Pulmonary Hemosiderosis

Respiratory Disease MONDO:0008346 Pathograph 40 Show in embeddings browser Respiratory disease Hemosiderosis

Pulmonary hemosiderosis is a rare respiratory disorder, usually represented clinically by idiopathic pulmonary hemosiderosis, in which recurrent diffuse alveolar hemorrhage causes blood to enter alveolar spaces. Alveolar macrophages ingest erythrocytes and accumulate hemosiderin, producing hemosiderin-laden macrophages in sputum, gastric aspirate, bronchoalveolar lavage, or lung tissue. Patients commonly present in childhood with iron deficiency anemia, cough, hemoptysis, pulmonary infiltrates or ground-glass opacities, dyspnea, and relapsing pulmonary hemorrhage. The initiating cause is idiopathic after exclusion of infections, cardiac disease, coagulation disorders, connective-tissue disease, vasculitis, celiac disease/Lane-Hamilton syndrome, and other secondary causes of diffuse alveolar hemorrhage.

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Classifications

Harrison's Part
RESPIRATORY IMMUNE RHEUMATOLOGIC
📘

Definitions

1
Orphanet idiopathic pulmonary hemosiderosis definition
A respiratory disease, most often beginning in childhood, caused by repeated episodes of otherwise unexplained diffuse alveolar hemorrhage with anemia, cough, and chest-imaging infiltrates.
OTHER
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"Idiopathic pulmonary hemosiderosis is a respiratory disease due to repeated episodes of diffuse alveolar hemorrhage without any underlying apparent cause"
Orphanet defines IPH by unexplained repeated diffuse alveolar hemorrhage.
PMID:30278795 SUPPORT Human clinical
"Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder that is responsible for recurrent episodes of diffuse alveolar hemorrhage"
The 107-patient pediatric cohort supports recurrent diffuse alveolar hemorrhage as the central clinical definition.
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Inheritance

1
Sporadic HP:0003745
Idiopathic pulmonary hemosiderosis occurs sporadically in the vast majority of patients, although occasional familial clustering and overrepresentation of Down syndrome (trisomy 21) in pediatric cohorts suggest underlying genetic or immunogenetic susceptibility factors.
Sporadic
Show evidence (2 references)
PMID:30278795 SUPPORT Human clinical
"All of the patients were sporadic patients, comprising 42 boys and 65 girls."
All 107 pediatric IPH cases in the largest single-center cohort were sporadic.
PMID:30278795 SUPPORT Human clinical
"In the present study, all of our patients were sporadic, with the highest incidence among 3- to 6-year-olds, similar to patients reported in previous studies."
Confirms sporadic occurrence across the cohort and consistency with prior pediatric series.
⚙

Pathophysiology

4
Recurrent idiopathic diffuse alveolar hemorrhage
The initiating lesion is recurrent bleeding into alveolar spaces without an identified secondary cause. Proposed environmental, allergic, autoimmune, and genetic contributors remain hypotheses rather than established causes.
alveolar capillary endothelial cell CL:0002144 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves alveolar capillary endothelial cell, annotated with capillary endothelial cell (CL:0002144). CL:0002144 is a cell type from the Cell Ontology.
hemostasis GO:0007599 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated hemostasis (GO:0007599). GO:0007599 is a biological process from the Gene Ontology. vascular permeability regulation GO:0043114 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated vascular permeability regulation, annotated with regulation of vascular permeability (GO:0043114). GO:0043114 is a biological process from the Gene Ontology.
alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Hemosiderin-laden alveolar macrophage accumulation
Recurrent hemorrhage-driven lung injury and remodeling
Diffuse alveolar hemorrhage
Hemoptysis
Cough
Dyspnea
Crackles
Fever
Pulmonary infiltrates
Ground-glass opacification on pulmonary HRCT
Nodular pattern on pulmonary HRCT
Show evidence (2 references)
PMID:15293620 SUPPORT REVIEW SYNTHESIS Human clinical
"Idiopathic pulmonary haemosiderosis is a rare cause of diffuse alveolar haemorrhage of unknown aetiology."
The clinical review supports unexplained diffuse alveolar hemorrhage as the initiating lesion.
PMID:30278795 SUPPORT Human clinical
"There are four main etiological hypotheses of IPH described in the literature, including environmental, allergic, autoimmune, and genetic hypotheses."
The cohort review supports keeping the upstream cause as unresolved rather than assigning a single causal trigger.
Autoimmune serologic contribution to hemorrhage susceptibility
A subset of pediatric idiopathic pulmonary hemosiderosis cases show ANCA, ANA, or coeliac antibody positivity, supporting autoimmunity as a modifier or contributor rather than a universal primary cause.
immune response GO:0006955 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated immune response (GO:0006955). GO:0006955 is a biological process from the Gene Ontology.
Downstream
Recurrent idiopathic diffuse alveolar hemorrhage
Autoimmune antibody positivity
Smooth muscle antibody positivity
Antineutrophil antibody positivity
Antinuclear antibody positivity
Rheumatoid factor positive
Show evidence (2 references)
PMID:24125570 SUPPORT Human clinical
"In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%)."
The cohort documents autoimmune serology in screened children with IPH, supporting an immune contribution in a subset.
PMID:24125570 SUPPORT Human clinical
"Analysis of potential contributors supports a role of auto-immunity in disease development and highlights the importance of genetic factors."
The authors explicitly interpret potential contributors as supporting an autoimmune role in disease development.
Hemosiderin-laden alveolar macrophage accumulation
Alveolar macrophages phagocytose extravasated erythrocytes after repeated hemorrhage and accumulate hemosiderin iron. Detection of these siderophages in sputum, gastric lavage fluid, bronchoalveolar lavage fluid, or lung tissue is a diagnostic hallmark and links pulmonary blood loss to systemic iron deficiency.
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.
phagocytosis GO:0006909 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased phagocytosis (GO:0006909). GO:0006909 is a biological process from the Gene Ontology. heme catabolic process GO:0042167 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased heme catabolic process (GO:0042167). GO:0042167 is a biological process from the Gene Ontology. intracellular iron ion homeostasis GO:0006879 ↕ DYSREGULATED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated intracellular iron ion homeostasis (GO:0006879). GO:0006879 is a biological process from the Gene Ontology.
alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Iron deficiency anemia
Pallor
Fatigue
Show evidence (2 references)
PMID:15293620 SUPPORT REVIEW SYNTHESIS Human clinical
"Many patients develop iron deficiency anaemia secondary to deposition of haemosiderin iron in the alveoli."
The clinical review connects alveolar hemosiderin deposition with iron deficiency anemia.
PMID:30278795 SUPPORT Human clinical
"Hemosiderin-laden macrophages were found in all of the patients."
The 107-patient cohort supports hemosiderin-laden macrophages as a consistent diagnostic finding.
Recurrent hemorrhage-driven lung injury and remodeling
Recurrent alveolar bleeding, iron/heme deposition, and inflammatory repair injure alveolar units and can progress to restrictive physiology, respiratory failure, and pulmonary fibrosis in severe or relapsing disease.
pulmonary alveolar type 2 cell CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 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.
wound healing GO:0042060 ↕ DYSREGULATED 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. response to oxidative stress GO:0006979 ↑ INCREASED 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. extracellular matrix organization GO:0030198 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology.
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
Restrictive ventilatory defect
Pulmonary fibrosis
Reticular pattern on pulmonary HRCT
Respiratory failure
Show evidence (2 references)
PMID:30278795 SUPPORT Human clinical
"Death may quickly occur with acute, massive, pulmonary hemorrhage or may occur over longer periods as the result of continued respiratory insufficiency and heart failure."
The cohort review supports chronic respiratory insufficiency as a consequence of persistent or recurrent pulmonary hemorrhage.
PMID:24125570 SUPPORT Human clinical
"One patient developed severe pulmonary fibrosis, and another with Down syndrome died as a result of severe pulmonary hemorrhage."
The French cohort supports pulmonary fibrosis as a severe downstream complication.
✶

Histopathology

1
Hemosiderin-laden alveolar macrophages without vasculitis
Sputum, bronchoalveolar lavage fluid, gastric lavage fluid, or lung biopsy can show siderophages reflecting prior alveolar hemorrhage; classic IPH lacks pulmonary vasculitis or immune-complex deposition on biopsy.
Show evidence (2 references)
PMID:15293620 SUPPORT REVIEW SYNTHESIS Human clinical
"Examination of sputum and bronchoalveolar lavage fluid can disclose haemosiderin-laden alveolar macrophages (siderophages)"
The review supports siderophages in respiratory samples as a characteristic finding.
PMID:15293620 SUPPORT REVIEW SYNTHESIS Human clinical
"the lung biopsy shows numerous siderophages in the alveoli, without any evidence of pulmonary vasculitis"
The review supports numerous alveolar siderophages without vasculitis as a histopathologic pattern.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Pulmonary Hemosiderosis Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

30
Blood 2
Iron deficiency anemia VERY_FREQUENT HP:0001891 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is iron deficiency anemia (HP:0001891). HP:0001891 is a phenotype from the Human Phenotype Ontology.
Sequelae: Failure to thrive Cardiomegaly Heart murmur Hepatosplenomegaly Hepatomegaly
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0001891 | Iron deficiency anemia | Very frequent (99-80%)"
Orphanet records iron deficiency anemia as very frequent.
PMID:30278795 SUPPORT Human clinical
"anemia (n = 100, 93.45%)"
The pediatric cohort found anemia in 100 of 107 patients.
Diffuse alveolar hemorrhage OCCASIONAL HP:0025420 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is diffuse alveolar hemorrhage (HP:0025420). HP:0025420 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0025420 | Diffuse alveolar hemorrhage | Occasional (29-5%)"
Orphanet records diffuse alveolar hemorrhage as occasional.
PMID:15293620 SUPPORT REVIEW SYNTHESIS Human clinical
"repetitive episodes of diffuse alveolar haemorrhage"
The clinical review supports recurrent diffuse alveolar hemorrhage as central to IPH.
Cardiovascular 3
Hepatosplenomegaly FREQUENT HP:0001433 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hepatosplenomegaly (HP:0001433). HP:0001433 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
Orphanet records hepatosplenomegaly as frequent.
Cardiomegaly OCCASIONAL HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0001640 | Cardiomegaly | Occasional (29-5%)"
Orphanet records cardiomegaly as occasional.
Heart murmur OCCASIONAL HP:0030148 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is heart murmur (HP:0030148). HP:0030148 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0030148 | Heart murmur | Occasional (29-5%)"
Orphanet records heart murmur as occasional.
Digestive 1
Hepatomegaly OCCASIONAL HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0002240 | Hepatomegaly | Occasional (29-5%)"
Orphanet records hepatomegaly as occasional.
Genitourinary 1
Glomerulonephritis VERY_RARE HP:0000099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is glomerulonephritis (HP:0000099). HP:0000099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0000099 | Glomerulonephritis | Very rare (<4-1%)"
Orphanet records glomerulonephritis as very rare.
Immune 7
Rheumatoid factor positive OCCASIONAL HP:0002923 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is rheumatoid factor positive (HP:0002923). HP:0002923 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0002923 | Rheumatoid factor positive | Occasional (29-5%)"
Orphanet records rheumatoid factor positivity as occasional.
Smooth muscle antibody positivity OCCASIONAL Anti-smooth muscle antibody positivity HP:0003262 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is smooth muscle antibody positivity, annotated with Anti-smooth muscle antibody positivity (HP:0003262). HP:0003262 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0003262 | Smooth muscle antibody positivity | Occasional (29-5%)"
Orphanet records smooth muscle antibody positivity as occasional.
Antineutrophil antibody positivity OCCASIONAL HP:0003453 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is antineutrophil antibody positivity (HP:0003453). HP:0003453 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0003453 | Antineutrophil antibody positivity | Occasional (29-5%)"
Orphanet records antineutrophil antibody positivity as occasional.
Antinuclear antibody positivity OCCASIONAL HP:0003493 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is antinuclear antibody positivity (HP:0003493). HP:0003493 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0003493 | Antinuclear antibody positivity | Occasional (29-5%)"
Orphanet records antinuclear antibody positivity as occasional.
Allergy OCCASIONAL HP:0012393 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is allergy (HP:0012393). HP:0012393 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0012393 | Allergy | Occasional (29-5%)"
Orphanet records allergy as occasional.
Autoimmune antibody positivity OCCASIONAL HP:0030057 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is autoimmune antibody positivity (HP:0030057). HP:0030057 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0030057 | Autoimmune antibody positivity | Occasional (29-5%)"
Orphanet records autoimmune antibody positivity as occasional.
Cow milk allergy VERY_RARE HP:0100327 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cow milk allergy (HP:0100327). HP:0100327 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0100327 | Cow milk allergy | Very rare (<4-1%)"
Orphanet records cow milk allergy as very rare.
Integument 1
Pallor FREQUENT HP:0000980 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pallor (HP:0000980). HP:0000980 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0000980 | Pallor | Frequent (79-30%)"
Orphanet records pallor as frequent.
Metabolism 1
Fever OCCASIONAL HP:0001945 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is fever (HP:0001945). HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0001945 | Fever | Occasional (29-5%)"
Orphanet records fever as occasional.
Respiratory 11
Hemoptysis FREQUENT HP:0002105 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is hemoptysis (HP:0002105). HP:0002105 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0002105 | Hemoptysis | Frequent (79-30%)"
Orphanet records hemoptysis as frequent.
PMID:30278795 SUPPORT Human clinical
"hemoptysis (n = 61, 57%)"
The pediatric cohort found hemoptysis in 61 of 107 patients at diagnosis.
Pulmonary infiltrates FREQUENT HP:0002113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pulmonary infiltrates (HP:0002113). HP:0002113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0002113 | Pulmonary infiltrates | Frequent (79-30%)"
Orphanet records pulmonary infiltrates as frequent.
Cough FREQUENT HP:0012735 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cough (HP:0012735). HP:0012735 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0012735 | Cough | Frequent (79-30%)"
Orphanet records cough as frequent.
PMID:30278795 SUPPORT Human clinical
"cough (n = 68, 63.55%)"
The pediatric cohort found cough in 68 of 107 patients at diagnosis.
Ground-glass opacification on pulmonary HRCT FREQUENT HP:0025179 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is ground-glass opacification on pulmonary HRCT, annotated with Ground-glass opacification (HP:0025179). HP:0025179 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0025179 | Ground-glass opacification on pulmonary HRCT | Frequent (79-30%)"
Orphanet records ground-glass opacification on pulmonary HRCT as frequent.
Restrictive ventilatory defect OCCASIONAL HP:0002091 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is restrictive ventilatory defect (HP:0002091). HP:0002091 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0002091 | Restrictive ventilatory defect | Occasional (29-5%)"
Orphanet records restrictive ventilatory defect as occasional.
Dyspnea OCCASIONAL HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0002094 | Dyspnea | Occasional (29-5%)"
Orphanet records dyspnea as occasional.
PMID:24125570 SUPPORT Human clinical
"dyspnea (n = 17, 68%)"
The French cohort recorded dyspnea at diagnosis in 17 of 25 children.
Pulmonary fibrosis OCCASIONAL HP:0002206 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pulmonary fibrosis (HP:0002206). HP:0002206 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0002206 | Pulmonary fibrosis | Occasional (29-5%)"
Orphanet records pulmonary fibrosis as occasional.
PMID:24125570 SUPPORT Human clinical
"One patient developed severe pulmonary fibrosis"
The French cohort documents pulmonary fibrosis as a severe complication.
Respiratory failure OCCASIONAL HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:99931 SUPPORT Other
"HP:0002878 | Respiratory failure | Occasional (29-5%)"
Orphanet records respiratory failure as occasional.
PMID:30278795 SUPPORT Human clinical
"three died from massive pulmonary hemorrhage and respiratory failure"
The pediatric cohort documents respiratory failure in fatal severe presentations.
Reticular pattern on pulmonary HRCT OCCASIONAL HP:0025390 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is reticular pattern on pulmonary HRCT (HP:0025390). HP:0025390 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0025390 | Reticular pattern on pulmonary HRCT | Occasional (29-5%)"
Orphanet records reticular pattern on pulmonary HRCT as occasional.
Nodular pattern on pulmonary HRCT OCCASIONAL HP:0025392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is nodular pattern on pulmonary HRCT (HP:0025392). HP:0025392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0025392 | Nodular pattern on pulmonary HRCT | Occasional (29-5%)"
Orphanet records nodular pattern on pulmonary HRCT as occasional.
Crackles OCCASIONAL HP:0030830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is crackles (HP:0030830). HP:0030830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0030830 | Crackles | Occasional (29-5%)"
Orphanet records crackles as occasional.
Constitutional 1
Fatigue FREQUENT HP:0012378 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is fatigue (HP:0012378). HP:0012378 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0012378 | Fatigue | Frequent (79-30%)"
Orphanet records fatigue as frequent.
Growth 1
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"HP:0001508 | Failure to thrive | Occasional (29-5%)"
Orphanet records failure to thrive as occasional.
Other 1
Down syndrome OCCASIONAL MONDO:0008608 Mondo Disease Ontology (MONDO) Relation: this clinical feature is this phenotype This clinical feature is Down syndrome (MONDO:0008608). MONDO:0008608 is a phenotype from the Mondo Disease Ontology.
Show evidence (1 reference)
PMID:24125570 SUPPORT Human clinical
"We identified 25 reported cases of IPH in children from the database (20 females and 5 males). Among them, 5 presented with Down syndrome."
The French pediatric cohort documents Down syndrome in 5 of 25 IPH cases, supporting an occasional comorbidity association.
🗃️

External Assertions

1
Orphanet idiopathic pulmonary hemosiderosis record
Orphanet structured disease record ORPHA:99931
Orphanet's ORPHA:99931 structured record provides the disease definition, childhood age of onset, epidemiology, cross-references, and HPO phenotype rows used in this entry.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"OMIM:178550 | Exact"
Orphanet records an exact OMIM cross-reference for idiopathic pulmonary hemosiderosis.
💊

Medical Actions

3
Systemic corticosteroid therapy
Action: corticosteroid agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is corticosteroid agent therapy, annotated with Systemic Corticosteroid Therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. Ontology label: Systemic Corticosteroid Therapy NCIT:C122080
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest. prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest.
Systemic corticosteroids are first-line therapy for acute episodes and are commonly used for initial control and maintenance, though recurrence during tapering is frequent.
Mechanism Target:
Recurrent idiopathic diffuse alveolar hemorrhage — Suppresses acute alveolar capillary bleeding and reduces relapse frequency.
Autoimmune serologic contribution to hemorrhage susceptibility — Attenuates immune-mediated inflammatory contributions to alveolar hemorrhage.
Recurrent hemorrhage-driven lung injury and remodeling — Limits hemorrhage-driven alveolar inflammation and progression toward pulmonary fibrosis.
Show evidence (3 references)
PMID:30278795 SUPPORT Human clinical
"Glucocorticoids and immunosuppressive agents are the first choice for treating IPH."
The pediatric cohort review supports glucocorticoids as first-choice treatment.
PMID:26289251 SUPPORT Human clinical
"Common medications respondents used for treatment at initial presentation and chronic maintenance therapy were corticosteroids (98.7 and 84.0 %, initial and chronic therapy respectively)"
The international physician survey supports common corticosteroid use for initial and chronic therapy.
PMID:33184706 SUPPORT REVIEW SYNTHESIS Human clinical
"Corticosteroid therapy represents the first line of treatment"
The treatment review supports corticosteroids as first-line therapy.
Steroid-sparing immunosuppressive therapy
Action: immune suppressant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is immune suppressant agent therapy, annotated with Immunosuppressive Therapy (NCIT:C15261). NCIT:C15261 is a clinical intervention from the NCI Thesaurus. Ontology label: Immunosuppressive Therapy NCIT:C15261
Agent: hydroxychloroquine CHEBI:5801 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydroxychloroquine (CHEBI:5801). CHEBI:5801 is a therapeutic agent from Chemical Entities of Biological Interest. azathioprine CHEBI:2948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azathioprine (CHEBI:2948). CHEBI:2948 is a therapeutic agent from Chemical Entities of Biological Interest. cyclophosphamide CHEBI:4027 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclophosphamide (CHEBI:4027). CHEBI:4027 is a therapeutic agent from Chemical Entities of Biological Interest. mycophenolate mofetil CHEBI:8764 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses mycophenolate mofetil (CHEBI:8764). CHEBI:8764 is a therapeutic agent from Chemical Entities of Biological Interest.
Hydroxychloroquine, azathioprine, cyclophosphamide, mycophenolate mofetil, and other immunomodulatory agents have been used when disease is severe, recurrent, steroid-refractory, or steroid-toxic.
Mechanism Target:
Recurrent idiopathic diffuse alveolar hemorrhage — Reduces frequency of alveolar hemorrhage flares during corticosteroid taper or refractory disease.
Autoimmune serologic contribution to hemorrhage susceptibility — Modulates autoimmune and lymphocyte-mediated contributors to alveolar bleeding.
Recurrent hemorrhage-driven lung injury and remodeling — Prevents cumulative hemorrhage-induced alveolar remodeling and fibrotic progression.
Show evidence (4 references)
PMID:33184706 SUPPORT REVIEW SYNTHESIS Human clinical
"Additional immunomodulatory/immunosuppressive medications have been used with varying success, especially in the setting of steroid-refractory disease."
The treatment review supports steroid-sparing immunosuppression for steroid-refractory IPH.
PMID:30806370 SUPPORT Human clinical
"We initiated hydroxy-chloroquine and azathioprine early in treatment along with steroids in seven children with idiopathic pulmonary hemosiderosis"
The pediatric series supports hydroxychloroquine and azathioprine as steroid-sparing options used with corticosteroids.
PMID:30806370 SUPPORT Human clinical
"early introduction of second line immunosuppressants helped in reducing disease flare and steroid toxicity without serious adverse effects."
The series supports benefit of early steroid-sparing immunosuppression in seven children.
+ 1 more reference
Supportive care for acute anemia and respiratory compromise
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
Supportive management includes acute stabilization, oxygen or respiratory support when needed, and transfusion for severe anemia while disease-directed immunosuppression is initiated.
Mechanism Target:
Iron deficiency anemia — Corrects severe acute or chronic anemia via red blood cell transfusion and iron repletion.
Respiratory failure — Stabilizes gas exchange during acute diffuse alveolar hemorrhage episodes.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"All of the 107 patients were provided symptomatic treatments before diagnosis, and 29 received blood transfusions."
The pediatric cohort documents symptomatic care and transfusion in a subset before definitive diagnosis.
🔬

Biochemical Markers

7
Hemoglobin (Decreased (microcytic hypochromic anemia))
Context: Decreased hemoglobin from chronic or recurrent intra-alveolar hemorrhage, often presenting as microcytic hypochromic anemia before overt hemoptysis.
Pathograph Readouts
Readout of Hemosiderin-laden alveolar macrophage accumulation Negative Diagnostic
Lower blood hemoglobin reflects cumulative intra-alveolar blood loss and functional sequestration of erythrocyte-derived iron inside alveolar macrophages.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
Documents microcytic hypochromic anemia with compensatory reticulocytosis in pediatric IPH.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
Demonstrates that microcytic hypochromic anemia is a predominant hematologic finding in pediatric IPH.
Serum Iron (Decreased)
Context: Systemic iron depletion resulting from intra-alveolar trapping of hemoglobin-derived iron within alveolar macrophages.
Pathograph Readouts
Readout of Hemosiderin-laden alveolar macrophage accumulation Negative Diagnostic
Decreased circulating iron reports functional systemic iron deficiency due to inability of alveolar macrophages to recycle pulmonary hemosiderin back to the bone marrow.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"A total of 72 patients underwent an iron metabolism test, and 64 (88.9%) showed iron deficiency anemia. Serum iron tests were performed in 72 patients, and a decrease in iron levels was detected in 64 patients."
Shows decreased serum iron in 64 of 72 tested pediatric IPH patients.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"A total of 72 patients underwent an iron metabolism test, and 64 (88.9%) showed iron deficiency anemia. Serum iron tests were performed in 72 patients, and a decrease in iron levels was detected in 64 patients."
Confirms decreased serum iron in 88.9% of tested pediatric IPH patients.
Transferrin Saturation (Decreased (accompanied by increased total iron-binding capacity in 45.1% of tested patients))
Context: Reflects iron-restricted erythropoiesis secondary to alveolar hemosiderin sequestration.
Pathograph Readouts
Readout of Hemosiderin-laden alveolar macrophage accumulation Negative Diagnostic
Decreased transferrin saturation and elevated total iron-binding capacity indicate systemic iron deficiency despite abundant pulmonary hemosiderin stores.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"Transferrin saturation was decreased in 62 (91.2%) of 68 patients. Serum ferritin tests were normal in 60 of 62 tested patients. The total iron binding capacity was increased in 32 (45.07%) of 71 tested patients."
Documents decreased transferrin saturation in 91.2% and increased TIBC in 45.07% of tested children with IPH.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"Transferrin saturation was decreased in 62 (91.2%) of 68 patients. Serum ferritin tests were normal in 60 of 62 tested patients. The total iron binding capacity was increased in 32 (45.07%) of 71 tested patients."
Establishes decreased transferrin saturation and elevated TIBC as characteristic iron-panel findings in IPH.
Serum Ferritin (Normal in isolated IPH (60/62 pediatric patients); decreased when coexisting with celiac disease)
Context: Serum ferritin is typically normal in isolated IPH despite microcytic hypochromic anemia because of intra-alveolar hemosiderin loading, helping distinguish IPH from nutritional iron deficiency anemia; conversely, low serum ferritin in an IPH patient suggests coexisting celiac disease (Lane-Hamilton syndrome).
Pathograph Readouts
Readout of Hemosiderin-laden alveolar macrophage accumulation Threshold dependent Diagnostic
Preserved serum ferritin in the setting of low serum iron and microcytic anemia reflects macrophage hemosiderin storage in the lungs, whereas low ferritin prompts evaluation for celiac malabsorption.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"Although IPH and nutritional iron deficiency anemia are characterized by microcytic hypochromic anemia, patients with IPH have normal serum ferritin levels."
Highlights normal serum ferritin as a key biochemical discriminator between isolated IPH and nutritional iron deficiency anemia.
Show evidence (2 references)
PMID:30278795 SUPPORT Human clinical
"Although IPH and nutritional iron deficiency anemia are characterized by microcytic hypochromic anemia, patients with IPH have normal serum ferritin levels."
Shows that isolated pediatric IPH maintains normal serum ferritin despite microcytic hypochromic anemia.
PMID:35088581 SUPPORT REVIEW SYNTHESIS Human clinical
"All pediatric patients with IPH should undergo screening for CD. Low serum ferritin in patients with IPH could be suggestive of coexisting CD. Strict GFD should be tried as the initial therapy."
Indicates that low serum ferritin in pediatric IPH serves as a biochemical clue to coexisting celiac disease (Lane-Hamilton syndrome).
Reticulocyte Count (Increased (elevated in 98.15% of tested pediatric patients))
Context: Compensatory bone marrow erythroid response to acute or recurrent alveolar hemorrhage.
Pathograph Readouts
Readout of Recurrent idiopathic diffuse alveolar hemorrhage Positive Diagnostic
Elevated reticulocyte count reflects active erythroid regeneration in response to ongoing pulmonary hemorrhage.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
Documents reticulocytosis in 53 of 54 tested pediatric IPH patients.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
Confirms high reticulocyte counts in 98.15% of tested patients.
Serum Total Bilirubin (Elevated in a subset of patients, particularly those with recurrent alveolar hemorrhage)
Context: Reflects catabolism of extravasated hemoglobin within alveolar spaces and correlates with recurrent disease course.
Pathograph Readouts
Correlates with Hemosiderin-laden alveolar macrophage accumulation Positive Prognostic
Elevated serum bilirubin from intra-alveolar heme degradation is significantly more frequent in children with recurrent IPH than in those who achieve sustained improvement.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"The rate of elevated bilirubin levels was significantly higher in children who had recurrent IPH than in those who were healed or improved"
Associates elevated bilirubin levels with recurrent IPH course in children.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"The rate of elevated bilirubin levels was significantly higher in children who had recurrent IPH than in those who were healed or improved"
Supports serum bilirubin elevation as a prognostic correlate of recurrent pediatric IPH.
Autoantibody Serology Panel (SMA, ANCA, ANA, Celiac Antibodies) (Variable (in the French pediatric cohort, ANCA were positive in 40%, ANA in 45%, and celiac disease antibodies in 28% of screened patients; negative in cohorts strictly excluding seropositive cases))
Context: Performed at presentation and follow-up both to exclude primary systemic vasculitis, anti-GBM disease, and connective tissue disease and to detect coexisting celiac disease or evolving autoimmune overlap.
Pathograph Readouts
Readout of Autoimmune serologic contribution to hemorrhage susceptibility Present/absent Diagnostic
Detection of SMA, ANCA, ANA, or celiac disease autoantibodies identifies patients with immune dysregulation or Lane-Hamilton syndrome.
Show evidence (1 reference)
PMID:24125570 SUPPORT Human clinical
"In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%)."
Documents ANCA, ANA, and celiac autoantibody positivity at initial screening in the French pediatric cohort.
Show evidence (2 references)
PMID:24125570 SUPPORT Human clinical
"In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%)."
Supports routine autoimmune and celiac serologic screening in pediatric IPH.
PMID:30278795 SUPPORT Human clinical
"Laboratory investigations for antinuclear antibodies (ANA), anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, antiphospholipid antibodies, and rheumatoid factor were negative in all patients."
Shows that negative systemic vasculitis and connective tissue autoantibodies help exclude secondary causes of diffuse alveolar hemorrhage.
🔬

Diagnosis

3
Chest radiography and computed tomography
Chest radiographs or CT are used to identify infiltrates, ground-glass opacity, nodular changes, cardiomegaly, or reticular interstitial changes compatible with alveolar hemorrhage and chronic injury.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"All of the patients showed abnormal chest X-rays or computed tomography scans."
The pediatric cohort supports chest imaging as a routine diagnostic component.
Hemosiderin-laden macrophage testing
Sputum, gastric lavage fluid, or bronchoalveolar lavage fluid can be tested for hemosiderin-laden macrophages; repeated gastric lavage or BAL can improve detection in children who cannot expectorate.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:30278795 SUPPORT Human clinical
"The positive rates of hemosiderin-laden macrophages in sputum, gastric lavage fluid, and bronchoalveolar lavage fluid were 91.66%, 98.21%, and 100%, respectively."
The cohort supports cytologic testing for hemosiderin-laden macrophages across respiratory and gastric samples.
PMID:30278795 SUPPORT Human clinical
"Chest imaging combined with repeated examinations for hemosiderin-laden macrophages in sputum, gastric lavage fluid, or bronchoalveolar lavage fluid are helpful for diagnosing IPH."
The cohort conclusion supports combined imaging and repeated siderophage testing.
Exclusion of secondary diffuse alveolar hemorrhage causes
IPH is diagnosed only after excluding secondary causes such as infection, bronchiectasis, interstitial pneumonia, neoplasm, cardiovascular disease, coagulation disorders, connective-tissue disease, celiac disease, and systemic vasculitis.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"exclusion of other diseases, which are associated with diffuse alveolar hemorrhage, such as bronchiectasis, interstitial pneumonia, neoplasms, cardiovascular disease, coagulation disorders, infections, connective tissue diseases, celiac disease, and systemic vasculitis."
The cohort's case definition supports exclusion of secondary DAH causes.
📈

Progression

3
Childhood onset
Age: Childhood
Orphanet lists childhood as the age-of-onset category.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"Age of onset: Childhood"
Orphanet records childhood onset.
Relapsing hemorrhage and diagnostic delay
Age: Childhood through adolescence
Pediatric IPH often presents variably rather than with the complete classic triad, leading to high misdiagnosis rates and recurrence during treatment taper or withdrawal.
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"The classic triad of pediatric IPH is not always present. The rates of misdiagnosis and recurrence of IPH are high."
The cohort directly supports variable presentation, misdiagnosis, and recurrence.
Chronic pulmonary morbidity
Repeated hemorrhage can cause recurrent respiratory insufficiency and, in a minority of patients, pulmonary fibrosis.
Show evidence (2 references)
PMID:30278795 SUPPORT Human clinical
"Death may quickly occur with acute, massive, pulmonary hemorrhage or may occur over longer periods as the result of continued respiratory insufficiency and heart failure."
The pediatric cohort review of prognosis links acute massive hemorrhage and chronic respiratory insufficiency to severe outcomes.
PMID:24125570 SUPPORT Human clinical
"One patient developed severe pulmonary fibrosis, and another with Down syndrome died as a result of severe pulmonary hemorrhage."
The French pediatric cohort documents severe fibrosis and fatal hemorrhage as uncommon but important complications.
📊

Prevalence

2
Europe
Annual incidence ≤0.1 per 100,000 <1 in 1,000,000 per year
Orphanet records annual incidence below 1 per million in Europe.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"<1 / 1 000 000 | Europe | Annual incidence | EXPERT"
Orphanet records the expert-estimated European annual incidence band.
Europe
Point prevalence Unknown point prevalence Unknown
Orphanet records European point prevalence as unknown.
Show evidence (1 reference)
ORPHA:99931 SUPPORT Other
"Unknown | Europe | Point prevalence | ORPHANET"
Orphanet records unknown European point prevalence.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Pulmonary Hemosiderosis:

Celiac Disease (Lane-Hamilton Syndrome) MONDO:0005130
Overlapping Features Coexistence of idiopathic pulmonary hemosiderosis and celiac disease, known as Lane-Hamilton syndrome (LHS), presents with diffuse alveolar hemorrhage and iron-deficiency anemia alongside gluten-sensitive enteropathy (often without overt gastrointestinal symptoms).
Distinguishing Features
  • Positive celiac disease serology (anti-tissue transglutaminase IgA, anti-endomysial, or anti-gliadin antibodies) and duodenal villous atrophy on biopsy
  • Low serum ferritin from intestinal iron malabsorption, contrasting with the normal serum ferritin typical of isolated IPH
  • Clinical remission of alveolar hemorrhage and anemia upon adherence to a strict gluten-free diet in the majority of patients
Show evidence (3 references)
PMID:35088581 SUPPORT REVIEW SYNTHESIS Human clinical
"Nearly one-third of pediatric patients with IPH test positive for Celiac disease (CD) serology. Several hypothetical mechanisms have been proposed to unify the coexistence of these two entities, also referred to as Lane-Hamilton syndrome (LHS)."
Establishes the high rate of celiac seropositivity in pediatric IPH and defines Lane-Hamilton syndrome.
PMID:35088581 SUPPORT REVIEW SYNTHESIS Human clinical
"All pediatric patients with IPH should undergo screening for CD. Low serum ferritin in patients with IPH could be suggestive of coexisting CD. Strict GFD should be tried as the initial therapy."
Supports universal celiac screening in IPH, low ferritin as a discriminator for coexisting CD, and response to gluten-free diet.
PMID:36324124 SUPPORT REVIEW SYNTHESIS Human clinical
"A substantial number of patients suffer from coexisting CD, also known as Lane-Hamilton syndrome (LHS), and all patients with IPH need to be evaluated for LHS by serology."
Reinforces mandatory serologic evaluation for Lane-Hamilton syndrome in all IPH patients.
Anti-Glomerular Basement Membrane Disease MONDO:0009303
Overlapping Features Autoimmune small-vessel disorder (Goodpasture disease) causing diffuse alveolar hemorrhage and iron-deficiency anemia that can clinically mimic IPH.
Distinguishing Features
  • Presence of circulating anti-glomerular basement membrane (anti-GBM) antibodies
  • Concurrent rapidly progressive glomerulonephritis and linear IgG deposition along alveolar and glomerular basement membranes, which are absent in IPH
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"Laboratory investigations for antinuclear antibodies (ANA), anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, antiphospholipid antibodies, and rheumatoid factor were negative in all patients."
Demonstrates that anti-GBM antibodies are tested and must be negative to establish a diagnosis of IPH.
Granulomatosis with Polyangiitis MONDO:0012105
Overlapping Features ANCA-associated systemic necrotizing small-vessel vasculitis that can present with acute diffuse alveolar hemorrhage, hemoptysis, and bilateral alveolar infiltrates resembling IPH.
Distinguishing Features
  • Necrotizing pulmonary capillaritis or granulomatous vasculitis on lung biopsy, whereas IPH shows bland alveolar hemorrhage with siderophages and no vasculitis
  • Extrapulmonary vasculitic involvement (upper airway/sinonasal disease, pauci-immune glomerulonephritis, systemic vasculitis)
Show evidence (2 references)
PMID:15293620 SUPPORT REVIEW SYNTHESIS Human clinical
"the lung biopsy shows numerous siderophages in the alveoli, without any evidence of pulmonary vasculitis"
Absence of pulmonary vasculitis on biopsy differentiates IPH from systemic necrotizing vasculitides.
PMID:30278795 SUPPORT Human clinical
"exclusion of other diseases, which are associated with diffuse alveolar hemorrhage, such as bronchiectasis, interstitial pneumonia, neoplasms, cardiovascular disease, coagulation disorders, infections, connective tissue diseases, celiac disease, and systemic vasculitis."
Identifies systemic vasculitis as a required exclusion in the differential diagnosis of diffuse alveolar hemorrhage.
Systemic Lupus Erythematosus MONDO:0007915
Overlapping Features Systemic autoimmune connective tissue disease capable of causing secondary diffuse alveolar hemorrhage and pulmonary hemosiderosis.
Distinguishing Features
  • Positive anti-double-stranded DNA (anti-dsDNA) or antiphospholipid antibodies and hypocomplementemia
  • Multiorgan lupus manifestations (nephritis, arthritis, mucocutaneous lesions, serositis) and immune-complex deposition on biopsy
Show evidence (1 reference)
PMID:30278795 SUPPORT Human clinical
"Laboratory investigations for antinuclear antibodies (ANA), anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, antiphospholipid antibodies, and rheumatoid factor were negative in all patients."
Excludes systemic lupus erythematosus and related connective tissue diseases via negative anti-dsDNA, ANA, and antiphospholipid serologies.
Nutritional Iron Deficiency Anemia
Overlapping Features The most common initial misdiagnosis of pediatric IPH (accounting for 24/107 patients in a large pediatric series and 60.0% of misdiagnosed patients in an international physician survey), because occult alveolar bleeding often presents with isolated microcytic hypochromic anemia, pallor, and fatigue before hemoptysis occurs.
Distinguishing Features
  • Decreased serum ferritin in nutritional iron deficiency anemia versus normal serum ferritin in 60 of 62 tested children with isolated IPH
  • Presence of hemosiderin-laden macrophages in sputum, gastric lavage fluid, or bronchoalveolar lavage fluid, pulmonary infiltrates on chest imaging, and reticulocytosis
Show evidence (3 references)
PMID:30278795 SUPPORT Human clinical
"Although IPH and nutritional iron deficiency anemia are characterized by microcytic hypochromic anemia, patients with IPH have normal serum ferritin levels."
Explains how normal serum ferritin distinguishes IPH from nutritional iron deficiency anemia despite shared microcytic hypochromic morphology.
PMID:30278795 SUPPORT Human clinical
"Misdiagnoses included the following: nutritional iron deficiency anemia (n = 24), bronchial pneumonia (n = 21), pulmonary tuberculosis (n = 6), hemolytic anemia (n = 4), upper respiratory tract infection (n = 4), bronchiectasis (n = 3), myocarditis (n = 1), intestinal diseases (n=1), and favism (n = 1)."
Documents that nutritional iron deficiency anemia was the most frequent misdiagnosis (24 of 107 pediatric patients).
PMID:26289251 SUPPORT Human clinical
"63.3 % of respondents had patients that were initially misdiagnosed with anemia (60.0 %) or gastrointestinal bleed (18.2 %)."
Documents that isolated anemia is the single most frequent initial misdiagnosis of IPH across international centers.
Tuberculosis MONDO:0018076
Overlapping Features Pulmonary tuberculosis and bacterial bronchopneumonia are frequent infectious misdiagnoses in children presenting with cough, hemoptysis, fever, and pulmonary infiltrates prior to siderophage testing.
Distinguishing Features
  • Microbiological or molecular detection of Mycobacterium tuberculosis and absence of diffuse alveolar siderophages
  • Lack of iron-sequestration microcytic anemia with normal ferritin and response to antituberculous therapy rather than corticosteroids
Show evidence (2 references)
PMID:30278795 SUPPORT Human clinical
"exclusion of other diseases, which are associated with diffuse alveolar hemorrhage, such as bronchiectasis, interstitial pneumonia, neoplasms, cardiovascular disease, coagulation disorders, infections, connective tissue diseases, celiac disease, and systemic vasculitis."
Confirms that pulmonary infections are major mimics that must be excluded when diagnosing IPH.
PMID:30278795 SUPPORT Human clinical
"Misdiagnoses included the following: nutritional iron deficiency anemia (n = 24), bronchial pneumonia (n = 21), pulmonary tuberculosis (n = 6), hemolytic anemia (n = 4), upper respiratory tract infection (n = 4), bronchiectasis (n = 3), myocarditis (n = 1), intestinal diseases (n=1), and favism (n = 1)."
Documents that bronchial pneumonia (n = 21) and pulmonary tuberculosis (n = 6) are frequent infectious misdiagnoses of pediatric IPH.
{ }

Source YAML

click to show 
name: Pulmonary Hemosiderosis
category: Respiratory Disease
creation_date: "2026-05-09T18:28:00Z"
synonyms:
- Idiopathic pulmonary hemosiderosis
- IPH
- Idiopathic pulmonary haemosiderosis
- Pulmonary haemosiderosis
description: >
  Pulmonary hemosiderosis is a rare respiratory disorder, usually represented
  clinically by idiopathic pulmonary hemosiderosis, in which recurrent diffuse
  alveolar hemorrhage causes blood to enter alveolar spaces. Alveolar
  macrophages ingest erythrocytes and accumulate hemosiderin, producing
  hemosiderin-laden macrophages in sputum, gastric aspirate, bronchoalveolar
  lavage, or lung tissue. Patients commonly present in childhood with iron
  deficiency anemia, cough, hemoptysis, pulmonary infiltrates or ground-glass
  opacities, dyspnea, and relapsing pulmonary hemorrhage. The initiating cause is
  idiopathic after exclusion of infections, cardiac disease, coagulation
  disorders, connective-tissue disease, vasculitis, celiac disease/Lane-Hamilton
  syndrome, and other secondary causes of diffuse alveolar hemorrhage.
disease_term:
  preferred_term: pulmonary hemosiderosis
  term:
    id: MONDO:0008346
    label: pulmonary hemosiderosis
parents:
- Respiratory disease
- Hemosiderosis
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
    notes: >
      Diffuse alveolar hemorrhage disorder characterized by recurrent
      intra-alveolar bleeding, alveolar siderophage accumulation, and potential
      progression to interstitial fibrosis and restrictive lung disease.
    evidence:
    - reference: PMID:15293620
      reference_title: "Idiopathic pulmonary haemosiderosis revisited."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Idiopathic pulmonary haemosiderosis is a rare cause of diffuse alveolar haemorrhage of unknown aetiology."
      explanation: Establishes idiopathic pulmonary hemosiderosis as a primary diffuse alveolar hemorrhage disorder of the respiratory system.
      quote_role: REVIEW_SYNTHESIS
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >
      Frequently associated with circulating autoantibodies (SMA, ANCA, ANA, or
      celiac autoantibodies) and managed with systemic corticosteroids and
      steroid-sparing immunosuppressive therapy.
    evidence:
    - reference: PMID:24125570
      reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Analysis of potential contributors supports a role of auto-immunity in disease development and highlights the importance of genetic factors."
      explanation: Supports immune-mediated pathogenesis in a substantial clinical subset of pediatric IPH.
inheritance:
- name: Sporadic
  inheritance_term:
    preferred_term: Sporadic
    term:
      id: HP:0003745
      label: Sporadic
  description: >
    Idiopathic pulmonary hemosiderosis occurs sporadically in the vast majority
    of patients, although occasional familial clustering and overrepresentation
    of Down syndrome (trisomy 21) in pediatric cohorts suggest underlying
    genetic or immunogenetic susceptibility factors.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients were sporadic patients, comprising 42 boys and 65 girls."
    explanation: All 107 pediatric IPH cases in the largest single-center cohort were sporadic.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the present study, all of our patients were sporadic, with the highest incidence among 3- to 6-year-olds, similar to patients reported in previous studies."
    explanation: Confirms sporadic occurrence across the cohort and consistency with prior pediatric series.
external_assertions:
- name: Orphanet idiopathic pulmonary hemosiderosis record
  source: Orphanet
  assertion_type: structured_disease_record
  external_id: ORPHA:99931
  url: http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=99931
  description: >
    Orphanet's ORPHA:99931 structured record provides the disease definition,
    childhood age of onset, epidemiology, cross-references, and HPO phenotype
    rows used in this entry.
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "OMIM:178550 | Exact"
    explanation: Orphanet records an exact OMIM cross-reference for idiopathic pulmonary hemosiderosis.
definitions:
- name: Orphanet idiopathic pulmonary hemosiderosis definition
  definition_type: OTHER
  description: >
    A respiratory disease, most often beginning in childhood, caused by repeated
    episodes of otherwise unexplained diffuse alveolar hemorrhage with anemia,
    cough, and chest-imaging infiltrates.
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Idiopathic pulmonary hemosiderosis is a respiratory disease due to repeated episodes of diffuse alveolar hemorrhage without any underlying apparent cause"
    explanation: Orphanet defines IPH by unexplained repeated diffuse alveolar hemorrhage.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic pulmonary hemosiderosis (IPH) is a rare disorder that is responsible for recurrent episodes of diffuse alveolar hemorrhage"
    explanation: The 107-patient pediatric cohort supports recurrent diffuse alveolar hemorrhage as the central clinical definition.
prevalence:
- population: Europe
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  percentage: "<1 / 1,000,000 annual incidence"
  notes: Orphanet records annual incidence below 1 per million in Europe.
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "<1 / 1 000 000 | Europe | Annual incidence | EXPERT"
    explanation: Orphanet records the expert-estimated European annual incidence band.
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: UNKNOWN
  percentage: Unknown point prevalence
  notes: Orphanet records European point prevalence as unknown.
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Unknown | Europe | Point prevalence | ORPHANET"
    explanation: Orphanet records unknown European point prevalence.
progression:
- phase: Childhood onset
  age_range: Childhood
  notes: Orphanet lists childhood as the age-of-onset category.
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Age of onset: Childhood"
    explanation: Orphanet records childhood onset.
- phase: Relapsing hemorrhage and diagnostic delay
  age_range: Childhood through adolescence
  notes: >
    Pediatric IPH often presents variably rather than with the complete classic
    triad, leading to high misdiagnosis rates and recurrence during treatment
    taper or withdrawal.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The classic triad of pediatric IPH is not always present. The rates of misdiagnosis and recurrence of IPH are high."
    explanation: The cohort directly supports variable presentation, misdiagnosis, and recurrence.
- phase: Chronic pulmonary morbidity
  notes: >
    Repeated hemorrhage can cause recurrent respiratory insufficiency and, in a
    minority of patients, pulmonary fibrosis.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death may quickly occur with acute, massive, pulmonary hemorrhage or may occur over longer periods as the result of continued respiratory insufficiency and heart failure."
    explanation: The pediatric cohort review of prognosis links acute massive hemorrhage and chronic respiratory insufficiency to severe outcomes.
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient developed severe pulmonary fibrosis, and another with Down syndrome died as a result of severe pulmonary hemorrhage."
    explanation: The French pediatric cohort documents severe fibrosis and fatal hemorrhage as uncommon but important complications.
pathophysiology:
- name: Recurrent idiopathic diffuse alveolar hemorrhage
  description: >
    The initiating lesion is recurrent bleeding into alveolar spaces without an
    identified secondary cause. Proposed environmental, allergic, autoimmune,
    and genetic contributors remain hypotheses rather than established causes.
  role: trigger
  cell_types:
  - preferred_term: alveolar capillary endothelial cell
    term:
      id: CL:0002144
      label: capillary endothelial cell
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: hemostasis
    term:
      id: GO:0007599
      label: hemostasis
    modifier: DYSREGULATED
  - preferred_term: vascular permeability regulation
    term:
      id: GO:0043114
      label: regulation of vascular permeability
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:15293620
    reference_title: "Idiopathic pulmonary haemosiderosis revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Idiopathic pulmonary haemosiderosis is a rare cause of diffuse alveolar haemorrhage of unknown aetiology."
    explanation: The clinical review supports unexplained diffuse alveolar hemorrhage as the initiating lesion.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There are four main etiological hypotheses of IPH described in the literature, including environmental, allergic, autoimmune, and genetic hypotheses."
    explanation: The cohort review supports keeping the upstream cause as unresolved rather than assigning a single causal trigger.
  downstream:
  - target: Hemosiderin-laden alveolar macrophage accumulation
    causal_link_type: DIRECT
  - target: Recurrent hemorrhage-driven lung injury and remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Diffuse alveolar hemorrhage
    causal_link_type: DIRECT
  - target: Hemoptysis
    causal_link_type: DIRECT
  - target: Cough
    causal_link_type: DIRECT
  - target: Dyspnea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Crackles
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pulmonary infiltrates
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Ground-glass opacification on pulmonary HRCT
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nodular pattern on pulmonary HRCT
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Autoimmune serologic contribution to hemorrhage susceptibility
  description: >
    A subset of pediatric idiopathic pulmonary hemosiderosis cases show ANCA,
    ANA, or coeliac antibody positivity, supporting autoimmunity as a modifier
    or contributor rather than a universal primary cause.
  role: modifier
  biological_processes:
  - preferred_term: immune response
    term:
      id: GO:0006955
      label: immune response
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%)."
    explanation: The cohort documents autoimmune serology in screened children with IPH, supporting an immune contribution in a subset.
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of potential contributors supports a role of auto-immunity in disease development and highlights the importance of genetic factors."
    explanation: The authors explicitly interpret potential contributors as supporting an autoimmune role in disease development.
  downstream:
  - target: Recurrent idiopathic diffuse alveolar hemorrhage
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Autoimmune antibody positivity
    causal_link_type: DIRECT
  - target: Smooth muscle antibody positivity
    causal_link_type: DIRECT
  - target: Antineutrophil antibody positivity
    causal_link_type: DIRECT
  - target: Antinuclear antibody positivity
    causal_link_type: DIRECT
  - target: Rheumatoid factor positive
    causal_link_type: DIRECT
- name: Hemosiderin-laden alveolar macrophage accumulation
  description: >
    Alveolar macrophages phagocytose extravasated erythrocytes after repeated
    hemorrhage and accumulate hemosiderin iron. Detection of these siderophages
    in sputum, gastric lavage fluid, bronchoalveolar lavage fluid, or lung
    tissue is a diagnostic hallmark and links pulmonary blood loss to systemic
    iron deficiency.
  role: effector
  cell_types:
  - preferred_term: alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  locations:
  - preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: phagocytosis
    term:
      id: GO:0006909
      label: phagocytosis
    modifier: INCREASED
  - preferred_term: heme catabolic process
    term:
      id: GO:0042167
      label: heme catabolic process
    modifier: INCREASED
  - preferred_term: intracellular iron ion homeostasis
    term:
      id: GO:0006879
      label: intracellular iron ion homeostasis
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:15293620
    reference_title: "Idiopathic pulmonary haemosiderosis revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Many patients develop iron deficiency anaemia secondary to deposition of haemosiderin iron in the alveoli."
    explanation: The clinical review connects alveolar hemosiderin deposition with iron deficiency anemia.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemosiderin-laden macrophages were found in all of the patients."
    explanation: The 107-patient cohort supports hemosiderin-laden macrophages as a consistent diagnostic finding.
  downstream:
  - target: Iron deficiency anemia
    causal_link_type: DIRECT
  - target: Pallor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fatigue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Recurrent hemorrhage-driven lung injury and remodeling
  description: >
    Recurrent alveolar bleeding, iron/heme deposition, and inflammatory repair
    injure alveolar units and can progress to restrictive physiology, respiratory
    failure, and pulmonary fibrosis in severe or relapsing disease.
  role: downstream_pathology
  cell_types:
  - preferred_term: pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: wound healing
    term:
      id: GO:0042060
      label: wound healing
    modifier: DYSREGULATED
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Death may quickly occur with acute, massive, pulmonary hemorrhage or may occur over longer periods as the result of continued respiratory insufficiency and heart failure."
    explanation: The cohort review supports chronic respiratory insufficiency as a consequence of persistent or recurrent pulmonary hemorrhage.
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient developed severe pulmonary fibrosis, and another with Down syndrome died as a result of severe pulmonary hemorrhage."
    explanation: The French cohort supports pulmonary fibrosis as a severe downstream complication.
  downstream:
  - target: Restrictive ventilatory defect
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pulmonary fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Reticular pattern on pulmonary HRCT
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Respiratory failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
histopathology:
- name: Hemosiderin-laden alveolar macrophages without vasculitis
  finding_term:
    preferred_term: Hemosiderin-laden alveolar macrophages
    term:
      id: NCIT:C35990
      label: Hemosiderin Deposition
  description: >
    Sputum, bronchoalveolar lavage fluid, gastric lavage fluid, or lung biopsy
    can show siderophages reflecting prior alveolar hemorrhage; classic IPH
    lacks pulmonary vasculitis or immune-complex deposition on biopsy.
  diagnostic: true
  evidence:
  - reference: PMID:15293620
    reference_title: "Idiopathic pulmonary haemosiderosis revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of sputum and bronchoalveolar lavage fluid can disclose haemosiderin-laden alveolar macrophages (siderophages)"
    explanation: The review supports siderophages in respiratory samples as a characteristic finding.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:15293620
    reference_title: "Idiopathic pulmonary haemosiderosis revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the lung biopsy shows numerous siderophages in the alveoli, without any evidence of pulmonary vasculitis"
    explanation: The review supports numerous alveolar siderophages without vasculitis as a histopathologic pattern.
    quote_role: REVIEW_SYNTHESIS
phenotypes:
- category: Hematologic
  name: Iron deficiency anemia
  frequency: VERY_FREQUENT
  description: Iron deficiency anemia is a cardinal manifestation of chronic pulmonary blood loss.
  phenotype_term:
    preferred_term: iron deficiency anemia
    term:
      id: HP:0001891
      label: Iron deficiency anemia
  sequelae:
  - target: Failure to thrive
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cardiomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Heart murmur
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatosplenomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatomegaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001891 | Iron deficiency anemia | Very frequent (99-80%)"
    explanation: Orphanet records iron deficiency anemia as very frequent.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anemia (n = 100, 93.45%)"
    explanation: The pediatric cohort found anemia in 100 of 107 patients.
- category: Constitutional
  name: Pallor
  frequency: FREQUENT
  description: Pallor accompanies anemia from recurrent pulmonary blood loss.
  phenotype_term:
    preferred_term: pallor
    term:
      id: HP:0000980
      label: Pallor
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000980 | Pallor | Frequent (79-30%)"
    explanation: Orphanet records pallor as frequent.
- category: Abdominal
  name: Hepatosplenomegaly
  frequency: FREQUENT
  description: Hepatosplenomegaly is a reported systemic finding.
  phenotype_term:
    preferred_term: hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
    explanation: Orphanet records hepatosplenomegaly as frequent.
- category: Pulmonary
  name: Hemoptysis
  frequency: FREQUENT
  description: Hemoptysis reflects alveolar hemorrhage but may be absent in children who cannot expectorate.
  phenotype_term:
    preferred_term: hemoptysis
    term:
      id: HP:0002105
      label: Hemoptysis
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002105 | Hemoptysis | Frequent (79-30%)"
    explanation: Orphanet records hemoptysis as frequent.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hemoptysis (n = 61, 57%)"
    explanation: The pediatric cohort found hemoptysis in 61 of 107 patients at diagnosis.
- category: Pulmonary
  name: Pulmonary infiltrates
  frequency: FREQUENT
  description: Chest imaging commonly shows pulmonary infiltrates during hemorrhagic episodes.
  phenotype_term:
    preferred_term: pulmonary infiltrates
    term:
      id: HP:0002113
      label: Pulmonary infiltrates
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002113 | Pulmonary infiltrates | Frequent (79-30%)"
    explanation: Orphanet records pulmonary infiltrates as frequent.
- category: Constitutional
  name: Fatigue
  frequency: FREQUENT
  description: Fatigue is consistent with anemia and chronic respiratory disease.
  phenotype_term:
    preferred_term: fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012378 | Fatigue | Frequent (79-30%)"
    explanation: Orphanet records fatigue as frequent.
- category: Pulmonary
  name: Cough
  frequency: FREQUENT
  description: Cough is one of the common respiratory manifestations.
  phenotype_term:
    preferred_term: cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012735 | Cough | Frequent (79-30%)"
    explanation: Orphanet records cough as frequent.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cough (n = 68, 63.55%)"
    explanation: The pediatric cohort found cough in 68 of 107 patients at diagnosis.
- category: Imaging
  name: Ground-glass opacification on pulmonary HRCT
  frequency: FREQUENT
  description: Ground-glass opacification on HRCT reflects alveolar filling during hemorrhage.
  phenotype_term:
    preferred_term: ground-glass opacification on pulmonary HRCT
    term:
      id: HP:0025179
      label: Ground-glass opacification
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025179 | Ground-glass opacification on pulmonary HRCT | Frequent (79-30%)"
    explanation: Orphanet records ground-glass opacification on pulmonary HRCT as frequent.
- category: Renal
  name: Glomerulonephritis
  frequency: VERY_RARE
  description: Glomerulonephritis suggests renal involvement or a pulmonary-renal differential diagnosis.
  phenotype_term:
    preferred_term: glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000099 | Glomerulonephritis | Very rare (<4-1%)"
    explanation: Orphanet records glomerulonephritis as very rare.
- category: Growth
  name: Failure to thrive
  frequency: OCCASIONAL
  description: Chronic illness and recurrent anemia can impair growth.
  phenotype_term:
    preferred_term: failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001508 | Failure to thrive | Occasional (29-5%)"
    explanation: Orphanet records failure to thrive as occasional.
- category: Cardiac
  name: Cardiomegaly
  frequency: OCCASIONAL
  description: Cardiomegaly can accompany severe chronic cardiopulmonary burden.
  phenotype_term:
    preferred_term: cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001640 | Cardiomegaly | Occasional (29-5%)"
    explanation: Orphanet records cardiomegaly as occasional.
- category: Constitutional
  name: Fever
  frequency: OCCASIONAL
  description: Fever can occur during acute presentations and may contribute to misdiagnosis as infection.
  phenotype_term:
    preferred_term: fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001945 | Fever | Occasional (29-5%)"
    explanation: Orphanet records fever as occasional.
- category: Pulmonary
  name: Restrictive ventilatory defect
  frequency: OCCASIONAL
  description: Restrictive physiology may emerge with chronic parenchymal injury or fibrosis.
  phenotype_term:
    preferred_term: restrictive ventilatory defect
    term:
      id: HP:0002091
      label: Restrictive ventilatory defect
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002091 | Restrictive ventilatory defect | Occasional (29-5%)"
    explanation: Orphanet records restrictive ventilatory defect as occasional.
- category: Pulmonary
  name: Dyspnea
  frequency: OCCASIONAL
  description: Dyspnea reflects impaired gas exchange during alveolar hemorrhage or chronic lung disease.
  phenotype_term:
    preferred_term: dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002094 | Dyspnea | Occasional (29-5%)"
    explanation: Orphanet records dyspnea as occasional.
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dyspnea (n = 17, 68%)"
    explanation: The French cohort recorded dyspnea at diagnosis in 17 of 25 children.
- category: Pulmonary
  name: Pulmonary fibrosis
  frequency: OCCASIONAL
  description: Severe or relapsing disease can progress to pulmonary fibrosis.
  phenotype_term:
    preferred_term: pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002206 | Pulmonary fibrosis | Occasional (29-5%)"
    explanation: Orphanet records pulmonary fibrosis as occasional.
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient developed severe pulmonary fibrosis"
    explanation: The French cohort documents pulmonary fibrosis as a severe complication.
- category: Abdominal
  name: Hepatomegaly
  frequency: OCCASIONAL
  description: Hepatomegaly is reported as an occasional systemic finding.
  phenotype_term:
    preferred_term: hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002240 | Hepatomegaly | Occasional (29-5%)"
    explanation: Orphanet records hepatomegaly as occasional.
- category: Pulmonary
  name: Respiratory failure
  frequency: OCCASIONAL
  description: Acute massive hemorrhage or chronic respiratory insufficiency can cause respiratory failure.
  phenotype_term:
    preferred_term: respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002878 | Respiratory failure | Occasional (29-5%)"
    explanation: Orphanet records respiratory failure as occasional.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "three died from massive pulmonary hemorrhage and respiratory failure"
    explanation: The pediatric cohort documents respiratory failure in fatal severe presentations.
- category: Comorbidity
  name: Down syndrome
  frequency: OCCASIONAL
  description: >
    Down syndrome is an associated comorbidity reported in pediatric idiopathic
    pulmonary hemosiderosis cohorts, not a defining feature of all cases.
  phenotype_term:
    preferred_term: Down syndrome
    term:
      id: MONDO:0008608
      label: Down syndrome
  evidence:
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 25 reported cases of IPH in children from the database (20 females and 5 males). Among them, 5 presented with Down syndrome."
    explanation: The French pediatric cohort documents Down syndrome in 5 of 25 IPH cases, supporting an occasional comorbidity association.
- category: Laboratory
  name: Rheumatoid factor positive
  frequency: OCCASIONAL
  description: Rheumatoid factor positivity is one of the reported autoimmune serologic abnormalities.
  phenotype_term:
    preferred_term: rheumatoid factor positive
    term:
      id: HP:0002923
      label: Rheumatoid factor positive
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002923 | Rheumatoid factor positive | Occasional (29-5%)"
    explanation: Orphanet records rheumatoid factor positivity as occasional.
- category: Laboratory
  name: Smooth muscle antibody positivity
  frequency: OCCASIONAL
  description: Smooth muscle antibody positivity is one of the reported autoimmune serologic abnormalities.
  phenotype_term:
    preferred_term: smooth muscle antibody positivity
    term:
      id: HP:0003262
      label: Anti-smooth muscle antibody positivity
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003262 | Smooth muscle antibody positivity | Occasional (29-5%)"
    explanation: Orphanet records smooth muscle antibody positivity as occasional.
- category: Laboratory
  name: Antineutrophil antibody positivity
  frequency: OCCASIONAL
  description: Antineutrophil antibody positivity is one of the reported autoimmune serologic abnormalities.
  phenotype_term:
    preferred_term: antineutrophil antibody positivity
    term:
      id: HP:0003453
      label: Antineutrophil antibody positivity
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003453 | Antineutrophil antibody positivity | Occasional (29-5%)"
    explanation: Orphanet records antineutrophil antibody positivity as occasional.
- category: Laboratory
  name: Antinuclear antibody positivity
  frequency: OCCASIONAL
  description: Antinuclear antibody positivity is one of the reported autoimmune serologic abnormalities.
  phenotype_term:
    preferred_term: antinuclear antibody positivity
    term:
      id: HP:0003493
      label: Antinuclear antibody positivity
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003493 | Antinuclear antibody positivity | Occasional (29-5%)"
    explanation: Orphanet records antinuclear antibody positivity as occasional.
- category: Immune
  name: Allergy
  frequency: OCCASIONAL
  description: Allergy is reported in a subset and is one hypothesized contributor rather than a proven cause.
  phenotype_term:
    preferred_term: allergy
    term:
      id: HP:0012393
      label: Allergy
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012393 | Allergy | Occasional (29-5%)"
    explanation: Orphanet records allergy as occasional.
- category: Imaging
  name: Reticular pattern on pulmonary HRCT
  frequency: OCCASIONAL
  description: Reticular pulmonary HRCT changes may reflect chronic interstitial injury.
  phenotype_term:
    preferred_term: reticular pattern on pulmonary HRCT
    term:
      id: HP:0025390
      label: Reticular pattern on pulmonary HRCT
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025390 | Reticular pattern on pulmonary HRCT | Occasional (29-5%)"
    explanation: Orphanet records reticular pattern on pulmonary HRCT as occasional.
- category: Imaging
  name: Nodular pattern on pulmonary HRCT
  frequency: OCCASIONAL
  description: Nodular pulmonary HRCT changes are reported in a subset.
  phenotype_term:
    preferred_term: nodular pattern on pulmonary HRCT
    term:
      id: HP:0025392
      label: Nodular pattern on pulmonary HRCT
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025392 | Nodular pattern on pulmonary HRCT | Occasional (29-5%)"
    explanation: Orphanet records nodular pattern on pulmonary HRCT as occasional.
- category: Pulmonary
  name: Diffuse alveolar hemorrhage
  frequency: OCCASIONAL
  description: Diffuse alveolar hemorrhage is the core lesion of IPH and can be recurrent.
  phenotype_term:
    preferred_term: diffuse alveolar hemorrhage
    term:
      id: HP:0025420
      label: Diffuse alveolar hemorrhage
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0025420 | Diffuse alveolar hemorrhage | Occasional (29-5%)"
    explanation: Orphanet records diffuse alveolar hemorrhage as occasional.
  - reference: PMID:15293620
    reference_title: "Idiopathic pulmonary haemosiderosis revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "repetitive episodes of diffuse alveolar haemorrhage"
    explanation: The clinical review supports recurrent diffuse alveolar hemorrhage as central to IPH.
- category: Laboratory
  name: Autoimmune antibody positivity
  frequency: OCCASIONAL
  description: Autoimmune serologic abnormalities support immune involvement in a subset.
  phenotype_term:
    preferred_term: autoimmune antibody positivity
    term:
      id: HP:0030057
      label: Autoimmune antibody positivity
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030057 | Autoimmune antibody positivity | Occasional (29-5%)"
    explanation: Orphanet records autoimmune antibody positivity as occasional.
- category: Cardiac
  name: Heart murmur
  frequency: OCCASIONAL
  description: Heart murmur is an occasional clinical finding.
  phenotype_term:
    preferred_term: heart murmur
    term:
      id: HP:0030148
      label: Heart murmur
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030148 | Heart murmur | Occasional (29-5%)"
    explanation: Orphanet records heart murmur as occasional.
- category: Pulmonary
  name: Crackles
  frequency: OCCASIONAL
  description: Crackles can occur with alveolar filling and parenchymal involvement.
  phenotype_term:
    preferred_term: crackles
    term:
      id: HP:0030830
      label: Crackles
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0030830 | Crackles | Occasional (29-5%)"
    explanation: Orphanet records crackles as occasional.
- category: Immune
  name: Cow milk allergy
  frequency: VERY_RARE
  description: Cow milk allergy is a rare reported associated finding and should not be treated as the primary IPH mechanism.
  phenotype_term:
    preferred_term: cow milk allergy
    term:
      id: HP:0100327
      label: Cow milk allergy
  evidence:
  - reference: ORPHA:99931
    reference_title: "Idiopathic pulmonary hemosiderosis"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100327 | Cow milk allergy | Very rare (<4-1%)"
    explanation: Orphanet records cow milk allergy as very rare.
diagnosis:
- name: Chest radiography and computed tomography
  description: >
    Chest radiographs or CT are used to identify infiltrates, ground-glass
    opacity, nodular changes, cardiomegaly, or reticular interstitial changes
    compatible with alveolar hemorrhage and chronic injury.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the patients showed abnormal chest X-rays or computed tomography scans."
    explanation: The pediatric cohort supports chest imaging as a routine diagnostic component.
- name: Hemosiderin-laden macrophage testing
  description: >
    Sputum, gastric lavage fluid, or bronchoalveolar lavage fluid can be tested
    for hemosiderin-laden macrophages; repeated gastric lavage or BAL can improve
    detection in children who cannot expectorate.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The positive rates of hemosiderin-laden macrophages in sputum, gastric lavage fluid, and bronchoalveolar lavage fluid were 91.66%, 98.21%, and 100%, respectively."
    explanation: The cohort supports cytologic testing for hemosiderin-laden macrophages across respiratory and gastric samples.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Chest imaging combined with repeated examinations for hemosiderin-laden macrophages in sputum, gastric lavage fluid, or bronchoalveolar lavage fluid are helpful for diagnosing IPH."
    explanation: The cohort conclusion supports combined imaging and repeated siderophage testing.
- name: Exclusion of secondary diffuse alveolar hemorrhage causes
  description: >
    IPH is diagnosed only after excluding secondary causes such as infection,
    bronchiectasis, interstitial pneumonia, neoplasm, cardiovascular disease,
    coagulation disorders, connective-tissue disease, celiac disease, and
    systemic vasculitis.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exclusion of other diseases, which are associated with diffuse alveolar hemorrhage, such as bronchiectasis, interstitial pneumonia, neoplasms, cardiovascular disease, coagulation disorders, infections, connective tissue diseases, celiac disease, and systemic vasculitis."
    explanation: The cohort's case definition supports exclusion of secondary DAH causes.
biochemical:
- name: Hemoglobin
  biomarker_term:
    preferred_term: Hemoglobin Measurement
    term:
      id: NCIT:C64848
      label: Hemoglobin Measurement
  loinc_term:
    id: LOINC:718-7
    label: Hemoglobin [Mass/volume] in Blood
  presence: Decreased (microcytic hypochromic anemia)
  context: >
    Decreased hemoglobin from chronic or recurrent intra-alveolar hemorrhage,
    often presenting as microcytic hypochromic anemia before overt hemoptysis.
  readouts:
  - target: Hemosiderin-laden alveolar macrophage accumulation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Lower blood hemoglobin reflects cumulative intra-alveolar blood loss and
      functional sequestration of erythrocyte-derived iron inside alveolar
      macrophages.
    evidence:
    - reference: PMID:30278795
      reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
      explanation: Documents microcytic hypochromic anemia with compensatory reticulocytosis in pediatric IPH.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
    explanation: Demonstrates that microcytic hypochromic anemia is a predominant hematologic finding in pediatric IPH.
- name: Serum Iron
  loinc_term:
    id: LOINC:2498-4
    label: Iron [Mass/volume] in Serum or Plasma
  presence: Decreased
  context: >
    Systemic iron depletion resulting from intra-alveolar trapping of
    hemoglobin-derived iron within alveolar macrophages.
  readouts:
  - target: Hemosiderin-laden alveolar macrophage accumulation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Decreased circulating iron reports functional systemic iron deficiency due
      to inability of alveolar macrophages to recycle pulmonary hemosiderin back
      to the bone marrow.
    evidence:
    - reference: PMID:30278795
      reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A total of 72 patients underwent an iron metabolism test, and 64 (88.9%) showed iron deficiency anemia. Serum iron tests were performed in 72 patients, and a decrease in iron levels was detected in 64 patients."
      explanation: Shows decreased serum iron in 64 of 72 tested pediatric IPH patients.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A total of 72 patients underwent an iron metabolism test, and 64 (88.9%) showed iron deficiency anemia. Serum iron tests were performed in 72 patients, and a decrease in iron levels was detected in 64 patients."
    explanation: Confirms decreased serum iron in 88.9% of tested pediatric IPH patients.
- name: Transferrin Saturation
  biomarker_term:
    preferred_term: Transferrin Saturation Measurement
    term:
      id: NCIT:C98792
      label: Transferrin Saturation Measurement
  loinc_term:
    id: LOINC:2502-3
    label: Iron saturation [Mass Fraction] in Serum or Plasma
  presence: Decreased (accompanied by increased total iron-binding capacity in 45.1% of tested patients)
  context: >
    Reflects iron-restricted erythropoiesis secondary to alveolar hemosiderin
    sequestration.
  readouts:
  - target: Hemosiderin-laden alveolar macrophage accumulation
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Decreased transferrin saturation and elevated total iron-binding capacity
      indicate systemic iron deficiency despite abundant pulmonary hemosiderin
      stores.
    evidence:
    - reference: PMID:30278795
      reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Transferrin saturation was decreased in 62 (91.2%) of 68 patients. Serum ferritin tests were normal in 60 of 62 tested patients. The total iron binding capacity was increased in 32 (45.07%) of 71 tested patients."
      explanation: Documents decreased transferrin saturation in 91.2% and increased TIBC in 45.07% of tested children with IPH.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transferrin saturation was decreased in 62 (91.2%) of 68 patients. Serum ferritin tests were normal in 60 of 62 tested patients. The total iron binding capacity was increased in 32 (45.07%) of 71 tested patients."
    explanation: Establishes decreased transferrin saturation and elevated TIBC as characteristic iron-panel findings in IPH.
- name: Serum Ferritin
  biomarker_term:
    preferred_term: Serum Ferritin
    term:
      id: NCIT:C224202
      label: Serum Ferritin
  loinc_term:
    id: LOINC:2276-4
    label: Ferritin [Mass/volume] in Serum or Plasma
  presence: Normal in isolated IPH (60/62 pediatric patients); decreased when coexisting with celiac disease
  context: >
    Serum ferritin is typically normal in isolated IPH despite microcytic
    hypochromic anemia because of intra-alveolar hemosiderin loading, helping
    distinguish IPH from nutritional iron deficiency anemia; conversely, low
    serum ferritin in an IPH patient suggests coexisting celiac disease
    (Lane-Hamilton syndrome).
  readouts:
  - target: Hemosiderin-laden alveolar macrophage accumulation
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Preserved serum ferritin in the setting of low serum iron and microcytic
      anemia reflects macrophage hemosiderin storage in the lungs, whereas low
      ferritin prompts evaluation for celiac malabsorption.
    evidence:
    - reference: PMID:30278795
      reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Although IPH and nutritional iron deficiency anemia are characterized by microcytic hypochromic anemia, patients with IPH have normal serum ferritin levels."
      explanation: Highlights normal serum ferritin as a key biochemical discriminator between isolated IPH and nutritional iron deficiency anemia.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although IPH and nutritional iron deficiency anemia are characterized by microcytic hypochromic anemia, patients with IPH have normal serum ferritin levels."
    explanation: Shows that isolated pediatric IPH maintains normal serum ferritin despite microcytic hypochromic anemia.
  - reference: PMID:35088581
    reference_title: "Association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients: A scoping review of the literature over the past 50 years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All pediatric patients with IPH should undergo screening for CD. Low serum ferritin in patients with IPH could be suggestive of coexisting CD. Strict GFD should be tried as the initial therapy."
    explanation: Indicates that low serum ferritin in pediatric IPH serves as a biochemical clue to coexisting celiac disease (Lane-Hamilton syndrome).
- name: Reticulocyte Count
  biomarker_term:
    preferred_term: Reticulocyte Count
    term:
      id: NCIT:C51947
      label: Reticulocyte Count
  presence: Increased (elevated in 98.15% of tested pediatric patients)
  context: >
    Compensatory bone marrow erythroid response to acute or recurrent alveolar
    hemorrhage.
  readouts:
  - target: Recurrent idiopathic diffuse alveolar hemorrhage
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated reticulocyte count reflects active erythroid regeneration in
      response to ongoing pulmonary hemorrhage.
    evidence:
    - reference: PMID:30278795
      reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
      explanation: Documents reticulocytosis in 53 of 54 tested pediatric IPH patients.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A red blood cell morphology test was performed in 97 of the anemic patients, of whom 57 (58.8%) showed microcytic hypochromic anemia. Reticulocyte counts were recorded in 54 patients, of whom 53 (98.15%) had high reticulocyte counts."
    explanation: Confirms high reticulocyte counts in 98.15% of tested patients.
- name: Serum Total Bilirubin
  biomarker_term:
    preferred_term: Serum Total Bilirubin Measurement
    term:
      id: NCIT:C61031
      label: Serum Total Bilirubin Measurement
  presence: Elevated in a subset of patients, particularly those with recurrent alveolar hemorrhage
  context: >
    Reflects catabolism of extravasated hemoglobin within alveolar spaces and
    correlates with recurrent disease course.
  readouts:
  - target: Hemosiderin-laden alveolar macrophage accumulation
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >
      Elevated serum bilirubin from intra-alveolar heme degradation is
      significantly more frequent in children with recurrent IPH than in those
      who achieve sustained improvement.
    evidence:
    - reference: PMID:30278795
      reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The rate of elevated bilirubin levels was significantly higher in children who had recurrent IPH than in those who were healed or improved"
      explanation: Associates elevated bilirubin levels with recurrent IPH course in children.
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The rate of elevated bilirubin levels was significantly higher in children who had recurrent IPH than in those who were healed or improved"
    explanation: Supports serum bilirubin elevation as a prognostic correlate of recurrent pediatric IPH.
- name: Autoantibody Serology Panel (SMA, ANCA, ANA, Celiac Antibodies)
  biomarker_term:
    preferred_term: Autoantibody Measurement
    term:
      id: NCIT:C181397
      label: Autoantibody Measurement
  presence: Variable (in the French pediatric cohort, ANCA were positive in 40%, ANA in 45%, and celiac disease antibodies in 28% of screened patients; negative in cohorts strictly excluding seropositive cases)
  context: >
    Performed at presentation and follow-up both to exclude primary systemic
    vasculitis, anti-GBM disease, and connective tissue disease and to detect
    coexisting celiac disease or evolving autoimmune overlap.
  readouts:
  - target: Autoimmune serologic contribution to hemorrhage susceptibility
    relationship: READOUT_OF
    direction: PRESENT_ABSENT
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Detection of SMA, ANCA, ANA, or celiac disease autoantibodies identifies
      patients with immune dysregulation or Lane-Hamilton syndrome.
    evidence:
    - reference: PMID:24125570
      reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%)."
      explanation: Documents ANCA, ANA, and celiac autoantibody positivity at initial screening in the French pediatric cohort.
  evidence:
  - reference: PMID:24125570
    reference_title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%)."
    explanation: Supports routine autoimmune and celiac serologic screening in pediatric IPH.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations for antinuclear antibodies (ANA), anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, antiphospholipid antibodies, and rheumatoid factor were negative in all patients."
    explanation: Shows that negative systemic vasculitis and connective tissue autoantibodies help exclude secondary causes of diffuse alveolar hemorrhage.
differential_diagnoses:
- name: Celiac Disease (Lane-Hamilton Syndrome)
  disease_term:
    preferred_term: celiac disease
    term:
      id: MONDO:0005130
      label: celiac disease
  description: >
    Coexistence of idiopathic pulmonary hemosiderosis and celiac disease, known
    as Lane-Hamilton syndrome (LHS), presents with diffuse alveolar hemorrhage
    and iron-deficiency anemia alongside gluten-sensitive enteropathy (often
    without overt gastrointestinal symptoms).
  distinguishing_features:
  - Positive celiac disease serology (anti-tissue transglutaminase IgA, anti-endomysial, or anti-gliadin antibodies) and duodenal villous atrophy on biopsy
  - Low serum ferritin from intestinal iron malabsorption, contrasting with the normal serum ferritin typical of isolated IPH
  - Clinical remission of alveolar hemorrhage and anemia upon adherence to a strict gluten-free diet in the majority of patients
  evidence:
  - reference: PMID:35088581
    reference_title: "Association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients: A scoping review of the literature over the past 50 years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Nearly one-third of pediatric patients with IPH test positive for Celiac disease (CD) serology. Several hypothetical mechanisms have been proposed to unify the coexistence of these two entities, also referred to as Lane-Hamilton syndrome (LHS)."
    explanation: Establishes the high rate of celiac seropositivity in pediatric IPH and defines Lane-Hamilton syndrome.
  - reference: PMID:35088581
    reference_title: "Association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients: A scoping review of the literature over the past 50 years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "All pediatric patients with IPH should undergo screening for CD. Low serum ferritin in patients with IPH could be suggestive of coexisting CD. Strict GFD should be tried as the initial therapy."
    explanation: Supports universal celiac screening in IPH, low ferritin as a discriminator for coexisting CD, and response to gluten-free diet.
  - reference: PMID:36324124
    reference_title: "Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A substantial number of patients suffer from coexisting CD, also known as Lane-Hamilton syndrome (LHS), and all patients with IPH need to be evaluated for LHS by serology."
    explanation: Reinforces mandatory serologic evaluation for Lane-Hamilton syndrome in all IPH patients.
- name: Anti-Glomerular Basement Membrane Disease
  disease_term:
    preferred_term: anti-glomerular basement membrane disease
    term:
      id: MONDO:0009303
      label: anti-glomerular basement membrane disease
  description: >
    Autoimmune small-vessel disorder (Goodpasture disease) causing diffuse
    alveolar hemorrhage and iron-deficiency anemia that can clinically mimic IPH.
  distinguishing_features:
  - Presence of circulating anti-glomerular basement membrane (anti-GBM) antibodies
  - Concurrent rapidly progressive glomerulonephritis and linear IgG deposition along alveolar and glomerular basement membranes, which are absent in IPH
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations for antinuclear antibodies (ANA), anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, antiphospholipid antibodies, and rheumatoid factor were negative in all patients."
    explanation: Demonstrates that anti-GBM antibodies are tested and must be negative to establish a diagnosis of IPH.
- name: Granulomatosis with Polyangiitis
  disease_term:
    preferred_term: granulomatosis with polyangiitis
    term:
      id: MONDO:0012105
      label: granulomatosis with polyangiitis
  description: >
    ANCA-associated systemic necrotizing small-vessel vasculitis that can
    present with acute diffuse alveolar hemorrhage, hemoptysis, and bilateral
    alveolar infiltrates resembling IPH.
  distinguishing_features:
  - Necrotizing pulmonary capillaritis or granulomatous vasculitis on lung biopsy, whereas IPH shows bland alveolar hemorrhage with siderophages and no vasculitis
  - Extrapulmonary vasculitic involvement (upper airway/sinonasal disease, pauci-immune glomerulonephritis, systemic vasculitis)
  evidence:
  - reference: PMID:15293620
    reference_title: "Idiopathic pulmonary haemosiderosis revisited."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the lung biopsy shows numerous siderophages in the alveoli, without any evidence of pulmonary vasculitis"
    explanation: Absence of pulmonary vasculitis on biopsy differentiates IPH from systemic necrotizing vasculitides.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exclusion of other diseases, which are associated with diffuse alveolar hemorrhage, such as bronchiectasis, interstitial pneumonia, neoplasms, cardiovascular disease, coagulation disorders, infections, connective tissue diseases, celiac disease, and systemic vasculitis."
    explanation: Identifies systemic vasculitis as a required exclusion in the differential diagnosis of diffuse alveolar hemorrhage.
- name: Systemic Lupus Erythematosus
  disease_term:
    preferred_term: systemic lupus erythematosus
    term:
      id: MONDO:0007915
      label: systemic lupus erythematosus
  description: >
    Systemic autoimmune connective tissue disease capable of causing secondary
    diffuse alveolar hemorrhage and pulmonary hemosiderosis.
  distinguishing_features:
  - Positive anti-double-stranded DNA (anti-dsDNA) or antiphospholipid antibodies and hypocomplementemia
  - Multiorgan lupus manifestations (nephritis, arthritis, mucocutaneous lesions, serositis) and immune-complex deposition on biopsy
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory investigations for antinuclear antibodies (ANA), anti-double-stranded DNA, antineutrophil cytoplasmic antibodies, antiglomerular basement membrane antibodies, antiphospholipid antibodies, and rheumatoid factor were negative in all patients."
    explanation: Excludes systemic lupus erythematosus and related connective tissue diseases via negative anti-dsDNA, ANA, and antiphospholipid serologies.
- name: Nutritional Iron Deficiency Anemia
  description: >
    The most common initial misdiagnosis of pediatric IPH (accounting for 24/107
    patients in a large pediatric series and 60.0% of misdiagnosed patients in
    an international physician survey), because occult alveolar bleeding often
    presents with isolated microcytic hypochromic anemia, pallor, and fatigue
    before hemoptysis occurs.
  distinguishing_features:
  - Decreased serum ferritin in nutritional iron deficiency anemia versus normal serum ferritin in 60 of 62 tested children with isolated IPH
  - Presence of hemosiderin-laden macrophages in sputum, gastric lavage fluid, or bronchoalveolar lavage fluid, pulmonary infiltrates on chest imaging, and reticulocytosis
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although IPH and nutritional iron deficiency anemia are characterized by microcytic hypochromic anemia, patients with IPH have normal serum ferritin levels."
    explanation: Explains how normal serum ferritin distinguishes IPH from nutritional iron deficiency anemia despite shared microcytic hypochromic morphology.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Misdiagnoses included the following: nutritional iron deficiency anemia (n = 24), bronchial pneumonia (n = 21), pulmonary tuberculosis (n = 6), hemolytic anemia (n = 4), upper respiratory tract infection (n = 4), bronchiectasis (n = 3), myocarditis (n = 1), intestinal diseases (n=1), and favism (n = 1)."
    explanation: Documents that nutritional iron deficiency anemia was the most frequent misdiagnosis (24 of 107 pediatric patients).
  - reference: PMID:26289251
    reference_title: "A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "63.3 % of respondents had patients that were initially misdiagnosed with anemia (60.0 %) or gastrointestinal bleed (18.2 %)."
    explanation: Documents that isolated anemia is the single most frequent initial misdiagnosis of IPH across international centers.
- name: Tuberculosis
  disease_term:
    preferred_term: tuberculosis
    term:
      id: MONDO:0018076
      label: tuberculosis
  description: >
    Pulmonary tuberculosis and bacterial bronchopneumonia are frequent
    infectious misdiagnoses in children presenting with cough, hemoptysis,
    fever, and pulmonary infiltrates prior to siderophage testing.
  distinguishing_features:
  - Microbiological or molecular detection of Mycobacterium tuberculosis and absence of diffuse alveolar siderophages
  - Lack of iron-sequestration microcytic anemia with normal ferritin and response to antituberculous therapy rather than corticosteroids
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "exclusion of other diseases, which are associated with diffuse alveolar hemorrhage, such as bronchiectasis, interstitial pneumonia, neoplasms, cardiovascular disease, coagulation disorders, infections, connective tissue diseases, celiac disease, and systemic vasculitis."
    explanation: Confirms that pulmonary infections are major mimics that must be excluded when diagnosing IPH.
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Misdiagnoses included the following: nutritional iron deficiency anemia (n = 24), bronchial pneumonia (n = 21), pulmonary tuberculosis (n = 6), hemolytic anemia (n = 4), upper respiratory tract infection (n = 4), bronchiectasis (n = 3), myocarditis (n = 1), intestinal diseases (n=1), and favism (n = 1)."
    explanation: Documents that bronchial pneumonia (n = 21) and pulmonary tuberculosis (n = 6) are frequent infectious misdiagnoses of pediatric IPH.
treatments:
- name: Systemic corticosteroid therapy
  description: >
    Systemic corticosteroids are first-line therapy for acute episodes and are
    commonly used for initial control and maintenance, though recurrence during
    tapering is frequent.
  target_mechanisms:
  - target: Recurrent idiopathic diffuse alveolar hemorrhage
    description: Suppresses acute alveolar capillary bleeding and reduces relapse frequency.
  - target: Autoimmune serologic contribution to hemorrhage susceptibility
    description: Attenuates immune-mediated inflammatory contributions to alveolar hemorrhage.
  - target: Recurrent hemorrhage-driven lung injury and remodeling
    description: Limits hemorrhage-driven alveolar inflammation and progression toward pulmonary fibrosis.
  treatment_term:
    preferred_term: corticosteroid agent therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
    - preferred_term: prednisone
      term:
        id: CHEBI:8382
        label: prednisone
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glucocorticoids and immunosuppressive agents are the first choice for treating IPH."
    explanation: The pediatric cohort review supports glucocorticoids as first-choice treatment.
  - reference: PMID:26289251
    reference_title: "A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common medications respondents used for treatment at initial presentation and chronic maintenance therapy were corticosteroids (98.7 and 84.0 %, initial and chronic therapy respectively)"
    explanation: The international physician survey supports common corticosteroid use for initial and chronic therapy.
  - reference: PMID:33184706
    reference_title: "Idiopathic pulmonary hemosiderosis: a review of the treatments used during the past 30 years and future directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Corticosteroid therapy represents the first line of treatment"
    explanation: The treatment review supports corticosteroids as first-line therapy.
- name: Steroid-sparing immunosuppressive therapy
  description: >
    Hydroxychloroquine, azathioprine, cyclophosphamide, mycophenolate mofetil,
    and other immunomodulatory agents have been used when disease is severe,
    recurrent, steroid-refractory, or steroid-toxic.
  target_mechanisms:
  - target: Recurrent idiopathic diffuse alveolar hemorrhage
    description: Reduces frequency of alveolar hemorrhage flares during corticosteroid taper or refractory disease.
  - target: Autoimmune serologic contribution to hemorrhage susceptibility
    description: Modulates autoimmune and lymphocyte-mediated contributors to alveolar bleeding.
  - target: Recurrent hemorrhage-driven lung injury and remodeling
    description: Prevents cumulative hemorrhage-induced alveolar remodeling and fibrotic progression.
  treatment_term:
    preferred_term: immune suppressant agent therapy
    term:
      id: NCIT:C15261
      label: Immunosuppressive Therapy
    therapeutic_agent:
    - preferred_term: hydroxychloroquine
      term:
        id: CHEBI:5801
        label: hydroxychloroquine
    - preferred_term: azathioprine
      term:
        id: CHEBI:2948
        label: azathioprine
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
    - preferred_term: mycophenolate mofetil
      term:
        id: CHEBI:8764
        label: mycophenolate mofetil
  evidence:
  - reference: PMID:33184706
    reference_title: "Idiopathic pulmonary hemosiderosis: a review of the treatments used during the past 30 years and future directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Additional immunomodulatory/immunosuppressive medications have been used with varying success, especially in the setting of steroid-refractory disease."
    explanation: The treatment review supports steroid-sparing immunosuppression for steroid-refractory IPH.
  - reference: PMID:30806370
    reference_title: "Early Initiation of Steroid-sparing Drugs in Idiopathic Pulmonary Hemosiderosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We initiated hydroxy-chloroquine and azathioprine early in treatment along with steroids in seven children with idiopathic pulmonary hemosiderosis"
    explanation: The pediatric series supports hydroxychloroquine and azathioprine as steroid-sparing options used with corticosteroids.
  - reference: PMID:30806370
    reference_title: "Early Initiation of Steroid-sparing Drugs in Idiopathic Pulmonary Hemosiderosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early introduction of second line immunosuppressants helped in reducing disease flare and steroid toxicity without serious adverse effects."
    explanation: The series supports benefit of early steroid-sparing immunosuppression in seven children.
  - reference: PMID:33184706
    reference_title: "Idiopathic pulmonary hemosiderosis: a review of the treatments used during the past 30 years and future directions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Cyclophosphamide, azathioprine, hydroxychloroquine, mycophenolate mofetil, and mesenchymal cell transplantation have been attempted to improve outcome and reduce side effects."
    explanation: The treatment review specifically names cyclophosphamide and mycophenolate mofetil among attempted steroid-sparing options.
- name: Supportive care for acute anemia and respiratory compromise
  description: >
    Supportive management includes acute stabilization, oxygen or respiratory
    support when needed, and transfusion for severe anemia while disease-directed
    immunosuppression is initiated.
  target_mechanisms:
  - target: Iron deficiency anemia
    description: Corrects severe acute or chronic anemia via red blood cell transfusion and iron repletion.
  - target: Respiratory failure
    description: Stabilizes gas exchange during acute diffuse alveolar hemorrhage episodes.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:30278795
    reference_title: "Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All of the 107 patients were provided symptomatic treatments before diagnosis, and 29 received blood transfusions."
    explanation: The pediatric cohort documents symptomatic care and transfusion in a subset before definitive diagnosis.
notes: >
  Pulmonary hemosiderosis in this entry follows the idiopathic pulmonary
  hemosiderosis concept mapped by ORPHA:99931 and MONDO:0008346. Celiac disease
  with pulmonary hemosiderosis is represented separately as Lane-Hamilton
  syndrome; IPH should be evaluated for that association but is not itself
  defined by gluten sensitivity. Etiologic hypotheses include environmental,
  allergic, autoimmune, and genetic contributors, but none is established enough
  to curate as a single upstream causal node.
references:
- reference: ORPHA:99931
  title: Idiopathic pulmonary hemosiderosis
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:15293620
  title: Idiopathic pulmonary haemosiderosis revisited.
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:24125570
  title: "New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort."
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:26289251
  title: A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis.
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:30278795
  title: Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients.
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:30806370
  title: Early Initiation of Steroid-sparing Drugs in Idiopathic Pulmonary Hemosiderosis.
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:33184706
  title: "Idiopathic pulmonary hemosiderosis: a review of the treatments used during the past 30 years and future directions."
  found_in:
  - Pulmonary_Hemosiderosis-deep-research-fallback.md
  findings: []
- reference: PMID:35088581
  title: "Association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients: A scoping review of the literature over the past 50 years."
  found_in: []
  findings: []
- reference: PMID:36324124
  title: "Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review."
  found_in: []
  findings: []
📚

References & Deep Research

References

9
ORPHA:99931
Idiopathic pulmonary hemosiderosis
No top-level findings curated for this source.
PMID:15293620
Idiopathic pulmonary haemosiderosis revisited.
No top-level findings curated for this source.
PMID:24125570
New insights into pediatric idiopathic pulmonary hemosiderosis: the French RespiRare cohort.
No top-level findings curated for this source.
PMID:26289251
A physician survey reveals differences in management of idiopathic pulmonary hemosiderosis.
No top-level findings curated for this source.
PMID:30278795
Clinical characteristics and prognosis of idiopathic pulmonary hemosiderosis in pediatric patients.
No top-level findings curated for this source.
PMID:30806370
Early Initiation of Steroid-sparing Drugs in Idiopathic Pulmonary Hemosiderosis.
No top-level findings curated for this source.
PMID:33184706
Idiopathic pulmonary hemosiderosis: a review of the treatments used during the past 30 years and future directions.
No top-level findings curated for this source.
PMID:35088581
Association between idiopathic pulmonary hemosiderosis and celiac disease in pediatric patients: A scoping review of the literature over the past 50 years.
No top-level findings curated for this source.
PMID:36324124
Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review.
No top-level findings curated for this source.

Deep Research

1

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

Pulmonary Hemosiderosis Deep-Research Fallback ▸

Pulmonary Hemosiderosis Deep-Research Fallback

Automated deep-research providers were attempted after local evidence-backed curation, but both stayed silent and were stopped by bounded timeouts:

  • timeout 120s just research-disorder falcon Pulmonary_Hemosiderosis returned 124 / signal 15.
  • timeout 60s just research-disorder openai Pulmonary_Hemosiderosis returned 124 / signal 15.

Because provider runs were unavailable, the curation used generated local caches and the disease-specific literature already fetched into references_cache/. The reviewed scope is idiopathic pulmonary hemosiderosis as represented by ORPHA:99931 and MONDO:0008346, with secondary diffuse alveolar hemorrhage causes and Lane-Hamilton syndrome kept outside the core disease definition.

Scope Confirmation

  • ORPHA:99931 supplied the disease definition, childhood onset, epidemiology, cross-references, and HPO phenotype rows.
  • PMID:30278795 supplied the large 107-patient pediatric cohort, clinical frequencies, diagnosis, prognosis, and glucocorticoid treatment evidence.
  • PMID:24125570 supplied the French RespiRare pediatric cohort, autoimmunity signals, Down syndrome comorbidity signal, diagnosis, fibrosis, and severe hemorrhage outcomes.
  • PMID:15293620 supplied recurrent diffuse alveolar hemorrhage, siderophages, alveolar hemosiderin deposition, and biopsy exclusion of vasculitis.
  • PMID:26289251 supplied physician-practice treatment patterns.
  • PMID:33184706 and PMID:30806370 supplied corticosteroid and steroid-sparing immunosuppressive treatment scope.

Review Follow-Up

The provider fallback was explicitly cross-checked for obvious curation gaps. PMID:24125570 supports autoimmune contribution in a subset through ANCA, ANA, and coeliac antibody positivity and through the authors' conclusion that autoimmunity contributes to disease development. The YAML now models this as an atomic modifier node rather than replacing the idiopathic upstream trigger.

The same cohort reported Down syndrome in 5 of 25 pediatric IPH cases. Because the current disease schema has no top-level comorbidities slot, the YAML represents this as a Comorbidity phenotype entry with a MONDO term binding and an exact cohort snippet.

PMID:33184706 names cyclophosphamide and mycophenolate mofetil among attempted steroid-sparing therapies. The YAML treatment entry now includes those therapeutic-agent bindings alongside hydroxychloroquine and azathioprine.