Hemosiderosis

In 1975, Thomas and Irwin divided pulmonary hemosiderosis 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 pulmonary hemosiderosis ^[2] can be divided into 3 groups.

Group 1 pulmonary hemosiderosis 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 pulmonary hemosiderosis 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.

Studies of patients with pulmonary hemosiderosis 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 pulmonary hemosiderosis is defined as pulmonary hemorrhage without demonstrable immunologic association. This category includes idopathic pulmonary hemosiderosis, bleeding disorders, cardiovascular diseases, widespread infection, and toxic inhalation. Idiopathic pulmonary hemosiderosis 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 idiopathic pulmonary hemosiderosis 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 idiopathic pulmonary hemosiderosis in infants. Subsequent data question this association.

Causes of primary pulmonary hemosiderosis include the following:

• Idiopathic pulmonary hemosiderosis - The most common cause of pulmonary hemosiderosis in childhood

• Heiner syndrome - Hypersensitivity to proteins from cow's milk

• Goodpasture syndrome - Anti-glomerular basement membrane (GBM) antibody–mediated hemosiderosis

Causes of secondary pulmonary hemosiderosis include the following:

• 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, bronchiolitis obliterans

• Immunologically mediated diseases - Systemic lupus erythematosus (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 - Stachybotrys atra, Memnoniella echinata

• Miscellaneous causes - Retained foreign body, pulmonary trauma, pulmonary alveolar proteinosis, congenital hyperammonemia

United States statistics

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

International statistics

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

Sex- and age-related demographics

Sex

In patients younger than 10 years, reports of idiopathic pulmonary hemosiderosis show equal distribution between males and females in the United States, Sweden, and Greece; however, in Japan the female-to-male ratio was 2.25:1. In patients older than 10 years, the male-to-female ratio is 2:1.

Age

Idiopathic pulmonary hemosiderosis 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.

The prognosis for the pulmonary hemosiderosis 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 idiopathic pulmonary hemosiderosis, the clinical course widely varies; 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 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 idiopathic pulmonary hemosiderosis found that the presence of antineutrophil cytoplasmic antibodies (ANCA) or other autoantibodies signal poor prognosis. The same study, in which the mean duration of follow-up was 17.2 years (range, 10-36 y), reported a survival rate of 80%

In pulmonary hemosiderosis associated with milk protein allergy, avoidance of dairy products is usually associated with complete remission. ^[3]

A study by Hizal et al found that the presence of hypoxia at initial presentation was a significant independent predictor of recurrent episodes in children with idiopathic pulmonary hemosiderosis. The median follow-up period was 3.3 years. ^[4]

Morbidity/mortality

No national database monitors children with pulmonary hemosiderosis. Patients with idiopathic pulmonary hemosiderosis 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.

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 idiopathic pulmonary hemosiderosis (IPH) who have lived for an exceptionally long time after the onset of their disease.