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Subtypes

5

Sensitizer-induced occupational asthma

Asthma caused by immunological sensitization to an agent encountered at work, after a latency period, and reproduced on re-exposure to that agent. The causative agents split into high molecular weight protein allergens (flour, enzymes, latex, animal proteins), which sensitize through conventional IgE-mediated routes, and low molecular weight chemicals (diisocyanates, acid anhydrides, persulfate salts, reactive dyes), which must first haptenate a carrier protein. Only the chemical arm conforms to the `chemical_respiratory_allergy` module, so the two arms are separate rows below rather than being collapsed into this one.

LMW-chemical
HMW-protein

Low molecular weight chemical sensitizer-induced

Sensitization to a reactive low molecular weight chemical, which must haptenate a carrier protein before the immune system can recognize it. This is the arm the `chemical_respiratory_allergy` module models, and the haptenation chain in this entry is scoped to it.

Isocyanate-induced

Show evidence (1 reference)

PMID:31690384 SUPPORT REVIEW SYNTHESIS Human clinical

"OA can be triggered by high-molecular-weight (HMW) proteins that act as complete allergens or by low-molecular-weight (LMW) sensitizers that act as haptens"

States the hapten-versus-complete-allergen division this row and the HMW-protein row are built on, and so why only this arm needs a haptenation step.

High molecular weight protein allergen-induced

Sensitization to an inhaled protein allergen — flour, enzymes, latex, or laboratory animal proteins — which is immunogenic as supplied and needs no haptenation step. Conventional IgE-mediated sensitization, with specific IgE usually detectable, unlike the chemical arm. Its mechanism is not curated here and it does not conform to `chemical_respiratory_allergy`, whose trigger node requires a reactive chemical; see `notes`.

Show evidence (1 reference)

PMID:12704360 SUPPORT PRIMARY RESULT Human clinical

"Laboratory animal allergy is a common occupational health problem affecting between 11% and 44% of exposed researchers."

Establishes this arm as a real and common cause of occupational sensitization, distinct from the chemical sensitizers.

Isocyanate-induced occupational asthma MONDO:0025556

The single largest cause of sensitizer-induced occupational asthma, from toluene, methylene diphenyl and hexamethylene diisocyanate used in polyurethane manufacture, spray painting and foam production. Specific IgE is detectable in only a minority of affected workers, so diagnosis rests on the work-related pattern and specific inhalation challenge rather than on serology.

Irritant-induced occupational asthma

Asthma caused by a non-immunological irritant injury to the airway, with no latency and no agent-specific immune memory. Includes reactive airways dysfunction syndrome after a single high-dose exposure, and the lower-intensity repeated-exposure form. Conforms to the `inhaled_irritant_airway_injury` module rather than to `chemical_respiratory_allergy`. No MONDO term covers this stratum: OLS returns only `MONDO:0004979` asthma for `irritant induced asthma` and nothing at all for `reactive airways dysfunction syndrome`, and `MONDO:0022742` has no children, so the row carries no `subtype_term`.

Show evidence (2 references)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"reactive airways dysfunction syndrome is a separate entity and a subtype of occupational asthma"

Supports treating the irritant-induced form as a stratum of this disease rather than a separate one, and names reactive airways dysfunction syndrome as belonging to it.

PMID:31690384 SUPPORT REVIEW SYNTHESIS Human clinical

"RADS is defined as an asthma-like syndrome that persists for >3 months and occurs within minutes to hours after a single exposure to a high concentration of a respiratory irritant"

Gives the definition of reactive airways dysfunction syndrome, including the absence of latency that distinguishes this stratum from the sensitizer one.

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Pathophysiology

6

Workplace Sensitizer Haptenation of Airway Proteins

A reactive low molecular weight chemical inhaled at the workplace binds nucleophilic residues on airway and serum proteins, generating the hapten-protein adduct that the immune system subsequently recognizes. This is the step that requires the agent to be chemically reactive, and it is why the low molecular weight agents behave differently from the protein allergens that sensitize directly.

respiratory airway UBERON:0001005

Downstream

Airway Epithelial Danger Signal Release on Workplace Exposure The haptenated epithelium and the reactive chemistry that produced it elicit an innate epithelial response.

Dendritic Cell Activation and Th2 Polarization The hapten-protein adduct is the antigen airway dendritic cells take up, so haptenation also feeds the dendritic cell step directly.

Show evidence (1 reference)

PMID:23743149 SUPPORT PRIMARY RESULT In vitro / ex vivo

"demonstrating increases in both number and complexity of conjugates formed with increasing MDI concentrations"

Measures covalent adduct formation between the commonest causative agent class and human protein, which is the haptenation step this node asserts.

Airway Epithelial Danger Signal Release on Workplace Exposure

The bronchial epithelium, lung fibroblasts and endothelium exposed to the sensitizer release IL-8, IL-6 and IL-1beta, generate reactive oxygen species, lose MUC1, and upregulate endothelial adhesion molecules. This innate response licenses dendritic cell maturation but is not by itself specific to a sensitizer, which is why an irritant exposure can produce a similar picture without sensitization following.

bronchial epithelial cell CL:0002328 lung fibroblast CL:0002553 endothelial cell CL:0000115

cytokine production involved in inflammatory response GO:0002534 ↑ INCREASED

Downstream

Dendritic Cell Activation and Th2 Polarization Epithelial danger signals supply the maturation context that makes antigen presentation sensitizing rather than tolerogenic.

Show evidence (1 reference)

PMID:38360295 SUPPORT PRIMARY RESULT In vitro / ex vivo

"sensitizers promoted an increase in IL-8, IL-6, and IL-1β production in the evaluated cell types"

Measures the danger-signal cytokines of this node in the human airway cell types it binds, after exposure to respiratory sensitizers.

Dendritic Cell Activation and Th2 Polarization

Airway dendritic cells take up the hapten-protein adduct, mature, and present it in a Th2-polarizing context. This is the step that distinguishes a workplace sensitizer from a workplace irritant, and therefore the step that separates this entry's two main subtypes: the irritant-induced stratum never reaches it.

dendritic cell CL:0000451

antigen processing and presentation GO:0019882 ↑ INCREASED

Downstream

Hapten-Specific T Cell Memory Presentation of the adduct by matured dendritic cells expands hapten-specific T cells and establishes memory.

Show evidence (1 reference)

PMID:28824649 SUPPORT PRIMARY RESULT In vitro / ex vivo

"OX40L expression in DCs was most consistently and significantly enhanced by respiratory sensitizers as compared to that by skin sensitizers"

Supports the Th2-polarizing character of this step, and that it discriminates respiratory sensitizers specifically.

Hapten-Specific T Cell Memory

Hapten-specific T cells expand and polarize toward a type 2 profile, with IL-4, IL-5 and IL-13 and airway eosinophilia. This establishes the immunological memory that gives sensitizer-induced occupational asthma its defining clinical features: a latency period before onset, and reproducible symptoms on re-exposure to that agent and not to others. Specific IgE may accompany it but frequently does not with low molecular weight agents.

T-helper 2 cell CL:0000546

T-helper 2 cell differentiation GO:0045064 ↑ INCREASED

Downstream

Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation Re-exposure at work drives the established hapten-specific response into airway inflammation and bronchoconstriction.

Show evidence (3 references)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"Workers with occupational asthma secondary to low molecular weight agents may not have elevated specific IgE levels"

Supports only the last sentence of this node, that specific IgE is frequently absent in this agent class. It does not evidence the T cell expansion or the type 2 polarization, which the two items below carry.

PMID:16271432 SUPPORT PRIMARY RESULT Model organism

"skin application followed by tracheal instillations of TDI led to local and systemic Th2-dominated immune responses"

Evidences the type 2 polarization this node asserts, for the agent class that causes most of this disease.

PMID:12419703 SUPPORT PRIMARY RESULT Model organism

"TMA-activated LNC isolated from BALB/c mice or BN rats elaborated high levels of the Th2-type cytokines interleukin (IL)-10 and IL-13, but relatively little of the Th1-type cytokines IL-12 or interferon gamma"

Evidences the type 2 cytokine profile of this node against a contact allergen comparator, so the polarization is a measured contrast and not an assumption.

Irritant Injury of the Airway Epithelial Barrier

In the irritant-induced stratum there is no haptenation and no agent-specific memory. A reactive inhaled irritant injures the epithelium directly, disrupting tight junctions and raising paracellular permeability, and the resulting inflammation produces asthma without a latency period. This is why irritant-induced occupational asthma begins within hours of a high-dose exposure rather than after months of low-level exposure.

bronchial epithelial cell CL:0002328

bicellular tight junction assembly GO:0070830 ↓ DECREASED

Downstream

Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation Direct epithelial injury and the inflammation it provokes produce airway hyperresponsiveness without an immunological sensitization step.

Show evidence (1 reference)

PMID:32588239 SUPPORT INDIRECT PRIMARY RESULT In vitro / ex vivo

"Thermal stress or acrolein disrupted zonula occludens-1 tight junctions, increased fluorescein isothiocyanate-dextran permeability but did not cause cell death or detachment"

Shows a reactive inhaled aldehyde producing junctional barrier failure without cell death, which is the non-immune injury route of this stratum. Graded INDIRECT because the study is of smoke inhalation injury in airway monolayers, so the inference to irritant-induced asthma in a worker is a step beyond what it measures.

Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation

The convergence point of both strata and the clinical disease. Airway smooth muscle contraction, airway hyperresponsiveness and variable airflow limitation, with the temporal pattern that defines the diagnosis: symptoms worse at work and improving away from it. Removal from exposure does not reliably resolve it, so this node represents a persistent state rather than a transient response to exposure. Both strata converge here by different routes: the sensitizer arm through hapten-specific memory, the irritant arm through direct epithelial injury. The `conforms_to` link is true of the sensitizer route; the irritant module's own consequence is mucociliary clearance failure rather than asthma, so it is deliberately not named as a second target.

smooth muscle contraction GO:0006939 ↑ INCREASED

bronchus UBERON:0002185

Downstream

Asthma symptoms with a work-related pattern Airflow limitation and hyperresponsiveness present clinically as work-related asthma symptoms.

Airway hyperresponsiveness This node is the state the methacholine or histamine challenge measures, so the measured phenotype is its direct expression.

Variable airflow limitation The variable component of the airflow limitation this node describes is what serial peak flow monitoring at and away from work records.

Show evidence (1 reference)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"Not all patients with occupational asthma will improve after removal from the workplace"

Supports treating this node as a persistent state: the disease does not reliably remit when the exposure stops.

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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Head and Neck 1

Occupational rhinitis Allergic rhinitis HP:0003193

Immune 1

Respiratory 5

Airway hyperresponsiveness HP:0032933

Show evidence (1 reference)

PMID:17040933 SUPPORT PRIMARY RESULT Human clinical

"The pooled prevalence of persistent NSBHR at follow-up was 73% (95% CI 66% to 79%)"

Quantifies how often this phenotype persists after exposure ceases, across 39 studies, which is why the entry treats hyperresponsiveness as a persistent state rather than a response to current exposure.

Wheezing HP:0030828

Dyspnea HP:0002094

Cough HP:0012735

Variable airflow limitation Reduced forced expiratory volume in one second HP:0032342

Constitutional 1

Chest tightness HP:0031352

🧬

Genetic Associations

9

Host susceptibility loci for diisocyanate asthma

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:21325943 SUPPORT REVIEW SYNTHESIS Human clinical

"Genotype combinations of IL-4 receptor-α and CD14 single nucleotide polymorphisms (SNPs) were significantly associated with diisocyanate asthma, but only in workers exposed to hexamethylene diisocyanate"

Reports a host genotype association specific to diisocyanate asthma, and specific to one agent within it, which is the susceptibility claim this record makes.

PMID:21325943 SUPPORT REVIEW SYNTHESIS Human clinical

"certain glutathione S-transferase genotypes (e.g. the GSTM1 null genotype) and N-acetyltransferase genotypes associated with slow acetylation phenotypes have been reported to be associated with diisocyanate asthma"

Supports the detoxification arm of this record: genotypes governing conjugation of the reactive agent modify risk, which connects host genetics to the haptenation trigger.

HLA class II association with protein allergen sensitization

Gene: HLA-DRB1 hgnc:4948 gene page MHC: HLA-DR7 serotype MRO:0000316 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:12704360 SUPPORT PRIMARY RESULT Human clinical

"HLA-DR7 was associated with sensitization (odds ratio [OR], 1.82; CI, 1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37) and, most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90-7.65)"

Measures the HLA class II association with occupational sensitization in a cross-sectional cohort of exposed workers, which is this record's claim.

HLA-DQB1

Gene: HLA-DQB1 hgnc:4944 gene page MHC: HLA-DQ5 serotype MRO:0000289 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:24994462 SUPPORT REVIEW SYNTHESIS Human clinical

"The most common HLA haplotypes in the different asthma phenotypes are HLA-DRB1in allergic asthma, HLA-DQB1in occupational asthma and HLA-DPB1 in aspirin-sensitive asthma"

Names this locus as the one most associated with occupational asthma specifically, which is why it is recorded without a subtype scope. The two missing spaces are the source's own typography and are quoted as printed.

PMID:15144476 SUPPORT PRIMARY RESULT Human clinical

"The linked alleles DQ5 (odds ratio [OR]=4.3; 95% confidence interval [95% CI]=1.7, 11) and DR1 (OR 3.0; 95% CI 1.2, 11) were more prevalent in cases than in referents"

Measures the DQ5 association with sensitization to acid anhydrides, a low molecular weight sensitizer class, in cases against exposed referents.

HLA-DRB1 haplotype in isocyanate-induced asthma

Gene: HLA-DRB1 hgnc:4948 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:16792590 SUPPORT PRIMARY RESULT Human clinical

"the allelic frequency of HLA DRB1*15-DPB1*05 in group I (10.6%) was significantly higher than that of group II (0%, P = 0.001)"

Measures the haplotype frequency in workers with isocyanate-induced asthma against exposed asymptomatic workers, which is this record's susceptibility claim.

HLA-DPB1

Gene: HLA-DPB1 hgnc:4940 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:24709764 SUPPORT PRIMARY RESULT Human clinical

"The HLA-E rs1573294 and HLA-DPB1 rs928976 SNPs were associated with an increased risk of DA"

Reports a variant-level association at this locus with diisocyanate-induced asthma. HLA-E is named in the same sentence but has no record here, because this entry curates only the loci it can state a mechanism for.

GSTM1

Gene: GSTM1 hgnc:4632 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:21325943 SUPPORT REVIEW SYNTHESIS Human clinical

"certain glutathione S-transferase genotypes (e.g. the GSTM1 null genotype) and N-acetyltransferase genotypes associated with slow acetylation phenotypes have been reported to be associated with diisocyanate asthma"

Names the GSTM1 null genotype as associated with diisocyanate asthma, which is this record's claim.

IL4R

Gene: IL4R hgnc:6015 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:21325943 SUPPORT REVIEW SYNTHESIS Human clinical

"Genotype combinations of IL-4 receptor-α and CD14 single nucleotide polymorphisms (SNPs) were significantly associated with diisocyanate asthma, but only in workers exposed to hexamethylene diisocyanate"

Reports the association for this locus, in combination with CD14 and restricted to one agent, which both records state.

CD14

Gene: CD14 hgnc:1628 gene page relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:21325943 SUPPORT REVIEW SYNTHESIS Human clinical

"Genotype combinations of IL-4 receptor-α and CD14 single nucleotide polymorphisms (SNPs) were significantly associated with diisocyanate asthma, but only in workers exposed to hexamethylene diisocyanate"

Reports the association for this locus, in combination with IL4R and restricted to one agent, which both records state.

Genetic susceptibility is partial and no locus is causative

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:36276967 SUPPORT PRIMARY RESULT Human clinical

"only a subset of workers exposed to diisocyanates develop diisocyanate-induced occupational asthma (diisocyanate asthma, DA), indicating that genetic susceptibility may play a role"

States the premise of this whole section: exposure is necessary but not sufficient, and host genotype is one of the reasons.

PMID:36276967 SUPPORT PRIMARY RESULT Human clinical

"antigen processing, lymphocyte activation, cytokine production regulation, and response to oxidative stress"

Names the functional themes the associated genes fall into, which is the two-arm division the per-gene records above are organised by.

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Medical Actions

3

Removal from exposure

Action: Therapeutic Procedure NCIT:C49236

Platform: Behavioral / lifestyle

Ending exposure to the causative agent is the definitive intervention, and the earlier it happens the better the outcome. It is not reliably curative: a substantial proportion of workers have persistent asthma and persistent airway hyperresponsiveness years after leaving the exposure, which is why the consequence node is modelled as a persistent state.

Mechanism Target:

INHIBITS Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation — Removing the causative exposure withdraws the driver of the airway response, though it does not reverse established disease in every worker.

Show evidence (4 references)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"Not all patients with occupational asthma will improve after removal from the workplace"

Supports that removal is not reliably curative. The two items below carry the controlled comparison and the quantified persistence.

PMID:23407122 SUPPORT REVIEW SYNTHESIS Human clinical

"complete removal from exposure resulted in the best outcome in terms of symptoms, lung function, and airway hyper-responsiveness. Reduction of exposure appeared to be less effective in terms of improving asthma but was also less likely to result in loss of income or unemployment"

Supports removal as the most effective intervention on clinical outcomes, against reduction of exposure as the comparator, and carries the trade-off in the same sentence: the clinically better option is the one more likely to cost the worker their job.

PMID:17040933 SUPPORT PRIMARY RESULT Human clinical

"The pooled prevalence of persistent NSBHR at follow-up was 73%"

Quantifies how often airway hyperresponsiveness persists after exposure ends, which is why this treatment is described as definitive but not reliably curative. Graded PRIMARY_RESULT because the pooled estimate is this review's own computation over 39 studies, not a figure it is restating.

+ 1 more reference

Workplace exposure elimination as primary prevention

Action: Therapeutic Procedure NCIT:C49236

Platform: Behavioral / lifestyle

Removing or substituting the sensitizer in the workplace so that workers are never exposed. This is a different intervention from the removal row above, which withdraws an already-affected worker: this one prevents the disease arising at all, and the evidence for it is the strongest in the field. Powder-free low-protein natural rubber latex gloves are the worked case, where substitution was followed by a sharp fall in new sensitization.

Mechanism Target:

INHIBITS Workplace Sensitizer Haptenation of Airway Proteins — Eliminating the agent from the workplace removes the reactive chemical that haptenates airway protein, so the chain never starts. This is why the intervention is preventive rather than therapeutic.

Show evidence (3 references)

PMID:22654083 SUPPORT REVIEW SYNTHESIS Human clinical

"Exposure elimination is the strongest and preferred primary preventive approach to reduce the burden of occupational asthma"

States the conclusion of a systematic review of 29 studies, and is the basis for recording this as a distinct intervention rather than folding it into removal from exposure.

PMID:22654083 SUPPORT REVIEW SYNTHESIS Human clinical

"There is strong evidence to recommend not using powdered allergen-rich natural rubber latex gloves"

Gives the one agent-specific recommendation the review grades as strong, which is the substitution the next item measures.

PMID:21775898 SUPPORT INDIRECT PRIMARY RESULT Human clinical

"After the intervention, new latex sensitization rates declined 16-fold, and 25% of previously sensitized employees reverted to negative skin tests"

Measures the effect of the substitution in a health care worker cohort, which turns the recommendation above into an interventional result. Note it measures sensitization, not asthma, so the step to disease prevention is an inference.

Anti-inflammatory asthma pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

Management of the airway inflammation alongside removal from exposure, with inhaled corticosteroid and bronchodilator therapy as in asthma generally. It treats the established airway disease and does nothing about the sensitization or the exposure, so it is adjunctive to removal rather than an alternative to it.

Mechanism Target:

INHIBITS Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation — Anti-inflammatory therapy reduces the airway inflammation that sustains hyperresponsiveness and airflow limitation.

Show evidence (1 reference)

PMID:15579371 SUPPORT REVIEW SYNTHESIS Human clinical

"Early diagnosis, adequate management of inflammation, and prevention of further exposure are essential to occupational asthma management."

Names management of inflammation as an essential component of treatment, alongside the prevention of further exposure that the other row covers.

🌍

Environmental Factors

2

Occupational exposure to chlorine

Inhalation of chlorine gas, in water treatment, cleaning, pulp bleaching and after accidental release. A representative irritant exposure for the irritant-induced stratum: it injures the airway epithelium directly, with no latency and no agent-specific immune memory.

Show evidence (1 reference)

PMID:33063819 SUPPORT REVIEW SYNTHESIS Human clinical

"A variety of agents were implicated, with chlorine or chlorine-releasing molecules most frequently reported"

Establishes chlorine as the most frequently reported cause of reactive airways dysfunction syndrome across reported cases, which is why it is the representative exposure for this stratum.

Mechanism Target:

TRIGGERS Irritant Injury of the Airway Epithelial Barrier — High-concentration irritant inhalation injures the epithelium directly, which is the initiating event of this stratum.

Occupational exposure to diisocyanates

Inhalation of toluene, methylene diphenyl or hexamethylene diisocyanate in polyurethane manufacture, spray painting, foam production and related trades. The leading single cause of sensitizer-induced occupational asthma.

Show evidence (1 reference)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"Low molecular weight isocyanates are the most common compounds that cause occupational asthma"

Supports recording diisocyanate exposure as the principal causative exposure for this disease.

Mechanism Target:

TRIGGERS Workplace Sensitizer Haptenation of Airway Proteins — Workplace inhalation is the route by which the reactive chemical reaches airway proteins and haptenates them.

Show evidence (1 reference)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"Low molecular weight isocyanates are the most common compounds that cause occupational asthma"

Establishes this exposure as the leading cause of the disease, and so as a trigger of the haptenation step it is linked to.

🔬

Biochemical Markers

2

Fractional exhaled nitric oxide

Pathograph Readouts

Readout of Hapten-Specific T Cell Memory Positive Diagnostic

A rise across challenge reports the type 2 response this node describes. It does not identify the sensitizer, and it is specific but insensitive, so a flat FeNO does not exclude a positive challenge.

Show evidence (1 reference)

PMID:39726396 SUPPORT PRIMARY RESULT Human clinical

"Increases in FeNO level ≥ 13 ppb and sputum eosinophils ≥ 1.25% were identified as the optimal threshold values for differentiating positive from negative SICs"

Establishes the measured link between a rise in this marker and a positive challenge, which is what this readout claims.

Induced sputum eosinophil count

Pathograph Readouts

Readout of Hapten-Specific T Cell Memory Positive Diagnostic

A rise across challenge reports the eosinophilia this node names directly. Discordance with FeNO in a substantial minority of positive challenges is why both are measured rather than either.

Show evidence (1 reference)

PMID:39726396 SUPPORT PRIMARY RESULT Human clinical

"Combining either a rise in FeNO ≥ 13 ppb or an increase in sputum eosinophils ≥ 1.25% increased the sensitivity to 77%"

Supports reading this marker alongside FeNO rather than instead of it, which is what the interpretation states.

🔬

Diagnosis

3

Spirometry with serial peak flow monitoring

Spirometry, with serial peak expiratory flow records kept at and away from work, is how the work-related pattern of airflow limitation is documented in practice. It establishes that airflow limitation varies with exposure; it does not identify the causative agent.

Spirometry NCIT:C85397

Specific inhalation challenge

Controlled exposure of the patient to the suspected workplace agent, with spirometry before and after. The only test that identifies the causative agent, and so the gold standard, but rarely performed — which is why most diagnoses rest on the clinical and temporal pattern instead.

No NCIT term is bound. Searched OLS (`ontology=ncit`) for `inhalation challenge`, which returns nothing; `provocation`, which returns only dosage-form classes for provocation-test preparations; and `challenge test`, which returns `NCIT:C99490 Proficiency Testing Challenge` and `NCIT:C78164 Histamine Challenge Test`. The last is a non-specific bronchial provocation test with histamine, a different procedure from challenge with the patient's own workplace agent, so binding it would assert the wrong test.

Show evidence (2 references)

PMID:21573916 SUPPORT REVIEW SYNTHESIS Human clinical

"The gold standard test, specific inhalation challenge, is rarely used."

Supports that specific inhalation challenge is seldom used in practice.

PMID:33652998 SUPPORT REVIEW SYNTHESIS Human clinical

"specific inhalation challenge (SIC) is considered as the reference standard"

Establishes this procedure as the reference standard for confirming the causative agent, which is the claim this row makes.

Airway inflammation measurement during specific inhalation challenge

Fractional exhaled nitric oxide and induced sputum eosinophil count, measured before and after a specific inhalation challenge. Neither identifies the agent; both raise the yield of the challenge, because a positive challenge can show a rise in one without the other.

Nitric Oxide Measurement NCIT:C112360

The bound term covers only the nitric oxide half of this row; NCIT has no single term for the paired measurement, and the sputum eosinophil count is carried in the `biochemical` section instead. Thresholds are quoted rather than recorded as `reference_ranges`, because they are challenge-response cut-offs for a change from baseline, not clinical normal intervals for a single value.

Show evidence (2 references)

PMID:39726396 SUPPORT PRIMARY RESULT Human clinical

"Increases in FeNO level ≥ 13 ppb and sputum eosinophils ≥ 1.25% were identified as the optimal threshold values for differentiating positive from negative SICs"

Gives both cut-offs, derived in 321 workers undergoing challenge, which is what makes this a usable diagnostic adjunct rather than a descriptive measurement.

PMID:39726396 SUPPORT PRIMARY RESULT Human clinical

"Combining either a rise in FeNO ≥ 13 ppb or an increase in sputum eosinophils ≥ 1.25% increased the sensitivity to 77%"

Supports the complementarity this row asserts: the two measurements together detect more positive challenges than either alone.

📈

Progression

2

Latency before onset

Sensitizer-induced

The sensitizer stratum has a symptom-free interval between first exposure and first symptoms, during which sensitization is established. Its length is not fixed and is not recorded here as a number, because the cited sources give it qualitatively. Its presence is what distinguishes this stratum from the irritant one, where onset follows exposure within minutes to hours.

Show evidence (1 reference)

PMID:31690384 SUPPORT REVIEW SYNTHESIS Human clinical

"RADS is defined as an asthma-like syndrome that persists for >3 months and occurs within minutes to hours after a single exposure to a high concentration of a respiratory irritant"

Supports this phase by contrast: it states the irritant stratum's immediate onset, which is the absence of the latency this phase describes.

Persistence after exposure ends

Removal from exposure does not end the disease in most workers. Airway hyperresponsiveness persists in around three quarters and symptomatic recovery occurs in under a third, and lung function continues to fall in a followed diisocyanate cohort even after cessation. This is the phase that makes the consequence node a persistent state rather than a response to current exposure.

Show evidence (2 references)

PMID:18394133 SUPPORT PRIMARY RESULT Human clinical

"forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) values decreased, with a median yearly reduction of FEV1 of 79 ml"

Measures continuing loss of lung function after exposure has stopped, which is the functional content of this phase. Hyperresponsiveness improved in the same cohort, so the phase is not uniform decline across every measure.

PMID:17040933 SUPPORT PRIMARY RESULT Human clinical

"The pooled prevalence of persistent NSBHR at follow-up was 73% (95% CI 66% to 79%)"

Quantifies persistence of the physiological hallmark across 39 studies, which is this phase's central claim.

📊

Prevalence

1

Adults

Unknown

Reported as a population attributable fraction — 16% of incident adult asthma is attributable to occupational exposure, pooled across nine longitudinal studies — and not as a population rate, so `rate_per_100000` is deliberately left empty and `measure_type` is `UNKNOWN`. A PAF and a prevalence have different denominators and must not be conflated, and `PrevalenceMeasureEnum` has no attributable-fraction value to record this properly. `prevalence_class` is left empty for the same reason: the Orphanet-aligned bands are magnitudes against a population denominator, so assigning one to a fraction of incident cases would state a rate this record does not carry, and the qualitative tiers are defined by prevalence thresholds this record likewise does not have. An earlier version of this record carried a 5% figure from a general allergy review; the pooled longitudinal estimate cited here supersedes it.

Show evidence (1 reference)

PMID:33141780 SUPPORT REVIEW SYNTHESIS Human clinical

"Data from nine longitudinal studies showed a population attributable fraction for the occupational contribution to incident asthma of 16%"

Gives the pooled population attributable fraction this record carries, from longitudinal rather than cross-sectional data.

{ }

Source YAML

click to show

name: Occupational Asthma
creation_date: "2026-11-09T01:00:00Z"
category: Complex
disease_term:
  preferred_term: occupational asthma
  term:
    id: MONDO:0022742
    label: occupational asthma
synonyms:
- Asthma, Occupational
- Asthmas, Occupational
- Industrial asthma
- Occupational Asthmas
parents:
- Asthma
has_subtypes:
- name: Sensitizer-induced
  display_name: Sensitizer-induced occupational asthma
  description: >-
    Asthma caused by immunological sensitization to an agent encountered at
    work, after a latency period, and reproduced on re-exposure to that agent.
    The causative agents split into high molecular weight protein allergens
    (flour, enzymes, latex, animal proteins), which sensitize through
    conventional IgE-mediated routes, and low molecular weight chemicals
    (diisocyanates, acid anhydrides, persulfate salts, reactive dyes), which
    must first haptenate a carrier protein. Only the chemical arm conforms to
    the `chemical_respiratory_allergy` module, so the two arms are separate
    rows below rather than being collapsed into this one.
  children:
  - LMW-chemical
  - HMW-protein
- name: LMW-chemical
  display_name: Low molecular weight chemical sensitizer-induced
  description: >-
    Sensitization to a reactive low molecular weight chemical, which must
    haptenate a carrier protein before the immune system can recognize it.
    This is the arm the `chemical_respiratory_allergy` module models, and the
    haptenation chain in this entry is scoped to it.
  evidence:
  - reference: PMID:31690384
    reference_title: Occupational immunologic lung disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      OA can be triggered by high-molecular-weight (HMW) proteins that act as
      complete allergens or by low-molecular-weight (LMW) sensitizers that act
      as haptens
    explanation: >-
      States the hapten-versus-complete-allergen division this row and the
      HMW-protein row are built on, and so why only this arm needs a
      haptenation step.
  children:
  - Isocyanate-induced
- name: HMW-protein
  display_name: High molecular weight protein allergen-induced
  description: >-
    Sensitization to an inhaled protein allergen — flour, enzymes, latex, or
    laboratory animal proteins — which is immunogenic as supplied and needs no
    haptenation step. Conventional IgE-mediated sensitization, with specific
    IgE usually detectable, unlike the chemical arm. Its mechanism is not
    curated here and it does not conform to
    `chemical_respiratory_allergy`, whose trigger node requires a reactive
    chemical; see `notes`.
  evidence:
  - reference: PMID:12704360
    reference_title: "HLA associations with occupational sensitization to rat lipocalin allergens: a model for other animal allergies?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Laboratory animal allergy is a common occupational health problem
      affecting between 11% and 44% of exposed researchers.
    explanation: >-
      Establishes this arm as a real and common cause of occupational
      sensitization, distinct from the chemical sensitizers.
- name: Isocyanate-induced
  display_name: Isocyanate-induced occupational asthma
  description: >-
    The single largest cause of sensitizer-induced occupational asthma, from
    toluene, methylene diphenyl and hexamethylene diisocyanate used in
    polyurethane manufacture, spray painting and foam production. Specific IgE
    is detectable in only a minority of affected workers, so diagnosis rests on
    the work-related pattern and specific inhalation challenge rather than on
    serology.
  subtype_term:
    preferred_term: isocyanate induced asthma
    term:
      id: MONDO:0025556
      label: isocyanate induced asthma
- name: Irritant-induced
  display_name: Irritant-induced occupational asthma
  description: >-
    Asthma caused by a non-immunological irritant injury to the airway, with no
    latency and no agent-specific immune memory. Includes reactive airways
    dysfunction syndrome after a single high-dose exposure, and the
    lower-intensity repeated-exposure form. Conforms to the
    `inhaled_irritant_airway_injury` module rather than to
    `chemical_respiratory_allergy`. No MONDO term covers this stratum: OLS
    returns only `MONDO:0004979` asthma for `irritant induced asthma` and
    nothing at all for `reactive airways dysfunction syndrome`, and
    `MONDO:0022742` has no children, so the row carries no `subtype_term`.
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      reactive airways dysfunction syndrome is a separate entity and a subtype
      of occupational asthma
    explanation: >-
      Supports treating the irritant-induced form as a stratum of this disease
      rather than a separate one, and names reactive airways dysfunction
      syndrome as belonging to it.
  - reference: PMID:31690384
    reference_title: Occupational immunologic lung disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      RADS is defined as an asthma-like syndrome that persists for >3 months
      and occurs within minutes to hours after a single exposure to a high
      concentration of a respiratory irritant
    explanation: >-
      Gives the definition of reactive airways dysfunction syndrome, including
      the absence of latency that distinguishes this stratum from the
      sensitizer one.
pathophysiology:
- name: Workplace Sensitizer Haptenation of Airway Proteins
  description: >-
    A reactive low molecular weight chemical inhaled at the workplace binds
    nucleophilic residues on airway and serum proteins, generating the
    hapten-protein adduct that the immune system subsequently recognizes. This
    is the step that requires the agent to be chemically reactive, and it is
    why the low molecular weight agents behave differently from the protein
    allergens that sensitize directly.
  role: trigger
  biological_scale: MOLECULAR
  subtypes:
  - LMW-chemical
  - Isocyanate-induced
  conforms_to: "chemical_respiratory_allergy#Covalent Protein Haptenation by a Low Molecular Weight Sensitizer"
  locations:
  - preferred_term: respiratory airway
    term:
      id: UBERON:0001005
      label: respiratory airway
  evidence:
  - reference: PMID:23743149
    reference_title: Characterization of methylene diphenyl diisocyanate-haptenated human serum albumin and hemoglobin.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      demonstrating increases in both number and complexity of conjugates
      formed with increasing MDI concentrations
    explanation: >-
      Measures covalent adduct formation between the commonest causative agent
      class and human protein, which is the haptenation step this node asserts.
  downstream:
  - target: Airway Epithelial Danger Signal Release on Workplace Exposure
    description: >-
      The haptenated epithelium and the reactive chemistry that produced it
      elicit an innate epithelial response.
  - target: Dendritic Cell Activation and Th2 Polarization
    description: >-
      The hapten-protein adduct is the antigen airway dendritic cells take up,
      so haptenation also feeds the dendritic cell step directly.
- name: Airway Epithelial Danger Signal Release on Workplace Exposure
  description: >-
    The bronchial epithelium, lung fibroblasts and endothelium exposed to the
    sensitizer release IL-8, IL-6 and IL-1beta, generate reactive oxygen
    species, lose MUC1, and upregulate endothelial adhesion molecules. This
    innate response licenses dendritic cell maturation but is not by itself
    specific to a sensitizer, which is why an irritant exposure can produce a
    similar picture without sensitization following.
  role: amplifier
  biological_scale: CELLULAR
  subtypes:
  - LMW-chemical
  - Isocyanate-induced
  conforms_to: "chemical_respiratory_allergy#Airway Epithelial Danger Signal Release"
  cell_types:
  - preferred_term: bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  - preferred_term: lung fibroblast
    term:
      id: CL:0002553
      label: fibroblast of lung
  - preferred_term: endothelial cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: cytokine production involved in inflammatory response
    term:
      id: GO:0002534
      label: cytokine production involved in inflammatory response
    modifier: INCREASED
  evidence:
  - reference: PMID:38360295
    reference_title: "Identification of toxicity-induced biomarkers in human non-immune airway cells exposed to respiratory sensitizers: A mechanistic approach."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      sensitizers promoted an increase in IL-8, IL-6, and IL-1β production in
      the evaluated cell types
    explanation: >-
      Measures the danger-signal cytokines of this node in the human airway
      cell types it binds, after exposure to respiratory sensitizers.
  downstream:
  - target: Dendritic Cell Activation and Th2 Polarization
    description: >-
      Epithelial danger signals supply the maturation context that makes
      antigen presentation sensitizing rather than tolerogenic.
- name: Dendritic Cell Activation and Th2 Polarization
  description: >-
    Airway dendritic cells take up the hapten-protein adduct, mature, and
    present it in a Th2-polarizing context. This is the step that distinguishes
    a workplace sensitizer from a workplace irritant, and therefore the step
    that separates this entry's two main subtypes: the irritant-induced
    stratum never reaches it.
  role: central_effector
  biological_scale: CELLULAR
  subtypes:
  - LMW-chemical
  - Isocyanate-induced
  conforms_to: "chemical_respiratory_allergy#Dendritic Cell Activation and Th2-Polarizing Antigen Presentation"
  cell_types:
  - preferred_term: dendritic cell
    term:
      id: CL:0000451
      label: dendritic cell
  biological_processes:
  - preferred_term: antigen processing and presentation
    term:
      id: GO:0019882
      label: antigen processing and presentation
    modifier: INCREASED
  evidence:
  - reference: PMID:28824649
    reference_title: Prediction of Chemical Respiratory and Contact Sensitizers by OX40L Expression in Dendritic Cells Using a Novel 3D Coculture System.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      OX40L expression in DCs was most consistently and significantly enhanced
      by respiratory sensitizers as compared to that by skin sensitizers
    explanation: >-
      Supports the Th2-polarizing character of this step, and that it
      discriminates respiratory sensitizers specifically.
  downstream:
  - target: Hapten-Specific T Cell Memory
    description: >-
      Presentation of the adduct by matured dendritic cells expands
      hapten-specific T cells and establishes memory.
- name: Hapten-Specific T Cell Memory
  description: >-
    Hapten-specific T cells expand and polarize toward a type 2 profile, with
    IL-4, IL-5 and IL-13 and airway eosinophilia. This establishes the
    immunological memory that gives sensitizer-induced occupational asthma its
    defining clinical features: a latency period before onset, and reproducible
    symptoms on re-exposure to that agent and not to others. Specific IgE may
    accompany it but frequently does not with low molecular weight agents.
  role: effector
  biological_scale: CELLULAR
  subtypes:
  - LMW-chemical
  - Isocyanate-induced
  conforms_to: "chemical_respiratory_allergy#Hapten-Specific T Cell Activation and Th2 Polarization"
  cell_types:
  - preferred_term: T-helper 2 cell
    term:
      id: CL:0000546
      label: T-helper 2 cell
  biological_processes:
  - preferred_term: T-helper 2 cell differentiation
    term:
      id: GO:0045064
      label: T-helper 2 cell differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Workers with occupational asthma secondary to low molecular weight agents
      may not have elevated specific IgE levels
    explanation: >-
      Supports only the last sentence of this node, that specific IgE is
      frequently absent in this agent class. It does not evidence the T cell
      expansion or the type 2 polarization, which the two items below carry.
  - reference: PMID:16271432
    reference_title: TDI can induce respiratory allergy with Th2-dominated response in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      skin application followed by tracheal instillations of TDI led to local
      and systemic Th2-dominated immune responses
    explanation: >-
      Evidences the type 2 polarization this node asserts, for the agent class
      that causes most of this disease.
  - reference: PMID:12419703
    reference_title: "Cytokine fingerprinting of chemical allergens: species comparisons and statistical analyses."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      TMA-activated LNC isolated from BALB/c mice or BN rats elaborated high
      levels of the Th2-type cytokines interleukin (IL)-10 and IL-13, but
      relatively little of the Th1-type cytokines IL-12 or interferon gamma
    explanation: >-
      Evidences the type 2 cytokine profile of this node against a contact
      allergen comparator, so the polarization is a measured contrast and not
      an assumption.
  downstream:
  - target: Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation
    description: >-
      Re-exposure at work drives the established hapten-specific response into
      airway inflammation and bronchoconstriction.
- name: Irritant Injury of the Airway Epithelial Barrier
  description: >-
    In the irritant-induced stratum there is no haptenation and no
    agent-specific memory. A reactive inhaled irritant injures the epithelium
    directly, disrupting tight junctions and raising paracellular permeability,
    and the resulting inflammation produces asthma without a latency period.
    This is why irritant-induced occupational asthma begins within hours of a
    high-dose exposure rather than after months of low-level exposure.
  role: trigger
  biological_scale: CELLULAR
  subtypes:
  - Irritant-induced
  conforms_to: "inhaled_irritant_airway_injury#Airway Epithelial Junctional Barrier Failure"
  cell_types:
  - preferred_term: bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_processes:
  - preferred_term: bicellular tight junction assembly
    term:
      id: GO:0070830
      label: bicellular tight junction assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:32588239
    reference_title: Ion transport mechanisms for smoke inhalation-injured airway epithelial barrier.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Thermal stress or acrolein disrupted zonula occludens-1 tight junctions,
      increased fluorescein isothiocyanate-dextran permeability but did not
      cause cell death or detachment
    explanation: >-
      Shows a reactive inhaled aldehyde producing junctional barrier failure
      without cell death, which is the non-immune injury route of this stratum.
      Graded INDIRECT because the study is of smoke inhalation injury in
      airway monolayers, so the inference to irritant-induced asthma in a
      worker is a step beyond what it measures.
  downstream:
  - target: Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation
    description: >-
      Direct epithelial injury and the inflammation it provokes produce airway
      hyperresponsiveness without an immunological sensitization step.
- name: Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation
  description: >-
    The convergence point of both strata and the clinical disease. Airway
    smooth muscle contraction, airway hyperresponsiveness and variable airflow
    limitation, with the temporal pattern that defines the diagnosis: symptoms
    worse at work and improving away from it. Removal from exposure does not
    reliably resolve it, so this node represents a persistent state rather than
    a transient response to exposure. Both strata converge here by different
    routes: the sensitizer arm through hapten-specific memory, the irritant arm
    through direct epithelial injury. The `conforms_to` link is true of the
    sensitizer route; the irritant module's own consequence is mucociliary
    clearance failure rather than asthma, so it is deliberately not named as a
    second target.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "chemical_respiratory_allergy#Airway Hyperresponsiveness and Variable Airflow Limitation"
  biological_processes:
  - preferred_term: smooth muscle contraction
    term:
      id: GO:0006939
      label: smooth muscle contraction
    modifier: INCREASED
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Not all patients with occupational asthma will improve after removal from
      the workplace
    explanation: >-
      Supports treating this node as a persistent state: the disease does not
      reliably remit when the exposure stops.
  downstream:
  - target: Asthma symptoms with a work-related pattern
    description: >-
      Airflow limitation and hyperresponsiveness present clinically as
      work-related asthma symptoms.
  - target: Airway hyperresponsiveness
    description: >-
      This node is the state the methacholine or histamine challenge measures,
      so the measured phenotype is its direct expression.
  - target: Variable airflow limitation
    description: >-
      The variable component of the airflow limitation this node describes is
      what serial peak flow monitoring at and away from work records.
phenotypes:
- name: Asthma symptoms with a work-related pattern
  category: Clinical
  description: >-
    Wheeze, cough, chest tightness and breathlessness that worsen on working
    days and improve away from work. The temporal relationship to work, rather
    than any feature of the symptoms themselves, is what identifies the disease.
  phenotype_term:
    preferred_term: Asthma
    term:
      id: HP:0002099
      label: Asthma
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Work-aggravated asthma and occupational asthma are two forms of asthma
      causally related to the workplace
    explanation: >-
      Establishes that the disease is causally related to the workplace. Note
      it does not evidence the temporal pattern itself, which the item below
      carries.
  - reference: PMID:12704360
    reference_title: "HLA associations with occupational sensitization to rat lipocalin allergens: a model for other animal allergies?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37)
    explanation: >-
      Measures respiratory symptoms occurring at work in sensitized workers,
      which is the work-related symptom pattern this phenotype describes.
- name: Airway hyperresponsiveness
  category: Clinical
  description: >-
    Exaggerated bronchoconstrictor response to inhaled stimuli, demonstrable by
    methacholine or histamine challenge, and the physiological hallmark shared
    by both strata.
  phenotype_term:
    preferred_term: Airway hyperresponsiveness
    term:
      id: HP:0032933
      label: Airway hyperresponsiveness
  evidence:
  - reference: PMID:17040933
    reference_title: "Outcome of occupational asthma after cessation of exposure: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The pooled prevalence of persistent NSBHR at follow-up was 73% (95% CI
      66% to 79%)
    explanation: >-
      Quantifies how often this phenotype persists after exposure ceases,
      across 39 studies, which is why the entry treats hyperresponsiveness as
      a persistent state rather than a response to current exposure.
- name: Wheezing
  category: Clinical
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
- name: Dyspnea
  category: Clinical
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
- name: Cough
  category: Clinical
  description: >-
    Cough on working days, improving away from work. One of the four symptoms
    the work-related pattern is recognised by, and sometimes the only one.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
- name: Chest tightness
  category: Clinical
  description: >-
    Chest tightness on working days, improving away from work. Named with
    wheeze, cough and breathlessness in the work-related symptom pattern.
  phenotype_term:
    preferred_term: Chest tightness
    term:
      id: HP:0031352
      label: Chest tightness
- name: Variable airflow limitation
  category: Clinical
  description: >-
    Reduced expiratory flow that varies with exposure, documented by serial
    peak expiratory flow monitoring at and away from work or by spirometry
    before and after a specific inhalation challenge.
  phenotype_term:
    preferred_term: Reduced forced expiratory volume in one second
    term:
      id: HP:0032342
      label: Reduced forced expiratory volume in one second
- name: Occupational rhinitis
  category: Clinical
  description: >-
    Work-related rhinitis frequently accompanies, and often precedes, the lower
    airway disease with the same causative agent.
  phenotype_term:
    preferred_term: Allergic rhinitis
    term:
      id: HP:0003193
      label: Allergic rhinitis
prevalence:
- population: Adults
  measure_type: UNKNOWN
  notes: >-
    Reported as a population attributable fraction — 16% of incident adult
    asthma is attributable to occupational exposure, pooled across nine
    longitudinal studies — and not as a population rate, so `rate_per_100000`
    is deliberately left empty and `measure_type` is `UNKNOWN`. A PAF and a
    prevalence have different denominators and must not be conflated, and
    `PrevalenceMeasureEnum` has no attributable-fraction value to record this
    properly. `prevalence_class` is left empty for the same reason: the
    Orphanet-aligned bands are magnitudes against a population denominator, so
    assigning one to a fraction of incident cases would state a rate this
    record does not carry, and the qualitative tiers are defined by prevalence
    thresholds this record likewise does not have. An earlier version of this
    record carried a 5% figure from a general allergy review; the pooled
    longitudinal estimate cited here supersedes it.
  evidence:
  - reference: PMID:33141780
    reference_title: Novel approaches in occupational asthma diagnosis and management.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Data from nine longitudinal studies showed a population attributable
      fraction for the occupational contribution to incident asthma of 16%
    explanation: >-
      Gives the pooled population attributable fraction this record carries,
      from longitudinal rather than cross-sectional data.
progression:
- phase: Latency before onset
  subtype: Sensitizer-induced
  notes: >-
    The sensitizer stratum has a symptom-free interval between first exposure
    and first symptoms, during which sensitization is established. Its length
    is not fixed and is not recorded here as a number, because the cited
    sources give it qualitatively. Its presence is what distinguishes this
    stratum from the irritant one, where onset follows exposure within minutes
    to hours.
  evidence:
  - reference: PMID:31690384
    reference_title: Occupational immunologic lung disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      RADS is defined as an asthma-like syndrome that persists for >3 months
      and occurs within minutes to hours after a single exposure to a high
      concentration of a respiratory irritant
    explanation: >-
      Supports this phase by contrast: it states the irritant stratum's
      immediate onset, which is the absence of the latency this phase
      describes.
- phase: Persistence after exposure ends
  notes: >-
    Removal from exposure does not end the disease in most workers. Airway
    hyperresponsiveness persists in around three quarters and symptomatic
    recovery occurs in under a third, and lung function continues to fall in a
    followed diisocyanate cohort even after cessation. This is the phase that
    makes the consequence node a persistent state rather than a response to
    current exposure.
  evidence:
  - reference: PMID:18394133
    reference_title: Inflammation and functional outcome in diisocyanate-induced asthma after cessation of exposure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)
      values decreased, with a median yearly reduction of FEV1 of 79 ml
    explanation: >-
      Measures continuing loss of lung function after exposure has stopped,
      which is the functional content of this phase. Hyperresponsiveness
      improved in the same cohort, so the phase is not uniform decline across
      every measure.
  - reference: PMID:17040933
    reference_title: "Outcome of occupational asthma after cessation of exposure: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The pooled prevalence of persistent NSBHR at follow-up was 73% (95% CI
      66% to 79%)
    explanation: >-
      Quantifies persistence of the physiological hallmark across 39 studies,
      which is this phase's central claim.
genetic:
- name: Host susceptibility loci for diisocyanate asthma
  relationship_type: SUSCEPTIBILITY
  subtype: Isocyanate-induced
  notes: >-
    Susceptibility to diisocyanate asthma is modified by host genotype at
    several loci: HLA class II alleles and haplotypes, glutathione
    S-transferase and N-acetyltransferase genotypes governing conjugation of
    the reactive agent, and IL-4 receptor-alpha with CD14 polymorphisms. The
    detoxification genotypes are mechanistically coherent with the chemistry of
    the trigger node — a worker who conjugates the electrophile less
    efficiently presents more of it to airway protein. No gene is causative;
    these are modifiers of risk in exposed workers.

    No external body has classified any of these gene-disease pairs, so
    `gene_disease_validity` is deliberately absent rather than being assigned
    here. This record states the shared mechanism; the per-gene records below
    carry each locus with its own binding and its own measured association.
  evidence:
  - reference: PMID:21325943
    reference_title: Genetics of occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Genotype combinations of IL-4 receptor-α and CD14 single nucleotide
      polymorphisms (SNPs) were significantly associated with diisocyanate
      asthma, but only in workers exposed to hexamethylene diisocyanate
    explanation: >-
      Reports a host genotype association specific to diisocyanate asthma, and
      specific to one agent within it, which is the susceptibility claim this
      record makes.
  - reference: PMID:21325943
    reference_title: Genetics of occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      certain glutathione S-transferase genotypes (e.g. the GSTM1 null
      genotype) and N-acetyltransferase genotypes associated with slow
      acetylation phenotypes have been reported to be associated with
      diisocyanate asthma
    explanation: >-
      Supports the detoxification arm of this record: genotypes governing
      conjugation of the reactive agent modify risk, which connects host
      genetics to the haptenation trigger.
- name: HLA class II association with protein allergen sensitization
  relationship_type: SUSCEPTIBILITY
  subtype: HMW-protein
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  mhc_term:
    preferred_term: HLA-DR7 serotype
    term:
      id: MRO:0000316
      label: HLA-DR7 serotype
  notes: >-
    In the high molecular weight arm, HLA class II type modifies the risk of
    becoming sensitized at all. HLA-DR7 was associated with sensitization to
    rat urinary proteins among laboratory animal workers and more strongly with
    sensitization accompanied by symptoms, while HLA-DR3 was protective. This
    is consistent with class II molecules controlling presentation of the
    allergen to T cells. DR7 and DR3 are HLA-DRB1 serotypes, so the locus is
    bound in `gene_term` and the serotype the study measured in `mhc_term`;
    only the DR7 association is bound there, because the slot is single-valued
    and DR3 is the protective comparator rather than this record's claim.
  evidence:
  - reference: PMID:12704360
    reference_title: "HLA associations with occupational sensitization to rat lipocalin allergens: a model for other animal allergies?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      HLA-DR7 was associated with sensitization (odds ratio [OR], 1.82; CI,
      1.12-2.97), respiratory symptoms at work (OR, 2.96; CI, 1.64-5.37) and,
      most strongly, sensitization with symptoms (OR, 3.81; CI, 1.90-7.65)
    explanation: >-
      Measures the HLA class II association with occupational sensitization in
      a cross-sectional cohort of exposed workers, which is this record's
      claim.
- name: HLA-DQB1
  relationship_type: SUSCEPTIBILITY
  gene_term:
    preferred_term: HLA-DQB1
    term:
      id: hgnc:4944
      label: HLA-DQB1
  notes: >-
    The class II locus most consistently associated with occupational asthma
    across agent classes, in contrast to HLA-DRB1 in general allergic asthma.
    The anhydride association below is carried at the serotype level in
    `mhc_term`, because DQ5 corresponds to DQB1*05 alleles rather than to the
    locus as a whole.
  mhc_term:
    preferred_term: HLA-DQ5 serotype
    term:
      id: MRO:0000289
      label: HLA-DQ5 serotype
  evidence:
  - reference: PMID:24994462
    reference_title: "HLA and asthma phenotypes/endotypes: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The most common HLA haplotypes in the different asthma phenotypes are
      HLA-DRB1in allergic asthma, HLA-DQB1in occupational asthma and HLA-DPB1
      in aspirin-sensitive asthma
    explanation: >-
      Names this locus as the one most associated with occupational asthma
      specifically, which is why it is recorded without a subtype scope. The
      two missing spaces are the source's own typography and are quoted as
      printed.
  - reference: PMID:15144476
    reference_title: Association of HLA-DQ5 and HLA-DR1 with sensitization to organic acid anhydrides.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The linked alleles DQ5 (odds ratio [OR]=4.3; 95% confidence interval
      [95% CI]=1.7, 11) and DR1 (OR 3.0; 95% CI 1.2, 11) were more prevalent
      in cases than in referents
    explanation: >-
      Measures the DQ5 association with sensitization to acid anhydrides, a
      low molecular weight sensitizer class, in cases against exposed
      referents.
- name: HLA-DRB1 haplotype in isocyanate-induced asthma
  relationship_type: SUSCEPTIBILITY
  subtype: Isocyanate-induced
  gene_term:
    preferred_term: HLA-DRB1
    term:
      id: hgnc:4948
      label: HLA-DRB1
  notes: >-
    The association is reported for the DRB1*15-DPB1*05 haplotype rather than
    for either locus alone, so this record and the HLA-DPB1 record below cite
    the same study and should be read together.
  evidence:
  - reference: PMID:16792590
    reference_title: "HLA DRB1*15-DPB1*05 haplotype: a susceptible gene marker for isocyanate-induced occupational asthma?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the allelic frequency of HLA DRB1*15-DPB1*05 in group I (10.6%) was
      significantly higher than that of group II (0%, P = 0.001)
    explanation: >-
      Measures the haplotype frequency in workers with isocyanate-induced
      asthma against exposed asymptomatic workers, which is this record's
      susceptibility claim.
- name: HLA-DPB1
  relationship_type: SUSCEPTIBILITY
  subtype: Isocyanate-induced
  gene_term:
    preferred_term: HLA-DPB1
    term:
      id: hgnc:4940
      label: HLA-DPB1
  notes: >-
    Carried both in the DRB1*15-DPB1*05 haplotype above and independently as a
    single nucleotide polymorphism association in a separate cohort.
  evidence:
  - reference: PMID:24709764
    reference_title: Genetic variants in the major histocompatibility complex class I and class II genes are associated with diisocyanate-induced Asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The HLA-E rs1573294 and HLA-DPB1 rs928976 SNPs were associated with an
      increased risk of DA
    explanation: >-
      Reports a variant-level association at this locus with
      diisocyanate-induced asthma. HLA-E is named in the same sentence but has
      no record here, because this entry curates only the loci it can state a
      mechanism for.
- name: GSTM1
  relationship_type: SUSCEPTIBILITY
  subtype: Isocyanate-induced
  gene_term:
    preferred_term: GSTM1
    term:
      id: hgnc:4632
      label: GSTM1
  notes: >-
    A detoxification rather than an antigen-presentation locus. The null
    genotype removes a conjugation route for the electrophilic sensitizer, so a
    worker who conjugates it less efficiently presents more of it to airway
    protein — which is the haptenation trigger node of this entry.
  evidence:
  - reference: PMID:21325943
    reference_title: Genetics of occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      certain glutathione S-transferase genotypes (e.g. the GSTM1 null
      genotype) and N-acetyltransferase genotypes associated with slow
      acetylation phenotypes have been reported to be associated with
      diisocyanate asthma
    explanation: >-
      Names the GSTM1 null genotype as associated with diisocyanate asthma,
      which is this record's claim.
- name: IL4R
  relationship_type: SUSCEPTIBILITY
  subtype: Isocyanate-induced
  gene_term:
    preferred_term: IL4R
    term:
      id: hgnc:6015
      label: IL4R
  notes: >-
    The receptor for the type 2 cytokine the hapten-specific T cell node
    produces, so this locus sits on the immune arm rather than the
    detoxification arm. The reported association is for genotype combinations
    with CD14, and only in hexamethylene diisocyanate-exposed workers, so it is
    agent-specific within the stratum.
  evidence:
  - reference: PMID:21325943
    reference_title: Genetics of occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Genotype combinations of IL-4 receptor-α and CD14 single nucleotide
      polymorphisms (SNPs) were significantly associated with diisocyanate
      asthma, but only in workers exposed to hexamethylene diisocyanate
    explanation: >-
      Reports the association for this locus, in combination with CD14 and
      restricted to one agent, which both records state.
- name: CD14
  relationship_type: SUSCEPTIBILITY
  subtype: Isocyanate-induced
  gene_term:
    preferred_term: CD14
    term:
      id: hgnc:1628
      label: CD14
  notes: >-
    Associated only in genotype combination with IL4R, and only in
    hexamethylene diisocyanate-exposed workers. Recorded as its own locus
    because the combination is not a haplotype at one locus; neither record
    asserts an independent effect.
  evidence:
  - reference: PMID:21325943
    reference_title: Genetics of occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Genotype combinations of IL-4 receptor-α and CD14 single nucleotide
      polymorphisms (SNPs) were significantly associated with diisocyanate
      asthma, but only in workers exposed to hexamethylene diisocyanate
    explanation: >-
      Reports the association for this locus, in combination with IL4R and
      restricted to one agent, which both records state.
- name: Genetic susceptibility is partial and no locus is causative
  relationship_type: SUSCEPTIBILITY
  notes: >-
    Recorded so the per-gene records above are not read as a sufficient
    account. Only a subset of exposed workers becomes sensitized, which is the
    observation that motivates looking for host genotype at all, and the
    reported loci explain a minority of that variance. The functional themes
    across them — antigen processing, lymphocyte activation, cytokine
    regulation, oxidative-stress response — are the same two arms the records
    above split on.
  evidence:
  - reference: PMID:36276967
    reference_title: "The genetics of occupational asthma development among workers exposed to diisocyanates: A systematic literature review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      only a subset of workers exposed to diisocyanates develop
      diisocyanate-induced occupational asthma (diisocyanate asthma, DA),
      indicating that genetic susceptibility may play a role
    explanation: >-
      States the premise of this whole section: exposure is necessary but not
      sufficient, and host genotype is one of the reasons.
  - reference: PMID:36276967
    reference_title: "The genetics of occupational asthma development among workers exposed to diisocyanates: A systematic literature review with meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      antigen processing, lymphocyte activation, cytokine production
      regulation, and response to oxidative stress
    explanation: >-
      Names the functional themes the associated genes fall into, which is the
      two-arm division the per-gene records above are organised by.
environmental:
- name: Occupational exposure to chlorine
  description: >-
    Inhalation of chlorine gas, in water treatment, cleaning, pulp bleaching
    and after accidental release. A representative irritant exposure for the
    irritant-induced stratum: it injures the airway epithelium directly, with
    no latency and no agent-specific immune memory.
  exposure_term:
    preferred_term: exposure to chlorine
    term:
      id: ECTO:9000077
      label: exposure to chlorine
  influences_mechanisms:
  - target: Irritant Injury of the Airway Epithelial Barrier
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      High-concentration irritant inhalation injures the epithelium directly,
      which is the initiating event of this stratum.
  evidence:
  - reference: PMID:33063819
    reference_title: Updated review of reported cases of reactive airways dysfunction syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      A variety of agents were implicated, with chlorine or chlorine-releasing
      molecules most frequently reported
    explanation: >-
      Establishes chlorine as the most frequently reported cause of reactive
      airways dysfunction syndrome across reported cases, which is why it is
      the representative exposure for this stratum.
- name: Occupational exposure to diisocyanates
  description: >-
    Inhalation of toluene, methylene diphenyl or hexamethylene diisocyanate in
    polyurethane manufacture, spray painting, foam production and related
    trades. The leading single cause of sensitizer-induced occupational asthma.
  exposure_term:
    preferred_term: exposure to isocyanates
    term:
      id: ECTO:9002153
      label: exposure to isocyanates
  influences_mechanisms:
  - target: Workplace Sensitizer Haptenation of Airway Proteins
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Workplace inhalation is the route by which the reactive chemical reaches
      airway proteins and haptenates them.
    evidence:
    - reference: PMID:21573916
      reference_title: Occupational asthma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: >-
        Low molecular weight isocyanates are the most common compounds that
        cause occupational asthma
      explanation: >-
        Establishes this exposure as the leading cause of the disease, and so
        as a trigger of the haptenation step it is linked to.
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Low molecular weight isocyanates are the most common compounds that cause
      occupational asthma
    explanation: >-
      Supports recording diisocyanate exposure as the principal causative
      exposure for this disease.
diagnosis:
- name: Spirometry with serial peak flow monitoring
  description: >-
    Spirometry, with serial peak expiratory flow records kept at and away from
    work, is how the work-related pattern of airflow limitation is documented
    in practice. It establishes that airflow limitation varies with exposure;
    it does not identify the causative agent.
  diagnosis_term:
    preferred_term: Spirometry
    term:
      id: NCIT:C85397
      label: Spirometry
- name: Specific inhalation challenge
  description: >-
    Controlled exposure of the patient to the suspected workplace agent, with
    spirometry before and after. The only test that identifies the causative
    agent, and so the gold standard, but rarely performed — which is why most
    diagnoses rest on the clinical and temporal pattern instead.
  notes: >-
    No NCIT term is bound. Searched OLS (`ontology=ncit`) for
    `inhalation challenge`, which returns nothing; `provocation`, which returns
    only dosage-form classes for provocation-test preparations; and
    `challenge test`, which returns `NCIT:C99490 Proficiency Testing
    Challenge` and `NCIT:C78164 Histamine Challenge Test`. The last is a
    non-specific bronchial provocation test with histamine, a different
    procedure from challenge with the patient's own workplace agent, so
    binding it would assert the wrong test.
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      The gold standard test, specific inhalation challenge, is rarely used.
    explanation: >-
      Supports that specific inhalation challenge is seldom used in practice.
  - reference: PMID:33652998
    reference_title: "Pulmonary Function Testing in Work-Related Asthma: An Overview from Spirometry to Specific Inhalation Challenge."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      specific inhalation challenge (SIC) is considered as the reference
      standard
    explanation: >-
      Establishes this procedure as the reference standard for confirming the
      causative agent, which is the claim this row makes.
- name: Airway inflammation measurement during specific inhalation challenge
  description: >-
    Fractional exhaled nitric oxide and induced sputum eosinophil count,
    measured before and after a specific inhalation challenge. Neither
    identifies the agent; both raise the yield of the challenge, because a
    positive challenge can show a rise in one without the other.
  diagnosis_term:
    preferred_term: Nitric Oxide Measurement
    term:
      id: NCIT:C112360
      label: Nitric Oxide Measurement
  notes: >-
    The bound term covers only the nitric oxide half of this row; NCIT has no
    single term for the paired measurement, and the sputum eosinophil count is
    carried in the `biochemical` section instead. Thresholds are quoted rather
    than recorded as `reference_ranges`, because they are challenge-response
    cut-offs for a change from baseline, not clinical normal intervals for a
    single value.
  evidence:
  - reference: PMID:39726396
    reference_title: Exhaled Nitric Oxide and Sputum Eosinophils Are Complementary Tools for Diagnosing Occupational Asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Increases in FeNO level ≥ 13 ppb and sputum eosinophils ≥ 1.25% were
      identified as the optimal threshold values for differentiating positive
      from negative SICs
    explanation: >-
      Gives both cut-offs, derived in 321 workers undergoing challenge, which
      is what makes this a usable diagnostic adjunct rather than a descriptive
      measurement.
  - reference: PMID:39726396
    reference_title: Exhaled Nitric Oxide and Sputum Eosinophils Are Complementary Tools for Diagnosing Occupational Asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Combining either a rise in FeNO ≥ 13 ppb or an increase in sputum
      eosinophils ≥ 1.25% increased the sensitivity to 77%
    explanation: >-
      Supports the complementarity this row asserts: the two measurements
      together detect more positive challenges than either alone.
biochemical:
- name: Fractional exhaled nitric oxide
  biomarker_term:
    preferred_term: fractional exhaled nitric oxide (FeNO)
    term:
      id: NCIT:C695
      label: Nitric Oxide
  notes: >-
    Nitric oxide in exhaled breath, raised in type 2 airway inflammation. In
    this disease it is read as a change across a specific inhalation challenge
    rather than as an absolute level.

    The bound term is the analyte, not the measurement; NCIT has no term for
    the fractional exhaled fraction itself, and `NCIT:C112360 Nitric Oxide
    Measurement` is a procedure rather than a biomarker, so it is bound on the
    `diagnosis` row instead. No LOINC code is bound: this entry has not been
    through the LOINC cache-seeding step, and a label typed from memory is
    what that step exists to prevent.
  readouts:
  - target: Hapten-Specific T Cell Memory
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A rise across challenge reports the type 2 response this node
      describes. It does not identify the sensitizer, and it is specific but
      insensitive, so a flat FeNO does not exclude a positive challenge.
    evidence:
    - reference: PMID:39726396
      reference_title: Exhaled Nitric Oxide and Sputum Eosinophils Are Complementary Tools for Diagnosing Occupational Asthma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Increases in FeNO level ≥ 13 ppb and sputum eosinophils ≥ 1.25% were
        identified as the optimal threshold values for differentiating positive
        from negative SICs
      explanation: >-
        Establishes the measured link between a rise in this marker and a
        positive challenge, which is what this readout claims.
- name: Induced sputum eosinophil count
  biomarker_term:
    preferred_term: sputum eosinophil percentage
    term:
      id: NCIT:C64550
      label: Eosinophil Count
  notes: >-
    Eosinophil percentage in induced sputum, the direct cellular counterpart of
    the airway eosinophilia the hapten-specific T cell node produces.

    The bound term is the generic count; NCIT has no sputum-specific
    eosinophil count term, and the specimen is carried in `preferred_term` and
    in this record's name. No LOINC code is bound, for the reason given on the
    FeNO record.
  readouts:
  - target: Hapten-Specific T Cell Memory
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      A rise across challenge reports the eosinophilia this node names
      directly. Discordance with FeNO in a substantial minority of positive
      challenges is why both are measured rather than either.
    evidence:
    - reference: PMID:39726396
      reference_title: Exhaled Nitric Oxide and Sputum Eosinophils Are Complementary Tools for Diagnosing Occupational Asthma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Combining either a rise in FeNO ≥ 13 ppb or an increase in sputum
        eosinophils ≥ 1.25% increased the sensitivity to 77%
      explanation: >-
        Supports reading this marker alongside FeNO rather than instead of it,
        which is what the interpretation states.
treatments:
- name: Removal from exposure
  description: >-
    Ending exposure to the causative agent is the definitive intervention, and
    the earlier it happens the better the outcome. It is not reliably curative:
    a substantial proportion of workers have persistent asthma and persistent
    airway hyperresponsiveness years after leaving the exposure, which is why
    the consequence node is modelled as a persistent state.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation
    treatment_effect: INHIBITS
    description: >-
      Removing the causative exposure withdraws the driver of the airway
      response, though it does not reverse established disease in every worker.
  evidence:
  - reference: PMID:21573916
    reference_title: Occupational asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Not all patients with occupational asthma will improve after removal from
      the workplace
    explanation: >-
      Supports that removal is not reliably curative. The two items below
      carry the controlled comparison and the quantified persistence.
  - reference: PMID:23407122
    reference_title: "Management of sensitizer-induced occupational asthma: avoidance or reduction of exposure?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      complete removal from exposure resulted in the best outcome in terms of
      symptoms, lung function, and airway hyper-responsiveness. Reduction of
      exposure appeared to be less effective in terms of improving asthma but
      was also less likely to result in loss of income or unemployment
    explanation: >-
      Supports removal as the most effective intervention on clinical
      outcomes, against reduction of exposure as the comparator, and carries
      the trade-off in the same sentence: the clinically better option is the
      one more likely to cost the worker their job.
  - reference: PMID:17040933
    reference_title: "Outcome of occupational asthma after cessation of exposure: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The pooled prevalence of persistent NSBHR at follow-up was 73%
    explanation: >-
      Quantifies how often airway hyperresponsiveness persists after exposure
      ends, which is why this treatment is described as definitive but not
      reliably curative. Graded PRIMARY_RESULT because the pooled estimate is
      this review's own computation over 39 studies, not a figure it is
      restating.
  - reference: PMID:17040933
    reference_title: "Outcome of occupational asthma after cessation of exposure: a systematic review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Reported rates of symptomatic recovery varied from 0% to 100%, with a
      pooled estimate of 32%
    explanation: >-
      Gives the complement of the persistence figure above: fewer than a third
      of workers recover symptomatically even after exposure ends, which is
      the measured basis for calling removal definitive but not curative.
- name: Workplace exposure elimination as primary prevention
  description: >-
    Removing or substituting the sensitizer in the workplace so that workers
    are never exposed. This is a different intervention from the removal row
    above, which withdraws an already-affected worker: this one prevents the
    disease arising at all, and the evidence for it is the strongest in the
    field. Powder-free low-protein natural rubber latex gloves are the worked
    case, where substitution was followed by a sharp fall in new
    sensitization.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Therapeutic Procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  notes: >-
    No NCIT term for a workplace engineering or substitution control was
    found. Searched OLS (`ontology=ncit`) for `exposure elimination`, which
    returns nothing, and `substitution`, which returns chemical and genetic
    substitution classes rather than a clinical action, so the generic
    therapeutic procedure term is bound and the specificity is carried in
    `preferred_term` on this row's name and description. The row is a
    population-level intervention rather than a patient-level one, which the
    schema has no separate slot for.
  target_mechanisms:
  - target: Workplace Sensitizer Haptenation of Airway Proteins
    treatment_effect: INHIBITS
    description: >-
      Eliminating the agent from the workplace removes the reactive chemical
      that haptenates airway protein, so the chain never starts. This is why
      the intervention is preventive rather than therapeutic.
  evidence:
  - reference: PMID:22654083
    reference_title: "Primary prevention: exposure reduction, skin exposure and respiratory protection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Exposure elimination is the strongest and preferred primary preventive
      approach to reduce the burden of occupational asthma
    explanation: >-
      States the conclusion of a systematic review of 29 studies, and is the
      basis for recording this as a distinct intervention rather than folding
      it into removal from exposure.
  - reference: PMID:22654083
    reference_title: "Primary prevention: exposure reduction, skin exposure and respiratory protection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      There is strong evidence to recommend not using powdered allergen-rich
      natural rubber latex gloves
    explanation: >-
      Gives the one agent-specific recommendation the review grades as strong,
      which is the substitution the next item measures.
  - reference: PMID:21775898
    reference_title: Prevention of IgE Sensitization to Latex in Health Care Workers After Reduction of Antigen Exposures.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      After the intervention, new latex sensitization rates declined 16-fold,
      and 25% of previously sensitized employees reverted to negative skin
      tests
    explanation: >-
      Measures the effect of the substitution in a health care worker cohort,
      which turns the recommendation above into an interventional result. Note
      it measures sensitization, not asthma, so the step to disease prevention
      is an inference.
- name: Anti-inflammatory asthma pharmacotherapy
  description: >-
    Management of the airway inflammation alongside removal from exposure,
    with inhaled corticosteroid and bronchodilator therapy as in asthma
    generally. It treats the established airway disease and does nothing about
    the sensitization or the exposure, so it is adjunctive to removal rather
    than an alternative to it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Work-Related Airway Hyperresponsiveness and Variable Airflow Limitation
    treatment_effect: INHIBITS
    description: >-
      Anti-inflammatory therapy reduces the airway inflammation that sustains
      hyperresponsiveness and airflow limitation.
  evidence:
  - reference: PMID:15579371
    reference_title: Occupational exposures as triggers of asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Early diagnosis, adequate management of inflammation, and prevention of
      further exposure are essential to occupational asthma management.
    explanation: >-
      Names management of inflammation as an essential component of treatment,
      alongside the prevention of further exposure that the other row covers.
  notes: >-
    No specific agent is bound in `therapeutic_agent`. The cited review states
    that inflammation must be managed but names no drug or class, and this
    entry does not assert a particular agent on its authority.
notes: >-
  Scope and the lump decision. This entry covers occupational asthma as the
  field defines it, both the sensitizer-induced and the irritant-induced
  stratum, because the name covers both and an entry named for the whole
  concept must model both. The two strata have genuinely different
  mechanisms — one immunological with latency, one not — so the pathophysiology
  nodes are scoped with `subtypes` and conform to different modules:
  the sensitizer chain to `chemical_respiratory_allergy`, the irritant node to
  `inhaled_irritant_airway_injury`. They converge at the shared consequence
  node. This entry is therefore the place in the KB where those two modules
  meet, which is the clinical reality: the same workplace chemical can irritate
  and sensitize.

  Work-aggravated asthma is excluded, and the entry is therefore narrower than
  the term it binds. MONDO:0022742 is defined, from MeSH, as "Asthma attacks
  caused, triggered, or exacerbated by OCCUPATIONAL EXPOSURE", so exacerbation
  of pre-existing asthma falls inside the bound concept. This entry
  deliberately covers only the caused forms, on the ground that exacerbation of
  existing disease is severity modification rather than a disease with an
  occupational cause, and its mechanism is the pre-existing asthma's. The
  field supports the distinction even though the bound term does not:
  PMID:26024347 defines work-exacerbated asthma as "asthma that is made worse,
  but was not initially caused, by workplace conditions", and places it beside
  occupational asthma under the wider umbrella of work-related asthma rather
  than inside occupational asthma. Note that PMID:21573916, cited elsewhere in
  this entry, groups the two together as "two forms of asthma causally related
  to the workplace" and applies "separate entity" to reactive airways
  dysfunction syndrome, which this entry *includes* — so that review is not
  the authority for this exclusion, and an earlier version of this note
  wrongly said it was.

  One recognised phenotype is not modelled at all: the occupational
  asthma–COPD overlap. PMID:33141780 lists it alongside the HMW, LMW and
  irritant-induced phenotypes, and it has neither a subtype row nor a
  pathophysiology node here. Adding it would need a decision about where
  fixed airflow obstruction sits relative to this entry and to COPD, which is
  not taken here.

  High molecular weight protein allergens are in scope as a cause but are not
  modelled mechanistically. Flour, enzymes, latex and animal proteins cause
  sensitizer-induced occupational asthma through conventional IgE-mediated
  sensitization with no haptenation step, so they do not conform to
  `chemical_respiratory_allergy`, whose trigger node requires a reactive
  chemical. Curating that arm needs its own nodes and is not done here. It has
  its own `has_subtypes` row (`HMW-protein`) carrying what this entry does
  say about it, and the haptenation chain is scoped to `LMW-chemical` rather
  than to the whole sensitizer stratum, so that nothing in the pathograph
  asserts haptenation for a flour or enzyme worker.

  The irritant stratum is declared and curated more thinly than the sensitizer
  one. It has one pathophysiology node against the sensitizer arm's four, one
  exposure (chlorine) against that arm's diisocyanates, and no phenotype,
  treatment or biomarker row scoped to it — every phenotype and treatment row
  here is either stratum-neutral or carries the sensitizer arm's evidence, the
  two inflammatory biomarkers read out a sensitizer-arm node, and of the two
  progression phases only the latency one is stratum-scoped, to the sensitizer
  side. Every bound susceptibility locus is likewise a sensitizer-arm record;
  no host-genotype modifier of irritant-induced disease is recorded, which may
  be a real absence in the literature rather than a gap in this entry. The stratum itself
  is sourced: the `Irritant-induced` subtype row carries the reactive airways
  dysfunction syndrome definition from PMID:31690384 and the subtype claim from
  PMID:21573916, and the chlorine exposure carries PMID:33063819, the RADS case
  review that makes chlorine its most frequently reported cause. What the
  mechanism node lacks is a human source of its own: its evidence is a smoke
  inhalation injury study whose agents are thermal stress and acrolein, graded
  INDIRECT because the step from an airway monolayer to asthma in a worker is
  an inference. Closing that asymmetry — a stratum-scoped phenotype row, a
  human irritant-injury source on the node — is the main outstanding work on
  this entry.

  No GeneReviews baseline applies. This is an acquired environmental disease,
  not a Mendelian one, so the GeneReviews step of the curation workflow does
  not apply; `just check-genereviews` is the verification.

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Review round 1: fix a false source claim, rescope subtypes, add deep-research evidence · 2026-11-09T01:27:24Z · View source

Second pass on the entry created in the preceding record, folding in an independent red-team review and the OpenScientist deep-research run (research/Occupational_Asthma-deep-research-openscientist.md) that were in flight when that record was written. The report had no reference_validation frontmatter, so validation was retro-fitted with validate-references: 41 of 41 citations resolved, 0 unresolved, 0 off topic. Every snippet adopted from it was then cached and exact-substring checked individually. Corrections to false or unevidenced claims. The notes paragraph justifying the work-aggravated asthma exclusion misread PMID:21573916, which in fact groups work-aggravated asthma with occupational asthma as two forms causally related to the workplace and applies 'separate entity' to reactive airways dysfunction syndrome, which this entry includes. Rewritten to cite PMID:26024347, which does define work-exacerbated asthma as made worse but not initially caused by work, and to record that MONDO:0022742's MeSH definition ('caused, triggered, or exacerbated') is broader than this entry, so the entry is deliberately narrower than its bound term. The Hapten-Specific T Cell Memory node asserted Th2 expansion and polarization with only an IgE-absence quote under it; PMID:16271432 and PMID:12419703 added, since conformance is not inheritance and the entry must carry its own evidence. Subtype rescoping. The haptenation chain was scoped to the whole Sensitizer-induced stratum while the entry's own text says high molecular weight protein allergens sensitize without haptenation, so the pathograph asserted haptenation for flour and enzyme workers. Added LMW-chemical and HMW-protein subtype rows under Sensitizer-induced and rescoped the four sensitizer nodes to LMW-chemical, with PMID:31690384 for the hapten versus complete allergen division. Prevalence corrected: the 5 percent figure from a general allergy review is superseded by a 16 percent population attributable fraction pooled across nine longitudinal studies (PMID:33141780). Irritant stratum strengthened: the chlorine exposure's review_notes waiver is replaced by real evidence (PMID:33063819, chlorine most frequently reported in RADS cases), and the RADS definition added (PMID:31690384). Other additions: a genetic section with diisocyanate susceptibility loci including the GSTM1 null genotype that ties host detoxification to the haptenation trigger (PMID:21325943) and HLA-DR7 in the protein-allergen arm (PMID:12704360); a pharmacotherapy treatment row (PMID:15579371); Cochrane and prognosis evidence on removal from exposure (PMID:23407122, PMID:17040933, 73 percent persistent airway hyperresponsiveness); the specific inhalation challenge reference-standard citation (PMID:33652998); the diagnosis row split into spirometry and specific inhalation challenge, the latter with the NCIT searches recorded since no term fits; three cell types bound on the epithelial node where one was bound but three were described; conforms_to declared on the convergence node; synonyms replaced with MONDO's own, since the previous list named this entry's own subtypes and included work-related asthma, which the entry excludes. The truncated acrolein snippet, which dropped its own subject, was fixed in this entry and in the inhaled_irritant_airway_injury module where it originated, and graded INDIRECT here. Recorded as not modelled: the occupational asthma-COPD overlap phenotype, and the mechanism of the protein-allergen arm. Conformance is now 6 links, 5 sharing a GO term with the module node. All gates pass: schema, terms, 37 snippets and 37 titles with zero issues across both files, and the offline KB gates including cross-file snippet grading.

Create: Occupational Asthma · 2026-11-09T01:10:29Z · View source

Created to give the chemical_respiratory_allergy module its first conformer (dismech#16878). Bound to MONDO:0022742. Duplicate preflight run across all three surfaces: no KB entry on origin/main holds MONDO:0022742 (Asthma, Byssinosis and Formaldehyde_Poisoning mention occupational asthma only in snippets or notes, and Byssinosis explicitly distinguishes itself from it), and no open PR or issue curates it. Scope decision: the entry covers both the sensitizer-induced and the irritant-induced stratum, because a patient can have irritant-induced occupational asthma with no sensitization, so an entry named for the whole concept cannot model only the immune route. The two strata have different mechanisms, so pathophysiology nodes are scoped with the subtypes foreign key and conform to two different modules - the four-node sensitizer chain to chemical_respiratory_allergy and the barrier-injury node to inhaled_irritant_airway_injury - converging at a shared consequence node. Isocyanate-induced is a child subtype carrying MONDO:0025556. The irritant-induced row carries no subtype_term: OLS returns only MONDO:0004979 asthma for 'irritant induced asthma'. Work-aggravated asthma is excluded as not caused by work. High molecular weight protein allergens are in scope as a cause but not modelled, since they sensitize without haptenation and so cannot conform to a module whose trigger node requires a reactive chemical. The prevalence record carries no rate_per_100000: the 5 percent figure is a share of adult asthma, not a population rate. check_conformance_content reports 5 links, 4 sharing a GO term with their module node and 1 anchor_no_process at the haptenation node, whose module counterpart binds no GO term by design because GO has no haptenation class. check_genereviews_baseline reports NO_CHAPTER for both collections, verifying the notes claim that no GeneReviews baseline applies. Schema, term and reference validation pass with 12 snippets and 12 titles and zero issues, as do the offline KB gates including cross-file snippet grading. An OpenScientist deep-research run on the disorder and an independent red-team review were in flight when this record was written; whatever they change will be recorded in a second record.

OpenScientist ▸

Occupational Asthma (MONDO:0022742): A Comprehensive Disease Characteristics Report

openscientist-autonomous 41 citations 2026-11-09T01:21:58.244135

Occupational Asthma (MONDO:0022742): A Comprehensive Disease Characteristics Report

MONDO:0022742 · ICD-11 CA23 (asthma, occupational) · ICD-10 J45 (+ external-cause codes; J68.3 for irritant/RADS) · MeSH "Asthma, Occupational" · no OMIM / no single Mendelian causal gene

Causal gene — stated up front, per instructions: Occupational asthma has no single Mendelian causal gene. It is a complex, polygenic, environmentally-caused disease in which an occupational inhalational exposure (sensitizer or irritant) is the necessary cause and host genetics act as susceptibility modifiers. The dominant susceptibility loci are the HLA class II genes on chromosome 6p21 — principally HLA-DQB1 (with agent-specific haplotypes such as HLA-DRB1*15–DPB1*05 for isocyanates and HLA-DQ5/DQB1*0501 + DR1 for acid anhydrides), together with non-HLA modifiers in oxidative-stress and antigen-processing pathways (GSTM1, GSTP1, CTNNA3, NAT1/2, TNF). This is a disease defined by its environmental cause plus a polygenic HLA-centred susceptibility background — not by a causal gene.

Summary

Occupational asthma (OA) is a complex, environmentally-caused, adult-onset form of asthma defined by variable airflow limitation and/or airway hyperresponsiveness attributable to causes in the working environment. The necessary cause of OA is workplace exposure — more than 400 agents are documented — acting upon a polygenic susceptibility background centred on the HLA class II region (principally HLA-DQB1, with agent-specific haplotypes), supplemented by non-HLA modifier genes in antigen-processing, lymphocyte-activation, cytokine-regulation, and oxidative-stress pathways (e.g., GSTM1/GSTP1, CTNNA3, NAT, TNF). OA is therefore categorized as a complex gene–environment disease, not a monogenic disorder.

OA is epidemiologically substantial: pooled longitudinal data attribute ~16–17% of adult-onset asthma to occupational exposures (population attributable fraction). It presents in two mechanistically distinct forms. Sensitizer-induced (allergic) OA follows a latency period of exposure and is driven either by high-molecular-weight (HMW, >10 kDa) complete protein allergens (flour/grain glycoproteins, enzymes/α-amylase, latex, animal danders, molds) or by low-molecular-weight (LMW) chemical haptens (isocyanates, acid anhydrides, platinum salts, persulfates, quaternary ammonium compounds) that conjugate to airway proteins to form neoantigens; both converge on an HLA class II → CD4⁺ Th2 (IL-4/IL-5/IL-13) → IgE / eosinophilic airway inflammation axis. Irritant-induced asthma, including reactive airways dysfunction syndrome (RADS), is a separate non-immunologic entity caused by direct epithelial injury after high-level irritant exposure (classically chlorine, ammonia, acid fumes), characteristically without a latency period or specific immune sensitization.

Diagnosis is confirmed by specific inhalation challenge (SIC), the reference standard, supported by spirometry, non-specific bronchial hyperresponsiveness testing, serial peak flow (OASYS), specific IgE, and the complementary inflammatory biomarkers FeNO and sputum eosinophils. Prognosis is frequently poor: only ~32% symptomatic recovery after exposure cessation, with persistent non-specific bronchial hyperresponsiveness in ~73%. Complete removal from exposure gives the best clinical outcome but the worst socioeconomic outcome (income/job loss), the central management trade-off. Primary prevention by exposure elimination/reduction is the single most effective intervention, with powder-free low-protein latex gloves providing landmark proof-of-principle. This report synthesizes 12 confirmed findings and 53 reviewed papers across all 15 requested disease-characteristic domains.

Key Findings

Finding 1 — OA is a complex, environmentally-caused disease with three main phenotypes and no single causal gene

Occupational asthma is asthma caused by workplace conditions. It is subdivided into sensitizer-induced (allergic) OA and irritant-induced (non-allergic) OA; together with work-exacerbated asthma (WEA) — pre-existing asthma made worse but not initially caused by work — these constitute the umbrella category work-related asthma (WRA). More than 400 workplace agents are implicated. The recognized disease phenotypes are: OA caused by HMW agents, OA caused by LMW agents, irritant-induced asthma, and an OA–COPD overlap phenotype.

As the review by Lemière and colleagues states: "OA is asthma caused by workplace conditions, and is subdivided into sensitizer-induced (allergic) OA and irritant-induced (nonallergic) OA. WEA is asthma that is made worse, but was not initially caused, by workplace conditions" (PMID: 26024347). The phenotypic subdivision is confirmed by Vandenplas et al.: "The main phenotypes of occupational asthma are: occupational asthma caused by high-molecular-weight (HMW) or low-molecular-weight (LMW) agents, irritant-induced asthma and occupational asthma-chronic obstructive pulmonary disease overlap" (PMID: 33141780). Evidence source: human clinical / aggregated disease-level reviews.

Finding 2 — Occupational exposures account for ~16–17% of adult-onset asthma

Pooled data from nine longitudinal studies yielded a population attributable fraction (PAF) of 16% for the occupational contribution to incident asthma: "Data from nine longitudinal studies showed a population attributable fraction for the occupational contribution to incident asthma of 16%" (PMID: 33141780). This is independently corroborated by the population-based Telemark 5-year cohort (n=7120), in which new-onset asthma incidence was 7.5 per 1000 person-years, ever exposure to vapour/gas/dust/fumes (VGDF) carried an odds ratio of 1.49 (95% CI 1.15–1.94) with a clear exposure–response (daily exposure OR 2.46, 95% CI 1.39–4.35): "The corresponding PAF for ever exposed to VGDF was 17% (95% CI 5.4% to 27.8%) and the risk of asthma onset increased with frequent VGDF exposure" (PMID: 39277201). GBD-2021 analysis separately attributed 13.9% of young-adult asthma DALYs to environmental/occupational risks (PMID: 42323982). Evidence source: human epidemiological cohorts.

Finding 3 — Causative agents divide into HMW complete allergens and LMW haptens; genetic susceptibility modifies risk

HMW proteins (>10 kDa) — flour/grain glycoproteins, fungal α-amylase and other enzymes, natural rubber latex, animal danders, avian and insect proteins, molds — act as complete allergens driving IgE sensitization. LMW agents — isocyanates, acid anhydrides, metals/platinum salts, quaternary ammonium compounds, persulfates — act as haptens that bind airway proteins. Only a subset of exposed workers develop disease, implicating genetic susceptibility. As Cannon et al. summarize: "OA can be triggered by high-molecular-weight (HMW) proteins that act as complete allergens or by low-molecular-weight (LMW) sensitizers that act as haptens" (PMID: 31690384). A systematic review/meta-analysis of diisocyanate asthma found: "only a subset of workers exposed to diisocyanates develop diisocyanate-induced occupational asthma (diisocyanate asthma, DA), indicating that genetic susceptibility may play a role", with associated gene functions spanning "antigen processing, lymphocyte activation, cytokine production regulation, and response to oxidative stress" (PMID: 36276967). Evidence source: human clinical + genetic meta-analysis.

Finding 4 — Specific inhalation challenge is the diagnostic gold standard; prognosis is often poor

Diagnosis combines clinical history, spirometry/bronchodilator responsiveness, non-specific bronchial hyperresponsiveness testing, specific IgE, serial peak-flow analysis (OASYS), and SIC as the reference standard: "specific inhalation challenge (SIC) is considered as the reference standard and represents the best way to confirm the specific cause of WRA" (PMID: 33652998). Specific IgE performance differs by agent class — for HMW agents sensitivity ~0.74/specificity ~0.71, for LMW agents sensitivity 0.28/specificity 0.89. A systematic review of 39 studies (1681 patients) quantified the poor prognosis: "Reported rates of symptomatic recovery varied from 0% to 100%, with a pooled estimate of 32% (95% CI 26% to 38%)" and "The pooled prevalence of persistent NSBHR at follow-up was 73% (95% CI 66% to 79%)" (PMID: 17040933). Severity at diagnosis and airway inflammation predict persistence; early diagnosis and removal improve outcome. Evidence source: human clinical / systematic review.

Finding 5 — HLA class II alleles are the principal susceptibility loci; specific haplotypes confer agent-specific risk

HLA-DQB1 is the haplotype most associated with occupational asthma, in contrast to HLA-DRB1 in general allergic asthma and HLA-DPB1 in aspirin-sensitive asthma: "The most common HLA haplotypes in the different asthma phenotypes are HLA-DRB1 in allergic asthma, HLA-DQB1 in occupational asthma and HLA-DPB1 in aspirin-sensitive asthma" (PMID: 24994462). Agent-specific associations have been mapped:

Sensitizer	HLA / genetic association	Effect size	PMID
Toluene diisocyanate (TDI)	DRB115–DPB105 haplotype	10.6% cases vs 0% exposed-asymptomatic, P=0.001	16792590
Diisocyanates (MHC SNPs)	HLA-E rs1573294	OR 6.27 (2.37–16.6)	24709764
Diisocyanates	HLA-DOA rs3128935	OR 19.69	24709764
Acid anhydrides (HHPA/MHHPA)	HLA-DQ5 / DQB1*0501	OR 4.3 (1.7–11)	15144476
Acid anhydrides	HLA-DR1	OR 3.0 (1.2–11)	15144476
Detergent enzyme (subtilisin)	HLA-DQ8 (predisposing)	transgenic mouse	16185928

Notably, DQB1*0501 is protective for isocyanate/plicatic-acid asthma while predisposing for anhydride sensitization, illustrating agent-specific allele effects. Non-HLA modifiers include glutathione-S-transferase genes (GSTM1/GSTP1), CTNNA3, NAT, and TNF, acting in oxidative-stress and antigen-processing pathways. Direct quotes: "the allelic frequency of HLA DRB1*15-DPB1*05 in group I (10.6%) was significantly higher than that of group II (0%, P = 0.001)" (PMID: 16792590); "The linked alleles DQ5 (odds ratio [OR]=4.3; 95% confidence interval [95% CI]=1.7, 11) and DR1 (OR 3.0; 95% CI 1.2, 11) were more prevalent in cases than in referents" (PMID: 15144476); "The HLA-E rs1573294 and HLA-DPB1 rs928976 SNPs were associated with an increased risk of DA" (PMID: 24709764). Evidence source: human genetic association studies.

Finding 6 — Immunopathogenesis: hapten–protein conjugates drive CD4⁺ Th2 responses with eosinophilic airway inflammation

LMW agents such as diisocyanates react with biological nucleophiles to form diisocyanate-adducted (hapten–carrier) biomolecules that act as neoantigens: "The importance of diisocyanate-adducted biomolecules will be emphasized and their potential contributions to pathogenesis discussed" (PMID: 11811926). Sensitization is associated with recruitment of CD4⁺ T lymphocytes and Th2 cytokine production: "The diisocyanate-induced sensitization, is associated with the recruitment of CD4 T lymphocytes to the lungs and the production of Th2-type cytokines, including IL-4, IL-5 and IL-13" (PMID: 22774468). A Wistar rat TDI-vapor model confirmed eosinophilic Th2 inflammation: "marked infiltration of eosinophils in the TDI-exposed rats. The cytokine assay showed that IL-4 and IL-5 were predominantly produced in the BAL fluid in vivo" (PMID: 24570807). Prevalence of diisocyanate asthma among exposed workers is ~5–15%. Evidence source: human clinical mechanism + rodent model.

Finding 7 — Primary prevention by exposure control is the most effective intervention

A systematic review of 29 studies concluded: "Exposure elimination is the strongest and preferred primary preventive approach to reduce the burden of occupational asthma" and "There is strong evidence to recommend not using powdered allergen-rich natural rubber latex gloves" (PMID: 22654083). Interventional proof-of-principle comes from a health-care-worker cohort: "After the intervention, new latex sensitization rates declined 16-fold, and 25% of previously sensitized employees reverted to negative skin tests" (PMID: 21775898); pre-intervention sensitization was dose-dependent on airborne latex antigen (low 2%, intermediate 8%, high 16%, P<0.0001). Germany's nationwide switch to low-protein powder-free gloves produced a steady decline in reported occupational latex allergy cases after 1998 (PMID: 12170275). Management of established disease centres on complete cessation of exposure plus standard asthma pharmacotherapy (inhaled corticosteroids ± bronchodilators; type-2 biologics — omalizumab, mepolizumab, dupilumab, tezepelumab — by extrapolation from severe type-2 asthma). Evidence source: human clinical / interventional + ecological.

Finding 8 — Animal and transgenic models recapitulate sensitizer-induced OA

Validated models include the Wistar rat exposed to TDI vapor (airway hyperresponsiveness, eosinophilic inflammation, IL-4/IL-5 in BAL); murine models of diisocyanate asthma, preferred for defined genome and reagent availability ("Murine models of diisocyanate-induced asthma have proved to be the most useful", PMID: 22774468); guinea pig and swine models of trimellitic anhydride ("Animal models revealed sIgG, sIgE, sIgA, and sIgM along with pulmonary lesions, cellular infiltrates, alveolar hemorrhage, and pneumonitis associated with TMA exposure", PMID: 32594360); and HLA-DQ8 / HLA class II transgenic mice reproducing detergent-enzyme hypersensitivity: "The DQ8 mice also developed allergic eosinophilic inflammatory reactions in the airways following intranasal instillations of this enzyme" (PMID: 16185928). Evidence source: model organism studies.

Finding 9 — Dominant risk factors are exposure intensity/duration, atopy, and concomitant rhinitis/conjunctivitis

Risk of sensitizer-induced OA rises with exposure intensity and duration and with host atopy. A florist study (n=128) found work-related asthma-like symptoms in 14.1%, with "The most prominent risk factors in florists were work intensity, work duration, and specific atopy" (PMID: 15189959); specific odds ratios were high work intensity OR 7.3 (1.1–51.8), long duration OR 5.1 (1.2–21.6), specific flower atopy OR 5.9 (1.4–24.3), and notably "excess risk for work-related asthma-like symptoms among those with allergic rhinitis (OR, 13.2; 95% CI, 3.1 to 56.4)" and conjunctivitis OR 8.4 (2.4–29.2). A pooled laboratory-animal-worker study (n=650) demonstrated the exposure–response for sensitization: "the likelihood of IgE-mediated sensitization increases with increasing exposure" (PMID: 10200019). Rhinitis frequently precedes/accompanies OA. Smoking is a risk factor for IgE sensitization to some HMW agents (platinum salts, anhydrides). Evidence source: human epidemiological studies.

Finding 10 — FeNO and sputum eosinophils are complementary biomarkers during SIC

A multicenter study (n=321 undergoing SIC, 156 positive) found post-challenge rises in FeNO and sputum eosinophils had similar diagnostic accuracy (AUC 0.78 and 0.81). Optimal thresholds were defined: "Increases in FeNO level ≥ 13 ppb and sputum eosinophils ≥ 1.25% were identified as the optimal threshold values for differentiating positive from negative SICs" — each ≥95% specific but of low sensitivity (55% and 62%) — and "Combining either a rise in FeNO ≥ 13 ppb or an increase in sputum eosinophils ≥ 1.25% increased the sensitivity to 77%" (PMID: 39726396). Increases were discordant in 38% of positives, indicating complementary information. Evidence source: human clinical / diagnostic accuracy study.

Finding 11 — Irritant-induced asthma / RADS is a distinct non-immunologic phenotype with rapid onset

Irritant-induced OA is a separate non-immunologic entity. RADS is an asthma-like syndrome persisting >3 months, beginning within minutes to hours after a single high-concentration irritant exposure: "RADS is defined as an asthma-like syndrome that persists for >3 months and occurs within minutes to hours after a single exposure to a high concentration of a respiratory irritant" (PMID: 31690384). Chlorine is the most common cause: "A variety of agents were implicated, with chlorine or chlorine-releasing molecules most frequently reported" (PMID: 33063819); other documented causes include ammonia, acid fumes, lithium hydroxide dust, and β-mercaptoethanol. Unlike sensitizer-induced OA, there is no latency period and no IgE/specific immune sensitization. Chronic moderate irritant exposure can also cause irritant-induced asthma "with latency": "there is epidemiological evidence for irritant-induced asthma with latency from chronic moderate exposure" (PMID: 30661311). Diagnosis uses Brooks (1985)/ACCP 2008 criteria with methacholine challenge (e.g., PC20 1.36–6.74 mg/mL). Evidence source: human clinical / case series + reviews.

Finding 12 — Complete removal gives best clinical but worst socioeconomic outcome; OA imposes major burden

A Cochrane review of workplace interventions found: "complete removal from exposure resulted in the best outcome in terms of symptoms, lung function, and airway hyper-responsiveness. Reduction of exposure appeared to be less effective in terms of improving asthma but was also less likely to result in loss of income or unemployment" (PMID: 23407122). A follow-up of 125 sensitizer-induced OA patients (median 18 months symptom duration before referral; 79% no longer exposed at 1 year) found unexposed patients had better symptoms (82% vs 53% improved, P=0.023) but "poorer outcomes in terms of career, income and how they felt treated by their employer" (PMID: 32307530). Diagnostic delay worsens prognosis: "In adult asthmatics, work-relatedness can account for 15%-33% of cases, but delays in diagnosis remain common and lead to worse outcomes" (PMID: 30661311). Evidence source: human clinical / systematic review + cohort.

Full Section-by-Section Report

1. Disease Information

Overview. Occupational asthma is adult-onset asthma — variable airflow obstruction, airway hyperresponsiveness, and airway inflammation — caused by agents or conditions in the workplace. It is the most common occupational lung disease in industrialized countries and belongs to the broader category of work-related asthma (WRA), which comprises OA (caused by work) and work-exacerbated asthma (worsened by, but not caused by, work) (PMID: 26024347).

Key identifiers. - Mondo: MONDO:0022742 (occupational asthma) - MeSH: "Asthma, Occupational" - ICD-10: J45 (asthma) with occupational specification; J68.3 (airway disease due to chemical fumes/vapors, for irritant/RADS) - ICD-11: CA23 (asthma) with external-cause coding for occupational origin - OMIM: Not applicable — no single Mendelian causal gene (complex trait) - Orphanet: Not a classic rare-disease entry; captured under occupational respiratory disorders

Synonyms: work-related asthma; occupational allergic asthma; sensitizer-induced occupational asthma; irritant-induced asthma; reactive airways dysfunction syndrome (RADS, for acute irritant form).

Data source type. Information is derived predominantly from aggregated disease-level resources — systematic reviews, occupational cohorts, registries (e.g., SHIELD, SWORD), and challenge-test case series — rather than from individual EHR records.

2. Etiology

Causal factors. The primary cause is environmental (occupational inhalational exposure), acting on a genetic susceptibility background. There is no infectious etiology. More than 400 agents are implicated, divided into HMW complete allergens and LMW chemical haptens, plus irritant agents (PMID: 34031758, PMID: 31690384).

Genetic risk factors. HLA class II alleles, principally HLA-DQB1, are the dominant susceptibility loci, with agent-specific haplotypes (Finding 5). Non-HLA modifiers: GSTM1/GSTP1 (oxidative stress), CTNNA3, NAT, TNF (PMID: 36276967, PMID: 24994462).

Environmental/occupational risk factors. Exposure intensity and duration (exposure–response relationship), high-risk occupations (bakers, farmers, spray painters, isocyanate/plastics workers, health-care workers, cleaners, woodworkers, laboratory-animal workers), atopy, and smoking (for some HMW agents) (PMID: 15189959, PMID: 10200019, PMID: 22794690). Exposure–response thresholds exist for specific allergens (wheat flour 1–2.4 mg/m³, fungal α-amylase 0.25 ng/m³, latex 0.6 ng/m³, rat allergen 0.7 µg/m³) (PMID: 9645589).

Protective factors. Reduction/elimination of exposure; engineering controls; respiratory protection (limited evidence); powder-free low-protein latex gloves (PMID: 22654083). HLA-DQB1*0501 is protective for isocyanate/plicatic-acid asthma. No well-established dietary protective factor is specific to OA.

Gene–environment interactions. The defining feature of OA: identical exposures produce disease only in genetically susceptible (e.g., HLA-DQB1-defined) individuals, and only a subset of exposed workers (~5–15% for diisocyanates) develop disease (PMID: 36276967).

3. Phenotypes

Phenotype	Type	HPO term	Onset	Course	Frequency
Wheezing	Symptom/sign	HP:0030828	Adult	Episodic, worse at work	Very common
Dyspnea	Symptom	HP:0002094	Adult	Episodic→persistent	Very common
Cough	Symptom	HP:0012735	Adult	Episodic	Common
Chest tightness	Symptom	HP:0004760	Adult	Episodic	Common
Airway hyperresponsiveness	Functional/lab	HP:0030830	Adult	Often persistent (~73%)	Majority
Airflow obstruction (↓FEV1)	Lab	HP:0002110	Adult	Variable/progressive	Majority
Sputum/blood eosinophilia	Lab abnormality	HP:0001880	Adult	Fluctuating	HMW/Th2 disease
Allergic rhinitis (often precedes OA)	Symptom	HP:0003193	Adult	Episodic	Frequent comorbid
Conjunctivitis	Sign	HP:0000509	Adult	Episodic	Frequent comorbid

Characteristic feature: symptom improvement away from work (weekends/holidays) and worsening on return — the clinical hallmark of sensitizer-induced OA. Quality-of-life impact is substantial, with career disruption, income loss, and unemployment documented (PMID: 32307530).

4. Genetic / Molecular Information

Causal genes: None (complex disease). Susceptibility genes: HLA-DQB1 (HGNC:4944), HLA-DRB1 (HGNC:4948), HLA-DPB1 (HGNC:4940), HLA-E, HLA-DOA, HLA-DQA2; modifiers GSTM1 (HGNC:4632), GSTP1 (HGNC:4638), CTNNA3, NAT1/NAT2, TNF. Variants are germline common polymorphisms/SNPs and HLA haplotypes (not classic pathogenic Mendelian variants), classified as susceptibility alleles, not ACMG pathogenic variants. Allele frequencies are population-level HLA frequencies. Functional consequences relate to altered antigen presentation (HLA) and reduced detoxification capacity (GST null genotypes → oxidative stress). Epigenetic/chromosomal abnormalities: No recurrent chromosomal abnormality; epigenetic contributions are plausible but not yet firmly established (PMID: 36276967, PMID: 24709764).

5. Environmental Information

Environmental/occupational factors. HMW: wheat/grain flour and glycoproteins, fungal/bacterial enzymes (α-amylase, subtilisin), natural rubber latex, animal danders/urinary proteins, avian proteins, molds. LMW haptens: diisocyanates (TDI, MDI, HDI; CHEBI toluene diisocyanate), acid anhydrides (trimellitic, phthalic, HHPA/MHHPA), platinum salts, persulfates (hairdressing), quaternary ammonium compounds, cleaning/disinfectant chemicals (chloramine, benzalkonium chloride). Irritants: chlorine (CHEBI:17997), ammonia (CHEBI:16134), acid fumes, lithium hydroxide dust, β-mercaptoethanol (PMID: 34031758, PMID: 34247391, PMID: 42427009).

Lifestyle factors. Smoking increases IgE sensitization to some HMW agents (platinum salts, anhydrides). Infectious agents: Not applicable — OA is non-infectious (molds and bacterial-derived enzymes act as allergens, not as infections).

6. Mechanism / Pathophysiology

Ordered causal chain — sensitizer-induced (allergic) OA:

Workplace inhalation exposure to an HMW allergen or LMW chemical → deposition on the airway epithelium.
(LMW branch) The hapten reacts with biological nucleophiles (airway/serum proteins, e.g., albumin) → forms a hapten–carrier conjugate (neoantigen) [demonstrated for diisocyanates; PMID: 11811926]. (HMW branch) The intact protein is a complete allergen requiring no conjugation.
Antigen uptake by dendritic/antigen-presenting cells and presentation on HLA class II molecules (principally HLA-DQ) → activates CD4⁺ T lymphocytes in genetically susceptible (HLA-DQB1-defined) hosts [inferred from HLA association + demonstrated CD4⁺ recruitment; PMID: 24994462, PMID: 22774468].
CD4⁺ T cells polarize to Th2 → secrete IL-4, IL-5, IL-13 → drive B-cell IgE class-switching and eosinophil recruitment/activation [demonstrated; PMID: 22774468, PMID: 24570807].
Re-exposure → IgE-mediated mast-cell degranulation + eosinophilic inflammation → airway smooth-muscle contraction, mucosal edema, mucus hypersecretion → variable airflow obstruction and bronchial hyperresponsiveness (clinical asthma).
Chronic inflammation → airway remodeling → persistent, often irreversible hyperresponsiveness even after exposure cessation [demonstrated; PMID: 17040933, PMID: 18394133].

Ordered causal chain — irritant-induced asthma / RADS:

Single high-concentration irritant exposure (e.g., chlorine, ammonia, LiOH dust) → direct toxic epithelial injury (no immune sensitization, no latency).
Epithelial denudation → neurogenic inflammation, oxidative stress, innate immune activation → bronchial hyperresponsiveness.
Airway injury/repair → persistent asthma-like syndrome (>3 months) with bronchial hyperresponsiveness [demonstrated clinically; PMID: 31690384, PMID: 42427009].

Molecular pathways / GO terms: antigen processing and presentation via MHC class II (GO:0019886), T-helper 2 cell differentiation (GO:0045064), IL-4/IL-5/IL-13 cytokine signaling, immune response (GO:0006955), eosinophil chemotaxis (GO:0048245), response to oxidative stress (GO:0006979), inflammatory response (GO:0006954). Cell types / CL terms: CD4⁺ Th2 lymphocyte (CL:0000899), eosinophil (CL:0000771), mast cell (CL:0000097), dendritic cell (CL:0000451), bronchial epithelial cell (CL:0002328), airway smooth muscle cell (CL:0000192), B cell/plasma cell (CL:0000786). Upstream: exposure, hapten conjugation, HLA presentation. Downstream: Th2 cytokines, IgE, eosinophilia, remodeling.

7. Anatomical Structures Affected

Primary organ: lung / bronchi (UBERON:0002048 lung; UBERON:0002185 bronchus); body system: respiratory system (UBERON:0001004).
Secondary involvement: upper airway — nasal mucosa/nose (UBERON:0001707) with occupational rhinitis; conjunctiva (UBERON:0001811) with conjunctivitis.
Tissue level: bronchial/airway epithelium, airway smooth muscle, lamina propria/submucosa.
Cell populations (CL): bronchial epithelial cell (CL:0002328), airway smooth muscle cell (CL:0000192), eosinophil (CL:0000771), CD4⁺ Th2 cell (CL:0000899), mast cell (CL:0000097).
Subcellular (GO CC): MHC class II protein complex (GO:0042613); secretory granules of eosinophils/mast cells.
Localization/lateralization: bilateral, diffuse airway involvement (PMID: 22794690, PMID: 31690384).

8. Temporal Development

Onset: adult-onset, work-age. Sensitizer-induced OA requires a latency period (weeks to years) of exposure for sensitization (insidious/subacute). RADS is acute, within minutes–hours of a single exposure.
Progression: episodic initially (worse at work, better away), may become persistent/progressive with ongoing exposure and remodeling.
Course/duration: often chronic and lifelong; persistent bronchial hyperresponsiveness in ~73% after cessation (PMID: 17040933).
Patterns: partial remission possible after cessation (~32% symptomatic recovery); critical period — early diagnosis and prompt removal markedly improve prognosis (PMID: 9383254, PMID: 30661311).

9. Inheritance and Population

Epidemiology: OA accounts for ~16–17% of adult-onset asthma (PAF) (PMID: 33141780, PMID: 39277201); work-relatedness 15–33% of adult asthma (PMID: 30661311). New-onset asthma incidence ~7.5/1000 person-years in an exposed population cohort.
Inheritance pattern: multifactorial/polygenic (not Mendelian). No single-gene inheritance, penetrance, expressivity, anticipation, mosaicism, founder effect, consanguinity, or carrier-frequency metrics apply classically; "penetrance" of HLA risk alleles is low and exposure-dependent.
Demographics: occupation-determined rather than ethnicity-determined. Sex ratio reflects workforce composition of exposed industries; age distribution: working adults; geographic distribution follows industrial/agricultural activity (PMID: 42323982, PMID: 39212906).

10. Diagnostics

Functional tests: spirometry with bronchodilator responsiveness; non-specific bronchial hyperresponsiveness (methacholine/histamine, PC20); serial peak expiratory flow at/away from work (OASYS).
Immunologic tests: specific IgE / skin-prick tests (HMW sensitivity ~0.74, specificity ~0.71; LMW sensitivity 0.28, specificity 0.89).
Inflammatory biomarkers: FeNO rise ≥13 ppb and sputum eosinophils ≥1.25% during SIC (each ≥95% specific; combined sensitivity 77%) (PMID: 39726396).
Reference standard: specific inhalation challenge (SIC) (PMID: 33652998, PMID: 22191204).
Genetic/omics testing: Not used diagnostically — HLA typing is a research tool.
Clinical criteria: work-relatedness by history + objective evidence; RADS by Brooks (1985)/ACCP 2008 criteria.
Differential diagnosis: work-exacerbated (pre-existing) asthma, hypersensitivity pneumonitis (CD4/CD8 <1 on BAL), COPD, eosinophilic bronchitis, vocal cord dysfunction (PMID: 22794690).

11. Outcome / Prognosis

Mortality: low; OA is rarely directly fatal (though fatal asthma attacks and fatal anaphylaxis to occupational allergens occur).
Morbidity/function: substantial — persistent airflow obstruction, chronic bronchial hyperresponsiveness (~73%), long-term FEV1 decline (median ~79 mL/year in one diisocyanate cohort) (PMID: 18394133).
Recovery: only ~32% symptomatic recovery after exposure cessation (PMID: 17040933).
Prognostic factors: severity at diagnosis, degree of airway inflammation, duration of symptoms before diagnosis, and promptness of removal. Favourable prognosis is associated with short symptom duration, immediate cessation, and milder hyperresponsiveness at diagnosis (PMID: 9383254, PMID: 15764901).
Socioeconomic burden: career disruption, income/job loss, especially after complete removal (PMID: 32307530).

12. Treatment

Cornerstone: removal from / avoidance of the causative exposure (NCIT: avoidance). Complete removal gives best clinical outcome; reduction is a clinical–socioeconomic compromise (PMID: 23407122).
Pharmacotherapy (NCIT): inhaled corticosteroids (NCIT:C1130), short-/long-acting β2-agonists / bronchodilators, leukotriene receptor antagonists, antihistamines — standard asthma therapy extrapolated to OA.
Advanced/biologic therapy: type-2 biologics — omalizumab (anti-IgE), mepolizumab (anti-IL-5), dupilumab (anti-IL-4Rα), tezepelumab (anti-TSLP) — effective in severe type-2 asthma and applied by extrapolation to severe type-2 OA (PMID: 32007172, PMID: 38878250).
No gene/cell/RNA therapy applies (no monogenic target).
Treatment strategy: accurate diagnosis → exposure management → pharmacotherapy → monitoring; personalized by phenotype (type-2 vs non-type-2) (PMID: 33141780, PMID: 34031758).

13. Prevention

Primary prevention (most effective): exposure elimination > reduction; substitution of safer materials; engineering controls; powder-free low-protein latex gloves (PMID: 22654083, PMID: 21775898, PMID: 12170275); enforceable exposure thresholds (TLVs) for allergens (PMID: 9645589).
Secondary prevention: medical surveillance of exposed workers; early symptom/sensitization detection; prompt removal (PMID: 40306950).
Tertiary prevention: optimizing asthma control, preventing irreversible remodeling.
Respiratory protection (PPE): limited supporting evidence; HEPA-filtered helmets reduce latex symptoms (PMID: 9847441).
Immunization / genetic counseling: not applicable.

14. Other Species / Natural Disease

Species used as models/affected: rat (Rattus norvegicus, NCBITaxon:10116), mouse (Mus musculus, NCBITaxon:10090), guinea pig (Cavia porcellus, NCBITaxon:10141), swine (Sus scrofa, NCBITaxon:9823) — all as experimental models (PMID: 24570807, PMID: 32594360).
Natural disease: OA is fundamentally a human occupational disease; no established naturally-occurring companion-animal equivalent. Orthologous susceptibility genes (HLA orthologs — murine H2/I-A/I-E; GST orthologs) exist. Zoonotic potential: none (non-infectious).

15. Model Organisms

Mammalian models: Wistar rat (TDI vapor) — airway hyperresponsiveness, eosinophilic inflammation, IL-4/IL-5 BAL (PMID: 24570807); murine diisocyanate models (preferred for defined genome/reagents) (PMID: 22774468); guinea pig/swine trimellitic-anhydride models (PMID: 32594360).
Genetic/humanized models: HLA-DQ8 and HLA class II transgenic mice reproducing detergent-enzyme (subtilisin BPN') hypersensitivity with antigen-specific T-cell responses, airway eosinophilia, and IgG1/IgE (PMID: 16185928).
Phenotype recapitulation: models reproduce Th2/eosinophilic airway inflammation, hyperresponsiveness, and HLA-dependent sensitization central to human OA.
Limitations: rodent airway anatomy/immunology differs from human; models capture sensitization/acute inflammation better than chronic remodeling and socioeconomic/persistence aspects.

Mechanistic Model / Interpretation

 WORKPLACE INHALATION EXPOSURE (>400 agents)
               │
┌──────────────────────┼───────────────────────┐
│                      │                        │
   HMW ALLERGEN          LMW HAPTEN                HIGH-LEVEL IRRITANT
   (flour, latex,        (isocyanate,             (chlorine, ammonia,
    enzymes, dander)      anhydride, Pt)           LiOH, acid fumes)
│                      │                        │
│              conjugates to airway            │  direct toxic
   complete            protein → HAPTEN–CARRIER         │  EPITHELIAL INJURY
   allergen            NEOANTIGEN                       │  (no latency,
│                      │                        │   no sensitization)
└──────────┬───────────┘                        │
   ▼                                     │
      HLA CLASS II (DQB1) PRESENTATION ──► CD4⁺ T cell   │
   │   [requires genetic susceptibility] │
   ▼                                     │
    Th2 POLARIZATION                             │
 IL-4 / IL-5 / IL-13                             │
   │                                     │
 ┌─────────┴─────────┐                           │
 ▼                   ▼                           │
    IgE class-switch   EOSINOPHIL recruitment            │
    (mast-cell arming)  + activation                     │
 └─────────┬─────────┘                           │
   ▼                                     ▼
AIRWAY INFLAMMATION, SMOOTH-MUSCLE CONTRACTION,
MUCUS, EDEMA ► VARIABLE AIRFLOW OBSTRUCTION + BHR
   │
   ▼
CHRONIC INFLAMMATION ► AIRWAY REMODELING
   │
   ▼
   PERSISTENT / OFTEN IRREVERSIBLE ASTHMA (~73% persistent BHR,
     only ~32% recover after exposure cessation)

The unifying interpretation is that OA is the paradigmatic gene–environment respiratory disease: an environmental exposure is necessary but not sufficient, with HLA-class-II-centred genetic susceptibility determining which exposed workers progress to sensitization and disease. The two sensitizer branches (HMW complete allergen; LMW hapten–carrier neoantigen) converge on a shared HLA-II → Th2 → IgE/eosinophil effector axis, while the irritant branch bypasses immunity entirely via direct epithelial toxicity. The therapeutic and preventive corollary follows directly from the causal chain: because the initiating lesion is the exposure, removing the exposure is both the most effective treatment and the only true primary prevention, yet it generates a clinical–socioeconomic trade-off that dominates real-world management.

Evidence Base

PMID	Title (abbrev.)	Supports finding(s)
26024347	Occupational asthma and work-exacerbated asthma	F1 (definition, WRA)
33141780	Novel approaches in OA diagnosis/management	F1, F2 (phenotypes, 16% PAF)
39277201	Telemark 5-year follow-up	F2 (17% PAF, exposure-response)
31690384	Occupational immunologic lung disease	F3, F11 (HMW/LMW, RADS)
36276967	Genetics of diisocyanate OA (meta-analysis)	F3, F5 (genetic susceptibility)
33652998	PFT in work-related asthma / SIC	F4 (SIC gold standard)
17040933	Outcome after cessation (systematic review)	F4, F12 (32% recovery, 73% BHR)
24994462	HLA and asthma phenotypes	F5 (HLA-DQB1 in OA)
16792590	DRB115-DPB105 in isocyanate OA	F5 (TDI haplotype)
15144476	HLA-DQ5/DR1 and acid anhydrides	F5 (anhydride HLA)
24709764	MHC class I/II SNPs in diisocyanate asthma	F5 (MHC SNPs)
11811926	Diisocyanate asthma immunopathogenesis	F6 (hapten–carrier adducts)
22774468	Pathogenetic aspects of diisocyanate asthma	F6, F8 (CD4⁺ Th2, mouse model)
24570807	IL-4/IL-5 in TDI-exposed Wistar rats	F6, F8 (eosinophilic Th2)
22654083	Primary prevention: exposure reduction	F7 (prevention hierarchy)
21775898	Prevention of latex IgE sensitization	F7 (16-fold reduction)
12170275	German latex prevention program	F7 (national decline)
16185928	HLA-DQ8 subtilisin hypersensitivity	F5, F8 (transgenic model)
32594360	Trimellitic anhydride animal models	F8 (TMA models)
15189959	Work-related symptoms among florists	F9 (risk factors)
10200019	Rat urinary allergen exposure-response	F9 (exposure-response)
39726396	FeNO + sputum eosinophils for OA	F10 (biomarkers)
33063819	Updated review of RADS cases	F11 (chlorine common)
30661311	Management of OA/WEA update	F11, F12 (latency, delay)
23407122	Avoidance vs reduction (Cochrane)	F12 (trade-off)
32307530	Follow-up survey of OA patients	F12 (socioeconomic burden)
9383254	Prognostic factors TDI-OA	Prognosis (early removal)
18394133	Inflammation/outcome after cessation	Prognosis (FEV1 decline)
42427009	RADS from lithium hydroxide dust	F11 (LiOH RADS)
9645589	Exposure-response thresholds	Prevention (TLVs)
32007172	Type-2 targeted therapeutics	Treatment (biologics)

Concordance and tension. The evidence base is strongly concordant across human cohorts, systematic reviews, and animal/transgenic models. The principal internal tension is the clinical–socioeconomic trade-off (Finding 12): the intervention with the best biological outcome (complete removal) produces the worst livelihood outcome, which the literature resolves pragmatically rather than definitively. A second nuance is the agent-specific directionality of HLA alleles (DQB1*0501 protective for isocyanates yet predisposing for anhydrides), cautioning against treating "HLA susceptibility" as a single uniform risk factor.

Limitations and Knowledge Gaps

No single causal gene / no Mendelian model. OA is polygenic; HLA and modifier-gene effects are modest, population-dependent, and not clinically actionable for prediction. Genetic testing has no current diagnostic role.
Mechanistic detail is richest for diisocyanates. The hapten–carrier → HLA-II → Th2 pathway is best demonstrated for isocyanates; mechanisms for many of the 400+ agents are inferred by analogy rather than directly demonstrated.
Irritant-induced asthma / RADS mechanisms (oxidative/neurogenic epithelial injury) are less molecularly resolved than the allergic pathway, and the boundary between acute RADS and "irritant-induced asthma with latency" is not sharply defined.
Biologic therapy evidence in OA specifically is extrapolated from severe type-2 asthma trials; no large OA-specific randomized trials of type-2 biologics exist.
Epigenetics, single-cell, and spatial transcriptomics of occupational airway tissue are largely unexplored — a genuine data gap.
Prognostic prediction remains imprecise; no validated molecular biomarker predicts who will recover versus develop persistent disease after cessation.
Health-equity dimension: occupational exposures and OA burden fall disproportionately on low-income and minority workers, and surveillance under-counts these risks (PMID: 39212906).

Proposed Follow-up Experiments / Actions

Agent-stratified GWAS / HLA fine-mapping across multiple sensitizers (isocyanates, anhydrides, flour, enzymes, latex) in harmonized cohorts to resolve shared vs agent-specific susceptibility loci and formalize the HLA-DQB1 signal.
Single-cell and spatial transcriptomics of bronchial biopsies pre/post specific inhalation challenge to map the dendritic → CD4⁺ Th2 → eosinophil axis in situ and identify remodeling drivers that predict persistence.
Prospective biomarker validation combining FeNO, sputum eosinophils, periostin, and serum specific-IgE as a multivariate predictor of (a) SIC positivity and (b) post-cessation recovery, enabling risk-stratified removal decisions.
Randomized or pragmatic trials of type-2 biologics specifically in severe sensitizer-induced OA, including workers unable to fully avoid exposure, to replace current extrapolation with direct evidence.
Mechanistic dissection of RADS using LiOH/chlorine inhalation models to characterize the oxidative/neurogenic injury pathway and test epithelial-protective interventions.
Implementation research on exposure-elimination programs (following the latex-glove template) for high-burden agents (flour, cleaning chemicals, isocyanates), coupled with socioeconomic-support interventions that mitigate the income/job-loss penalty of removal.
Enforceable allergen exposure limits (TLVs) development and surveillance for agents lacking thresholds, extending the demonstrated exposure–response evidence base.

Report compiled from 12 confirmed findings and 53 reviewed papers across all 15 disease-characteristic domains. Evidence types span human epidemiological cohorts, human clinical/diagnostic studies, systematic reviews/meta-analyses, genetic association studies, and rodent/transgenic model-organism studies.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome	Count
References checked	41
Resolved	41
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	41
On topic	32
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	41
Resolved	35
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	5
Terms whose name was checked	12
Terms named correctly	1
Terms named as a different term	11

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

HP:0030828 (1 mention) - the report calls it "Symptom/sign"; HP calls it Wheezing
HP:0002094 (1 mention) - the report calls it "Symptom"; HP calls it Dyspnea
HP:0012735 (1 mention) - the report calls it "Symptom"; HP calls it Cough
HP:0004760 (1 mention) - the report calls it "Symptom"; HP calls it obsolete Congenital septal defect
HP:0030830 (1 mention) - the report calls it "Functional/lab"; HP calls it Crackles
HP:0002110 (1 mention) - the report calls it "Lab"; HP calls it Bronchiectasis
HP:0001880 (1 mention) - the report calls it "Lab abnormality"; HP calls it Increased total eosinophil count
HP:0003193 (1 mention) - the report calls it "Symptom"; HP calls it Allergic rhinitis
HP:0000509 (1 mention) - the report calls it "Sign"; HP calls it Conjunctivitis
UBERON:0001707 (1 mention) - the report calls it "Secondary involvement: upper airway — nasal mucosa/nose"; UBERON calls it nasal cavity**
NCIT:C1130 (1 mention) - the report calls it "inhaled corticosteroids"; NCIT calls it Hydroxyl Radical

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

HP:0004760 (obsolete Congenital septal defect) (1 mention)

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Deep Research

Occupational Asthma (MONDO:0022742): A Comprehensive Disease Characteristics Report

Summary

Key Findings

Finding 1 — OA is a complex, environmentally-caused disease with three main phenotypes and no single causal gene

Finding 2 — Occupational exposures account for ~16–17% of adult-onset asthma

Finding 3 — Causative agents divide into HMW complete allergens and LMW haptens; genetic susceptibility modifies risk

Finding 4 — Specific inhalation challenge is the diagnostic gold standard; prognosis is often poor

Finding 5 — HLA class II alleles are the principal susceptibility loci; specific haplotypes confer agent-specific risk

Finding 6 — Immunopathogenesis: hapten–protein conjugates drive CD4⁺ Th2 responses with eosinophilic airway inflammation

Finding 7 — Primary prevention by exposure control is the most effective intervention

Finding 8 — Animal and transgenic models recapitulate sensitizer-induced OA

Finding 9 — Dominant risk factors are exposure intensity/duration, atopy, and concomitant rhinitis/conjunctivitis

Finding 10 — FeNO and sputum eosinophils are complementary biomarkers during SIC

Finding 11 — Irritant-induced asthma / RADS is a distinct non-immunologic phenotype with rapid onset

Finding 12 — Complete removal gives best clinical but worst socioeconomic outcome; OA imposes major burden

Full Section-by-Section Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms