Deployment-Related Constrictive Bronchiolitis

Environmental Pathograph 23 Show in embeddings browser Occupational Lung Disease Bronchiolitis

Deployment-related constrictive bronchiolitis (DRCB) is a biopsy-defined small airways disease of military personnel deployed to Iraq, Afghanistan and the wider Southwest Asia theatre, who inhaled high concentrations of respirable particulate matter from desert dust, open-air burn pit smoke, engine exhaust and occupational vapours, gases, dusts and fumes. Affected personnel present years after deployment with exertional dyspnea and an inability to sustain pre-deployment exercise performance, while chest radiography, spirometry and lung volumes are typically normal, so the diagnosis has historically required surgical lung biopsy. The defining lesion is extrinsic narrowing of membranous (non-cartilaginous) bronchioles by subepithelial fibrosis and smooth-muscle hypertrophy, accompanied by peribronchiolar deposition of grey-black, partly polarizable particulate pigment. Quantitative histomorphometry shows the injury is not confined to the airway: the same lungs carry CD4 and CD8 T cell infiltration of airway walls with B-cell lymphoid follicles, muscularized and collagen-rich distal pulmonary arteries, fibrotic interalveolar septa with reduced capillary density, and visceral pleural inflammation or fibrosis. Because of that multicompartmental pattern, the same entity is also reported as post-deployment respiratory syndrome (PDRS), and an expert Delphi panel placed both under the broader descriptor deployment-related respiratory disease (DRRD). Mechanistic work in mice implicates sustained injury to club cells, the progenitor cells of the distal airway epithelium, with alveolar macrophage accumulation, TGF-beta activation and peribronchiolar collagen deposition as the fibrotic limb, and oxidative stress in the endothelium as the vascular limb. There is no approved pharmacotherapy; management is exposure cessation, symptom-directed treatment and rehabilitation.

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Mappings
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Pathophys.
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Histopath.
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Phenotypes
6
Gaps
23
Pathograph
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Medical Actions
2
Differentials
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Models
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References
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Mappings

MONDO
MONDO:0100127 toxic bronchiolitis obliterans Not Yet Curated
skos:narrowMatch manual curation
?

Discussions and Knowledge Gaps

6
Should a MONDO new-term request be filed for deployment-related constrictive bronchiolitis, or is `MONDO:0100127` toxic bronchiolitis obliterans an adequate home for it?
OPEN QUESTION OPEN open_mondo_anchor
Attached to
disease#Deployment-Related Constrictive Bronchiolitis
MONDO has no class for this entity under any of its three names (DRCB, PDRS, DRRD). The nearest class, `MONDO:0100127` toxic bronchiolitis obliterans, is strictly broader and also covers diacetyl, nitrogen dioxide and sulfur mustard bronchiolitis. The argument for a distinct class is that this entity has a defining exposure setting, an operational histologic threshold (20% airway wall thickening), a distinctive normal-spirometry phenotype, and a multicompartmental pathology that ordinary toxic bronchiolitis obliterans does not carry. The argument against is that it may be the same lesion with a different exposure, in which case a MONDO class would encode an epidemiological grouping rather than a disease. The dismech agent cannot file in the MONDO tracker; this needs a curator to forward it.
Until this resolves, the entry has no `disease_term` and records `MONDO:0100127` as a `skos:narrowMatch` mapping instead.
Is this entry one disease with three names, or has the entity's scope genuinely widened from a bronchiolar lesion to a multicompartmental one?
INTERPRETATION OPEN interp_drcb_pdrs_drrd_naming
Attached to
disease#Deployment-Related Constrictive Bronchiolitis pathophysiology#Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles pathophysiology#Interalveolar Septal Fibrosis and Capillary Rarefaction pathophysiology#Visceral Pleural Inflammation and Fibrosis
The 2011 index series described a bronchiolocentric lesion in otherwise normal parenchyma. Quantitative morphometry of overlapping and later biopsies then found arterial, alveolar-septal and pleural changes in the same lungs, and the Vanderbilt group renamed the entity post-deployment respiratory syndrome to reflect that. A 2023 Delphi panel took a third position: it kept constrictive bronchiolitis as a histologic pattern and introduced deployment-related respiratory disease as a broad clinical descriptor subsuming it. These are not simply synonyms, because they disagree about whether the bronchiole is the seat of the disease. This entry is curated at the biopsy-defined entity and records all three names as synonyms, with the non-bronchiolar compartments as their own pathophysiology nodes so the disagreement is visible in the pathograph rather than buried in prose.
Show evidence (2 references)
PMID:36343686 SUPPORT Other
"deployment-related respiratory disease (DRRD) was proposed as a broad term to subsume a wide range of potential syndromes and conditions identified through noninvasive evaluation or when surgical lung biopsy reveals evidence of multicompartmental lung injury that may include CB."
The consensus position that DRRD is the umbrella and CB one pattern within it.
PMID:34081035 SUPPORT Human Clinical
"Diffuse fibrosis with excessive collagen accumulation in airway walls, blood vessel walls, alveolar tissue, and visceral pleura is a prominent pathologic feature detected in the lungs of soldiers with PDRS."
The multicompartmental claim that motivated the PDRS renaming.
Is the retained peribronchiolar particulate material causal, or only a marker of exposure intensity?
KNOWLEDGE GAP OPEN kgap_particulate_causality
Attached to
pathophysiology#Retained Peribronchiolar Particulate Burden
Near every biopsy in the index series showed peribronchiolar pigment with polarizable material, and burn-pit combustion signatures are recoverable from lung tissue, but no study has shown that the retained material drives the fibrotic lesion rather than co-occurring with the exposure that does. The 2026 ATS workshop names this explicitly as one of three outstanding gaps, and the leading mechanistic model deliberately bypasses the question by inducing club cell injury genetically.
Show evidence (1 reference)
PMID:42360728 SUPPORT Human Clinical
"the contribution of exposure-related foreign material in the lung to clinical and pathologic findings"
The ATS workshop's own statement of this gap.
Which specific deployment exposures, at what dose and duration, produce small airways disease?
KNOWLEDGE GAP OPEN kgap_exposure_dose_response
Attached to
environmental#Deployment inhalation of respirable particulate matter pathophysiology#Distal Deposition of Respirable Deployment Particulate Matter
Individual-level exposure was never measured during deployment, so every exposure-response analysis rests on retrospective self-report. The index cohort contains soldiers with an identified point-source exposure and soldiers with none whose disease was indistinguishable, so no single agent accounts for the entity. Closing this gap requires either historical exposure reconstruction or prospective monitoring in future deployments.
Show evidence (1 reference)
PMID:42360728 SUPPORT Human Clinical
"the extent and mechanisms through which specific exposures result in impaired pulmonary function, small airways disease, and potentially future chronic pulmonary diseases"
The ATS workshop's statement of the exposure-mechanism gap.
The sulfur dioxide mouse attributes exercise limitation to pulmonary vascular disease rather than to the airway lesion; does that hold in humans, where pulmonary hypertension is not an established feature of this disease?
HUMAN MODEL MISMATCH OPEN hmm_pulmonary_hypertension_vascular_limb
Attached to
pathophysiology#Distal Pulmonary Arterial Remodeling phenotypes#Exercise intolerance
In the sulfur dioxide model, small airway abnormalities were explicitly not sufficient to alter lung mechanics, and it was pulmonary vascular remodeling that produced pulmonary hypertension and reduced exercise tolerance. Human morphometry does show arterial muscularization and raised wall-to-lumen ratio in the same lungs, so the substrate is present, but pulmonary hypertension is not a reported clinical feature of DRCB and the human exercise limitation is usually attributed to the airway lesion. If the mouse is right, the disease is being investigated in the wrong compartment and the diagnostic pathway, which is built around airway histology, is looking in the wrong place. If it is wrong, the model's headline physiological result does not transfer.
Proposed experiments
Right heart catheterisation and cardiopulmonary exercise testing in biopsy-proven DRCB
exp_drcb_exercise_hemodynamics
Measure pulmonary artery pressures and pulmonary vascular resistance at rest and during exercise in individuals with biopsy-proven DRCB, alongside quantitative-CT small airways measures, and test which better explains the exercise limitation.
Would support
pathophysiology#Distal Pulmonary Arterial Remodeling
Would refute
pathophysiology#Distal Pulmonary Arterial Remodeling
Supporting outcome
  • Exercise pulmonary vascular resistance correlates with exercise limitation independently of quantitative-CT functional small airways disease.
Refuting outcome
  • Pulmonary haemodynamics are normal at rest and on exercise, and the limitation tracks small airways measures alone.
Show evidence (1 reference)
PMID:38410870 SUPPORT INDIRECT Model Organism
"Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice."
The model result that creates the mismatch with the human framing.
Should the inhaled-particulate to small-airway-fibrosis chain be factored out into a mechanism module that this entry, Sulfur_Mustard_Poisoning and other inhalational bronchiolitis entries could conform to?
CURATION TODO OPEN curation_todo_occupational_smallairway_module
Attached to
pathophysiology#Sustained Club Cell Injury in Membranous Bronchioles pathophysiology#Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
Issue #10976 raised the module option alongside the disease-entry option. This entry took the disease-entry route because the entity has its own exposure setting, diagnostic criteria and natural history. A module remains attractive, since the club-cell-injury-to-peribronchiolar-fibrosis chain is not specific to deployment, but it needs at least two other entries with curated bronchiolar nodes to conform to it, and today only Sulfur_Mustard_Poisoning describes bronchiolitis obliterans mechanistically. The generic fibrotic chain is already covered by `conforms_to` links to `fibrotic_response` on five nodes here, so a new module would have to earn its place by adding the airway-specific steps (club cell progenitor loss, squamous metaplasia, extrinsic luminal narrowing) that `fibrotic_response` does not carry.
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Pathophysiology

13
Distal Deposition of Respirable Deployment Particulate Matter
Respirable particulate matter inhaled during deployment penetrates to the membranous and respiratory bronchioles. Review of the deployment exposure literature identifies sandstorm dust, burn pit combustion products, improvised explosive device emissions and diesel exhaust particles as the principal contributors.
bronchiole UBERON:0002186 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bronchiole (UBERON:0002186). UBERON:0002186 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Retained Peribronchiolar Particulate Burden
Sustained Club Cell Injury in Membranous Bronchioles
Show evidence (1 reference)
PMID:34808040 SUPPORT Human Clinical
"These include, but are not limited to, exposures to high levels of particulate matter (PM) from sandstorms, burn pit combustion products, improvised explosive devices, and diesel exhaust particles."
Enumerates the particulate sources that constitute this initiating exposure.
Retained Peribronchiolar Particulate Burden
Inhaled material is not cleared. Biopsies show grey-black pigment deposited around membranous bronchioles, the great majority of it containing birefringent (polarizable) particulate, and lacy black pigment is visible on the visceral pleural surface at the time of surgery. Whether this retained material is causal or merely a marker of exposure intensity is one of the three knowledge gaps named by the 2026 ATS workshop.
bronchiole UBERON:0002186 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bronchiole (UBERON:0002186). UBERON:0002186 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Sustained Club Cell Injury in Membranous Bronchioles
Peribronchiolar Myeloid and Alveolar Macrophage Accumulation
Visceral Pleural Inflammation and Fibrosis The retained particulate is found on the visceral pleural surface itself, not only around bronchioles, which is the observed link between the retained burden and the pleural compartment of the lesion.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"Thirty-seven of the biopsy samples showed the deposition of grayish black peribronchiolar pigment, with 36 showing polarizable material within the pigment."
Establishes retained, birefringent particulate in a peribronchiolar distribution as a near-universal finding in the index biopsy series.
Sustained Club Cell Injury in Membranous Bronchioles
Club cells are the local progenitor population that repairs the distal airway epithelium after inhaled toxicant injury. Sustained loss of that progenitor compartment is the mechanistic hypothesis for how a diffuse inhalational exposure becomes a fibrotic small-airway lesion, and in mice it is sufficient on its own: no external antigen and no lymphocyte activation is required to produce constrictive bronchiolitis.
club cell CL:0000158 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves club cell (CL:0000158). CL:0000158 is a cell type from the Cell Ontology.
Wound Healing GO:0042060 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Wound Healing (GO:0042060). GO:0042060 is a biological process from the Gene Ontology. ↕ DYSREGULATED
bronchiolar epithelium UBERON:0002051 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bronchiolar epithelium, annotated with epithelium of bronchiole (UBERON:0002051). UBERON:0002051 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
CC-DTA sustained club cell injury mouse Mouse perturbs The model imposes the node directly, by targeted club cell death, rather than reproducing the exposure that is thought to cause it in humans.
Repetitive sulfur dioxide exposure mouse Mouse perturbs Inhaled sulfur dioxide is delivered by the physiological route and produces airway wall remodeling, so unlike the CC-DTA model it tests an actual deployment-relevant inhalational exposure.
Downstream
Peribronchiolar Myeloid and Alveolar Macrophage Accumulation
Bronchiolar Epithelial Thinning and Squamous Metaplasia
Show evidence (2 references)
PMID:34954211 SUPPORT INDIRECT Model Organism
"Club cells are local progenitors critical for repairing the airway epithelium after exposure to various airborne toxins, and a prior study using an inducible transgenic murine model reported that 10 days of sustained targeted club cell injury causes constrictive bronchiolitis."
States the progenitor role of club cells and that sustained injury to them is sufficient to cause constrictive bronchiolitis; INDIRECT because the sufficiency demonstration is a transgenic mouse, not a human exposure.
PMID:34954211 SUPPORT INDIRECT Model Organism
"The current findings demonstrate that sustained club cell injury is sufficient to induce CB and that external antigenic stimuli accompanied by host lymphocyte activation is not required."
Separates the epithelial-injury limb from the lymphocytic limb: the lymphocytic bronchiolitis seen in patients is not required for the fibrotic lesion to form.
Bronchiolar Epithelial Thinning and Squamous Metaplasia
Loss of the club-cell progenitor pool leaves a thinned bronchiolar epithelium that undergoes squamous metaplasia. The same epithelial change is seen in the mouse model and in human DRCB biopsies, which is the strongest single point of correspondence between the two.
bronchiolar epithelium UBERON:0002051 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in bronchiolar epithelium, annotated with epithelium of bronchiole (UBERON:0002051). UBERON:0002051 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
Show evidence (1 reference)
PMID:34954211 SUPPORT INDIRECT Model Organism
"Additional evidence that epithelial cell injury plays a role in the pathogenesis of DRCB stems from the observation that in both murine CB caused by sustained club cell injury and in DRCB, epithelial thinning and squamous cell metaplasia of the small airways was identified."
Reports the same epithelial lesion in the model and in human DRCB tissue; INDIRECT because the human side is a small comparative sample rather than a controlled human series.
Peribronchiolar Myeloid and Alveolar Macrophage Accumulation
Epithelial injury recruits myeloid cells to the small airway wall and lumen. Alveolar and monocyte-derived exudate macrophages persist into the chronic phase and acquire an alternatively activated (CD206-high) phenotype; intraluminal collections of large foamy macrophages are present in both the mouse model and human DRCB biopsies.
alveolar macrophage CL:0000583 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alveolar macrophage (CL:0000583). CL:0000583 is a cell type from the Cell Ontology. monocyte-derived exudate macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte-derived exudate macrophage, annotated with macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
Inflammatory Response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory Response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED Leukocyte Migration GO:0050900 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Leukocyte Migration (GO:0050900). GO:0050900 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
TGF-beta Activation and Myofibroblast Recruitment
Show evidence (2 references)
PMID:34954211 SUPPORT INDIRECT Model Organism
"Transition to a chronic phase was characterized by up-regulated expression of oxidative stress-associated genes, increased activation of transforming growth factor-β, accumulation of alternatively activated macrophages, and enhanced peribronchiolar collagen deposition."
Links persistent alternatively activated macrophages and oxidative stress to the chronic fibrotic phase in the model.
PMID:34954211 SUPPORT Human Clinical
"Peribronchiolar infiltrates were also present in DRCB (Figure 6, E and F), as were numerous collections of large intraluminal foamy macrophages (Figure 6, G and H)."
Confirms the same peribronchiolar and intraluminal macrophage pattern in human DRCB tissue, not only in the mouse. This sentence is the human comparison arm of a paper whose primary experiment is a mouse model, so it is graded HUMAN_CLINICAL for the tissue it reports on.
TGF-beta Activation and Myofibroblast Recruitment
Persistent macrophage accumulation raises free active TGF-beta1 in the airway, driving mesenchymal cell activation. Depleting alveolar macrophages in the mouse model lowers active TGF-beta1 and ameliorates the constrictive lesion, which makes this the most directly interventionally supported step in the chain.
myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology. fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
TGF-beta Receptor Signaling GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased TGF-beta Receptor Signaling, annotated with transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
CC-DTA sustained club cell injury mouse Mouse rescues Depleting alveolar macrophages with clodronate liposomes lowers free active TGF-beta1 and reduces peribronchiolar collagen, placing macrophage-driven TGF-beta activation causally upstream of the fibrotic lesion.
Downstream
Peribronchiolar Collagen Deposition
Show evidence (1 reference)
PMID:34954211 SUPPORT INDIRECT Model Organism
"Depletion of alveolar macrophages in mice decreased activation of transforming growth factor-β and ameliorated constrictive bronchiolitis."
An interventional result placing macrophage-driven TGF-beta activation upstream of the constrictive lesion; INDIRECT because the intervention was performed in mice.
Peribronchiolar Collagen Deposition
Activated mesenchymal cells deposit collagen in the subepithelium and around the bronchiole. In affected soldiers, morphometry shows increased collagen density in the bronchiolar subepithelium with no change in epithelial height, adventitial thickness or subepithelial elastin: the matrix change is specifically collagen.
myofibroblast CL:0000186 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves myofibroblast, annotated with myofibroblast cell (CL:0000186). CL:0000186 is a cell type from the Cell Ontology.
ECM Organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ECM Organization, annotated with extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED Collagen Fibril Organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Collagen Fibril Organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
Show evidence (2 references)
PMID:34081035 SUPPORT Human Clinical
"Bronchioles from soldiers had increased thickness of the lamina propria, smooth muscle hypertrophy, and increased collagen content."
Quantitative morphometry of the collagen increase in human bronchiolar walls.
PMID:34081035 SUPPORT Human Clinical
"No differences were observed in epithelial height, adventitial thickness, or elastin content within the subepithelium."
Constrains the claim: the airway-wall change is collagen-specific, which is why this node is an ECM node rather than a general thickening node.
Lymphocytic Bronchiolitis and Lymphoid Follicle Formation
Airway walls carry a more than three-fold increase in CD4 and CD8 T cells, with B-cell lymphoid follicles adjacent to small airways in 64% of affected soldiers and within alveolar tissue in 56%, against 12% and 6% in non-diseased controls. Airway tissue gene expression is skewed to Th1-type pro-inflammatory programs. This chronic adaptive immune activation is the reason the disease is suspected of being progressive rather than a fixed scar.
CD4-positive T cell CL:0000624 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD4-positive T cell, annotated with CD4-positive, alpha-beta T cell (CL:0000624). CL:0000624 is a cell type from the Cell Ontology. CD8-positive T cell CL:0000625 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves CD8-positive T cell, annotated with CD8-positive, alpha-beta T cell (CL:0000625). CL:0000625 is a cell type from the Cell Ontology.
T Cell Activation GO:0042110 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased T Cell Activation (GO:0042110). GO:0042110 is a biological process from the Gene Ontology. ↑ INCREASED Toll-like Receptor Signaling GO:0002224 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Toll-like Receptor Signaling, annotated with toll-like receptor signaling pathway (GO:0002224). GO:0002224 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
Show evidence (3 references)
PMID:34081035 SUPPORT Human Clinical
"Infiltration of CD4 and CD8 T lymphocytes was noted within airway walls, along with increased formation of lymphoid follicles."
Establishes the lymphocytic component of the airway lesion in humans.
PMID:34081035 SUPPORT Human Clinical
"For comparison, lymphoid follicles were rarely present in ND control lungs (12% had lymphoid follicles adjacent to small airways and 6% within alveolar tissue)."
Supplies the control comparison that makes the follicle finding a disease feature rather than an incidental one.
PMID:35579689 SUPPORT Human Clinical
"Gene expression analysis provides further insights into possible disease mechanisms, with upregulation of mainly Th-1 type pro-inflammatory pathways (e.g., NF-κB, Toll-like receptor, and T-cell signaling)."
Names the signalling programs upregulated in affected airway tissue.
Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
The defining lesion. Membranous (non-cartilaginous) bronchioles are narrowed from outside the lumen by subepithelial fibrosis, smooth-muscle hypertrophy or both, in a lung whose parenchyma is otherwise normal on routine histology. The operational histologic threshold used in later work is a 20% increase in airway wall thickness with chronic inflammation and peribronchiolar collagen.
airway smooth muscle cell CL:4033017 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves airway smooth muscle cell, annotated with bronchiolar smooth muscle cell (CL:4033017). CL:4033017 is a cell type from the Cell Ontology.
membranous bronchiole UBERON:0002186 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in membranous bronchiole, annotated with bronchiole (UBERON:0002186). UBERON:0002186 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
CC-DTA sustained club cell injury mouse Mouse recapitulates Sustained club cell injury produces airway wall thickening with subepithelial matrix deposition, peribronchiolar infiltrates and intraluminal macrophage clusters that match the human lesion.
Downstream
Functional Small Airways Disease and Expiratory Air Trapping
Show evidence (2 references)
PMID:21774710 SUPPORT Human Clinical
"The case definition for constrictive bronchiolitis was the presence of extrinsic narrowing of the luminal wall caused by subepithelial fibrosis, smooth-muscle hypertrophy in membranous bronchioles (non-cartilaginous airways having a complete fibromuscular wall), or both in a patient with..."
The case definition of the defining lesion, including its anatomical level.
PMID:34954211 SUPPORT Human Clinical
"Most biopsies identified small airway disease, with a subset of 38 soldiers exhibiting histopathologic evidence of deployment-related constrictive bronchiolitis (DRCB), defined as a 20% increase in airway wall thickness with associated findings of chronic inflammation and peribronchiolar..."
Gives the quantitative histologic threshold now used to call DRCB.
Distal Pulmonary Arterial Remodeling
Pulmonary arteries running with the affected bronchovascular bundles are themselves remodeled: medial smooth-muscle hypertrophy plus adventitial thickening raise the wall-to-lumen ratio. In the sulfur dioxide mouse model this vascular limb, not the airway limb, is what produces pulmonary hypertension and reduced exercise tolerance, and it is driven by endothelial oxidative stress via isolevuglandin adducts and SOD2 acetylation.
pulmonary arterial smooth muscle cell CL:0002591 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pulmonary arterial smooth muscle cell, annotated with smooth muscle cell of the pulmonary artery (CL:0002591). CL:0002591 is a cell type from the Cell Ontology.
Smooth Muscle Cell Proliferation GO:0048661 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Smooth Muscle Cell Proliferation, annotated with positive regulation of smooth muscle cell proliferation (GO:0048661). GO:0048661 is a biological process from the Gene Ontology. ↑ INCREASED Response to Oxidative Stress GO:0006979 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Response to Oxidative Stress (GO:0006979). GO:0006979 is a biological process from the Gene Ontology. ↑ INCREASED
pulmonary artery UBERON:0002012 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary artery (UBERON:0002012). UBERON:0002012 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Repetitive sulfur dioxide exposure mouse Mouse recapitulates Repetitive sulfur dioxide produces pulmonary vascular remodeling that causes pulmonary hypertension and reduced exercise tolerance, and the remodeling is prevented by scavenging isolevuglandins or by Sirtuin-3 overexpression.
Downstream
Exercise intolerance
Show evidence (2 references)
PMID:34081035 SUPPORT Human Clinical
"In adjacent arteries, smooth muscle hypertrophy and adventitial thickening resulted in increased wall-to-lumen ratio in affected soldiers."
Establishes the arterial remodeling in human tissue.
PMID:38410870 SUPPORT INDIRECT Model Organism
"Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice."
Assigns the exercise limitation to the vascular rather than the airway compartment; INDIRECT because it is a mouse result being used to interpret a human symptom.
Interalveolar Septal Fibrosis and Capillary Rarefaction
Interalveolar septa in affected soldiers carry increased collagen and elastin together with reduced blood capillary density, but without the architectural distortion, honeycombing or fibroblast foci of a usual interstitial pneumonia. This is the alveolar compartment of the multicompartmental injury and a plausible contributor to the reduced diffusing capacity seen on pulmonary function testing.
pulmonary alveolus UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary alveolus, annotated with alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Decreased DLCO
Show evidence (2 references)
PMID:34081035 SUPPORT Human Clinical
"In alveolar parenchyma, collagen and elastin content were increased and capillary density was reduced in interalveolar septa from soldiers compared to control subjects."
Establishes the alveolar matrix and capillary changes by morphometry.
PMID:34081035 SUPPORT Human Clinical
"While we did not identify substantial distortion of lung parenchyma, honeycombing, or formation of fibroblast foci, we speculate that diffuse interstitial fibrosis, which replaces normal connective tissue with dense collagen deposits, may affect functional lung compliance and contribute to..."
Marks the boundary with fibrosing interstitial pneumonia and records the authors' own hedge about the functional consequence.
Visceral Pleural Inflammation and Fibrosis
Visceral pleural inflammation, fibrosis or both are present in the large majority of affected soldiers, with diffuse CD4 and CD8 T cell infiltration extending into the pleura. Pleural involvement is one of the findings that puts this entity outside a purely bronchiolar diagnosis.
pleural mesothelial cell CL:1000491 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pleural mesothelial cell, annotated with mesothelial cell of pleura (CL:1000491). CL:1000491 is a cell type from the Cell Ontology.
visceral pleura UBERON:0002401 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in visceral pleura (UBERON:0002401). UBERON:0002401 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:34081035 SUPPORT Human Clinical
"In addition, pleural involvement with inflammation and/or fibrosis was present in the majority (92%) of soldiers."
Quantifies pleural involvement in the morphometric series.
Functional Small Airways Disease and Expiratory Air Trapping
The physiological expression of the narrowed bronchioles. Conventional spirometry and lung volumes are usually normal, so the abnormality is detected as functional small airways disease on quantitative expiratory CT and as abnormal reactance and distal airway resistance on impulse oscillometry.
lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Exertional dyspnea
Exercise intolerance
Show evidence (2 references)
PMID:40399908 SUPPORT Human Clinical
"Individual unadjusted QCT metrics for functional small airways disease and high attenuation area were elevated in DRCB and FDSV cohorts (relative to Control)."
Demonstrates measurable functional small airways disease in biopsy-proven DRCB relative to controls.
PMID:36038588 SUPPORT Human Clinical
"These tests support the concept of airways hyperresponsiveness and distal airways narrowing, respectively."
Oscillometry evidence for distal airway narrowing in symptomatic deployers whose routine spirometry was unrevealing.
✶

Histopathology

2
Extrinsic narrowing of membranous bronchioles by subepithelial fibrosis
The diagnostic lesion, requiring surgical lung biopsy. Membranous bronchioles show mural thickening with mixed airway wall inflammation; larger airways and alveolar structures are otherwise normal on routine histology.
Show evidence (2 references)
PMID:21774710 SUPPORT Human Clinical
"At low magnification, biopsy samples showed scattered small densities, which at higher magnification were identifiable as membranous bronchioles with variable mural thickening, mixed airway-wall inflammation, and peribronchiolar deposition of grayish black pigment."
Describes the diagnostic histology as seen at biopsy.
PMID:21774710 SUPPORT Human Clinical
"Alveolar structures and larger airways were otherwise normal in all 38 soldiers."
Records the negative finding that makes the lesion bronchiolocentric on routine histology, in contrast with the quantitative morphometry that later found alveolar and pleural changes.
Squamous metaplasia of the bronchiolar epithelium
Epithelial thinning with squamous metaplasia accompanies the airway wall thickening, and is the specific feature shared with the club-cell-injury mouse model.
Show evidence (1 reference)
PMID:34954211 SUPPORT Human Clinical
"Histopathologic analysis of this biopsy revealed findings of squamous metaplasia and airway wall thickening (Figure 5, C and D) similar to those observed in CC-DTA mice on protocol day 20."
Records the finding in human DRCB tissue alongside the model comparison.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Deployment-Related Constrictive Bronchiolitis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Respiratory 3
Exertional dyspnea Universal in reported series (this is the presenting symptom) HP:0002875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exertional dyspnea (HP:0002875), qualified as temporality chronic. HP:0002875 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:34081035 SUPPORT Human Clinical
"Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity."
Establishes the symptom and its persistence.
Decreased DLCO HP:0045051 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased DLCO (HP:0045051). HP:0045051 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"Spirometric values, lung volumes, and measures of carbon monoxide diffusing capacity were within normal limits in 13 soldiers; 19 had an isolated low carbon monoxide diffusing capacity with normal spirometric values and lung volumes."
Gives the pulmonary-function pattern, including how often everything is normal.
Wheezing 15.6% in the past 12 months among deployed US veterans HP:0030828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wheezing (HP:0030828). HP:0030828 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37968126 SUPPORT Human Clinical
"The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively."
Source of the frequency recorded above: 15.6% is the reported 12-month wheeze prevalence in this deployed-veteran cohort.
PMID:37968126 SUPPORT Human Clinical
"Exposure to VGDF was associated with dyspnoea (OR 1.29; 95% CI 1.14 to 1.58) and wheeze (OR 1.18; 95% CI 1.02 to 1.35)."
Associates wheeze with the deployment occupational exposure. This is an odds ratio, so it supports the phenotype-exposure link and not the frequency above.
Constitutional 1
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"The results of pulmonary-function and cardiopulmonary-exercise testing were generally within normal population limits but were inferior to those of the military control subjects."
Shows the exercise limitation is real but only detectable against a fit military reference population.
💊

Medical Actions

3
Cessation of further inhalational exposure
Action: exposure cessationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is exposure cessation, annotated with Preventive Intervention (NCIT:C15843). NCIT:C15843 is a clinical intervention from the NCI Thesaurus. Ontology label: Preventive Intervention NCIT:C15843
Platform: Behavioral / lifestyle
Removing the individual from continuing inhalational hazard is the only intervention with a clear mechanistic rationale, since the disease is driven by sustained epithelial injury from a modifiable exposure. It is preventive rather than restorative: the established fibrotic narrowing does not reverse.
Mechanism Target:
Sustained Club Cell Injury in Membranous Bronchioles — Ending the exposure removes the driver of continuing club cell injury, which is the step the mouse model identifies as sufficient to initiate the lesion.
Symptom-directed and supportive management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
In the absence of disease-modifying therapy, care is symptom-directed. Inhaled bronchodilator and corticosteroid trials are commonly given but have no demonstrated effect on the constrictive lesion.
Show evidence (1 reference)
PMID:35579689 SUPPORT Human Clinical
"there is no currently approved pharmacotherapy for distal lung diseases such as post-deployment constrictive bronchiolitis."
States the therapeutic vacuum this treatment entry exists to record; no disease-modifying option is claimed.
Pulmonary rehabilitation
Action: pulmonary rehabilitationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pulmonary rehabilitation (NCIT:C157966). NCIT:C157966 is a clinical intervention from the NCI Thesaurus. Ontology label: Pulmonary Rehabilitation NCIT:C157966
Platform: Behavioral / lifestyle
Exercise-based rehabilitation for the exertional limitation that defines the presentation. Recorded as standard supportive management for a chronic exertional respiratory limitation; no trial in this specific population has been performed.
Target Phenotypes: Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
🌍

Environmental Factors

3
Deployment inhalation of respirable particulate matter
exposure to respirable particulate matter during military deployment ECTO:7000116 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to respirable particulate matter during military deployment, annotated with exposure to respirable suspended particulate matter (ECTO:7000116). ECTO:7000116 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Hazard type: CHEMICAL
Route: INHALATION
Duration: INTERMEDIATE
Exposome domain: SPECIFIC EXTERNAL
Land-based deployers to Afghanistan and Southwest Asia inhaled high concentrations of respirable particulate matter from geologic desert dust, open-air burn pit smoke, engine and generator exhaust, and occupational vapours, gases, dusts and fumes. Individual-level exposure was never systematically measured during deployment, which is the principal limitation of every exposure-response analysis in this disease.
Show evidence (2 references)
PMID:42360728 SUPPORT Human Clinical
"Workshop participants agreed that there is substantial evidence linking deployment-related exposures to respiratory symptoms, pulmonary diagnoses, and lung pathology."
ATS workshop consensus that the exposure-disease link is supported, which is the warrant for treating deployment exposure as causal here.
PMID:37968126 SUPPORT Human Clinical
"Exposures to burn pit smoke and military occupational VGDF during deployment were associated with an increased odds of chronic respiratory symptoms among US Veterans."
Quantitative exposure-symptom association in a 1960-veteran cohort.
Mechanism Target:
TRIGGERS Distal Deposition of Respirable Deployment Particulate Matter — Inhalation during deployment is the route by which the particulate burden reaches the distal airway, and is the initiating event of this entry.
Show evidence (1 reference)
PMID:42360728 SUPPORT Human Clinical
"Land-based military deployers to Afghanistan and/or Southwest Asia (SWA) encountered exposure to high concentrations of respirable particulate matter (PM) from multiple sources, including desert dust, burn pit smoke, and military occupations."
Names the exposure and its sources in the deployed population this entry is about.
Open-air burn pit smoke
exposure to open-air burn pit smoke ECTO:7000059 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to open-air burn pit smoke, annotated with exposure to smoke (ECTO:7000059). ECTO:7000059 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Open-air waste burning on forward operating bases generated combustion products that are recoverable from lung tissue years later: polycyclic aromatic hydrocarbons, and oxidized titanium and iron. Burn pit smoke was among the most frequently reported heavy exposures in deployed cohorts.
Show evidence (2 references)
PMID:37968126 SUPPORT Human Clinical
"Heavy exposures to multiple inhalational exposures were commonly reported, including burn pit smoke (72.7%) and VGDF (72.0%)."
Establishes how widespread heavy burn-pit exposure was in the deployed population.
PMID:36038588 SUPPORT Human Clinical
"All also had detectable titanium and iron in the lungs."
Metal content of the retained material, supporting inhalation of burned metals rather than tobacco or ambient urban particulate.
Mechanism Target:
TRIGGERS Retained Peribronchiolar Particulate Burden — Combustion products from burn pit smoke are physically retained in the lungs of affected personnel, which is the material basis of the peribronchiolar pigment seen at biopsy.
Show evidence (1 reference)
PMID:36038588 SUPPORT Human Clinical
"We detected the presence of polycyclic aromatic hydrocarbons (PAH)-which are products of incomplete combustion-in the lung tissue of all five warfighters."
Directly links a burn-pit combustion signature to retained material in the lung tissue of biopsied deployers.
Sulfur-mine fire plume (Al-Mishraq, Mosul, 2003)
inhalation of sulfur dioxide from the Al-Mishraq sulfur-mine fire ECTO:9000196 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is inhalation of sulfur dioxide from the Al-Mishraq sulfur-mine fire, annotated with exposure to sulfur dioxide (ECTO:9000196). ECTO:9000196 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
A 2003 fire at a large sulfur mine near Mosul produced a sulfur dioxide plume over the area where much of the index Fort Campbell cohort was barracked. This is the single best-characterised point-source exposure in the disease, and it is the exposure the sulfur dioxide mouse model was built to mimic. It is not, however, necessary for the disease: soldiers with no sulfur-mine exposure had indistinguishable presentations and biopsies.
Show evidence (2 references)
PMID:21774710 SUPPORT Human Clinical
"The plume had levels of sulfur dioxide as high as 125 ppm and extended for miles over the area where most of the Fort Campbell troops and other soldiers had been barracked."
Quantifies the sulfur dioxide concentration and the population exposed.
PMID:21774710 REFUTE Human Clinical
"The presenting symptoms, smoking histories, evaluations, and biopsy samples of the 10 soldiers who did not report exposure to the sulfurmine fire were indistinguishable from those of the 28 soldiers who did report such exposure."
Refutes the stronger claim that the sulfur-mine fire is the necessary cause; the same disease occurs without it, which is why the general particulate exposure rather than this plume is the entry's primary environmental trigger.
Mechanism Target:
TRIGGERS Sustained Club Cell Injury in Membranous Bronchioles — Inhaled sulfur dioxide at plume concentrations is an airway epithelial toxicant, and repetitive sulfur dioxide exposure reproduces the airway and vascular remodelling of this disease in mice.
Show evidence (1 reference)
PMID:38410870 SUPPORT INDIRECT Model Organism
"we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease."
Supports sulfur dioxide as a sufficient trigger for the syndrome's airway and vascular pathology; graded INDIRECT because the demonstration is in mice, not in exposed personnel.
🔬

Diagnosis

2
Surgical lung biopsy after an unrevealing noninvasive evaluation
Because symptoms, examination, radiography and routine pulmonary function testing are all typically normal, the historical diagnostic pathway has been video-assisted thoracoscopic lung biopsy in symptomatic previously deployed personnel whose noninvasive workup found no explanation.
surgical lung biopsy NCIT:C51748 NCI Thesaurus (NCIT)
Results: Extrinsic narrowing of membranous bronchioles by subepithelial fibrosis and/or smooth-muscle hypertrophy, with peribronchiolar pigment, in otherwise normal parenchyma.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"A total of 49 soldiers underwent thoracoscopic lung biopsy after noninvasive evaluation did not provide an explanation for their symptoms."
Describes the diagnostic pathway as actually applied in the index cohort.
Quantitative CT phenotyping as a noninvasive alternative
A quantitative CT-derived probability index built on biopsy-proven DRCB identifies a subset of symptomatic formerly deployed veterans with small-airway abnormality and more intense self-reported exposure effects. This is a research phenotyping tool, not a validated diagnostic test.
quantitative chest computed tomography NCIT:C17204 NCI Thesaurus (NCIT)
Results: Elevated functional small airways disease and high attenuation area relative to controls; a DRCB probability index above 0.5 selects veterans with oscillometric and quantitative-CT small airways disease.
Show evidence (1 reference)
PMID:40399908 SUPPORT Human Clinical
"The FDSV subjects whose DRCB-PI was > 0.5 had greater evidence of small airways disease (assessed by oscillometry and QCT) and self-reported more intense immediate health effects to their exposures to military burn pit smoke, and sand and dust."
Reports what the noninvasive index selects for.
🩻

Imaging Findings

1
Expiratory air trapping on high-resolution chest CT About one quarter of biopsy-proven cases
Imaging is normal in most affected personnel. Mild air trapping or centrilobular nodules are present in roughly a quarter, so a normal high-resolution CT does not exclude the disease, which is precisely why surgical biopsy has been needed.
Ct
Expiratory air trapping HP:0032968 Human Phenotype Ontology (HP)
Show evidence (2 references)
PMID:21774710 SUPPORT Human Clinical
"All soldiers with constrictive bronchiolitis had normal results on chest radiography, but about one quarter were found to have mosaic air trapping or centrilobular nodules on chest CT."
Gives both the finding and its low sensitivity.
PMID:21774710 SUPPORT Human Clinical
"In this descriptive case series, 80 soldiers from Fort Campbell, Kentucky, with inhalational exposures during service in Iraq and Afghanistan were evaluated for dyspnea on exertion that prevented them from meeting the U.S. Army's standards for physical fitness. ... A total of 49 soldiers..."
Restores deployment exposures, the reason for thoracoscopic biopsy and the CT results before the discussion sentence. The quarter-frequency result concerns air trapping or centrilobular nodules together, not a separate estimate for air trapping alone.
📈

Progression

3
Deployment exposure
Land-based deployment to Afghanistan or Southwest Asia with repeated or sustained inhalation of respirable particulate matter. Median deployment duration in the VA cooperative cohort was 11.7 months.
Show evidence (1 reference)
PMID:37968126 SUPPORT Human Clinical
"The cohort mean age was 40.7 years with a median deployment duration of 11.7 months."
Establishes the duration of the exposure window in a large deployed cohort.
Post-deployment exertional limitation
Return from deployment with new exertional dyspnea and failure to meet a previously achievable physical-fitness standard, with a normal chest examination and normal chest radiograph.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"The results of physical examination of the chest were normal in all the soldiers."
Documents that the clinical examination is uninformative at the point of presentation, which is what drives the invasive diagnostic pathway.
Persistent chronic phase
Duration: 1 to 15 years of reported follow-up
Exertional dyspnea persists over years of follow-up and total lung capacity declines, without the parenchymal distortion or honeycombing of a conventional fibrosing interstitial pneumonia.
Show evidence (1 reference)
PMID:34081035 SUPPORT Human Clinical
"Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity."
Establishes persistence and physiological decline over long follow-up.
📊

Prevalence

2
US veterans deployed to Afghanistan and Southwest Asia (VA Cooperative Study "Service and Health Among Deployed Veterans", n=1960)
Period Prevalence 7300.0 per 100,000 >1 in 1,000
Self-reported dyspnoea in the past 12 months in a deployed-veteran cohort. This is the symptom that brings personnel to evaluation, NOT the prevalence of biopsy-proven constrictive bronchiolitis, which is unknown because the diagnosis requires surgical lung biopsy and no population-based biopsy series exists.
Show evidence (1 reference)
PMID:37968126 SUPPORT Human Clinical
"The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively."
Gives the denominator-based symptom prevalence in a deployed veteran cohort, which is the population from which DRCB cases are drawn.
Fort Campbell soldiers referred for unexplained post-deployment exertional dyspnea who proceeded to surgical lung biopsy (n=49)
Unknown Common
A referral-series proportion, not a population rate: 38 of 49 biopsied soldiers had constrictive bronchiolitis. It says how often the lesion explains otherwise-unexplained post-deployment dyspnea, and says nothing about how common the disease is among deployers.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"Of the 49 soldiers who underwent lung biopsy, all biopsy samples were abnormal, with 38 soldiers having changes that were diagnostic of constrictive bronchiolitis."
Source of the 38/49 referral-series proportion, and of the observation that every biopsy in the series was abnormal.
⚖️

Clinical Burden

High
The disease ends military careers. In the original Fort Campbell series half of the affected soldiers left the service with a disability rating, and the symptom is by definition one that prevents meeting an occupational fitness requirement.
Show evidence (1 reference)
PMID:21774710 SUPPORT Human Clinical
"Of the 38 soldiers with constrictive bronchiolitis, 19 (50%) had left the service with a disability rating"
Quantifies occupational loss in the index cohort.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Deployment-Related Constrictive Bronchiolitis:

Asthma
Overlapping Features New-onset asthma is the other major post-deployment respiratory diagnosis and is the one for which the US Department of Veterans Affairs has issued a service-connection presumption. It is separated from constrictive bronchiolitis by bronchodilator responsiveness and by not requiring biopsy.
Distinguishing Features
  • Reversible airflow obstruction with bronchodilator and controller response
  • Diagnosable noninvasively, without surgical lung biopsy
  • Constrictive bronchiolitis instead has fixed extrinsic airway narrowing, usually normal spirometry, and no approved pharmacotherapy
Show evidence (1 reference)
PMID:35579689 SUPPORT Human Clinical
"the Department of Veterans Affairs acknowledged these exposure–disease linkages and issued a presumption connecting asthma, chronic rhinitis, and sinusitis diagnosed within 10 years of military service in veterans with particulate matter exposure during SWA military deployment (9)."
Establishes asthma as the recognised alternative post-deployment respiratory diagnosis in the same exposed population.
Other biopsy diagnoses in previously deployed personnel
Overlapping Features Eleven of the 49 biopsied soldiers in the index series had a different pathological diagnosis that explained their dyspnea. A previously deployed individual with unexplained dyspnea does not have constrictive bronchiolitis by default.
Distinguishing Features
  • Established by the surgical lung biopsy itself
  • The Delphi consensus explicitly stresses considering alternative diagnoses before attributing symptoms to constrictive bronchiolitis
Show evidence (2 references)
PMID:21774710 SUPPORT Human Clinical
"In the remaining 11 soldiers, diagnoses other than constrictive bronchiolitis that could explain the presenting dyspnea were established."
Quantifies the alternative-diagnosis yield in the index biopsy series.
PMID:36343686 SUPPORT Other
"Twenty-five of 28 statements reached consensus, including the definition of CB as a histologic pattern of lung injury that occurs in some previously deployed individuals while recognizing the importance of considering alternative diagnoses."
Expert consensus that alternative diagnoses must be actively considered.
🐁

Animal Models

2
CC-DTA sustained club cell injury mouse
An inducible transgenic model in which diphtheria toxin A expression is restricted to club cells, producing sustained progenitor-cell injury without any inhaled toxicant. It reproduces the epithelial, inflammatory and fibrotic features of DRCB and allows the macrophage-TGF-beta limb to be tested interventionally.
Species
Mouse
Genotype
CC-DTA (club-cell-restricted, doxycycline-inducible diphtheria toxin A), doxycycline for 10 consecutive days
Publication
PMID:34954211
Pathograph links
Sustained Club Cell Injury in Membranous Bronchioles perturbs fidelity: moderate observes: cellular The model imposes the node directly, by targeted club cell death, rather than reproducing the exposure that is thought to cause it in humans.
Limitations: Club cell death is induced genetically by diphtheria toxin A, not by inhaled particulate matter, so the model asserts nothing about which deployment exposure produces club cell injury or at what dose. The authors chose this design precisely because the causative exposure type, dose and duration in humans are unknown.
Show evidence (1 reference)
PMID:34954211 SUPPORT Model Organism
"Ingestion of doxycycline by CC-DTA mice activates diphtheria toxin-A expression only in club cells, leading to targeted autonomous cell death."
Describes how the model imposes the targeted club cell injury.
TGF-beta Activation and Myofibroblast Recruitment rescues fidelity: moderate observes: tissue Depleting alveolar macrophages with clodronate liposomes lowers free active TGF-beta1 and reduces peribronchiolar collagen, placing macrophage-driven TGF-beta activation causally upstream of the fibrotic lesion.
Limitations: Clodronate liposome depletion is not compartment-selective over time, since exudate macrophages rebounded 7.3-fold, so the experiment cannot separate alveolar from recruited macrophage contributions, and the authors note an antifibrotic role for the rebounding population cannot be excluded.
Readouts
Peribronchiolar collagen deposition
Direction: DECREASED
Interpretation: Macrophage depletion reduces the matrix endpoint of the fibrotic limb.
Show evidence (1 reference)
PMID:34954211 SUPPORT Model Organism
"More importantly, CL- versus empty liposome–treated doxycycline-exposed CC-DTA mice demonstrated a striking reduction in peribronchiolar collagen deposition, as assessed by picrosirius red and trichrome staining at protocol day 20 (Figure 8C) and quantified by total lung hydroxyproline assay (Figure 8D)."
Reports the collagen measurement after macrophage depletion.
Free active TGF-beta1 in bronchoalveolar lavage fluid
Direction: DECREASED
Interpretation: Confirms the mediator itself falls, not only its downstream matrix endpoint.
Show evidence (1 reference)
PMID:34954211 SUPPORT Model Organism
"Lastly, reduced peribronchiolar fibrosis in CL-treated doxycycline-exposed CC-DTA mice was associated with substantial decreased levels of free activated TGF-β1 in BALF (relative to doxycycline-exposed CC-DTA mice receiving Els) (Figure 8E)."
Reports the TGF-beta1 measurement accompanying the collagen reduction.
Show evidence (1 reference)
PMID:34954211 SUPPORT Model Organism
"depletion of alveolar macrophages in mice subjected to sustained club cell injury decreased activation of TGF-β and ameliorated CB."
Supports treating this model as informative for the macrophage-TGF-beta node.
Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles recapitulates fidelity: moderate observes: tissue Sustained club cell injury produces airway wall thickening with subepithelial matrix deposition, peribronchiolar infiltrates and intraluminal macrophage clusters that match the human lesion.
Limitations: The comparison on the human side rested on a very small amount of tissue: the authors state that quantitative or semiquantitative analysis of macrophage accumulation in DRCB was constrained by the paucity of research tissue, so the correspondence is qualitative and image-based.
Show evidence (1 reference)
PMID:34954211 SUPPORT Model Organism
"Comparative histopathologic analysis demonstrated that sustained club cell injury was sufficient to induce epithelial metaplasia, airway wall thickening, peribronchiolar infiltrates, and clusters of intraluminal airway macrophages that recapitulated key abnormalities observed in DRCB."
States the histopathologic correspondence with the human lesion.
Show evidence (1 reference)
PMID:34954211 SUPPORT Model Organism
"Collectively, these findings implicate sustained club cell injury in the development of DRCB and delineate pathways that may yield biomarkers and treatment targets for this disorder."
The authors' own statement of what the model is informative for.
Repetitive sulfur dioxide exposure mouse
An inhalational model built around the sulfur dioxide exposure reported by the index cohort. It reproduces adaptive immune activation, airway wall remodeling and pulmonary vascular disease, and identifies endothelial oxidative stress (isolevuglandin adducts, SOD2 acetylation) as the driver of the vascular limb.
Species
Mouse
Genotype
Wild-type, with a Sirtuin-3 overexpressing transgenic arm
Publication
PMID:38410870
Pathograph links
Distal Pulmonary Arterial Remodeling recapitulates fidelity: moderate observes: tissue Repetitive sulfur dioxide produces pulmonary vascular remodeling that causes pulmonary hypertension and reduced exercise tolerance, and the remodeling is prevented by scavenging isolevuglandins or by Sirtuin-3 overexpression.
Limitations: Pulmonary hypertension has not been established as a feature of human DRCB; this model assigns the exercise limitation to the vascular compartment on the strength of a mouse phenotype. Sulfur dioxide is also only one of the candidate deployment exposures and was not reported by a substantial fraction of the index cohort.
Readouts
Pulmonary vascular remodeling after isolevuglandin scavenging
Direction: ABOLISHED
Interpretation: Identifies the isolevuglandin-Sirt3-SOD2 oxidative axis as necessary for the vascular lesion in this model.
Show evidence (1 reference)
PMID:38410870 SUPPORT Model Organism
"In addition, 2-HOBA treatment or Siruin-3 overexpression in a transgenic mouse model prevented vascular remodeling following SO2 exposure."
Reports the two interventions that prevented the vascular remodeling.
Show evidence (1 reference)
PMID:38410870 SUPPORT Model Organism
"our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress appears to mediate PV remodeling in this model."
The authors' statement of what the model recapitulates and the mediator it implicates.
Sustained Club Cell Injury in Membranous Bronchioles perturbs fidelity: low observes: tissue Inhaled sulfur dioxide is delivered by the physiological route and produces airway wall remodeling, so unlike the CC-DTA model it tests an actual deployment-relevant inhalational exposure.
Limitations: The model does not demonstrate club-cell-specific injury; it shows airway wall remodeling downstream of an inhalational exposure, so the mapping onto this specific node is inferred from the CC-DTA work rather than shown here.
Show evidence (1 reference)
PMID:38410870 SUPPORT Model Organism
"we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease."
States the airway and immune features the inhalational model reproduces.
Show evidence (1 reference)
PMID:38410870 SUPPORT Model Organism
"SO2 exposure led to increased formation of isolevuglandins (isoLGs) adducts and superoxide dismutase 2 (SOD2) acetylation in endothelial cells, which were attenuated by treatment with the isoLG scavenger 2-hydroxybenzylamine acetate (2-HOBA)."
The molecular finding that makes this model informative beyond phenotype matching.
{ }

Source YAML

click to show 
name: Deployment-Related Constrictive Bronchiolitis
creation_date: "2026-09-12T12:00:00Z"
category: Environmental
categories:
- Occupational and Environmental Lung Disease
- Toxic Exposure Disorder
- Small Airways Disease
parents:
- Occupational Lung Disease
- Bronchiolitis
synonyms:
- DRCB
- post-deployment respiratory syndrome
- PDRS
- deployment-related distal lung disease
- Iraq/Afghanistan war lung injury
- constrictive bronchiolitis in previously deployed military personnel
description: >-
  Deployment-related constrictive bronchiolitis (DRCB) is a biopsy-defined small
  airways disease of military personnel deployed to Iraq, Afghanistan and the
  wider Southwest Asia theatre, who inhaled high concentrations of respirable
  particulate matter from desert dust, open-air burn pit smoke, engine exhaust
  and occupational vapours, gases, dusts and fumes. Affected personnel present
  years after deployment with exertional dyspnea and an inability to sustain
  pre-deployment exercise performance, while chest radiography, spirometry and
  lung volumes are typically normal, so the diagnosis has historically required
  surgical lung biopsy. The defining lesion is extrinsic narrowing of membranous
  (non-cartilaginous) bronchioles by subepithelial fibrosis and smooth-muscle
  hypertrophy, accompanied by peribronchiolar deposition of grey-black, partly
  polarizable particulate pigment. Quantitative histomorphometry shows the injury
  is not confined to the airway: the same lungs carry CD4 and CD8 T cell
  infiltration of airway walls with B-cell lymphoid follicles, muscularized and
  collagen-rich distal pulmonary arteries, fibrotic interalveolar septa with
  reduced capillary density, and visceral pleural inflammation or fibrosis.
  Because of that multicompartmental pattern, the same entity is also reported as
  post-deployment respiratory syndrome (PDRS), and an expert Delphi panel placed
  both under the broader descriptor deployment-related respiratory disease
  (DRRD). Mechanistic work in mice implicates sustained injury to club cells, the
  progenitor cells of the distal airway epithelium, with alveolar macrophage
  accumulation, TGF-beta activation and peribronchiolar collagen deposition as
  the fibrotic limb, and oxidative stress in the endothelium as the vascular
  limb. There is no approved pharmacotherapy; management is exposure cessation,
  symptom-directed treatment and rehabilitation.
notes: >-
  This entry deliberately carries no `disease_term`. MONDO has no class for
  deployment-related constrictive bronchiolitis, for post-deployment respiratory
  syndrome, or for deployment-related respiratory disease: an OLS search of MONDO
  for "deployment related respiratory disease" returns nothing, and the nearest
  classes are `MONDO:0100123` toxic bronchiolitis and `MONDO:0100127` toxic
  bronchiolitis obliterans, both of which are broader inhalational-toxicant
  categories that also cover diacetyl (popcorn worker's) bronchiolitis, silo
  filler's disease and sulfur mustard injury. `MONDO:0100127` is recorded in
  `mappings.mondo_mappings` with `skos:narrowMatch` rather than being reused bare
  as this entry's anchor. A MONDO new-term request is the right follow-up; see
  the `open_mondo_anchor` discussion.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0100127
      label: toxic bronchiolitis obliterans
    mapping_predicate: skos:narrowMatch
    mapping_source: manual curation
    notes: >-
      DRCB is one inhalational cause of toxic bronchiolitis obliterans, so the
      MONDO class is strictly broader than this entry. Recorded as a mapping, not
      as `disease_term`, so the entry does not claim a MONDO identity it does not
      have.
references:
- reference: PMID:21774710
  title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
- reference: PMID:34081035
  title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
- reference: PMID:42360728
  title: "Deployment-related respiratory health: bridging the gap between clinical and epidemiological associations and disease mechanisms: an official American Thoracic Society Workshop Report."
- reference: PMID:36343686
  title: "Consensus Statements on Deployment-Related Respiratory Disease, Inclusive of Constrictive Bronchiolitis: A Modified Delphi Study."
prevalence:
- population: >-
    US veterans deployed to Afghanistan and Southwest Asia (VA Cooperative Study
    "Service and Health Among Deployed Veterans", n=1960)
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 7300.0
  notes: >-
    Self-reported dyspnoea in the past 12 months in a deployed-veteran cohort.
    This is the symptom that brings personnel to evaluation, NOT the prevalence
    of biopsy-proven constrictive bronchiolitis, which is unknown because the
    diagnosis requires surgical lung biopsy and no population-based biopsy series
    exists.
  evidence:
  - reference: PMID:37968126
    reference_title: "Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively."
    explanation: >-
      Gives the denominator-based symptom prevalence in a deployed veteran
      cohort, which is the population from which DRCB cases are drawn.
- population: >-
    Fort Campbell soldiers referred for unexplained post-deployment exertional
    dyspnea who proceeded to surgical lung biopsy (n=49)
  measure_type: UNKNOWN
  prevalence_class: COMMON
  notes: >-
    A referral-series proportion, not a population rate: 38 of 49 biopsied
    soldiers had constrictive bronchiolitis. It says how often the lesion
    explains otherwise-unexplained post-deployment dyspnea, and says nothing
    about how common the disease is among deployers.
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 49 soldiers who underwent lung biopsy, all biopsy samples were abnormal, with 38 soldiers having changes that were diagnostic of constrictive bronchiolitis."
    explanation: >-
      Source of the 38/49 referral-series proportion, and of the observation that
      every biopsy in the series was abnormal.
progression:
- phase: Deployment exposure
  notes: >-
    Land-based deployment to Afghanistan or Southwest Asia with repeated or
    sustained inhalation of respirable particulate matter. Median deployment
    duration in the VA cooperative cohort was 11.7 months.
  evidence:
  - reference: PMID:37968126
    reference_title: "Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cohort mean age was 40.7 years with a median deployment duration of 11.7 months."
    explanation: Establishes the duration of the exposure window in a large deployed cohort.
- phase: Post-deployment exertional limitation
  notes: >-
    Return from deployment with new exertional dyspnea and failure to meet a
    previously achievable physical-fitness standard, with a normal chest
    examination and normal chest radiograph.
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of physical examination of the chest were normal in all the soldiers."
    explanation: >-
      Documents that the clinical examination is uninformative at the point of
      presentation, which is what drives the invasive diagnostic pathway.
- phase: Persistent chronic phase
  duration: 1 to 15 years of reported follow-up
  notes: >-
    Exertional dyspnea persists over years of follow-up and total lung capacity
    declines, without the parenchymal distortion or honeycombing of a
    conventional fibrosing interstitial pneumonia.
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity."
    explanation: Establishes persistence and physiological decline over long follow-up.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    The disease ends military careers. In the original Fort Campbell series half
    of the affected soldiers left the service with a disability rating, and the
    symptom is by definition one that prevents meeting an occupational fitness
    requirement.
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 38 soldiers with constrictive bronchiolitis, 19 (50%) had left the service with a disability rating"
    explanation: Quantifies occupational loss in the index cohort.
environmental:
- name: Deployment inhalation of respirable particulate matter
  description: >-
    Land-based deployers to Afghanistan and Southwest Asia inhaled high
    concentrations of respirable particulate matter from geologic desert dust,
    open-air burn pit smoke, engine and generator exhaust, and occupational
    vapours, gases, dusts and fumes. Individual-level exposure was never
    systematically measured during deployment, which is the principal limitation
    of every exposure-response analysis in this disease.
  exposure_term:
    preferred_term: exposure to respirable particulate matter during military deployment
    term:
      id: ECTO:7000116
      label: exposure to respirable suspended particulate matter
  exposure_classifications:
    hazard_agent_type:
    - classification_value: CHEMICAL
      notes: >-
        Respirable particulate matter is a chemical/mineral agent in the
        occupational-hygiene schemes, not a physical or biological agent.
    exposure_route:
    - classification_value: INHALATION
      notes: >-
        Only the respirable fraction reaching the membranous and respiratory
        bronchioles is relevant to this lesion.
    exposure_duration:
    - classification_value: INTERMEDIATE
      notes: >-
        ATSDR intermediate duration (15-364 days), matching the median 11.7 month
        deployment in the VA cooperative cohort; repeat deployments push some
        individuals into the chronic band.
    exposome_domain:
    - classification_value: SPECIFIC_EXTERNAL
      notes: >-
        An identifiable, occupationally bounded external agent in Wild's specific
        external domain.
  influences_mechanisms:
  - target: Distal Deposition of Respirable Deployment Particulate Matter
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Inhalation during deployment is the route by which the particulate burden
      reaches the distal airway, and is the initiating event of this entry.
    evidence:
    - reference: PMID:42360728
      reference_title: "Deployment-related respiratory health: bridging the gap between clinical and epidemiological associations and disease mechanisms: an official American Thoracic Society Workshop Report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Land-based military deployers to Afghanistan and/or Southwest Asia (SWA) encountered exposure to high concentrations of respirable particulate matter (PM) from multiple sources, including desert dust, burn pit smoke, and military occupations."
      explanation: Names the exposure and its sources in the deployed population this entry is about.
  evidence:
  - reference: PMID:42360728
    reference_title: "Deployment-related respiratory health: bridging the gap between clinical and epidemiological associations and disease mechanisms: an official American Thoracic Society Workshop Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Workshop participants agreed that there is substantial evidence linking deployment-related exposures to respiratory symptoms, pulmonary diagnoses, and lung pathology."
    explanation: >-
      ATS workshop consensus that the exposure-disease link is supported, which is
      the warrant for treating deployment exposure as causal here.
  - reference: PMID:37968126
    reference_title: "Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposures to burn pit smoke and military occupational VGDF during deployment were associated with an increased odds of chronic respiratory symptoms among US Veterans."
    explanation: Quantitative exposure-symptom association in a 1960-veteran cohort.
- name: Open-air burn pit smoke
  description: >-
    Open-air waste burning on forward operating bases generated combustion
    products that are recoverable from lung tissue years later: polycyclic
    aromatic hydrocarbons, and oxidized titanium and iron. Burn pit smoke was
    among the most frequently reported heavy exposures in deployed cohorts.
  exposure_term:
    preferred_term: exposure to open-air burn pit smoke
    term:
      id: ECTO:7000059
      label: exposure to smoke
  influences_mechanisms:
  - target: Retained Peribronchiolar Particulate Burden
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Combustion products from burn pit smoke are physically retained in the lungs
      of affected personnel, which is the material basis of the peribronchiolar
      pigment seen at biopsy.
    evidence:
    - reference: PMID:36038588
      reference_title: "Iraq/Afghanistan war lung injury reflects burn pits exposure."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We detected the presence of polycyclic aromatic hydrocarbons (PAH)-which are products of incomplete combustion-in the lung tissue of all five warfighters."
      explanation: >-
        Directly links a burn-pit combustion signature to retained material in the
        lung tissue of biopsied deployers.
  evidence:
  - reference: PMID:37968126
    reference_title: "Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heavy exposures to multiple inhalational exposures were commonly reported, including burn pit smoke (72.7%) and VGDF (72.0%)."
    explanation: Establishes how widespread heavy burn-pit exposure was in the deployed population.
  - reference: PMID:36038588
    reference_title: "Iraq/Afghanistan war lung injury reflects burn pits exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All also had detectable titanium and iron in the lungs."
    explanation: >-
      Metal content of the retained material, supporting inhalation of burned
      metals rather than tobacco or ambient urban particulate.
- name: Sulfur-mine fire plume (Al-Mishraq, Mosul, 2003)
  description: >-
    A 2003 fire at a large sulfur mine near Mosul produced a sulfur dioxide plume
    over the area where much of the index Fort Campbell cohort was barracked.
    This is the single best-characterised point-source exposure in the disease,
    and it is the exposure the sulfur dioxide mouse model was built to mimic. It
    is not, however, necessary for the disease: soldiers with no sulfur-mine
    exposure had indistinguishable presentations and biopsies.
  exposure_term:
    preferred_term: inhalation of sulfur dioxide from the Al-Mishraq sulfur-mine fire
    term:
      id: ECTO:9000196
      label: exposure to sulfur dioxide
  influences_mechanisms:
  - target: Sustained Club Cell Injury in Membranous Bronchioles
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      Inhaled sulfur dioxide at plume concentrations is an airway epithelial
      toxicant, and repetitive sulfur dioxide exposure reproduces the airway and
      vascular remodelling of this disease in mice.
    evidence:
    - reference: PMID:38410870
      reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease."
      explanation: >-
        Supports sulfur dioxide as a sufficient trigger for the syndrome's airway
        and vascular pathology; graded INDIRECT because the demonstration is in
        mice, not in exposed personnel.
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The plume had levels of sulfur dioxide as high as 125 ppm and extended for miles over the area where most of the Fort Campbell troops and other soldiers had been barracked."
    explanation: Quantifies the sulfur dioxide concentration and the population exposed.
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The presenting symptoms, smoking histories, evaluations, and biopsy samples of the 10 soldiers who did not report exposure to the sulfurmine fire were indistinguishable from those of the 28 soldiers who did report such exposure."
    explanation: >-
      Refutes the stronger claim that the sulfur-mine fire is the necessary cause;
      the same disease occurs without it, which is why the general particulate
      exposure rather than this plume is the entry's primary environmental
      trigger.
pathophysiology:
- name: Distal Deposition of Respirable Deployment Particulate Matter
  description: >-
    Respirable particulate matter inhaled during deployment penetrates to the
    membranous and respiratory bronchioles. Review of the deployment exposure
    literature identifies sandstorm dust, burn pit combustion products,
    improvised explosive device emissions and diesel exhaust particles as the
    principal contributors.
  role: trigger
  biological_scale: TISSUE
  locations:
  - preferred_term: bronchiole
    term:
      id: UBERON:0002186
      label: bronchiole
  downstream:
  - target: Retained Peribronchiolar Particulate Burden
  - target: Sustained Club Cell Injury in Membranous Bronchioles
  evidence:
  - reference: PMID:34808040
    reference_title: "Role of Particulate Matter from Afghanistan and Iraq in Deployment-Related Lung Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These include, but are not limited to, exposures to high levels of particulate matter (PM) from sandstorms, burn pit combustion products, improvised explosive devices, and diesel exhaust particles."
    explanation: Enumerates the particulate sources that constitute this initiating exposure.
- name: Retained Peribronchiolar Particulate Burden
  description: >-
    Inhaled material is not cleared. Biopsies show grey-black pigment deposited
    around membranous bronchioles, the great majority of it containing
    birefringent (polarizable) particulate, and lacy black pigment is visible on
    the visceral pleural surface at the time of surgery. Whether this retained
    material is causal or merely a marker of exposure intensity is one of the
    three knowledge gaps named by the 2026 ATS workshop.
  role: driver
  biological_scale: TISSUE
  locations:
  - preferred_term: bronchiole
    term:
      id: UBERON:0002186
      label: bronchiole
  downstream:
  - target: Sustained Club Cell Injury in Membranous Bronchioles
  - target: Peribronchiolar Myeloid and Alveolar Macrophage Accumulation
  - target: Visceral Pleural Inflammation and Fibrosis
    description: >-
      The retained particulate is found on the visceral pleural surface itself,
      not only around bronchioles, which is the observed link between the
      retained burden and the pleural compartment of the lesion.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21774710
      reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Lacy black pigment was noted on the visceral pleural surface during biopsy in 37 of the soldiers."
      explanation: >-
        Places the retained particulate at the visceral pleural surface in most of
        the index biopsy series. The steps between deposition there and the
        pleural inflammation and fibrosis are not established, hence
        INDIRECT_UNKNOWN_INTERMEDIATES.
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirty-seven of the biopsy samples showed the deposition of grayish black peribronchiolar pigment, with 36 showing polarizable material within the pigment."
    explanation: >-
      Establishes retained, birefringent particulate in a peribronchiolar
      distribution as a near-universal finding in the index biopsy series.
- name: Sustained Club Cell Injury in Membranous Bronchioles
  description: >-
    Club cells are the local progenitor population that repairs the distal airway
    epithelium after inhaled toxicant injury. Sustained loss of that progenitor
    compartment is the mechanistic hypothesis for how a diffuse inhalational
    exposure becomes a fibrotic small-airway lesion, and in mice it is sufficient
    on its own: no external antigen and no lymphocyte activation is required to
    produce constrictive bronchiolitis.
  role: driver
  conforms_to: "fibrotic_response#Tissue Injury"
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: club cell
    term:
      id: CL:0000158
      label: club cell
  locations:
  - preferred_term: bronchiolar epithelium
    term:
      id: UBERON:0002051
      label: epithelium of bronchiole
  biological_processes:
  - preferred_term: Wound Healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DYSREGULATED
  downstream:
  - target: Peribronchiolar Myeloid and Alveolar Macrophage Accumulation
  - target: Bronchiolar Epithelial Thinning and Squamous Metaplasia
  evidence:
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Club cells are local progenitors critical for repairing the airway epithelium after exposure to various airborne toxins, and a prior study using an inducible transgenic murine model reported that 10 days of sustained targeted club cell injury causes constrictive bronchiolitis."
    explanation: >-
      States the progenitor role of club cells and that sustained injury to them
      is sufficient to cause constrictive bronchiolitis; INDIRECT because the
      sufficiency demonstration is a transgenic mouse, not a human exposure.
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "The current findings demonstrate that sustained club cell injury is sufficient to induce CB and that external antigenic stimuli accompanied by host lymphocyte activation is not required."
    explanation: >-
      Separates the epithelial-injury limb from the lymphocytic limb: the
      lymphocytic bronchiolitis seen in patients is not required for the fibrotic
      lesion to form.
- name: Bronchiolar Epithelial Thinning and Squamous Metaplasia
  description: >-
    Loss of the club-cell progenitor pool leaves a thinned bronchiolar epithelium
    that undergoes squamous metaplasia. The same epithelial change is seen in the
    mouse model and in human DRCB biopsies, which is the strongest single point
    of correspondence between the two.
  role: consequence
  biological_scale: CELLULAR
  locations:
  - preferred_term: bronchiolar epithelium
    term:
      id: UBERON:0002051
      label: epithelium of bronchiole
  downstream:
  - target: Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
  evidence:
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Additional evidence that epithelial cell injury plays a role in the pathogenesis of DRCB stems from the observation that in both murine CB caused by sustained club cell injury and in DRCB, epithelial thinning and squamous cell metaplasia of the small airways was identified."
    explanation: >-
      Reports the same epithelial lesion in the model and in human DRCB tissue;
      INDIRECT because the human side is a small comparative sample rather than a
      controlled human series.
- name: Peribronchiolar Myeloid and Alveolar Macrophage Accumulation
  description: >-
    Epithelial injury recruits myeloid cells to the small airway wall and lumen.
    Alveolar and monocyte-derived exudate macrophages persist into the chronic
    phase and acquire an alternatively activated (CD206-high) phenotype;
    intraluminal collections of large foamy macrophages are present in both the
    mouse model and human DRCB biopsies.
  role: amplifier
  conforms_to: "fibrotic_response#Inflammatory Recruitment and Amplification"
  biological_scale: TISSUE
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: monocyte-derived exudate macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: Leukocyte Migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  downstream:
  - target: TGF-beta Activation and Myofibroblast Recruitment
  evidence:
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Transition to a chronic phase was characterized by up-regulated expression of oxidative stress-associated genes, increased activation of transforming growth factor-β, accumulation of alternatively activated macrophages, and enhanced peribronchiolar collagen deposition."
    explanation: >-
      Links persistent alternatively activated macrophages and oxidative stress to
      the chronic fibrotic phase in the model.
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peribronchiolar infiltrates were also present in DRCB (Figure 6, E and F), as were numerous collections of large intraluminal foamy macrophages (Figure 6, G and H)."
    explanation: >-
      Confirms the same peribronchiolar and intraluminal macrophage pattern in
      human DRCB tissue, not only in the mouse. This sentence is the human
      comparison arm of a paper whose primary experiment is a mouse model, so it
      is graded HUMAN_CLINICAL for the tissue it reports on.
- name: TGF-beta Activation and Myofibroblast Recruitment
  description: >-
    Persistent macrophage accumulation raises free active TGF-beta1 in the
    airway, driving mesenchymal cell activation. Depleting alveolar macrophages in
    the mouse model lowers active TGF-beta1 and ameliorates the constrictive
    lesion, which makes this the most directly interventionally supported step in
    the chain.
  role: central_effector
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  biological_processes:
  - preferred_term: TGF-beta Receptor Signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  downstream:
  - target: Peribronchiolar Collagen Deposition
  evidence:
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Depletion of alveolar macrophages in mice decreased activation of transforming growth factor-β and ameliorated constrictive bronchiolitis."
    explanation: >-
      An interventional result placing macrophage-driven TGF-beta activation
      upstream of the constrictive lesion; INDIRECT because the intervention was
      performed in mice.
- name: Peribronchiolar Collagen Deposition
  description: >-
    Activated mesenchymal cells deposit collagen in the subepithelium and around
    the bronchiole. In affected soldiers, morphometry shows increased collagen
    density in the bronchiolar subepithelium with no change in epithelial height,
    adventitial thickness or subepithelial elastin: the matrix change is
    specifically collagen.
  role: effector
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  biological_scale: TISSUE
  cell_types:
  - preferred_term: myofibroblast
    term:
      id: CL:0000186
      label: myofibroblast cell
  biological_processes:
  - preferred_term: ECM Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: Collagen Fibril Organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  downstream:
  - target: Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bronchioles from soldiers had increased thickness of the lamina propria, smooth muscle hypertrophy, and increased collagen content."
    explanation: Quantitative morphometry of the collagen increase in human bronchiolar walls.
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No differences were observed in epithelial height, adventitial thickness, or elastin content within the subepithelium."
    explanation: >-
      Constrains the claim: the airway-wall change is collagen-specific, which is
      why this node is an ECM node rather than a general thickening node.
- name: Lymphocytic Bronchiolitis and Lymphoid Follicle Formation
  description: >-
    Airway walls carry a more than three-fold increase in CD4 and CD8 T cells,
    with B-cell lymphoid follicles adjacent to small airways in 64% of affected
    soldiers and within alveolar tissue in 56%, against 12% and 6% in
    non-diseased controls. Airway tissue gene expression is skewed to Th1-type
    pro-inflammatory programs. This chronic adaptive immune activation is the
    reason the disease is suspected of being progressive rather than a fixed
    scar.
  notes: >-
    This node deliberately has no upstream edge. The sources establish the
    lymphocytic infiltrate and the follicles as a disease feature against
    controls, and they establish that a range of deployment inhalational
    exposures precede the syndrome, but none of them demonstrates which
    mechanism node drives the adaptive immune arm. PMID:34954211 argues the
    other way for the obvious candidate: in the mouse, sustained club cell
    injury reproduces the fibrotic lesion with no external antigen and no
    lymphocyte activation required. The node is therefore left rootless rather
    than attached to a guess.
  role: amplifier
  biological_scale: TISSUE
  cell_types:
  - preferred_term: CD4-positive T cell
    term:
      id: CL:0000624
      label: "CD4-positive, alpha-beta T cell"
  - preferred_term: CD8-positive T cell
    term:
      id: CL:0000625
      label: "CD8-positive, alpha-beta T cell"
  biological_processes:
  - preferred_term: T Cell Activation
    term:
      id: GO:0042110
      label: T cell activation
    modifier: INCREASED
  - preferred_term: Toll-like Receptor Signaling
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
    modifier: INCREASED
  downstream:
  - target: Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Infiltration of CD4 and CD8 T lymphocytes was noted within airway walls, along with increased formation of lymphoid follicles."
    explanation: Establishes the lymphocytic component of the airway lesion in humans.
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For comparison, lymphoid follicles were rarely present in ND control lungs (12% had lymphoid follicles adjacent to small airways and 6% within alveolar tissue)."
    explanation: >-
      Supplies the control comparison that makes the follicle finding a disease
      feature rather than an incidental one.
  - reference: PMID:35579689
    reference_title: "Histopathologic Insights into Distal Lung Injury and Inflammation following Military Deployment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene expression analysis provides further insights into possible disease mechanisms, with upregulation of mainly Th-1 type pro-inflammatory pathways (e.g., NF-κB, Toll-like receptor, and T-cell signaling)."
    explanation: Names the signalling programs upregulated in affected airway tissue.
- name: Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
  description: >-
    The defining lesion. Membranous (non-cartilaginous) bronchioles are narrowed
    from outside the lumen by subepithelial fibrosis, smooth-muscle hypertrophy or
    both, in a lung whose parenchyma is otherwise normal on routine histology.
    The operational histologic threshold used in later work is a 20% increase in
    airway wall thickness with chronic inflammation and peribronchiolar collagen.
  role: consequence
  conforms_to: "fibrotic_response#Architectural Distortion and Organ Dysfunction"
  biological_scale: TISSUE
  cell_types:
  - preferred_term: airway smooth muscle cell
    term:
      id: CL:4033017
      label: bronchiolar smooth muscle cell
  locations:
  - preferred_term: membranous bronchiole
    term:
      id: UBERON:0002186
      label: bronchiole
  downstream:
  - target: Functional Small Airways Disease and Expiratory Air Trapping
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The case definition for constrictive bronchiolitis was the presence of extrinsic narrowing of the luminal wall caused by subepithelial fibrosis, smooth-muscle hypertrophy in membranous bronchioles (non-cartilaginous airways having a complete fibromuscular wall), or both in a patient with otherwise normal lung parenchyma."
    explanation: The case definition of the defining lesion, including its anatomical level.
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most biopsies identified small airway disease, with a subset of 38 soldiers exhibiting histopathologic evidence of deployment-related constrictive bronchiolitis (DRCB), defined as a 20% increase in airway wall thickness with associated findings of chronic inflammation and peribronchiolar collagen deposition."
    explanation: Gives the quantitative histologic threshold now used to call DRCB.
- name: Distal Pulmonary Arterial Remodeling
  description: >-
    Pulmonary arteries running with the affected bronchovascular bundles are
    themselves remodeled: medial smooth-muscle hypertrophy plus adventitial
    thickening raise the wall-to-lumen ratio. In the sulfur dioxide mouse model
    this vascular limb, not the airway limb, is what produces pulmonary
    hypertension and reduced exercise tolerance, and it is driven by endothelial
    oxidative stress via isolevuglandin adducts and SOD2 acetylation.
  notes: >-
    This node deliberately has no upstream edge. PMID:34081035 finds the
    arterial remodeling in arteries adjacent to affected bronchioles, but treats
    it as one compartment of a diffuse multicompartment injury rather than as a
    consequence of the airway lesion, and no source in this entry establishes a
    mechanism node upstream of it in humans. The one causal account available is
    the SO2 mouse, whose ROS/isoLG/Sirt3-SOD2 route is recorded on that model's
    modeled_mechanisms link rather than asserted as a human pathograph edge.
  role: driver
  biological_scale: TISSUE
  cell_types:
  - preferred_term: pulmonary arterial smooth muscle cell
    term:
      id: CL:0002591
      label: smooth muscle cell of the pulmonary artery
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  biological_processes:
  - preferred_term: Smooth Muscle Cell Proliferation
    term:
      id: GO:0048661
      label: positive regulation of smooth muscle cell proliferation
    modifier: INCREASED
  - preferred_term: Response to Oxidative Stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  downstream:
  - target: Exercise intolerance
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In adjacent arteries, smooth muscle hypertrophy and adventitial thickening resulted in increased wall-to-lumen ratio in affected soldiers."
    explanation: Establishes the arterial remodeling in human tissue.
  - reference: PMID:38410870
    reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice."
    explanation: >-
      Assigns the exercise limitation to the vascular rather than the airway
      compartment; INDIRECT because it is a mouse result being used to interpret a
      human symptom.
- name: Interalveolar Septal Fibrosis and Capillary Rarefaction
  description: >-
    Interalveolar septa in affected soldiers carry increased collagen and elastin
    together with reduced blood capillary density, but without the architectural
    distortion, honeycombing or fibroblast foci of a usual interstitial
    pneumonia. This is the alveolar compartment of the multicompartmental injury
    and a plausible contributor to the reduced diffusing capacity seen on
    pulmonary function testing.
  notes: >-
    This node deliberately has no upstream edge, for the same reason as
    Distal Pulmonary Arterial Remodeling: PMID:34081035 reports the septal
    matrix and capillary changes as a compartment of a diffuse injury affecting
    all distal lung compartments, and does not place any mechanism node upstream
    of them. The authors' own statement about the functional consequence is a
    hedge ("we speculate"), which is recorded on the second evidence item below.
  role: consequence
  biological_scale: TISSUE
  locations:
  - preferred_term: pulmonary alveolus
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Decreased DLCO
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In alveolar parenchyma, collagen and elastin content were increased and capillary density was reduced in interalveolar septa from soldiers compared to control subjects."
    explanation: Establishes the alveolar matrix and capillary changes by morphometry.
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While we did not identify substantial distortion of lung parenchyma, honeycombing, or formation of fibroblast foci, we speculate that diffuse interstitial fibrosis, which replaces normal connective tissue with dense collagen deposits, may affect functional lung compliance and contribute to dyspnea on exertion."
    explanation: >-
      Marks the boundary with fibrosing interstitial pneumonia and records the
      authors' own hedge about the functional consequence.
- name: Visceral Pleural Inflammation and Fibrosis
  description: >-
    Visceral pleural inflammation, fibrosis or both are present in the large
    majority of affected soldiers, with diffuse CD4 and CD8 T cell infiltration
    extending into the pleura. Pleural involvement is one of the findings that
    puts this entity outside a purely bronchiolar diagnosis.
  role: consequence
  biological_scale: TISSUE
  cell_types:
  - preferred_term: pleural mesothelial cell
    term:
      id: CL:1000491
      label: mesothelial cell of pleura
  locations:
  - preferred_term: visceral pleura
    term:
      id: UBERON:0002401
      label: visceral pleura
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, pleural involvement with inflammation and/or fibrosis was present in the majority (92%) of soldiers."
    explanation: Quantifies pleural involvement in the morphometric series.
- name: Functional Small Airways Disease and Expiratory Air Trapping
  description: >-
    The physiological expression of the narrowed bronchioles. Conventional
    spirometry and lung volumes are usually normal, so the abnormality is detected
    as functional small airways disease on quantitative expiratory CT and as
    abnormal reactance and distal airway resistance on impulse oscillometry.
  role: consequence
  biological_scale: ORGANISM
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  downstream:
  - target: Exertional dyspnea
  - target: Exercise intolerance
  evidence:
  - reference: PMID:40399908
    reference_title: "Use of quantitative CT chest imaging to derive and assess a radiographic phenotype of deployment-related constrictive bronchiolitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individual unadjusted QCT metrics for functional small airways disease and high attenuation area were elevated in DRCB and FDSV cohorts (relative to Control)."
    explanation: >-
      Demonstrates measurable functional small airways disease in biopsy-proven
      DRCB relative to controls.
  - reference: PMID:36038588
    reference_title: "Iraq/Afghanistan war lung injury reflects burn pits exposure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These tests support the concept of airways hyperresponsiveness and distal airways narrowing, respectively."
    explanation: >-
      Oscillometry evidence for distal airway narrowing in symptomatic deployers
      whose routine spirometry was unrevealing.
phenotypes:
- category: Clinical
  name: Exertional dyspnea
  description: >-
    Breathlessness on exertion that appeared during or after deployment and
    prevents the individual from sustaining a previously achievable level of
    physical work. It persists over years of follow-up.
  phenotype_term:
    preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
    temporality: CHRONIC
  frequency: Universal in reported series (this is the presenting symptom)
  evidence:
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical follow-up of 29 soldiers (ranging from 1 to 15 y) showed persistence of exertional dyspnea in all individuals and a decline in total lung capacity."
    explanation: Establishes the symptom and its persistence.
- category: Clinical
  name: Exercise intolerance
  description: >-
    Objective exercise limitation. In the index cohort, maximal oxygen consumption
    and anaerobic threshold sat at the lower limit of the normal population range
    but were clearly inferior to military control subjects, which is why testing
    against population norms misses the disease.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of pulmonary-function and cardiopulmonary-exercise testing were generally within normal population limits but were inferior to those of the military control subjects."
    explanation: >-
      Shows the exercise limitation is real but only detectable against a fit
      military reference population.
- category: Physiological
  name: Decreased DLCO
  description: >-
    An isolated reduction in the carbon monoxide diffusing capacity with normal
    spirometry and lung volumes is the commonest pulmonary function abnormality,
    and matches the alveolar septal fibrosis and capillary rarefaction seen on
    morphometry.
  phenotype_term:
    preferred_term: Decreased DLCO
    term:
      id: HP:0045051
      label: Decreased DLCO
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spirometric values, lung volumes, and measures of carbon monoxide diffusing capacity were within normal limits in 13 soldiers; 19 had an isolated low carbon monoxide diffusing capacity with normal spirometric values and lung volumes."
    explanation: >-
      Gives the pulmonary-function pattern, including how often everything is
      normal.
- category: Clinical
  name: Wheezing
  description: >-
    Wheeze is the commonest chronic respiratory symptom reported by deployed
    veterans and, with chronic bronchitis, forms part of the broader
    deployment-related respiratory disease presentation from which biopsy-proven
    constrictive bronchiolitis is separated.
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
  frequency: 15.6% in the past 12 months among deployed US veterans
  evidence:
  - reference: PMID:37968126
    reference_title: "Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The prevalence of dyspnoea, chronic bronchitis and wheeze in the past 12 months was 7.3%, 8.2% and 15.6%, respectively."
    explanation: >-
      Source of the frequency recorded above: 15.6% is the reported 12-month
      wheeze prevalence in this deployed-veteran cohort.
  - reference: PMID:37968126
    reference_title: "Chronic respiratory symptoms following deployment-related occupational and environmental exposures among US veterans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exposure to VGDF was associated with dyspnoea (OR 1.29; 95% CI 1.14 to 1.58) and wheeze (OR 1.18; 95% CI 1.02 to 1.35)."
    explanation: >-
      Associates wheeze with the deployment occupational exposure. This is an
      odds ratio, so it supports the phenotype-exposure link and not the
      frequency above.
histopathology:
- name: Extrinsic narrowing of membranous bronchioles by subepithelial fibrosis
  description: >-
    The diagnostic lesion, requiring surgical lung biopsy. Membranous bronchioles
    show mural thickening with mixed airway wall inflammation; larger airways and
    alveolar structures are otherwise normal on routine histology.
  finding_term:
    preferred_term: subepithelial fibrosis of membranous bronchioles
    term:
      id: NCIT:C3044
      label: Fibrosis
  diagnostic: true
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At low magnification, biopsy samples showed scattered small densities, which at higher magnification were identifiable as membranous bronchioles with variable mural thickening, mixed airway-wall inflammation, and peribronchiolar deposition of grayish black pigment."
    explanation: Describes the diagnostic histology as seen at biopsy.
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Alveolar structures and larger airways were otherwise normal in all 38 soldiers."
    explanation: >-
      Records the negative finding that makes the lesion bronchiolocentric on
      routine histology, in contrast with the quantitative morphometry that later
      found alveolar and pleural changes.
- name: Squamous metaplasia of the bronchiolar epithelium
  description: >-
    Epithelial thinning with squamous metaplasia accompanies the airway wall
    thickening, and is the specific feature shared with the club-cell-injury mouse
    model.
  finding_term:
    preferred_term: squamous metaplasia
    term:
      id: NCIT:C3237
      label: Squamous Metaplasia
  evidence:
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Histopathologic analysis of this biopsy revealed findings of squamous metaplasia and airway wall thickening (Figure 5, C and D) similar to those observed in CC-DTA mice on protocol day 20."
    explanation: Records the finding in human DRCB tissue alongside the model comparison.
imaging_findings:
- name: Expiratory air trapping on high-resolution chest CT
  modality: CT
  description: >-
    Imaging is normal in most affected personnel. Mild air trapping or
    centrilobular nodules are present in roughly a quarter, so a normal
    high-resolution CT does not exclude the disease, which is precisely why
    surgical biopsy has been needed.
  imaging_finding_term:
    preferred_term: Expiratory air trapping
    term:
      id: HP:0032968
      label: Expiratory air trapping
  frequency: About one quarter of biopsy-proven cases
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All soldiers with constrictive bronchiolitis had normal results on chest radiography, but about one quarter were found to have mosaic air trapping or centrilobular nodules on chest CT."
    explanation: Gives both the finding and its low sensitivity.
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this descriptive case series, 80 soldiers from Fort Campbell, Kentucky, with inhalational
      exposures during service in Iraq and Afghanistan were evaluated for dyspnea on exertion that
      prevented them from meeting the U.S. Army's standards for physical fitness. ... A total of 49
      soldiers underwent thoracoscopic lung biopsy after noninvasive evaluation did not provide an
      explanation for their symptoms. ... All soldiers with constrictive bronchiolitis had normal
      results on chest radiography, but about one quarter were found to have mosaic air trapping or
      centrilobular nodules on chest CT. ... Only a few soldiers had high-resolution CT showing the
      centrilobular nodularity or expiratory air trapping that can be associated with constrictive
      bronchiolitis.
    explanation: >-
      Restores deployment exposures, the reason for thoracoscopic biopsy and the CT results before
      the discussion sentence. The quarter-frequency result concerns air trapping or centrilobular
      nodules together, not a separate estimate for air trapping alone.
diagnosis:
- name: Surgical lung biopsy after an unrevealing noninvasive evaluation
  description: >-
    Because symptoms, examination, radiography and routine pulmonary function
    testing are all typically normal, the historical diagnostic pathway has been
    video-assisted thoracoscopic lung biopsy in symptomatic previously deployed
    personnel whose noninvasive workup found no explanation.
  diagnosis_term:
    preferred_term: surgical lung biopsy
    term:
      id: NCIT:C51748
      label: Lung Biopsy
  results: >-
    Extrinsic narrowing of membranous bronchioles by subepithelial fibrosis and/or
    smooth-muscle hypertrophy, with peribronchiolar pigment, in otherwise normal
    parenchyma.
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 49 soldiers underwent thoracoscopic lung biopsy after noninvasive evaluation did not provide an explanation for their symptoms."
    explanation: Describes the diagnostic pathway as actually applied in the index cohort.
- name: Quantitative CT phenotyping as a noninvasive alternative
  description: >-
    A quantitative CT-derived probability index built on biopsy-proven DRCB
    identifies a subset of symptomatic formerly deployed veterans with
    small-airway abnormality and more intense self-reported exposure effects. This
    is a research phenotyping tool, not a validated diagnostic test.
  diagnosis_term:
    preferred_term: quantitative chest computed tomography
    term:
      id: NCIT:C17204
      label: Computed Tomography
  results: >-
    Elevated functional small airways disease and high attenuation area relative
    to controls; a DRCB probability index above 0.5 selects veterans with
    oscillometric and quantitative-CT small airways disease.
  evidence:
  - reference: PMID:40399908
    reference_title: "Use of quantitative CT chest imaging to derive and assess a radiographic phenotype of deployment-related constrictive bronchiolitis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The FDSV subjects whose DRCB-PI was > 0.5 had greater evidence of small airways disease (assessed by oscillometry and QCT) and self-reported more intense immediate health effects to their exposures to military burn pit smoke, and sand and dust."
    explanation: Reports what the noninvasive index selects for.
differential_diagnoses:
- name: Asthma
  description: >-
    New-onset asthma is the other major post-deployment respiratory diagnosis and
    is the one for which the US Department of Veterans Affairs has issued a
    service-connection presumption. It is separated from constrictive
    bronchiolitis by bronchodilator responsiveness and by not requiring biopsy.
  distinguishing_features:
  - Reversible airflow obstruction with bronchodilator and controller response
  - Diagnosable noninvasively, without surgical lung biopsy
  - >-
    Constrictive bronchiolitis instead has fixed extrinsic airway narrowing,
    usually normal spirometry, and no approved pharmacotherapy
  evidence:
  - reference: PMID:35579689
    reference_title: "Histopathologic Insights into Distal Lung Injury and Inflammation following Military Deployment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the Department of Veterans Affairs acknowledged these exposure–disease linkages and issued a presumption connecting asthma, chronic rhinitis, and sinusitis diagnosed within 10 years of military service in veterans with particulate matter exposure during SWA military deployment (9)."
    explanation: >-
      Establishes asthma as the recognised alternative post-deployment respiratory
      diagnosis in the same exposed population.
- name: Other biopsy diagnoses in previously deployed personnel
  description: >-
    Eleven of the 49 biopsied soldiers in the index series had a different
    pathological diagnosis that explained their dyspnea. A previously deployed
    individual with unexplained dyspnea does not have constrictive bronchiolitis
    by default.
  distinguishing_features:
  - Established by the surgical lung biopsy itself
  - >-
    The Delphi consensus explicitly stresses considering alternative diagnoses
    before attributing symptoms to constrictive bronchiolitis
  evidence:
  - reference: PMID:21774710
    reference_title: "Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the remaining 11 soldiers, diagnoses other than constrictive bronchiolitis that could explain the presenting dyspnea were established."
    explanation: Quantifies the alternative-diagnosis yield in the index biopsy series.
  - reference: PMID:36343686
    reference_title: "Consensus Statements on Deployment-Related Respiratory Disease, Inclusive of Constrictive Bronchiolitis: A Modified Delphi Study."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Twenty-five of 28 statements reached consensus, including the definition of CB as a histologic pattern of lung injury that occurs in some previously deployed individuals while recognizing the importance of considering alternative diagnoses."
    explanation: Expert consensus that alternative diagnoses must be actively considered.
treatments:
- name: Cessation of further inhalational exposure
  description: >-
    Removing the individual from continuing inhalational hazard is the only
    intervention with a clear mechanistic rationale, since the disease is driven
    by sustained epithelial injury from a modifiable exposure. It is preventive
    rather than restorative: the established fibrotic narrowing does not reverse.
  treatment_term:
    preferred_term: exposure cessation
    term:
      id: NCIT:C15843
      label: Preventive Intervention
  therapeutic_modality: BEHAVIORAL
  target_mechanisms:
  - target: Sustained Club Cell Injury in Membranous Bronchioles
    description: >-
      Ending the exposure removes the driver of continuing club cell injury, which
      is the step the mouse model identifies as sufficient to initiate the lesion.
  notes: >-
    No trial has tested exposure cessation as an intervention in this disease; the
    rationale is mechanistic and preventive, and is recorded as such rather than
    as evidenced clinical benefit.
- name: Symptom-directed and supportive management
  description: >-
    In the absence of disease-modifying therapy, care is symptom-directed. Inhaled
    bronchodilator and corticosteroid trials are commonly given but have no
    demonstrated effect on the constrictive lesion.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:35579689
    reference_title: "Histopathologic Insights into Distal Lung Injury and Inflammation following Military Deployment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there is no currently approved pharmacotherapy for distal lung diseases such as post-deployment constrictive bronchiolitis."
    explanation: >-
      States the therapeutic vacuum this treatment entry exists to record; no
      disease-modifying option is claimed.
- name: Pulmonary rehabilitation
  description: >-
    Exercise-based rehabilitation for the exertional limitation that defines the
    presentation. Recorded as standard supportive management for a chronic
    exertional respiratory limitation; no trial in this specific population has
    been performed.
  treatment_term:
    preferred_term: pulmonary rehabilitation
    term:
      id: NCIT:C157966
      label: Pulmonary Rehabilitation
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  notes: >-
    Left deliberately without an evidence item: no study of pulmonary
    rehabilitation in deployment-related constrictive bronchiolitis was found, so
    there is no quotable result. Recorded because it is what patients receive, and
    flagged here rather than supported with a citation about a different disease.
animal_models:
- name: CC-DTA sustained club cell injury mouse
  species: Mouse
  genotype: >-
    CC-DTA (club-cell-restricted, doxycycline-inducible diphtheria toxin A),
    doxycycline for 10 consecutive days
  publication: PMID:34954211
  description: >-
    An inducible transgenic model in which diphtheria toxin A expression is
    restricted to club cells, producing sustained progenitor-cell injury without
    any inhaled toxicant. It reproduces the epithelial, inflammatory and fibrotic
    features of DRCB and allows the macrophage-TGF-beta limb to be tested
    interventionally.
  modeled_mechanisms:
  - target: Sustained Club Cell Injury in Membranous Bronchioles
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The model imposes the node directly, by targeted club cell death, rather
      than reproducing the exposure that is thought to cause it in humans.
    limitations: >-
      Club cell death is induced genetically by diphtheria toxin A, not by inhaled
      particulate matter, so the model asserts nothing about which deployment
      exposure produces club cell injury or at what dose. The authors chose this
      design precisely because the causative exposure type, dose and duration in
      humans are unknown.
    evidence:
    - reference: PMID:34954211
      reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ingestion of doxycycline by CC-DTA mice activates diphtheria toxin-A expression only in club cells, leading to targeted autonomous cell death."
      explanation: Describes how the model imposes the targeted club cell injury.
  - target: TGF-beta Activation and Myofibroblast Recruitment
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Depleting alveolar macrophages with clodronate liposomes lowers free active
      TGF-beta1 and reduces peribronchiolar collagen, placing macrophage-driven
      TGF-beta activation causally upstream of the fibrotic lesion.
    limitations: >-
      Clodronate liposome depletion is not compartment-selective over time, since
      exudate macrophages rebounded 7.3-fold, so the experiment cannot separate
      alveolar from recruited macrophage contributions, and the authors note an
      antifibrotic role for the rebounding population cannot be excluded.
    readouts:
    - name: Peribronchiolar collagen deposition
      target: TGF-beta Activation and Myofibroblast Recruitment
      direction: DECREASED
      interpretation: >-
        Macrophage depletion reduces the matrix endpoint of the fibrotic limb.
      evidence:
      - reference: PMID:34954211
        reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "More importantly, CL- versus empty liposome–treated doxycycline-exposed CC-DTA mice demonstrated a striking reduction in peribronchiolar collagen deposition, as assessed by picrosirius red and trichrome staining at protocol day 20 (Figure 8C) and quantified by total lung hydroxyproline assay (Figure 8D)."
        explanation: Reports the collagen measurement after macrophage depletion.
    - name: Free active TGF-beta1 in bronchoalveolar lavage fluid
      target: TGF-beta Activation and Myofibroblast Recruitment
      direction: DECREASED
      interpretation: >-
        Confirms the mediator itself falls, not only its downstream matrix
        endpoint.
      evidence:
      - reference: PMID:34954211
        reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Lastly, reduced peribronchiolar fibrosis in CL-treated doxycycline-exposed CC-DTA mice was associated with substantial decreased levels of free activated TGF-β1 in BALF (relative to doxycycline-exposed CC-DTA mice receiving Els) (Figure 8E)."
        explanation: Reports the TGF-beta1 measurement accompanying the collagen reduction.
    evidence:
    - reference: PMID:34954211
      reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "depletion of alveolar macrophages in mice subjected to sustained club cell injury decreased activation of TGF-β and ameliorated CB."
      explanation: >-
        Supports treating this model as informative for the macrophage-TGF-beta
        node.
  - target: Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Sustained club cell injury produces airway wall thickening with subepithelial
      matrix deposition, peribronchiolar infiltrates and intraluminal macrophage
      clusters that match the human lesion.
    limitations: >-
      The comparison on the human side rested on a very small amount of tissue:
      the authors state that quantitative or semiquantitative analysis of
      macrophage accumulation in DRCB was constrained by the paucity of research
      tissue, so the correspondence is qualitative and image-based.
    evidence:
    - reference: PMID:34954211
      reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Comparative histopathologic analysis demonstrated that sustained club cell injury was sufficient to induce epithelial metaplasia, airway wall thickening, peribronchiolar infiltrates, and clusters of intraluminal airway macrophages that recapitulated key abnormalities observed in DRCB."
      explanation: States the histopathologic correspondence with the human lesion.
  evidence:
  - reference: PMID:34954211
    reference_title: "Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Collectively, these findings implicate sustained club cell injury in the development of DRCB and delineate pathways that may yield biomarkers and treatment targets for this disorder."
    explanation: The authors' own statement of what the model is informative for.
- name: Repetitive sulfur dioxide exposure mouse
  species: Mouse
  genotype: Wild-type, with a Sirtuin-3 overexpressing transgenic arm
  publication: PMID:38410870
  description: >-
    An inhalational model built around the sulfur dioxide exposure reported by the
    index cohort. It reproduces adaptive immune activation, airway wall remodeling
    and pulmonary vascular disease, and identifies endothelial oxidative stress
    (isolevuglandin adducts, SOD2 acetylation) as the driver of the vascular limb.
  modeled_mechanisms:
  - target: Distal Pulmonary Arterial Remodeling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Repetitive sulfur dioxide produces pulmonary vascular remodeling that causes
      pulmonary hypertension and reduced exercise tolerance, and the remodeling is
      prevented by scavenging isolevuglandins or by Sirtuin-3 overexpression.
    limitations: >-
      Pulmonary hypertension has not been established as a feature of human DRCB;
      this model assigns the exercise limitation to the vascular compartment on the
      strength of a mouse phenotype. Sulfur dioxide is also only one of the
      candidate deployment exposures and was not reported by a substantial fraction
      of the index cohort.
    readouts:
    - name: Pulmonary vascular remodeling after isolevuglandin scavenging
      target: Distal Pulmonary Arterial Remodeling
      direction: ABOLISHED
      interpretation: >-
        Identifies the isolevuglandin-Sirt3-SOD2 oxidative axis as necessary for
        the vascular lesion in this model.
      evidence:
      - reference: PMID:38410870
        reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "In addition, 2-HOBA treatment or Siruin-3 overexpression in a transgenic mouse model prevented vascular remodeling following SO2 exposure."
        explanation: Reports the two interventions that prevented the vascular remodeling.
    evidence:
    - reference: PMID:38410870
      reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress appears to mediate PV remodeling in this model."
      explanation: >-
        The authors' statement of what the model recapitulates and the mediator it
        implicates.
  - target: Sustained Club Cell Injury in Membranous Bronchioles
    relationship: PERTURBS
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Inhaled sulfur dioxide is delivered by the physiological route and produces
      airway wall remodeling, so unlike the CC-DTA model it tests an actual
      deployment-relevant inhalational exposure.
    limitations: >-
      The model does not demonstrate club-cell-specific injury; it shows airway
      wall remodeling downstream of an inhalational exposure, so the mapping onto
      this specific node is inferred from the CC-DTA work rather than shown here.
    evidence:
    - reference: PMID:38410870
      reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular (PV) disease."
      explanation: States the airway and immune features the inhalational model reproduces.
  evidence:
  - reference: PMID:38410870
    reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SO2 exposure led to increased formation of isolevuglandins (isoLGs) adducts and superoxide dismutase 2 (SOD2) acetylation in endothelial cells, which were attenuated by treatment with the isoLG scavenger 2-hydroxybenzylamine acetate (2-HOBA)."
    explanation: The molecular finding that makes this model informative beyond phenotype matching.
discussions:
- discussion_id: open_mondo_anchor
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Should a MONDO new-term request be filed for deployment-related constrictive
    bronchiolitis, or is `MONDO:0100127` toxic bronchiolitis obliterans an
    adequate home for it?
  attaches_to:
  - disease#Deployment-Related Constrictive Bronchiolitis
  rationale: >-
    MONDO has no class for this entity under any of its three names (DRCB, PDRS,
    DRRD). The nearest class, `MONDO:0100127` toxic bronchiolitis obliterans, is
    strictly broader and also covers diacetyl, nitrogen dioxide and sulfur mustard
    bronchiolitis. The argument for a distinct class is that this entity has a
    defining exposure setting, an operational histologic threshold (20% airway
    wall thickening), a distinctive normal-spirometry phenotype, and a
    multicompartmental pathology that ordinary toxic bronchiolitis obliterans does
    not carry. The argument against is that it may be the same lesion with a
    different exposure, in which case a MONDO class would encode an
    epidemiological grouping rather than a disease. The dismech agent cannot file
    in the MONDO tracker; this needs a curator to forward it.
  notes: >-
    Until this resolves, the entry has no `disease_term` and records
    `MONDO:0100127` as a `skos:narrowMatch` mapping instead.
- discussion_id: interp_drcb_pdrs_drrd_naming
  kind: INTERPRETATION
  status: OPEN
  prompt: >-
    Is this entry one disease with three names, or has the entity's scope
    genuinely widened from a bronchiolar lesion to a multicompartmental one?
  attaches_to:
  - disease#Deployment-Related Constrictive Bronchiolitis
  - pathophysiology#Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
  - pathophysiology#Interalveolar Septal Fibrosis and Capillary Rarefaction
  - pathophysiology#Visceral Pleural Inflammation and Fibrosis
  rationale: >-
    The 2011 index series described a bronchiolocentric lesion in otherwise normal
    parenchyma. Quantitative morphometry of overlapping and later biopsies then
    found arterial, alveolar-septal and pleural changes in the same lungs, and the
    Vanderbilt group renamed the entity post-deployment respiratory syndrome to
    reflect that. A 2023 Delphi panel took a third position: it kept constrictive
    bronchiolitis as a histologic pattern and introduced deployment-related
    respiratory disease as a broad clinical descriptor subsuming it. These are not
    simply synonyms, because they disagree about whether the bronchiole is the
    seat of the disease. This entry is curated at the biopsy-defined entity and
    records all three names as synonyms, with the non-bronchiolar compartments as
    their own pathophysiology nodes so the disagreement is visible in the
    pathograph rather than buried in prose.
  evidence:
  - reference: PMID:36343686
    reference_title: "Consensus Statements on Deployment-Related Respiratory Disease, Inclusive of Constrictive Bronchiolitis: A Modified Delphi Study."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "deployment-related respiratory disease (DRRD) was proposed as a broad term to subsume a wide range of potential syndromes and conditions identified through noninvasive evaluation or when surgical lung biopsy reveals evidence of multicompartmental lung injury that may include CB."
    explanation: The consensus position that DRRD is the umbrella and CB one pattern within it.
  - reference: PMID:34081035
    reference_title: "Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diffuse fibrosis with excessive collagen accumulation in airway walls, blood vessel walls, alveolar tissue, and visceral pleura is a prominent pathologic feature detected in the lungs of soldiers with PDRS."
    explanation: The multicompartmental claim that motivated the PDRS renaming.
- discussion_id: kgap_particulate_causality
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is the retained peribronchiolar particulate material causal, or only a marker
    of exposure intensity?
  attaches_to:
  - pathophysiology#Retained Peribronchiolar Particulate Burden
  rationale: >-
    Near every biopsy in the index series showed peribronchiolar pigment with
    polarizable material, and burn-pit combustion signatures are recoverable from
    lung tissue, but no study has shown that the retained material drives the
    fibrotic lesion rather than co-occurring with the exposure that does. The 2026
    ATS workshop names this explicitly as one of three outstanding gaps, and the
    leading mechanistic model deliberately bypasses the question by inducing club
    cell injury genetically.
  evidence:
  - reference: PMID:42360728
    reference_title: "Deployment-related respiratory health: bridging the gap between clinical and epidemiological associations and disease mechanisms: an official American Thoracic Society Workshop Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the contribution of exposure-related foreign material in the lung to clinical and pathologic findings"
    explanation: The ATS workshop's own statement of this gap.
- discussion_id: kgap_exposure_dose_response
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which specific deployment exposures, at what dose and duration, produce small
    airways disease?
  attaches_to:
  - environmental#Deployment inhalation of respirable particulate matter
  - pathophysiology#Distal Deposition of Respirable Deployment Particulate Matter
  rationale: >-
    Individual-level exposure was never measured during deployment, so every
    exposure-response analysis rests on retrospective self-report. The index cohort
    contains soldiers with an identified point-source exposure and soldiers with
    none whose disease was indistinguishable, so no single agent accounts for the
    entity. Closing this gap requires either historical exposure reconstruction or
    prospective monitoring in future deployments.
  evidence:
  - reference: PMID:42360728
    reference_title: "Deployment-related respiratory health: bridging the gap between clinical and epidemiological associations and disease mechanisms: an official American Thoracic Society Workshop Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the extent and mechanisms through which specific exposures result in impaired pulmonary function, small airways disease, and potentially future chronic pulmonary diseases"
    explanation: The ATS workshop's statement of the exposure-mechanism gap.
- discussion_id: hmm_pulmonary_hypertension_vascular_limb
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    The sulfur dioxide mouse attributes exercise limitation to pulmonary vascular
    disease rather than to the airway lesion; does that hold in humans, where
    pulmonary hypertension is not an established feature of this disease?
  attaches_to:
  - pathophysiology#Distal Pulmonary Arterial Remodeling
  - phenotypes#Exercise intolerance
  rationale: >-
    In the sulfur dioxide model, small airway abnormalities were explicitly not
    sufficient to alter lung mechanics, and it was pulmonary vascular remodeling
    that produced pulmonary hypertension and reduced exercise tolerance. Human
    morphometry does show arterial muscularization and raised wall-to-lumen ratio
    in the same lungs, so the substrate is present, but pulmonary hypertension is
    not a reported clinical feature of DRCB and the human exercise limitation is
    usually attributed to the airway lesion. If the mouse is right, the disease is
    being investigated in the wrong compartment and the diagnostic pathway, which
    is built around airway histology, is looking in the wrong place. If it is
    wrong, the model's headline physiological result does not transfer.
  proposed_experiments:
  - experiment_id: exp_drcb_exercise_hemodynamics
    name: Right heart catheterisation and cardiopulmonary exercise testing in biopsy-proven DRCB
    description: >-
      Measure pulmonary artery pressures and pulmonary vascular resistance at rest
      and during exercise in individuals with biopsy-proven DRCB, alongside
      quantitative-CT small airways measures, and test which better explains the
      exercise limitation.
    would_support:
    - pathophysiology#Distal Pulmonary Arterial Remodeling
    supporting_outcome:
    - >-
      Exercise pulmonary vascular resistance correlates with exercise limitation
      independently of quantitative-CT functional small airways disease.
    would_refute:
    - pathophysiology#Distal Pulmonary Arterial Remodeling
    refuting_outcome:
    - >-
      Pulmonary haemodynamics are normal at rest and on exercise, and the
      limitation tracks small airways measures alone.
  evidence:
  - reference: PMID:38410870
    reference_title: "Repetitive sulfur dioxide exposure in mice models post-deployment respiratory syndrome."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Although abnormalities in small airways were not sufficient to alter lung mechanics, PV remodeling resulted in the development of pulmonary hypertension and reduced exercise tolerance in SO2-exposed mice."
    explanation: The model result that creates the mismatch with the human framing.
- discussion_id: curation_todo_occupational_smallairway_module
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Should the inhaled-particulate to small-airway-fibrosis chain be factored out
    into a mechanism module that this entry, Sulfur_Mustard_Poisoning and other
    inhalational bronchiolitis entries could conform to?
  attaches_to:
  - pathophysiology#Sustained Club Cell Injury in Membranous Bronchioles
  - pathophysiology#Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles
  rationale: >-
    Issue #10976 raised the module option alongside the disease-entry option. This
    entry took the disease-entry route because the entity has its own exposure
    setting, diagnostic criteria and natural history. A module remains attractive,
    since the club-cell-injury-to-peribronchiolar-fibrosis chain is not specific to
    deployment, but it needs at least two other entries with curated bronchiolar
    nodes to conform to it, and today only Sulfur_Mustard_Poisoning describes
    bronchiolitis obliterans mechanistically. The generic fibrotic chain is already
    covered by `conforms_to` links to `fibrotic_response` on five nodes here, so a
    new module would have to earn its place by adding the airway-specific steps
    (club cell progenitor loss, squamous metaplasia, extrinsic luminal narrowing)
    that `fibrotic_response` does not carry.
review_notes: >-
  Curated from issue #10976 (ATS workshop report PMID:42360728). Scope decision:
  curated as the biopsy-defined mechanistic entity rather than as the broad DRRD
  umbrella, because DRRD explicitly subsumes asthma and chronic rhinosinusitis,
  which are separate diseases with their own mechanisms, and a dismech Grouping
  needs existing member entries it does not yet have. See the
  `interp_drcb_pdrs_drrd_naming` discussion.

  Deliberately not curated here: pulmonary hypertension is NOT recorded as a human
  phenotype. It is a mouse result, and recording it as a human feature would be
  exactly the model-to-human over-reach the
  `hmm_pulmonary_hypertension_vascular_limb` discussion exists to flag. Genetic
  susceptibility is likewise absent; no gene-level work in this disease was found,
  and the entry says nothing rather than speculating.

  Every mouse-derived evidence item carries `evidence_source: MODEL_ORGANISM`, and
  those used to support a step in the human chain are additionally graded
  `directness: INDIRECT`. One sentence from PMID:34954211, a mouse-model paper,
  reports its human comparison arm and is graded `HUMAN_CLINICAL` for the tissue
  it describes. Human histopathology and physiology claims are all sourced to
  human series.

  No deep-research report backs this entry. The structured source used in its
  place is the American Thoracic Society Workshop Report on deployment-related
  respiratory health (PMID:42360728), which supplied the entity definition, the
  scope boundary against DRRD, and the reference trail followed into the primary
  literature. A
  deep-research run over this disease would still be worth doing and is not
  blocked by anything here.

  Three pathophysiology nodes carry no upstream edge on purpose - Lymphocytic
  Bronchiolitis and Lymphoid Follicle Formation, Distal Pulmonary Arterial
  Remodeling, and Interalveolar Septal Fibrosis and Capillary Rarefaction. The
  sources treat these as compartments of one diffuse multicompartment injury
  without placing a mechanism node upstream of them, so each node's `notes`
  records that rather than the graph asserting an unsourced edge.
📚

References & Deep Research

References

4
PMID:21774710
Constrictive bronchiolitis in soldiers returning from Iraq and Afghanistan.
No top-level findings curated for this source.
PMID:34081035
Postdeployment Respiratory Syndrome in Soldiers With Chronic Exertional Dyspnea.
No top-level findings curated for this source.
PMID:42360728
Deployment-related respiratory health: bridging the gap between clinical and epidemiological associations and disease mechanisms: an official American Thoracic Society Workshop Report.
No top-level findings curated for this source.
PMID:36343686
Consensus Statements on Deployment-Related Respiratory Disease, Inclusive of Constrictive Bronchiolitis: A Modified Delphi Study.
No top-level findings curated for this source.