Idiopathic pulmonary hemosiderosis

INTRODUCTION — Idiopathic pulmonary hemosiderosis (IPH) is a rare disease, found primarily in children, that is characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH). When no underlying cause for repeated episodes of DAH is apparent (table 1), the entity is referred to as IPH [1]. Among patients with IPH, recurrent alveolar bleeding can eventually produce pulmonary hemosiderosis and fibrosis.

The clinical features, treatment, and prognosis of IPH will be reviewed here. A general discussion of the DAH syndromes is provided separately. (See "The diffuse alveolar hemorrhage syndromes" and "Approach to the infant and child with diffuse lung disease (interstitial lung disease)".)

PATHOGENESIS — The primary defect and clinical feature in IPH is recurrent alveolar hemorrhage. The exact etiology of IPH is unknown. The favorable response to immunosuppressive therapy suggests that immune processes may be involved. A structural defect in the alveolar capillaries, either in the alveolar basement membrane or in the alveolar endothelial cell, may predispose to the condition [1-5]. The accumulation of neutrophils in the alveoli also may play a role [6].

●Immunologic abnormalities – An immunologic mechanism for recurrent alveolar hemorrhage has been suggested but not established. Immune complexes have been demonstrated in the plasma of several patients; however, immunohistochemical examination of lung tissue has not identified immune complex deposition [2,3,7-10]. The possibility that autoimmune mechanisms play a role in IPH is suggested by the observation that approximately 25 percent of patients present with various autoantibodies at diagnosis [11] and approximately 25 percent of patients with the condition who survive for more than 10 years subsequently develop autoimmune disorders [12,13].

Links between IPH and ingested protein antigens have also been hypothesized, based upon the following observations:

•Coexistence of celiac disease and IPH, also known as Lane-Hamilton syndrome, has been reported in a large number of cases, and introduction of a gluten-free diet has been associated with remission of pulmonary symptoms in several patients with IPH [14-22]. (See "Diagnosis of celiac disease in adults" and "Management of celiac disease in adults".)

•Circulating antibodies against cow's milk have been detected in a number of children with the disorder, suggesting that IPH may be associated with a hypersensitivity reaction to milk [23-25]. However, other investigators have failed to reproduce these findings [7].

●Iron metabolism – The pathologic consequences of recurrent alveolar hemorrhage are likely related to accumulation of free iron in pulmonary cells and tissue, which induces formation of highly toxic free hydroxyl radicals (Fenton reaction) that can eventually lead to cell necrosis and tissue remodeling with pulmonary fibrosis [26,27]. The mechanisms involved may be similar to those responsible for the fibrosis in the liver, pancreas, and heart that occurs in genetic (hereditary) hemochromatosis and other iron overload syndromes. (See "Approach to the patient with suspected iron overload" and "Clinical manifestations and diagnosis of hereditary hemochromatosis".)

The monocyte-macrophage system, which is involved in processing free iron, displays great heterogeneity between different organs. Alveolar macrophages are less able to degrade erythrocytes and reprocess hemoglobin iron than macrophages in the liver, spleen, and bone marrow [26,28]. It is thought that excess free iron leads to production of hydroxyl radicals and consequent tissue injury [26,29]. However, iron induces intense production of intracellular ferritin, which normally protects the lung macrophages against free iron and oxidation [30].

Iron deficiency anemia is observed in IPH due to alveolar hemorrhage and depletion of body iron reserves in the liver, spleen, and bone marrow. Accumulation of substantial amounts of iron within alveolar macrophages stimulates intracellular ferritin production and iron is initially stored in ferritin molecules, which are then processed into intracellular hemosiderin complexes. The iron in hemosiderin within the alveolar macrophages becomes functionally trapped and unavailable for the synthesis of hemoglobin by erythroblasts in the bone marrow [26]. Nevertheless, the iron trapped in intracellular hemosiderin complexes stimulates the macrophages to produce ferritin, which subsequently induces an increase in the serum ferritin level [8]. This explains why patients can present with iron deficiency anemia despite relatively normal serum ferritin levels.

EPIDEMIOLOGY AND RISK FACTORS — The exact incidence and prevalence of IPH are largely unknown. A retrospective review of records from a tertiary pediatric hospital in northern Taiwan noted five cases over 25 years [31]. A separate pediatric registry report (2008 to 2013) noted 20 girls and five boys [32], while a literature review of adult-onset cases described almost twice as many males as females [33].

Eighty percent of cases of IPH occur in children, generally manifesting before 10 years of age [34]. In adults, most cases are recognized between 20 and 40 years of age, although IPH can occur at any age [34]. Familial clustering has been described in several reports [23,35,36], suggesting that hereditary factors play a role in the development of IPH and/or that environmental factors might precipitate the disease in genetically predisposed individuals [37].

Older series of IPH probably included many patients who would not currently be considered to fit diagnostic criteria of the syndrome, including patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (such as granulomatosis with polyangiitis and microscopic polyarteritis nodosa) and other rheumatic disorders [1]. Sensitive assays for detection of autoimmune antibodies, new scintigraphic methods, and less invasive techniques for lung biopsy have permitted a more refined classification of patients with diffuse alveolar hemorrhage (DAH) that were not available when early series were performed. (See "The diffuse alveolar hemorrhage syndromes".)

The contribution of environmental exposures as risk factors for development IPH remains speculative. Exposures to second-hand smoke and indoor molds, particularly Stachybotrys chartarum, have been suggested as causative factors in infants with IPH [38-41]. Neither of these associations has been confirmed.

Down syndrome may be a predisposing factor among children with IPH [42-44]. In a registry series that included nine children with pulmonary hemosiderosis and Down syndrome, one had serologic evidence of celiac disease, one had antibodies to cow’s milk proteins, and three probably had IPH without detectable antibodies, although lung biopsy was not obtained [42]. Children with Down syndrome tended to have more severe disease at presentation, were more likely to develop pulmonary hypertension, and were more likely to succumb to the disease, although comorbidities (eg, cardiomyopathy, sleep apnea) may have contributed to the poor prognosis.

CLINICAL MANIFESTATIONS — The clinical presentation of IPH varies from an acute onset illness with hemoptysis and dyspnea to an insidious process characterized by fatigue, anemia, and slowly progressive exertional dyspnea. In some cases, anemia is the presenting manifestation.

Symptoms and signs

●Children – IPH often begins in children with recurrent episodes of dyspnea (68 to 85 percent), cough (48 to 100 percent), and fever (73 percent) [32,45]. Initially, the cough is predominantly nonproductive. Hemoptysis, occasionally with large amounts of expectorated blood, occurs in 44 to 58 percent, depending on the series [32,42,45]. Younger children are less likely to expectorate. Growth failure and moderate to severe anemia may be the presenting findings [1,46]. (See "The diffuse alveolar hemorrhage syndromes".)

On examination, pallor, cough, and tachypnea (at rest or with exertion) may be prominent. Lung examination may reveal clear lungs or crackles [1]. Approximately 20 percent of patients have enlargement of the liver and/or spleen [47,48].

●Adults – Most adults with IPH present before 40 years of age, but initial presentations up to age 83 have been reported [33]. The most frequent presenting symptoms in adults are hemoptysis (81 percent), exertional dyspnea (64 percent), and fatigue possibly due to iron deficiency anemia [8]. Hemoptysis may range from occasional blood-streaked sputum to daily significant hemoptysis [8,23,33,35]. Rapid asphyxiation due to massive pulmonary hemorrhage has been reported [23]. (See "Evaluation and management of life-threatening hemoptysis".)

Associated signs in adults include fever (14 percent), crackles, and clubbing of the fingers (8 percent) [1,33]. Case reports describe crackles in some patients [1].

Iron deficiency anemia — Iron deficiency anemia, which can range from mild to severe, is generally the sole laboratory abnormality in patients with IPH, although neutropenia and eosinophilia have been reported 5 to 10 days before the onset of episodes of alveolar hemorrhage [6].

Bone marrow biopsy typically shows hyperplastic erythropoiesis, usually without stainable hemosiderin iron [8,47]. Based on estimates of the mean erythrocyte survival time, the circulating survival time of erythrocytes is reduced due to extravasation in the lungs [8]. Plasma bilirubin and urinary excretion of urobilinogen may be increased. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Diagnostic approach to anemia in adults".)

Several caveats apply to understanding anemia in patients with IPH:

●Following a bleeding episode, a high number of reticulocytes may be present in the blood, mimicking hemolytic anemia. However, specific tests for hemolysis are negative [8]. (See "Diagnosis of hemolytic anemia in adults".)

●Since hemorrhagic sputum is often swallowed, children often present with a positive test for fecal occult blood. This can result in a fruitless search for a source of gastrointestinal bleeding. (See "Evaluation of occult gastrointestinal bleeding".)

●Serum ferritin concentration is generally higher in IPH than one would expect in anemia due to other types of blood loss, because serum ferritin reflects the nonmobilizable hemosiderin iron located in the alveolar macrophages in the lungs of patients with IPH [49,50]. Cases of IPH with normal or even elevated serum ferritin despite iron deficiency anemia (ie, absent bone marrow iron) have been reported [8,46]. This can mislead the clinician, who may think that iron deficiency can be excluded with a normal or elevated serum ferritin. Therefore, histochemical estimation of bone marrow iron in a bone marrow aspirate is important in patients with IPH as well as in other patients with diffuse alveolar hemorrhage (DAH) syndromes.

EVALUATION — The evaluation of suspected IPH follows steps to assess the severity of respiratory impairment and anemia, confirm alveolar hemorrhage, and narrow the broad differential diagnosis of diffuse alveolar hemorrhage (DAH) (table 1).

Our approach — Our approach to the evaluation of patients with suspected IPH aims to confirm the presence of alveolar hemorrhage and exclude other causes of DAH (table 2 and algorithm 1).

We include the following steps:

●Assess blood cell counts and determine whether iron deficiency anemia is present (table 3). Iron deficiency anemia in a patient with hemoptysis may suggest acute on chronic bleeding. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

●Screening tests for coagulopathy (eg, platelet count, prothrombin time, international normalized ratio, and partial thromboplastin time).

●Urinalysis to assess for pulmonary-renal syndrome (eg, granulomatosis with polyangiitis, microscopic polyangiitis, anti-glomerular basement membrane disease).

●Screen for autoimmune disorders, such as antinuclear antibodies (ANA), anti-double-stranded deoxyribonucleic acid (anti-dsDNA), antineutrophil cytoplasmic antibodies (ANCA), anti-glomerular basement membrane (GBM) antibodies, antiphospholipid (APL) antibodies, rheumatoid factor, cryoglobulins (table 2). (See "The diffuse alveolar hemorrhage syndromes", section on 'Laboratory testing'.)

●Obtain additional tests to exclude infection, if the clinical presentation is similar to acute respiratory distress syndrome. (See "Acute respiratory distress syndrome: Clinical features, diagnosis, and complications in adults".)

●If the clinical suspicion for IPH is high, screen for celiac disease. (See 'Laboratory testing' below.)

●Obtain high resolution chest computed tomography (HRCT). Typical findings include ground glass opacities that may be diffuse or patchy. (See 'Imaging' below.)

●Perform flexible bronchoscopy with sequential bronchoalveolar lavage (BAL) in an area of apparent radiographic involvement, or if diffuse involvement, a dependent lobe (eg, the right middle lobe). Sequential BAL with progressively more hemorrhagic effluent is one way to diagnosis alveolar hemorrhage. Hemosiderin-laden alveolar macrophages are a sign of recurrent or chronic alveolar hemorrhage and are almost always present in BAL fluid in IPH. They confirm the presence of alveolar hemorrhage but cannot be used as the sole diagnostic criterion for IPH. (See 'Bronchoscopy' below.)

●Obtain lung biopsy if confident diagnosis cannot be made based on laboratory testing and BAL. (See 'Lung biopsy' below.)

Laboratory testing — No laboratory tests are specific for IPH, so testing is designed to identify other potential causes of alveolar hemorrhage (table 2). The selection of tests may be adjusted depending on whether the patient presents with acute alveolar hemorrhage or a history of recurrent episodes of dyspnea associated with hemoptysis, and whether prior testing is available. In general, the goals of testing are to assess for iron deficiency anemia and celiac disease, exclude bleeding disorders and alternative processes in the differential diagnosis.

Screening for celiac disease with a serologic test for IgA anti-tissue transglutaminase (TTG) antibodies may yield a diagnosis of Lane Hamilton syndrome [20,21]. Occasional (2 to 10 percent) false negatives are noted (eg, IgA deficiency, gluten-free diet), so additional testing may be necessary in some patients, such as IgG antibody against synthetic deamidated gliadin peptides (IgG anti-dGli) and HLA-DQ2/DQ8. (See "Diagnosis of celiac disease in adults".)

Presence of coagulopathy, thrombocytopenia, hepatic dysfunction, or glomerulonephritis would suggest an alternate diagnosis. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder" and "The diffuse alveolar hemorrhage syndromes".)

The role of testing for antibodies to cow's milk (IgG and IgE) is unclear, as an etiologic role has not been proven. We do not routinely perform this testing. (See 'Pathogenesis' above.)

Imaging — Following an acute episode with pulmonary bleeding, chest radiographs demonstrate patchy opacities that partially regress during the symptom-free phase (image 1 and image 2) [8,47]. The rate of resolution of opacities depends on the magnitude of the alveolar bleeding; partial regression takes approximately four to eight weeks.

On HRCT, these opacities have ground glass characteristics. Unilateral or bilateral poorly defined opacities with an alveolar filling pattern are most prominent in the middle and lower lung fields. The opacities vary in intensity according to the magnitude of alveolar bleeding and the period of time elapsed since the latest bleeding episode. A “crazy-paving” pattern is also described, with ground glass opacities due to current hemorrhage and interlobular septal thickening due to deposition of hemosiderin in the interstitium [51].

Patients with long-standing disease may occasionally develop multiple honeycomb cysts, which are characteristically focal and localized predominantly to the posterior and lateral basal segments [52]. (See "High resolution computed tomography of the lungs".)

In patients with dyspnea and suspicion of pulmonary emboli, a computed tomography pulmonary angiography or ventilation-perfusion scanning should be performed in order to confirm or exclude the diagnosis. (See "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Computed tomography pulmonary angiography' and "Clinical presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute pulmonary embolism", section on 'Ventilation perfusion scan'.)

Pulmonary function tests — Pulmonary function tests (PFTs: spirometry, lung volumes, diffusing capacity for carbon monoxide [DLCO]) are obtained in stable patients over age 6 and typically show restrictive abnormalities, with reductions in total lung capacity (TLC), forced vital capacity (FVC), a normal or increased forced expiratory volume in one second (FEV₁)/FVC ratio [8,53].

DLCO may be chronically reduced in patients in whom parenchymal fibrosis has developed. On the other hand, DLCO may be increased during an acute bleeding episode, due to avid binding of carbon monoxide by hemoglobin in erythrocytes that have spilled into the alveoli, thereby producing an inappropriately high DLCO [54]. When the intra-alveolar erythrocytes and the hemoglobin they contain are degraded, the DLCO declines to prehemorrhage levels. While theoretically helpful, measurement of DLCO in the setting of acute hemoptysis is often not feasible.

Pulse oximetry may show hypoxemia, particularly during acute episodes and with exercise, and arterial blood gases may show eucapnia or hypocapnia.

Sputum examination — Prussian blue staining of a sputum sample may confirm the presence alveolar macrophages [55]. However, not all patients raise sputum, and the test has a low sensitivity. Furthermore, BAL is usually needed to evaluate other causes of diffuse alveolar hemorrhage (DAH), such as infection.

Inducing sputum for examination is not advisable due to the potential risk of exacerbating bleeding.

In the past, gastric aspirates or gastric lavage were sometimes obtained in children who were unable to expectorate sputum, but BAL has largely replaced gastric aspirates and lavage in this setting. (See 'Bronchoscopy' below.)

Bronchoscopy — Flexible bronchoscopy with BAL is performed in most patients and directed to segments of the lung where the HRCT shows ground glass opacification, or a dependent area, if disease is diffuse. Three sequential instillations are performed at the same site; observation of progressively more hemorrhagic fluid with each successive lavage suggests alveolar hemorrhage. (See "Basic principles and technique of bronchoalveolar lavage" and "Role of bronchoalveolar lavage in diagnosis of interstitial lung disease".)

In IPH, differential cell counts of BAL fluid show a predominance of alveolar macrophages, typically containing hemosiderin (picture 1). Lavage fluid is sent for microbiologic studies to exclude infectious etiologies and cytologic analysis to look for malignant cells, viral inclusion bodies, and hemosiderin-laden macrophages. Prussian blue staining is used to identify and quantitate hemosiderin-laden macrophages. Rarely, BAL is falsely negative [45]. (See 'Histopathology' below.)

Transbronchial forceps lung biopsy (TBLB) has a reasonable yield for providing supportive pathologic data, and it should be the biopsy procedure of first choice in stable adults and children [56,57]. Usually, we obtain four to eight TBLB specimens from one lung, preferably taken in segments showing ground glass opacification. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial lung biopsy' and "Flexible bronchoscopy in adults: Associated diagnostic and therapeutic procedures", section on 'Transbronchial biopsy'.)

If the TBLB specimens are inconclusive, larger specimens may be obtained by transbronchial cryobiopsy (TBCB), depending of the availability and experience of this procedure in the institution [58]. However, TBCB carries a higher risk of complications than TBLB, especially bleeding [59], and so far there are no reports of the use of TBCB in the diagnosis of IPH. (See "Role of lung biopsy in the diagnosis of interstitial lung disease", section on 'Transbronchial cryobiopsy'.)

Lung biopsy — If a diagnosis cannot be made clinically or on TBLB or TBCB specimens, larger biopsy samples, obtained by video-assisted thoracoscopic surgery (VATS) or thoracotomy, are needed for a confident diagnosis of IPH. (See "Role of lung biopsy in the diagnosis of interstitial lung disease".)

The main purpose of lung biopsy is to exclude other causes of DAH that would be treated differently, such as pulmonary capillaritis or lung-limited anti-GBM disease. The decision to proceed with a lung biopsy is partly guided by the age of the patient, severity of the disease, risk for severe procedure complications, and potential therapeutic benefit for the patient.

Lung biopsy is often deferred in children with a typical clinical presentation with alveolar hemorrhage, iron deficiency anemia, and celiac disease.

For an adult with no cause of DAH identifiable by history, serologic testing (ie, negative ANA, ANCA, anti-GBM antibody as well as other autoantibodies), or microbiologic studies, we typically pursue a tissue diagnosis. An exception might be a patient with known celiac disease or a positive test for IgA anti-tissue transglutaminase antibody who has no recurrences of alveolar hemorrhage on a gluten-free diet. (See 'Treatment of concomitant celiac disease' below.)

Histopathology — Lung histopathology in IPH at the time of acute alveolar hemorrhage typically shows nonspecific findings of blood-filled alveolar spaces, free hemosiderin, and macrophages containing hemosiderin [1-3,8,60]. Prussian blue staining is used to identify hemosiderin in and around alveolar macrophages (picture 1 and picture 2). Alveolar septal thickening may be present, and type 2 pneumocyte hyperplasia is common (picture 3 and picture 4). These findings are indistinguishable from anti-glomerular basement membrane disease.

A key feature of IPH is the absence of histologic or immunohistochemical evidence of capillaritis, which differentiates it from processes such as granulomatosis with polyangiitis, microscopic polyangiitis, and systemic lupus erythematosus [61,62]. In particular, infiltration with neutrophils and nuclear dust in the alveolar septa are not seen, and immune complexes are not present on immunofluorescent staining.

In advanced cases of IPH, the lungs macroscopically have a striking brown appearance due to hemosiderosis and varying degrees of consolidation and fibrosis. Localized interstitial fibrosis with collagen deposition is a prominent feature in patients with long-standing disease [2-4,8,10,14].

While not commonly performed, electron microscopy demonstrates swollen, vacuolated alveolar endothelial cells [2]. The basement membrane of the alveolar capillaries may be focally thickened; localized discontinuities with rupture of the membrane have also been inconsistently described [2,3,5,10]. Absence of electron-dense material along the basement membrane is evidence against immune complex deposition [2].

DIAGNOSIS — The diagnosis of IPH largely relies on demonstration of alveolar hemorrhage and exclusion of other disorders in which diffuse alveolar hemorrhage (DAH) is a cardinal sign (table 1 and algorithm 1), because there is no feature that is pathognomonic for IPH [1,63]. The diagnosis of IPH is supported by the combination of compatible clinical findings (eg, hemoptysis, cough, dyspnea), compatible test results (eg, opacities on chest radiograph, iron deficiency anemia, negative serologic tests for rheumatic and immune-mediated diseases), and the presence of hemosiderin-laden alveolar macrophages on bronchoalveolar lavage (BAL) and lung biopsy specimens.

●In children, a confident clinical diagnosis can be made with a clinical presentation, laboratory testing, high resolution computed tomography (HRCT) pattern, and BAL findings that are typical for IPH, negative serology for immune-mediated diseases, and positive testing for celiac disease [20-22,45]. Transbronchial or thoracoscopic lung biopsy are typically deferred unless the patient does not respond to therapy or celiac disease is excluded. (See 'Laboratory testing' above.)

●In adults, lung biopsy is often needed to fully exclude other causes of alveolar hemorrhage (table 1) (see 'Bronchoscopy' above and 'Lung biopsy' above). Lung biopsies should not reveal any other specific pathology, such as vasculitis/capillaritis, deposition of immunoglobulins, granulomas (indicate mycobacterial infection, sarcoidosis, or granulomatosis with polyangiitis), or other evidence of infection. (See 'Histopathology' above.)

In addition to light microscopy, biopsy specimens, preferably frozen, should be examined with immunofluorescence technique using a panel of antibodies against immunoglobulins and complement fractions in order to search for immune complexes. The finding of immune complex deposition would argue against the diagnosis of IPH. (See 'Histopathology' above.)

Lane-Hamilton syndrome (association of IPH and celiac disease) is reported in adults, so an evaluation for celiac disease is appropriate, if not already performed. (See 'Laboratory testing' above and "Diagnosis of celiac disease in adults".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of initial and recurrent episodes of alveolar hemorrhage is broad and includes infectious causes, rheumatic diseases, immune-mediated diseases, drug-induced lung toxicity, thromboembolic disease, bleeding disorders, and a variety of neoplasms (table 1). Causes of diffuse alveolar hemorrhage (DAH) in children and adults are discussed in greater detail separately. (See "Hemoptysis in children", section on 'Causes of hemoptysis' and "The diffuse alveolar hemorrhage syndromes".)

●Infection – A broad spectrum of lung infections are associated with alveolar hemorrhage, usually in the setting of acute respiratory distress syndrome, including severe bacterial pneumonia (eg, Streptococcus pneumoniae, Legionella pneumophila, Staphylococcus aureus), viral pneumonia (particularly influenza A), leptospirosis, and Pneumocystic jirovecii pneumonia. (See "Acute respiratory distress syndrome: Epidemiology, pathophysiology, pathology, and etiology in adults", section on 'Pneumonia' and "Seasonal influenza in children: Clinical features and diagnosis" and "Seasonal influenza in adults: Clinical manifestations and diagnosis" and "Leptospirosis: Epidemiology, microbiology, clinical manifestations, and diagnosis".)

Infectious etiologies can usually be excluded by the testing described above (see 'Evaluation' above), with particular attention to community-acquired infections (eg, influenza, coronavirus disease 2019 [COVID-19]), exposures (eg, contaminated water, birds, farm animals, mice, rabbits) and underlying immune compromise. A spectrum of microbiologic studies can be performed on bronchoalveolar lavage (BAL) samples, depending on the clinical setting. (See "Basic principles and technique of bronchoalveolar lavage", section on 'Microbiologic analysis'.)

●Rheumatic diseases – Rheumatic diseases associated with alveolar hemorrhage include systemic lupus erythematosus, antiphospholipid (APL) antibody syndrome, granulomatosis with polyangiitis, microscopic polyangiitis, anti-glomerular basement membrane (GBM) antibody (Goodpasture) disease, and mixed cryoglobulinemia. Often the extrapulmonary and serologic manifestations of these diseases will guide the diagnosis (eg, renal or cutaneous involvement), but virtually all patients with DAH should be evaluated for these processes [64]. (See "The diffuse alveolar hemorrhage syndromes" and "Pulmonary manifestations of systemic lupus erythematosus in adults", section on 'Pulmonary hemorrhage' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Anti-GBM (Goodpasture) disease: Pathogenesis, clinical manifestations, and diagnosis" and "Diagnosis of antiphospholipid syndrome" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

●Thoracic endometriosis – Thoracic endometriosis involving the lung parenchyma can cause recurrent catamenial hemoptysis, although bleeding is usually minor. (See "Clinical features, diagnostic approach, and treatment of adults with thoracic endometriosis", section on 'Hemoptysis'.)

●Medications – A number of medications are associated with alveolar hemorrhage, and use of these agents should be carefully sought. The mechanisms of DAH vary among the different agents and include acute lung toxicity with diffuse alveolar damage (amiodarone, infliximab, nitrofurantoin, penicillamine), drug-induced lupus (penicillamine), drug-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (methimazole, propylthiouracil). (See "The diffuse alveolar hemorrhage syndromes", section on 'Drug-induced diffuse alveolar hemorrhage' and "Drug-induced lupus".)

●Inhalational exposures – Inhalational exposures that have been associated with alveolar hemorrhage include crack cocaine (possibly related to ANCA-associated vasculitis induced by the cutting agent levamisole) and trimellitic anhydride, which is used in the manufacture of resins, paints, and plastic. A careful history can be used to exclude these possibilities. (See "The diffuse alveolar hemorrhage syndromes", section on 'Clues to a specific etiology'.)

TREATMENT — IPH is a rare condition that does not lend itself to controlled treatment trials. As a result, therapy is based upon reported experiences in individual cases or small case series [8,47,65-68]. Systemic glucocorticoids are the mainstay of therapy for acute alveolar hemorrhage [68]. For patients with concomitant celiac disease, a gluten-free diet may prevent recurrent episodes; for most other patients, chronic suppression can be achieved with a low dose of oral glucocorticoids, although some patients require additional immunosuppressive agents.

Acute alveolar hemorrhage — Most patients with acute alveolar hemorrhage due to IPH will receive initial empiric antibiotics until infection has been confidently excluded.

Supportive care — Patients with acute alveolar hemorrhage due to IPH often have hypoxemia requiring supplemental oxygen.

Systemic glucocorticoids — Systemic glucocorticoids are the mainstay of therapy for acute alveolar hemorrhage due to IPH. The use of systemic glucocorticoids for IPH grew out of the impression of an immune pathogenesis. Case reports and case series suggest that systemic glucocorticoids reduce the morbidity and mortality of acute episodes of alveolar bleeding [1,8,10,47,65-71].

For the treatment of acute episodes of alveolar hemorrhage without respiratory failure, we suggest induction treatment with an initial dose of prednisone or prednisolone 0.5 to 0.75 mg/kg per day (up to 60 mg/day). Induction treatment should continue until pulmonary bleeding has stopped and the chest radiograph shows partial or complete regression of newly acquired opacifications, which usually requires four to eight weeks. At this point, prednisone or prednisolone should be tapered by 5 mg every other week to a maintenance dose of 10 to 15 mg/day.

Respiratory failure due to alveolar hemorrhage — Some patients present with respiratory failure due to severe alveolar hemorrhage. These patients require prompt attention to immunosuppressive therapy. While formal studies are lacking, we suggest using combined therapy with high-dose glucocorticoids and a second immunosuppressive agent in these severely ill patients, as this approach has been beneficial in patients with other immunologic causes of diffuse alveolar hemorrhage (DAH). (See "The diffuse alveolar hemorrhage syndromes", section on 'Additional immunosuppressive therapy'.)

Ventilatory support — When alveolar hemorrhage is widespread, patients can develop hypoxemic respiratory failure that requires noninvasive or invasive mechanical ventilation. The implementation of noninvasive or invasive mechanical ventilation for acute respiratory failure is discussed separately. (See "Initiating mechanical ventilation in children" and "Acute respiratory distress syndrome: Fluid management, pharmacotherapy, and supportive care in adults" and "Acute respiratory distress syndrome: Ventilator management strategies for adults" and "Noninvasive ventilation in adults with acute respiratory failure: Benefits and contraindications".)

High-dose glucocorticoids — For adults with respiratory failure due to severe alveolar hemorrhage, we suggest intravenous methylprednisolone in a pulse dose, 500 to 2000 mg per day (in divided doses) for up to five days, based on its use for other immunologic causes of DAH [66]. In children, pulse dose methylprednisolone dosing is typically 20 mg/kg per day, intravenously. (See "The diffuse alveolar hemorrhage syndromes", section on 'Glucocorticoids'.)

Once the patient has stabilized, the glucocorticoid is transitioned to an oral preparation (eg, equivalent of prednisone or prednisolone 0.5 to 1 mg/kg per day) with gradual tapering to a maintenance dose [45,72]. (See 'Glucocorticoids' below.)

Immunosuppressive agents — A few case reports describe the use of an immunosuppressive agent in addition to oral glucocorticoids in the setting of respiratory failure. Examples include cyclophosphamide [73,74], hydroxychloroquine [45,74], azathioprine [74], mycophenolate, and rituximab [68]. The decision about which specific immunosuppressive agent to select depends on the anticipated responsiveness to glucocorticoids, age of the patient, severity of illness, and clinician familiarity with the individual agents; the optimal indications, dosing, and duration of therapy have not been determined. (See "The diffuse alveolar hemorrhage syndromes", section on 'Additional immunosuppressive therapy'.)

Extracorporeal membrane oxygenation — Extracorporeal membrane oxygenation (ECMO) may be able to support the rare patient who develops intractable hypoxemia due to acute alveolar hemorrhage [70,75]. ECMO has also been used to support patients through DAH from other causes. In separate reports, two children with IPH and respiratory failure due to severe pulmonary hemorrhage were supported with ECMO until immunosuppressive therapy controlled the hemorrhage [70,75]. The use of ECMO is limited to centers with specialized expertise. (See "Extracorporeal life support in adults in the intensive care unit: Overview".)

Prevention of recurrence — For untreated patients, IPH is characterized by recurrent episodes of alveolar hemorrhage over many years and a portion of these patients will develop fibrotic lung disease due to recurrent hemorrhage. Thus, efforts to prevent recurrent hemorrhage are indicated. For patients with concomitant celiac disease, a gluten-free diet may be sufficient to stop further episodes. For patients without celiac disease, we suggest chronic suppressive therapy with oral glucocorticoids. The optimal dose and duration has not been determined. Additional immunosuppressive therapy is occasionally needed.

While data in support of an association between IPH and cow’s milk allergy are conflicting, if there is suspicion or evidence of allergy to cow’s milk, this nutrient should be excluded from the diet to observe whether it might have a positive effect on the disease.

Glucocorticoids — Many patients with IPH appear to respond favorably to chronic oral glucocorticoids, with decreased frequency of episodes of acute alveolar hemorrhage and a delay in or arrest of fibrotic changes [8,10,66,69].

●Dose and duration – The optimal dose and duration of oral glucocorticoids to prevent recurrences of alveolar hemorrhage has not been determined. After the initial treatment with high-dose glucocorticoids described above, we taper prednisone (or equivalent) to 10 to 15 mg/day. In general, if the patient is free of recurrent events for 18 to 24 months, we further taper and discontinue prednisone.

In children, if there is recurrence of bleeding after tapering, treatment should be resumed and continued for another 24 to 36 months before tapering is tried again. If there is still recurrence after the second treatment period, long-term treatment should be considered at least until adult age.

In adults, the recurrence rate is generally lower than in children and tapering is reasonable after 12 to 18 months without any recurrences. The longer the recurrence free period, the less likely the patient will have recurrence.

During chronic glucocorticoid therapy, patients should be monitored appropriately for side effects. Infectious complications, including Legionella pneumonia and fatal invasive pulmonary aspergillosis, have been reported in patients with IPH receiving glucocorticoids or other immunosuppressive agents [76,77]. (See "Major adverse effects of systemic glucocorticoids".)

●Efficacy – The survival rate of IPH has improved significantly with glucocorticoid treatment [68]. In a series of 23 children with IPH, low-dose oral prednisone was associated with prolonged survival (one death in 2 to 14 years of monitoring) compared with historical controls [47,66]. In another series of 17 patients, long-term glucocorticoid therapy was associated with a five-year Kaplan-Meier survival of 86 percent [69].

Immunosuppressive drugs — An immunosuppressive agent may be added to initial oral glucocorticoid therapy in patients who have recurrent episodes of hemorrhage that limit tapering of oral glucocorticoids. However, evidence supporting the efficacy of this approach is limited. In a physician survey, agents used in addition to glucocorticoids for maintenance therapy of IPH included hydroxychloroquine (64 percent), azathioprine (37 percent), and cyclophosphamide (16 percent) [74].

Separately, a number of reports describe successful use of azathioprine or hydroxychloroquine in combination with oral glucocorticoids for maintenance therapy [1,4,31,45,74,78-80]. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Antimalarial drugs in the treatment of rheumatic disease".)

Other immunosuppressive drugs, such as cyclophosphamide, 6-mercaptopurine, rituximab, or mycophenolate [68], are occasionally employed in patients with a particularly severe presentation or an inadequate response to glucocorticoids, but their efficacy is also not well established [73,74,81-83]. Maintenance therapy aiming for a glucocorticoid-sparing effect has been reported with 6-mercaptopurine in a small number of patients, although recurrences requiring dose adjustment were noted. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "Overview of azathioprine and mercaptopurine use in inflammatory bowel disease".)

Treatment of concomitant celiac disease — Patients with evidence of concomitant celiac disease should follow a gluten-free diet as treatment for their celiac disease. A gluten-free diet will often prevent recurrent episodes of alveolar hemorrhage and enable the patient to avoid the potential adverse effects of an alternative treatment with long-term glucocorticoids [14-23]. The diagnosis and management of celiac disease are discussed separately. (See "Diagnosis of celiac disease in children" and "Management of celiac disease in children" and "Diagnosis of celiac disease in adults" and "Management of celiac disease in adults".)

Lung transplantation for advanced fibrosis — Single lung transplantation has been reported, but disease recurrence within the allograft appears to be a problem [71,84]. In one report, a 24-year-old woman with pulmonary insufficiency due to IPH developed graft failure of the single left lung allograft, and retransplantation was performed after nine months [71]. The patient succumbed to respiratory failure three months after the second transplantation. Autopsy showed no evidence of infection or rejection, but did reveal findings compatible with IPH in the transplanted lungs. In another report, IPH recurred three years after bilateral lung transplantation [84]. (See "Lung transplantation: General guidelines for recipient selection".)

MONITORING — Based on clinical experience, the most useful parameters to follow for assessing whether a patient is having a beneficial response to therapy include:

●Frequency and intensity of hemoptysis

●Regression of iron deficiency anemia

●Improvement in chest radiograph opacities

●Pulse oxygen saturation by oximetry, at rest and during six-minute walk test

●Diffusing capacity for carbon monoxide (DLCO)

FUTURE DIRECTIONS — Alternative preparations for delivery of systemic glucocorticoids have been assessed in IPH. As an example, liposteroid [85] (a preparation of dexamethasone palmitate in lipid microspheres not available in the United States) 0.8 mg/kg per day, administered intravenously for three consecutive days was effective in a series of nine children with acute presentation of IPH [86]. Monthly intravenous infusion of liposteroid dexamethasone palmitate 0.8 mg/kg was effective as maintenance therapy in patients who had recurrent alveolar hemorrhage despite oral glucocorticoid therapy [86].

High-dose inhaled glucocorticoids may be an alternative to oral glucocorticoids after initial stabilization with oral glucocorticoid [45,87,88]. Inhaled glucocorticoid treatment was assessed in an observational study in 26 children whose IPH was treated with an initial course of prednisolone and hydroxychloroquine: 17 patients had no recurrence, 5 patients had a recurrence requiring a course of prednisolone, and 4 patients had frequent recurrences and were treated with chronic prednisolone and azathioprine [45]. Additional study is needed to determine the safety of this approach.

Individual case reports describe success with methotrexate and intravenous immune globulin [89].

PROGNOSIS — The prognosis of IPH is difficult to assess because of the small series of patients, short observation times, and incomplete follow-up. The two most frequent causes of death are acute respiratory failure due to copious and diffuse pulmonary hemorrhage and chronic respiratory failure due to pulmonary hemosiderosis and fibrosis [6,47,65].

Survival times vary widely [8,32,33,47,69]. As an example, one series of 17 pediatric patients documented a five-year survival rate of 86 percent [69]. A separate series of 25 children reported disease control in 23 (92 percent) at 5.5 years, progressive pulmonary fibrosis in one and death due to pulmonary hemorrhage in another [32].

In adults, the course is often prolonged, symptoms are less pronounced, and the prognosis may be more favorable, although data are limited [8,33].

SUMMARY AND RECOMMENDATIONS

●Idiopathic pulmonary hemosiderosis (IPH) is a rare clinical entity of unknown etiology, characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH) and often presenting with hemoptysis. Iron deficiency anemia may develop due to sequestration of red cell hemoglobin iron to hemosiderin iron in the alveolar macrophages. Deposition of abundant hemosiderin iron in the lungs can lead to pulmonary fibrosis. (See 'Pathogenesis' above and 'Clinical manifestations' above.)

●Coexistence of celiac disease has been reported in patients with IPH (Lane-Hamilton syndrome) and provides support for a potential immunologic mechanism. (See 'Pathogenesis' above.)

●The clinical presentation of IPH varies from an acute illness with hemoptysis and dyspnea to an insidious process characterized by fatigue, anemia, and slowly progressive exertional dyspnea. Occasionally, iron deficiency anemia is the presenting manifestation. (See 'Clinical manifestations' above.)

●The evaluation of suspected IPH follows steps to assess the severity of respiratory impairment and anemia, confirm alveolar hemorrhage, and narrow the broad differential diagnosis of DAH (table 1 and algorithm 1). (See 'Evaluation' above.)

●During an acute episode, the chest radiograph and high resolution computed tomography (HRCT) demonstrate ground glass opacities that are often bilateral. Examination of sputum (when available) and bronchoalveolar lavage (BAL) fluid reveals hemosiderin-laden alveolar macrophages. (See 'Evaluation' above.)

●The diagnosis of IPH largely relies on demonstration of alveolar hemorrhage and exclusion of other disorders in which DAH is a cardinal sign (table 1), as no feature is pathognomonic. (See 'Diagnosis' above.)

•In children, a confident clinical diagnosis can be made in patients with DAH, negative serology for immune-mediated diseases, and positive testing for celiac disease.

•In adults, the diagnosis of IPH requires lung biopsy documentation of large numbers of hemosiderin-laden macrophages in the alveoli, without evidence of vasculitis, capillaritis, infection, granulomas, or deposition of immunoglobulins in any specific pattern. (See 'Histopathology' above.)

●For the treatment of acute episodes of alveolar hemorrhage related to IPH, we suggest systemic glucocorticoid therapy (Grade 2B).

•The typical initial dose is oral prednisone or prednisolone 0.5 to 0.75 mg/kg per day (up to 60 mg/day), or the equivalent dose intravenously. (See 'Systemic glucocorticoids' above.)

•For adults with impending or actual respiratory failure due to acute alveolar hemorrhage, we typically use a higher dose of methylprednisolone (eg, 500 to 2000 mg/day in divided doses, intravenously for up to five days. For children in this setting, the usual pulse dose of methylprednisolone is 20 mg/kg per day. (See 'High-dose glucocorticoids' above.)

●After resolution of the acute episode of alveolar hemorrhage, oral glucocorticoids are gradually tapered to the equivalent of prednisone 10 to 15 mg/day, as tolerated. In the absence of recurrences over 12 to 18 months in adults and 18 to 24 months in children, we further taper and discontinue prednisone. (See 'Prevention of recurrence' above.)

●In patients who have severe initial disease or have recurrent episodes of alveolar hemorrhage that limit tapering of systemic glucocorticoid, we suggest using a combination of systemic glucocorticoids with another immunosuppressive agent (eg, azathioprine, hydroxychloroquine, 6-mercaptopurine, cyclophosphamide, or mycophenolate) (Grade 2C). (See 'Immunosuppressive agents' above and 'Immunosuppressive drugs' above.)

●A gluten-free diet may prevent recurrent episodes of alveolar hemorrhage in patients with coexistent celiac disease. (See 'Treatment of concomitant celiac disease' above and "Management of celiac disease in adults".)