AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Pulmonary hemosiderosis (PH) is characterized by repeated episodes of intra-alveolar bleeding that lead to abnormal accumulation of iron as hemosiderin in alveolar macrophages and subsequent development of pulmonary fibrosis and severe anemia.

PH can occur as a primary disease of the lungs or can be secondary to cardiovascular or systemic disease. In children, primary PH is more common than secondary types.

Three variants of primary PH are recognized: (1) PH associated with antibody to the basement membrane of the lung and kidney (ie, Goodpasture syndrome), (2) PH associated with hypersensitivity to proteins in cow's milk (ie, Heiner syndrome), and (3) idiopathic PH (IPH).

The diagnosis of isolated PH or IPH is a diagnosis of exclusion, requiring thorough review and elimination of other causes of primary and secondary PH.

Pathophysiology

In 1975, Thomas and Irwin divided PH into 3 categories: one category in which anti–glomerular basement membrane (anti-GBM) is present, a second category in which immune complexes are found, and a third category in which neither can be demonstrated.

Following this classification, the pathophysiology of PH can be divided into 3 groups.

Group 1 PH is defined by pulmonary hemorrhage associated with circulating anti-GBM antibodies. This condition defines Goodpasture syndrome. This syndrome is characterized by linear immunofluorescence deposition of immunoglobulin and complement along the basement membrane of the lung tissue and the kidney glomeruli and is associated with vascular damage and diffuse defragmentation of the basement membrane on electron microscopy.

Group 2 PH is defined as pulmonary hemorrhage and immune complex disease. This combination has been reported as a rare manifestation of systemic lupus erythematosus (SLE) and other connective tissue disorders, including cryoglobulinemia, Henoch-Schönlein purpura, mixed connective tissue disease, and Wegener granulomatosis. Recent studies of patients with PH associated with hypersensitivity to cow's milk (ie, Heiner syndrome) have demonstrated circulating immune complexes; alveolar deposits of immunoglobulin G (IgG), immunoglobulin A (IgA), and C3; peripheral blood eosinophilia; and delayed hypersensitivity to proteins from cow's milk.

Group 3 PH is defined as pulmonary hemorrhage without demonstrable immunologic association. This category includes IPH, bleeding disorders, cardiovascular diseases, widespread infection, and toxic inhalation. IPH is morphologically characterized by intra-alveolar hemorrhage and subsequent abnormal accumulation of iron in the form of hemosiderin inside pulmonary macrophages. Recurrent episodes of hemorrhage lead to thickening of the alveolar basement membrane and interstitial fibrosis. Transmission electron microscopy of lung biopsies has shown that the major damage in this disorder involves capillary endothelium and its basement membrane, but no electro-dense deposits have been identified.

In the early 1990s, the incidence of acute IPH in young infants increased in several midwestern US cities, especially in the Cleveland area. Epidemiological research led to the discovery of heavy growth of the toxigenic fungus Stachybotrys atra in almost all of the case homes, suggesting that exposure to that mold can cause IPH in infants. Subsequent data question this association.

Frequency

United States

IPH is an uncommon yet well-recognized disorder. Exact figures regarding prevalence are lacking. Familial recurrence has been reported but is rare.

International

IPH is a rare disorder, with a reported yearly incidence of 0.24 (Sweden) and 1.23 (Japan) cases per million children.

Mortality/Morbidity

• No national database monitors children with PH.
• Patients with IPH have a mean survival rate of 2.5-5 years after diagnosis. Death can occur acutely from massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.

Sex

• In patients younger than 10 years, reports of IPH show equal distribution between males and females in the United States, Sweden, and Greece; however, the equal sex distribution reported in these countries was not observed in Japan, where the female-to-male ratio was 2.25:1.
• In patients older than 10 years, the male-to-female ratio is 2:1.

Age

• IPH may occur in people of any age, from the neonatal period to late adulthood, but it is most common in children aged 1-7 years.
• Goodpasture syndrome usually occurs in young adult males and is rare in infants.
• Heiner syndrome is usually diagnosed in children aged 6 months to 2 years.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• A triad of hemoptysis, iron deficiency anemia, and diffuse pulmonary infiltrates characterizes pulmonary hemosiderosis (PH).
• Clinical presentation can range from an insidious onset to a fulminant course.
• Hemoptysis may or may not be present in children. The absence of this symptom does not rule out the diagnosis of PH.
• Sudden decrease in hematocrit levels associated with the onset of active respiratory disease is strongly suggestive of PH.
• Nonspecific recurrent or chronic pulmonary symptoms, such as cough (dry or productive), dyspnea, tachypnea, and wheezing, are observed in most patients.
• With severe pulmonary hemorrhage, hypoxemia and frank respiratory failure may result.
• Symptoms of chronic fatigue, severe exercise limitation, and growth failure may accompany long-standing PH.
• In Heiner syndrome, common clinical symptoms include chronic rhinitis, recurrent otitis media, recurrent cough, and poor weight gain. In these patients, symptoms improve when cow's milk is removed from the diet.
• PH, while uncommon, can occur in association with a wide variety of clinical disorders, many of which have overlapping features of glomerulonephritis and immune complex diseases.
• von Willebrand disease, the most common inherited bleeding disorder, has multiple variants. Patients with this condition tend to have mucocutaneous bleeding and can present with pulmonary hemorrhage.
• The combination of idiopathic pulmonary hemosiderosis (IPH) and celiac disease is extremely rare. In this case, pulmonary bleeding can occur in association with severe anemia and gastrointestinal symptoms (eg, diarrhea, steatorrhea, flatulence) or even in the absence of the latter.

Physical

• After an acute episode of pulmonary hemorrhage, the physical examination may reveal the following:
• • Tachypnea
  • Dyspnea (use of accessory muscles, retractions, flaring)
  • Pallor
  • Tachycardia
  • Cyanosis
  • Crackles
  • Wheezing
  • Fever
• Long-standing severe PH is associated with the following:
• • Clubbing
  • Growth failure

Causes

• Primary PH
• • IPH - The most common cause of pulmonary hemosiderosis in childhood
  • Heiner syndrome - Hypersensitivity to proteins from cow's milk
  • Goodpasture syndrome - Anti-GBM antibody–mediated hemosiderosis
• Secondary PH
• • Congenital or acquired cardiopulmonary abnormalities - Bronchogenic cyst, pulmonary sequestration, congenital arteriovenous fistula, tetralogy of Fallot, Eisenmenger complex, mitral valve stenosis, pulmonic valve stenosis, congenital pulmonary vein stenosis, pulmonary arterial stenosis, pulmonary embolism, left ventricular failure
  • Infections and their complications - Bacterial pneumonia, sepsis (disseminated intravascular coagulation [DIC]), pulmonary abscess, bronchiectasis, and bronchiolitis obliterans
  • Immunologically mediated diseases - SLE, periarteritis nodosa, Wegener granulomatosis, Henoch-Schönlein purpura, immune complex–mediated glomerulonephritis, allergic bronchopulmonary aspergillosis
  • Neoplasms - Primary bronchial tumors (adenoma, carcinoid, sarcoma, hemangioma, angioma) or metastatic lesions (sarcoma, Wilms tumor, osteogenic sarcoma)
  • Drugs - Penicillamine, cocaine
  • Toxins - Pesticide substances (synthetic peritroids)
  • Environmental molds - S atra, Memnoniella echinata
  • Miscellaneous causes - Retained foreign body, pulmonary trauma, pulmonary alveolar proteinosis, congenital hyperammonemia

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Interstitial lung disease

See Secondary PH under Causes.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• CBC
• • Microcytic and hypochromic anemia are present.
  • Eosinophilia has been present in approximately one eighth of reported cases. Most of these cases are associated with Heiner syndrome.
• Stool guaiac test results - Frequently positive
• Analysis of gastric lavages - Positive for iron-laden macrophages
• Immunoglobulin E level - High levels possible in Heiner syndrome
• Serologic analysis
• • Titers of serum precipitins to casein and lactalbumin are elevated in Heiner syndrome.
  • Circulating anti-GBM antibodies are present in patients with Goodpasture syndrome.
  • Antineutrophil cytoplasmic antibodies (C-ANCA) are present in patients with Wegener granulomatosis.
  • Antinuclear antibodies and anti-DNA antibodies are positive in SLE.
  • Serologic markers for celiac disease include gliadin antibodies and reticulin antibodies. If findings are positive, then consider performing a jejunal biopsy.
• Sputum analysis
• • Perform stain, culture, and sensitivity for bacteria, fungi, and mycobacteria.
  • Cytology may reveal hemosiderin-laden macrophages, which suggests bleeding during the preceding months and ongoing bleeding for more than 3-4 days.
• Urinalysis - Hematuria and/or proteinuria in pulmonary hemosiderosis (PH) secondary to immune-mediated glomerulonephritis, Goodpasture syndrome, and SLE
• Prothrombin time/activated partial thromboplastin time - Used to rule out bleeding disorders
• Von Willebrand factor antigen and Ristocetin cofactor levels - May be obtained to assess for von Willebrand disease
• IgA antiendomysial antibody level - Facilitates the diagnosis of celiac disease (However, histologic examination of a duodenal biopsy sample remains the criterion standard.)

Imaging Studies

• Chest radiography
• • The most common finding is patchy alveolar infiltrates that are often perihilar or basilar and are usually bilateral. Infiltrates may be migratory.
  • Interstitial changes are found in long-standing PH.
  • Occasionally, chest radiograph findings may be normal.
  • Hilar lymph nodes may be enlarged, especially in the acute stage.
  • Resolution, often with a persistent reticular pattern, occurs in less than 2 weeks.
• CT scanning
• • May show areas of increased pulmonary density due to intra-alveolar hemorrhage and/or hemosiderin-laden macrophages, even when the chest radiograph findings appear normal
  • Useful in distinguishing superimposed infections from fresh hemorrhages
  • Helpful if focal pulmonary causes, endobronchial lesions, or vascular malformations are suspected
  • Useful in demonstrating the exact localization of lesions for open lung biopsy
• Nuclear scanning
• • The lungs of healthy patients do not take up RBCs labeled with chromium isotope (⁵¹Cr) or technetium Tc 99 (⁹⁹Tc) pertechnetate.
  • Scans with abnormal pulmonary uptake 12-24 hours after the injection have been observed in patients with pulmonary hemorrhage.
• Ventilation/perfusion scanning - Important if pulmonary embolism is suspected

Other Tests

After an episode of acute hemorrhage, pulmonary function testing (PFT) demonstrates decreased compliance, airflow obstruction, and an increase in the diffusing capacity for carbon monoxide (due to increased hemoglobin uptake of carbon monoxide by sequestrated RBCs in the lungs). In long-standing PH, PFT results demonstrate a restrictive pattern.

Procedures

• Flexible bronchoscopy
• • Performed to assess the anatomy of the airways for pulmonary malformations, endobronchial lesions, retained foreign body, and airway compression
  • Used to perform bronchoalveolar lavage (BAL)
• Bronchoalveolar lavage
• • Hemosiderin-laden macrophages: Hemosiderin-laden macrophages are diagnostic for PH. They are usually cleared from the alveoli and airways within a few months of the bleeding. The microphages are observed 2-3 days after acute bleeding.
  • Malignant cells in cases of neoplasms (extremely uncommon in pediatric patients)
  • Positive stains and cultures for bacteria, fungi, and mycobacteria in cases of infection
• Open lung biopsy

Histologic Findings

Findings in the lung vary with the stage of the disease. In the early stages, interstitial and intra-alveolar hemorrhages predominate, with collections of both free hemosiderin and hemosiderin-laden macrophages found in the alveolar spaces and in the interstitium. As the disease progresses, interstitial fibrosis develops. Immunofluorescence and electron microscopy of the lung and kidney tissue may differentiate idiopathic pulmonary hemosiderosis (IPH) from Goodpasture syndrome and immune complex–mediated diseases.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

The treatment of pulmonary hemosiderosis (PH) is directed toward management of the acute crises and long-term therapy.

• Management of episodes of acute pulmonary hemorrhage includes the following:
• • Oxygen supplementation
  • Blood transfusion to correct severe anemia and shock
  • Supportive respiratory therapy for excessive secretions and bronchospasm
  • Mechanical ventilatory support for respiratory failure
  • Extracorporeal membrane oxygenation (proven to be effective after failure of conventional mechanical ventilation)
  • Immunosuppressive therapy
• Long-term immunosuppressive therapy in hemosiderosis management remains controversial.
• The main treatment for milk-associated PH is avoidance of milk and dairy products.
• Treatment of secondary hemosiderosis is usually directed toward the underlying condition. A gluten-free diet is indicated in cases of celiac disease associated with PH, even in the absence of gastrointestinal symptoms.

Surgical Care

Surgical care is not indicated.

Consultations

• Pediatric pulmonologist
• Pediatric nephrologist when PH is associated with abnormal urinalysis findings

Diet

In patients with Heiner syndrome, the main treatment is avoidance of milk and dairy products.
Patients with hemosiderosis associated with celiac disease who are treated with a gluten-free diet show improvement of clinical symptoms and show improvement on radiography findings within 2 weeks.

Activity

No activity limitation is indicated.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

For isolated pulmonary hemosiderosis (IPH), corticosteroids are believed to be useful in the management of the acute alveolar hemorrhage stage. Failure to respond adequately to corticosteroids alone or unacceptable corticosteroid adverse effects may be indications for using other forms of immunosuppression (eg, azathioprine, chloroquine, cyclophosphamide). Published experience with these medications has been very limited and is confined to case reports. Inhaled corticosteroids also have been used, but current reports are insufficient.

Case reports have described the use of other immunosuppressive medications in the long-term management of IPH. One report commented on the use of chloroquine in 3 children with IPH, with improvement in the course of their disease. Another report mentioned the efficacy of a combination of azathioprine and corticosteroids in abating acute exacerbations of the disease in a child with IPH. The long-term efficacy of immunosuppressive therapy is still in doubt.

Drug Category: Immunosuppressive agents

These agents are used for patients with conditions caused by immune dysregulation and autoimmunity. A lack of knowledge about the pathogenetic mechanisms involved in IPH makes the theoretical basis of such therapies unclear.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Periodic evaluation of growth, oxygen saturation, pulmonary and renal function, and hemography and chest radiography findings is appropriate.
• Long-term steroid use requires frequent monitoring for possible adverse effects.

Deterrence/Prevention

• Patients with Heiner syndrome should avoid milk and dairy products.

Complications

• Respiratory failure requiring mechanical ventilatory support may occur after an episode of acute pulmonary hemorrhage.
• Chronic cor pulmonale with pulmonary hypertension secondary to pulmonary fibrosis has been described in a minority of patients with IPH who have lived for an exceptionally long time after the onset of their disease.

Prognosis

• The prognosis for the pulmonary hemosiderosis (PH) syndromes as a group is difficult to determine because of the infrequency of the diagnosis and the variability among cases and etiologies. Furthermore, no national database monitors children with PH.
• When focusing on IPH, the clinical course varies greatly; however, the prognosis has always been regarded as poor, with a mean survival of 2.5-3 years after diagnosis. Death can occur acutely from massive hemorrhage or after progressive pulmonary insufficiency and right heart failure. The available therapeutic modalities are not associated with a better outcome.
• One study of 30 children with idiopathic pulmonary hemosiderosis (IPH) listed the following prognostic criteria:
• • The severity of the disease at its onset does not correlate with the survival.
  • Females survive longer than males.
  • Young age at the onset of disease seems to carry a less favorable prognosis.
  • Common therapeutic modalities have not improved outcome.
• Another retrospective study of 15 children with IPH found that the presence of antineutrophil cytoplasmic antibodies (ANCA) or other autoantibodies signal poor prognosis.
• In PH associated with milk protein allergy, avoidance of dairy products is usually associated with complete remission.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to diagnose pulmonary hemosiderosis (PH) leads to pulmonary fibrosis and irreversible loss of pulmonary function.

Special Concerns

• Early initiation of immunomodulatory therapy can lead to preservation of pulmonary function in pediatric patients.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Akyar S, Ozbek SS. Computed tomography findings in idiopathic pulmonary hemosiderosis. Respiration. 1993;60(1):63-4. [Medline].
• CDC. Investigation of acute idiopathic pulmonary hemorrhage among infants - Massachusetts, December 2002-June 2003. MMWR Morb Mortal Wkly Rep. Sep 10 2004;53(35):817-20. [Medline].
• Dearborn DG. Pulmonary hemorrhage in infants and children. Curr Opin Pediatr. Jun 1997;9(3):219-24. [Medline].
• Hoca, Nevin Taci. Dayioglu, Didem. Ogretensoy, Mihriban. Pulmonary hemosiderosis in association with celia disease. Lung. Sep-Oct 2006;184(5):297-300. [Medline].
• Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir J. Jul 2004;24(1):162-70. [Medline].
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• Kayser K, Plodziszewska M, Waitr E, et al. Diffuse pulmonary hemosiderosis after exposure to pesticides. A case report. Respiration. 1998;65(3):214-8. [Medline].
• Kiper N, Gocmen A, Ozcelik U, et al. Long-term clinical course of patients with idiopathic pulmonary hemosiderosis (1979-1994): prolonged survival with low-dose corticosteroid therapy. Pediatr Pulmonol. Mar 1999;27(3):180-4. [Medline].
• Le Clainche L, Le Bourgeois M, Fauroux B, et al. Long-term outcome of idiopathic pulmonary hemosiderosis in children. Medicine (Baltimore). Sep 2000;79(5):318-26. [Medline].
• Malhotra P, Aggarwal R, Aggarwal AN, et al. Coeliac disease as a cause of unusually severe anaemia in a young man with idiopathic pulmonary haemosiderosis. Respir Med. Apr 2005;99(4):451-3. [Medline].
• McCoy KS. Hemosiderosis. In: Taussig LM, Landau LI, eds. Pediatric Respiratory Medicine. St. Louis, Mo: Mosby; 1999:835-40.
• Milman N, Pedersen FM. Idiopathic pulmonary haemosiderosis. Epidemiology, pathogenic aspects and diagnosis. Respir Med. Jul 1998;92(7):902-7. [Medline].
• Pinto LA, Oliveira A, Collaziol S, et al. Postinfectious bronchiolitis obliterans accompanied by pulmonary hemosiderosis in childhood. J Bras Pneumol. Nov-Dec 2006;32(6):587-91. [Medline].
• Rossi GA, Balzano E, Battistini E, et al. Long-term prednisone and azathioprine treatment of a patient with idiopathic pulmonary hemosiderosis. Pediatr Pulmonol. Jul 1992;13(3):176-80. [Medline].
• Saeed MM, Woo MS, MacLaughlin EF, et al. Prognosis in pediatric idiopathic pulmonary hemosiderosis. Chest. Sep 1999;116(3):721-5. [Medline]. [Full Text].
• Sun LC, Tseng YR, Huang SC, et al. Extracorporeal membrane oxygenation to rescue profound pulmonary hemorrhage due to idiopathic pulmonary hemosiderosis in a child. Pediatr Pulmonol. Sep 2006;41(9):900-3. [Medline].
• Torres MJ, Giron MD, Corzo JL, et al. Release of inflammatory mediators after cow's milk intake in a newborn with idiopathic pulmonary hemosiderosis. J Allergy Clin Immunol. Dec 1996;98(6 Pt 1):1120-3. [Medline].
• Zaki M, al Saleh Q, al Mutari G. Effectiveness of chloroquine therapy in idiopathic pulmonary hemosiderosis. Pediatr Pulmonol. Aug 1995;20(2):125-6. [Medline].

Article Last Updated: Aug 23, 2007