Obstructive pattern with limited reversibility	Air-trapping, bronchiectasis, emphysema
Hypersensitivity pneumonitis	Respiratory & systemic	Mold, bacteria, avian proteins, vegetable & animal dust, chemicals	Specific IgG detection, ↑BALF CD8+ T cells, airway neutrophils	Restrictive pattern, reduced DLCO	Mosaicism, ground-glass opacities, centrilobular nodules, reticulation, traction bronchiectasis
Idiopathic pulmonary fibrosis	Respiratory & systemic	Vapors, gases, dust, fumes, metal dust, wood dust, silica dust	Allergy skin testing typically negative, UIP lung biopsy	Restrictive pattern (irreversible at late stage), reduced DLCO	Honeycombing, ground-glass opacities, traction bronchiectasis, reticulation

COPD: Chronic obstructive pulmonary disease, DLCO: Diffusing capacity of carbon monoxide, FEV₁: Forced expiratory volume in one second, UIP: Usual interstitial pneumonia

TESTING

Lung function

Lung function testing is recommended in exposed, at-risk persons, as spirometry is particularly valuable for workers with pre-existing obstructive diseases or smokers (100, 101) to monitor lung function over time and establish a dose-response effect (102, 103). For example, swine confinement workers often exhibit an accelerated loss of lung function, evidenced by a decrease in FEV₁ during a work shift (104, 105). Changes in lung function (FEV₁) across a workweek, particularly in textile workers, aid in predicting disease (106). A restrictive ventilatory defect may also be observed in HP or IPF, as well as impaired gas exchange (reduced DLCO) and/or hypoxemia during exercise (107).

Measuring fractional exhaled nitric oxide (FeNO) may also be warranted. Exhaled NO increased from baseline value of 7.5 (5.7–13.7) to 13.4 (10.5–17.5) parts per billion after swine facility exposure (108). In addition, the rise in FeNO post-work shift, along with diminished pulmonary function, established across-shift FeNO as an effective, non-invasive method to assess airway inflammation in textile workers (109). Serial FeNO measurements at home versus work settings can further validate a dose-response relationship (110).

Laboratory tests

The detection of serum-specific IgE and IgG antibodies of organic dust components can be beneficial to establishing causation. For example, patients with grain dust-induced symptoms may be sensitized to dust mites or cereal flour proteins (i.e., wheat, rye, and barley) (111). However, the presence of specific IgE antibodies may not be indicative of symptomatic exposure, as in individuals exposed to corn dust, where specific IgE, IgG, and IgG4 antibodies were identified in both symptomatic and asymptomatic subjects (112). Conversely, a cohort study of workers with asthma-like symptoms following grain dust exposure, confirmed through inhalation challenges, lacked evidence for specific serum antibodies (113).

The identification of antigen-specific IgG antibodies is a key diagnostic criterion for HP (Table I). Elevated antibody titers following exposure, or a decrease in levels after avoiding exposure, can further support this diagnosis. However, the absence of these antibodies does not rule out the disease, and their presence alone is not definitive, as they may merely indicate exposure in asymptomatic individuals (87). In a study involving asymptomatic swine confinement workers, the presence of IgG antibodies to specific porcine proteins was noted, while IgE-mediated reactions to these proteins were rare (71).

Skin testing

Allergy skin prick testing may also be useful. Over 15% of grain handlers exhibiting airway symptoms demonstrated sensitization by skin testing to storage mites (Lepidoglyphus destructor and Acarus siro) and molds (Candida) (114). Additionally, skin test sensitization to wheat and rye has been linked to a decrease in lung function during a work shift in grain workers (102). However, the relationship between asthmatic response and symptoms with positive grain dust extract skin testing remains unclear (113, 114). An improvement of quality and standardization of these complex allergen extracts may potentially increase diagnostic accuracy (111).

Bronchoalveolar lavage

Bronchoscopy with bronchoalveolar lavage fluid (BALF) analyses represents an additional tool to characterize the pattern of airway inflammation. BALF from workers recently exposed to swine environments demonstrated increased levels of neutrophils, lymphocytes, and macrophages compared to those exposed for longer durations (115, 116). Moreover, higher BALF concentrations of IL-1β, IL-6, IL-8/CXCL8, and TNF-α were demonstrated in exposed versus non-exposed individuals (117). Notably, swine workers with at least 1.6 years of exposure demonstrated increased levels of IL-6, whereas TNF-α was not detected following acute exposure (118). In chronic stages of exposure, BALF may reveal an increased concentration of total cells, neutrophils, albumin, fibronectin, and hyaluronan (104) and striking increases in BALF cell mRNA for IL-17A (119).

In HP, the BALF cellular profile is typically characterized by marked lymphocytosis (greater than 50%) and a predominance of CD8⁺ T cells (also reflected in a low CD4⁺/CD8⁺ ratio) (87). This pattern is common in the acute and subacute stages of the disease. Following intense exposure or during resolution stages, a significant increase in neutrophils may also be observed.

BALF can be used to distinguish between exposed workers who develop HP or alveolitis and those who remain asymptomatic. This distinction is based on a low CD4⁺/CD8⁺ ratio for HP and elevated levels of hyaluronan for alveolitis (87, 116). Despite these indicators, limited data have been demonstrated for significant differences in cell counts within BALF between farmers exhibiting respiratory symptoms and those without symptoms (120). This highlights a need for further research to validate the efficacy of BALF in differentiating symptomatic from asymptomatic exposed workers as most studies compare exposed workers (including symptomatic and asymptomatic workers) with unexposed controls (104, 116).

Inhalation challenges

Inhalation challenges have confirmed the capacity of organic dust to induce respiratory symptoms and enabled analysis of lung function and inflammation profiles (121, 122). Inhalation tests using extracts from durum wheat and corn dust have proven particularly useful in demonstrating airway hyperresponsiveness in grain handlers (123). These challenges have also been useful in assessing the impact of endotoxins and dust mites in triggering airway inflammation in sensitized patients, although the results have been mixed (113, 114, 124). In cases of suspected HP, inhalation challenges are recommended to help identify the specific causative agent. The effectiveness, applications, and safety of allergen challenge tests in respiratory disorders have been recently reevaluated (125). These tests are predominately viewed as tools for research purposes. In the United States, inhalation challenges to identify the cause of HP are generally not performed, primarily due to regulatory constraints.

Imaging

Chest imaging, notably high-resolution computed tomography (HRCT), can assess the disease activity and aid in diagnosis (Table I) (99). Chest radiograph findings are often nonspecific, including patterns like ground-glass or interstitial opacities, consolidations, or micronodules, but may appear normal in many patients (87). HRCT is recommended for symptomatic individuals with abnormal lung function tests, and it is valuable in determining the necessity and location for lung biopsy (126). In the active or early stages of disease, transient pulmonary infiltrates, isolated diffuse ground-glass opacities, mosaicism, and centrilobular nodules may be observed (127). Bronchial wall thickening and air trapping can be identified in obstructive diseases like asthma and COPD/chronic bronchitis (128). In HP, mosaicism and diffuse ground-glass centrilobular nodules may indicate small airway involvement. During the fibrotic stages HP and IPF, features such as reticulation, traction bronchiectasis, and architectural distortion are observed, signaling irreversible disease (127).

MANAGEMENT AND PREVENTION

The management of airway diseases caused by organic dust involves both supportive care and standard medical interventions. The primary focus is on reducing exposure to the offending dust, managing symptoms, and preventing disease progression (Table III). Industries that have adopted newer built buildings with modern and presumedcleaner technologies have shown better respiratory health outcomes than older counterparts (129). Although personal protective equipment (PPE) such as respirators are recommended and can reduce airway inflammatory consequences in swine barn workers (130), PPE has not been shown to reduce swine barn air-induced airway hyperresponsiveness (130). Moreover, lung function decline occurs in cotton textile mill workers despite use of a face mask (62).

Table III.

Exposure reduction and environmental controls for management and prevention strategies of organic dust exposure-associated lung disease.

Focus Area	Description
Environmental Risk Assessment	Applicable to agriculture, textile, woodworking, and construction industries. Avoidance of high dust and endotoxin exposure tasks. However, this may not be socio-economically feasible (137).
Environmental Monitoring	Regular air quality monitoring. Use of air sampling devices to measure the concentration of organic dust particles.
Environmental Controls	Implementation of engineering controls -Improving ventilation systems (138). -Incorporating dust extraction and collection systems. -Using mobile recirculating ventilation systems (139). -Ensuring that machinery and equipment are well-maintained.
Work Practice Controls	Modification of task execution to reduce dust exposure. -Wetting down surfaces to prevent dust from becoming airborne. -Using tools and machinery that produce less dust. -Ensuring proper cleaning and maintenance procedures. -Adopting newer, cleaner technologies (129).
Personal Protective Equipment:	Incorporation of PPE: masks, respirators, and protective clothing. -Proper training and education are required.
Education and Training	Workers should be educated on: - Risks of organic dust exposure. - Recognizing hazardous conditions. - Proper use of control measures and PPE. Regular training sessions can reinforce this knowledge and keep workers informed about new practices or equipment.
Policy and Regulation Compliance	-Compliance with local and international health and safety regulations. -Adherence to occupational exposure limits for different types of dust. -Implementation of recommended safety practices.
Worker Health Surveillance and Education	-Baseline/pre-work health examinations. -Regular health examinations, including lung function tests, chest x-rays, and allergy testing. -Education on trigger avoidance and proper medication use. -Support groups and counseling can also be beneficial. -Smoking cessation, as smoking represents an additive effect. -Medical plan with rescue inhalers, bracelets as necessary.

PPE: Personal protective equipment

Pharmacological Treatment

Pharmacologic treatment can be dependent upon the severity and type of airway disease. Available therapies include bronchodilators, corticosteroids, and antihistamines; however, there is no evidence that use of inhaled bronchodilators alleviates symptoms or slows disease progression (99). Biologics including the anti-IgE monoclonal antibody, omalizumab, has been successfully used in cases of severe occupational asthma caused by cereal allergens (131–133) and low molecular weight agents (134). Given that workers exposed to organic dust typically exhibit a neutrophilic asthma phenotype/endotype (as opposed to eosinophilic phenotype), there may be theoretical benefit with treatments effective in Type-2-low asthma, such as tezepelumab (135). However, this therapy has not been specifically explored in symptomatic workers.

In severe HP or IPF, immunosuppressant agents including azathioprine and mycophenolate mofetil may be used. Antifibrotic agents pirfenidone and nintedanib have also been utilized to slow the progression of IPF and lung function decline (136).

Pulmonary Rehabilitation

Pulmonary rehabilitation may be necessary for those with significant respiratory impairment. This includes exercises to strengthen the respiratory muscles, improve lung function, and help with breath control.

FUTURE DIRECTIONS

The future research directions in the field of airway diseases associated with organic dust exposure are broad and multifaceted (Table IV). Advancements are necessary to improve the prevention, early detection, and effective management of airway diseases associated with organic dust exposure, ultimately leading to improved health outcomes for affected individuals.

Table IV.

Key Areas of future research and development to advance knowledge and care of individuals with organic dust-associated respiratory disease.

Focus Area	Comment
Mechanism of Disease	In-depth understanding of the cellular and molecular pathways involved to aid in developing targeted therapies and interventions. Research into understanding resolution and recovery following organic dust exposure to develop novel targeted approaches. Further evaluation of the role of organic dust in the pathogenesis of IPF, as little is known. Understanding and differentiating IPF from other forms of ILD that are directly caused by organic dust exposure, such as HP, which can present with fibrosis but has a distinct pathogenesis and clinical course from IPF.
Long-term Health Effects	Longitudinal studies to track the long-term health impacts of organic dust exposure. Understanding the progression of diseases over time and identifying any late-onset effects.
Genetic and Environmental Interactions	Understanding how genetic predisposition interacts with environmental exposure to organic dust. Deciphering why some individuals are more susceptible to developing airway diseases than others.
Improved Diagnostic Tools	Developing more sensitive and specific diagnostic tools for early detection of airway diseases related to organic dust. Tools needed range from biomarkers, imaging techniques, and lung function tests.
Better Exposure Assessment Methods	Advancing methods for assessing and quantifying organic dust exposure in different environments. Improving the understanding of dose-response relationships and knowledge of accurate exposure limits.
Preventive Strategies and Interventions	Developing more effective preventative strategies and interventions, including improved personal protective equipment, workplace modifications, and educational programs.
Treatment Modalities	Exploring new treatment options, including pharmacological and non-pharmacological therapies. Assessing the efficacy of existing treatments in managing symptoms and slowing disease progression.
Impact of Climate Change	Understanding how climate change might influence the generation and distribution of organic dust and the subsequent impact on airway disease
Public Health Policies	Developing and evaluating public health policies and guidelines to protect workers in high-risk industries. Assessing the economic impact of such diseases on individuals and healthcare systems.
Global Perspectives	Considering the global diversity in types of organic dust and varying workplace standards. Developing a global consensus and applicable guidelines through international collaborative research.

IPF: Idiopathic pulmonary fibrosis, ILD: Interstitial lung disease

Abbreviations:

AHR

Airway hyperresponsiveness

BALF

Bronchoalveolar lavage fluid

COPD

Chronic obstructive pulmonary disease

CI

Confidence interval

FEV₁

Forced expiratory volume in one second

FVC

Forced volume capacity

FeNO

Fractional exhaled nitric oxide

HP

Hypersensitivity pneumonitis

IPF

Idiopathic pulmonary fibrosis

IL

Interleukin

ILC

Innate lymphoid cells

LPS

Lipopolysaccharide

MyD88

Myeloid differentiation factor 88

OR

Odds ratio

aOR

adjust odds ratio

ODTS

Organic dust toxic syndrome

PPE

Personal protective equipment

TLR

Toll-like receptor

TNF

Tumor necrosis factor

U.S.

United States

WRA

Work-related asthma