Continuing Education Activity

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by repeated episodes of a diffuse alveolar hemorrhage resulting in the accumulation of hemosiderin inside pulmonary macrophages. Early recognition and prompt diagnosis can help reduce the high morbidity and mortality associated with this condition. This activity reviews the evaluation and treatment of IPH and highlights the role of the interprofessional team in the care of patients with this condition.

Objectives:

• Review the etiology of idiopathic pulmonary hemosiderosis.
• Describe the most common presentation of idiopathic pulmonary hemosiderosis.
• Explain the treatment options available for idiopathic pulmonary hemosiderosis.
• Summarize the importance of coordination and communication amongst the interprofessional team to enhance the care of patients with idiopathic pulmonary hemosiderosis.

Introduction

Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by repeated episodes of a diffuse alveolar hemorrhage, which over time, can lead to multiple respiratory complications and permanent lung damage. Though the exact cause of IPH is not well-understood, some believe the disease is from autoimmune damage to the capillaries of the alveoli leading to repeated bleeding into the alveolar space. It is because of this repetitive bleeding that permanent damage occurs, leading to significant morbidity and mortality. When no cause for repeated episodes of diffuse alveolar hemorrhage is apparent, the entity is referred to as IPH.[1] The diagnosis of IPH is a diagnosis of exclusion, requiring a thorough review and elimination of other causes of primary and secondary pulmonary hemosiderosis.

Etiology

The etiology is uncertain but likely to be multifactorial. Possible associations include toxic insecticides (epidemiological studies in rural Greece), premature birth, and fungal toxin exposure. In the 1990s, the incidence of acute idiopathic pulmonary hemosiderosis (IPH) in young infants in several midwestern US cities increased, especially in the Cleveland area. Epidemiological research led to the discovery of substantial growth of the toxigenic fungus Stachybotrys atra in the homes of almost all of the cases, suggesting that exposure to that mold can cause IPH in infants. Subsequent data did not prove this association. Pulmonary hemosiderosis is associated with rheumatoid arthritis, thyrotoxicosis, celiac disease, and autoimmune hemolytic anemia, suggesting a potential autoimmune mechanism.

Epidemiology

Due to the rare nature of idiopathic pulmonary hemosiderosis (IPH), the incidence and prevalence of the disease are relatively unknown. Many patients previously reported to have IPH are likely misdiagnosed and have a diffuse alveolar hemorrhage. A Swedish study from 1984 estimated an incidence of 0.24 per million children per year, using data collected from 1950-1979.[2] A retrospective study from Japan estimated approximately 1.23 cases per million per year.[3]

Approximately 80% of cases occur in children, most of which are diagnosed in the first decade of life.[4] Adult-onset IPH accounts for approximately 20% of cases; however, there may be an unknown fraction of these cases, which were un-diagnosed childhood-onset IPH. Gender distribution of IPH appears to be equally balanced between males and females in childhood-onset IPH. However, there are almost twice as many males as females diagnosed with adult-onset IPH.[5][6] Familial clustering has been noted in several reports suggestive of some genetic component.[7][8][9]

Pathophysiology

The alveolar macrophages are responsible for the repeated clean-up of excess blood. As the macrophages degrade the erythrocytes, the excess iron from heme degradation within the alveolar macrophages stimulates intracellular ferritin molecules. Further processing of the ferritin leads to hemosiderin complexes; unfortunately, this form of iron is unable to be used by the body and leads to iron-deficient states. Meanwhile, the increased iron load from repetitive bleeding quickly saturates the alveolar macrophages intra-cytoplasmic ferritin, and each macrophage is unable to synthesize any additional iron. Unbound free iron leads to oxidative stress on the alveoli, which can lead to pulmonary fibrosis. This has been demonstrated in prior studies of patients with hemochromatosis and concomitant idiopathic pulmonary fibrosis.

Pulmonary hemosiderosis is typically grouped into three categories based on disease characteristics.

Group 1 pulmonary hemosiderosis is defined by pulmonary hemorrhage associated with circulating anti-glomerular basement membrane (anti-GBM) antibodies. Anti-GBM diseases are small vessel vasculitis affecting the capillary system, where there is immunoglobulin and complement deposition along basement membranes of primarily the lungs and the kidneys such as in Goodpasture syndrome. A majority of these patients will develop glomerular crescent formation with rapidly progressive glomerulonephritis; however, on average, 40%-60% of patients with anti-GBM diseases will develop an alveolar hemorrhage. Diffuse alveolar hemorrhage presents clinically in these patients, and a diagnostic broncho-alveolar lavage may demonstrate hemosiderin-laden macrophages. Unlike idiopathic pulmonary hemosiderosis, group 1 pulmonary hemosiderosis is stratified based on kidney biopsy, showing linear deposits of IgG under direct immunofluorescence. Lung biopsy samples are not used in the diagnosis of anti-GBM disease and would likely have no specific information.[2][10]

Group 2 pulmonary hemosiderosis is defined by pulmonary hemorrhage with immune complex disease. Immune complexes are antigen-antibody complexes formed by joining IgG or IgM to a soluble antigen, which triggers complement activation. The result of this immune complex formation is a break in the vascular-endothelial barrier and alveolar-epithelial barrier leading to alveolar edema, hemorrhage, and massive infiltration of polymorphonuclear neutrophils (PMNs). This activation of PMNs and macrophages release large amounts of oxidants and proteases, leading to damage to the alveolar wall leading to potential acute lung injury and alveolar hemorrhage, which may present itself as an acute respiratory distress syndrome (ARDS). Recurrent episodes of these immune complex-mediated lung injuries inevitably lead to pulmonary scarring and fibrosis. Associated conditions, although rare, include systemic lupus erythematosus (SLE), Henoch-Schonlein purpura, Wegener’s granulomatosis, and mixed connective tissue disease.[11][12][13]

Group 3 pulmonary hemosiderosis is defined as pulmonary hemorrhage without known immunologic association, also known as idiopathic pulmonary hemosiderosis (IPH). As previously noted, repeated episodes of diffuse alveolar hemorrhage result in the accumulation of iron in the form of hemosiderin inside pulmonary macrophages. These recurrent episodes also lead to the thickening of alveolar basement membranes and interstitial fibrosis. Therefore, IPH is considered a diagnosis of exclusion after having ruled out primary and secondary causes of pulmonary hemosiderosis.

Histopathology

Histopathological findings in the lung vary with the stage of the disease. In the early stages, interstitial and intra-alveolar hemorrhage predominate, with collections of both free hemosiderin and hemosiderin-filled macrophages found in the alveolar spaces and the interstitium. When the disease progresses, interstitial fibrosis ensues. Immunofluorescence and electron microscopy of the biopsy specimen taken from lung and kidney may differentiate idiopathic pulmonary fibrosis (IPH) from Goodpasture syndrome and immune complex-mediated diseases.

History and Physical

The clinical presentation of idiopathic pulmonary hemosiderosis (IPH) varies from an acute onset illness with hemoptysis and dyspnea to a chronic cough and dyspnea to repetitive hemoptysis with fatigue, anemia, and slowly progressive dyspnea. In some cases, asymptomatic anemia is the only finding present. In adults, respiratory symptoms tend to be more prominent; however, children present with failure to thrive and anemia.[14]

IPH presents in two phases. The first as an acute phase corresponds with intra-alveolar bleeding episodes associated with cough, dyspnea, hemoptysis, and potentially respiratory failure. The second chronic phase is characterized by the slow resolution of previous symptoms with or without treatment.

Patients who present in the acute phase of the disease show a wide variety of signs and symptoms, including but not limited to respiratory failure, cough, hemoptysis, and worsening anemia. However, many patients may present with a normal physical exam. Rapid asphyxiation due to massive pulmonary hemorrhage has also been reported. Generally, patients who present in the chronic phase of the disease demonstrate exam findings of pallor, emaciation, hepato-splenomegaly, failure to thrive, or even a completely normal exam. In patients with fibrosis, bilateral crackles and finger clubbing may also be present.[1][15]

Evaluation

A complete blood count on a patient with pulmonary hemosiderosis will show varying degrees of anemia in the absence of quantitative or qualitative platelet defects, liver or kidney disease, other coagulopathies, or any inflammatory syndromes.

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are done to evaluate for bleeding disorders.

Urinalysis for hematuria and proteinuria to rule out secondary pulmonary hemosiderosis is mandatory.

Anti-glomerular basement membrane antibodies, anti-neutrophil cytoplasmic antibodies, antinuclear and anti-DNA antibodies are also done.

Sputum testing with hematoxylin-eosin and Prussian blue stains may demonstrate erythrocytes and hemosiderin-laden macrophages, indicating intra-alveolar bleeding. Stains and cultures for mycobacteria, bacteria, and fungus are done to rule out the infective cause.

Bronchoalveolar lavage (BAL) has a higher diagnostic yield than sputum testing. BAL will demonstrate alveolar macrophages filled with hemosiderin and intact erythrocytes and occasionally neutrophils.

Pulmonary function testing generally shows a restrictive pattern of varying severity. The carbon monoxide diffusing capacity (DLCO) can be elevated during the acute phase. Still, it will most likely be low or normal during the chronic period of idiopathic pulmonary hemosiderosis (IPH).[3]

Plain film chest radiographs taken during an acute phase of IPH exacerbation may show diffuse alveolar infiltrates greatest at the lung bases. Computed tomography (CT) scans will demonstrate corresponding ground-glass attenuation in a similar distribution, as seen in a standard chest x-ray. During remission, the pulmonary infiltrate tends to be absorbed, leading to an interstitial reticular and micronodular pattern of opacities in the same areas with variable degrees of fibrosis.[1][16]

Chromium and technetium-based perfusion scans will show intra-alveolar bleeding; however, their use in clinical practice is limited. The lungs of healthy patients do not take up red blood cells labeled with chromium isotope or technetium Tc 99 pertechnetate. Scans with abnormal pulmonary uptake 12-24 hours after the injection have been observed in patients with pulmonary hemorrhage.

Treatment / Management

There are currently no gold standard treatments to date, and further studies are needed to help drive better management strategies. Most therapy and recommendations are based on the observation and clinical experience of the provider. Treatment is also based on the presentation and acute versus chronic nature of the patient.

There have been trials/studies done, including elective splenectomy, high dose systemic steroids, inhaled steroids, and immunosuppressant drugs. Blood should be transfused to correct severe anemia and shock. A study by de Jongh et al. recommended screening for hemosiderosis in all patients receiving multiple transfusions.[17] Of the many approaches to idiopathic pulmonary hemosiderosis (IPH) treatment, systemic steroids, and immunosuppressant therapy have shown the most favorable outcomes when used independently or in combination. Current recommendations for an acute phase IPH call for 0.5 to 0.75 mg/kg per day (up to 60 mg/day) initial dosing of prednisolone, which is tapered once chest radiograph shows improvement in new opacifications.[1]

Patients with acute IPH and respiratory failure secondary to alveolar hemorrhage may require invasive ventilation support. In these patients, it is also recommended to consider immunosuppressive therapy in addition to high-dose systemic corticosteroids. For patients with this presentation, it is recommended they be started on intravenous methylprednisolone in pulse dosing of 500 to 2000 mg/day for five days. In children, pulse dosing is weight-based at 20 mg/kg per day. Once patients clinically stabilize, they can be switched to oral steroids with tapering down to a maintenance dose of 10 to 15 mg/day.[18][19]

Immunosuppressive agents such as cyclophosphamide, hydroxychloroquine, and azathioprine have been shown to help with severe disease; however, at this time, optimal dosing and duration of therapy are poorly defined.[20][21]

Preventative measures include maintenance doses of prednisone or prednisolone of 10 to 15 mg/kg/day. In general, if the patient does not have any recurrence in 18 to 24 months, further tapering and discontinuation of steroids can be attempted.[22]

Differential Diagnosis

There is a long list of differentials for patients presenting with an initial or subsequent episode of alveolar hemorrhage; those include infectious etiologies, rheumatic disease, drug-induced injury, thromboembolic disease, bleeding disorders, and neoplasms.

Alveolar hemorrhage that occurs in the setting of infections typically presents as an acute respiratory distress syndrome. Infections associated with hemorrhage include bacterial pneumonia such as Streptococcus pneumoniae, Staphylococcus aureus, and Legionella. Viral types of pneumonia associated with pulmonary hemorrhage have also been documented, specifically with influenza A. Pulmonary hemorrhage has also been seen with fungal infections like Pneumocystis jirovecii.

Rheumatic disease associated with alveolar hemorrhage includes disease processes such as systemic lupus erythematosus, antiphospholipid antibody syndrome, Goodpasture disease, microscopic, and granulomatous polyangiitis, and mixed cryoglobulinemias. These are often diagnosed based on extrapulmonary and serologic manifestations rather than alveolar hemorrhage being the initial presentation.

Virtually any disease process can be associated or attributed to drug-induced injury, including alveolar hemorrhage. Acute lung toxicity with diffuse alveolar damage has been seen with medications such as amiodarone, nitrofurantoin, and infliximab. Penicillamine has been known to cause both acute lung toxicity, and drug-induced lupus, both complications can lead to hemorrhage.

Prognosis

The prognosis is variable, with some patients showing spontaneous remission and others progressing to death. The duration of disease in the literature ranges from death within days, following a severe acute illness, to survival with cor pulmonale associated with the chronic illness after twenty years. Patients with idiopathic pulmonary hemosiderosis (IPH) have a mean survival rate of 2.5 to 5 years after diagnosis. Deaths can occur acutely from massive hemorrhage or after progressive pulmonary insufficiency and right heart failure.

Complications

Complications and long-term effects of idiopathic pulmonary hemosiderosis (IPH) vary depending on the severity and frequency of recurrence. Iron deficiency anemia and pulmonary fibrosis are the two most common complications of IPH. In the acute phase, IPH complications vary from simple complications such as shortness of breath to death due to choking of airways because of massive bleed and shock. Chronic complications may occur from progressive pulmonary insufficiency/severe respiratory distress and right heart failure. Death may occur as a result of massive bleeding.

Consultations

An interprofessional team approach can help to manage patients with idiopathic pulmonary hemosiderosis (IPH) efficiently. A collaboration between the following specialties is recommended:

• Pulmonology
• Nephrology
• Intensive care unit
• Rheumatology
• Thoracic surgeon

Deterrence and Patient Education

Once diagnosed with idiopathic pulmonary hemosiderosis (IPH), patient education is directed towards preventing the recurrence of bleeding. For patients with concomitant celiac disease, a gluten-free diet may be sufficient to prevent further episodes. Otherwise, many patients respond to chronic oral glucocorticoids which effects are two-fold. Steroids not only help prevent recurrent events but it has been shown to delay the development of fibrotic changes within the lung.

Enhancing Healthcare Team Outcomes

Idiopathic pulmonary hemosiderosis (IPH), while a relatively rare disease process, poses a diagnostic dilemma as it is misdiagnosed or often missed entirely. Due to the rarity of the disease, there is a lack of ongoing prospective studies. Further studies, including case reviews, from multiple providers and facilities, would be beneficial to patients with ongoing IPH and those diagnosed in the future.

In patients with known IPH, early recognition of recurrence or exacerbations by health care professionals can improve outcomes and prevent further morbidity and mortality. It is crucial to approach patients with IPH with an interprofessional team of specialists, including primary care providers, hospitalists, and a pulmonologist, through the entire disease process from an acute event to outpatient follow-up. Interprofessional team collaboration is important in the optimal treatment of patients with this condition.