A 77-year-old man presented for evaluation of hemoptysis after a 7-month history of cough, progressive dyspnea, and intermittent hemoptysis, which consisted of tablespoon amounts of bright red blood and occurred up to eight times per day. Episodes of intermittent blood-streaked sputum had occurred for 18 months. He denied fevers, rigors, chest pain, palpitations, headaches, nasal symptoms, gastroesophageal reflux, melena, hematochezia, or hematuria. There were no known liver, kidney, or hematologic disorders. The physical examination findings were normal, except for a 4/6 apical pansystolic murmur.
Three years earlier, the patient had experienced an episode of out-of-hospital cardiac arrest that had been attributed to a subendocardial myocardial infarction, from which he was successfully resuscitated. Subsequently, cardiac catheterization revealed severe three-vessel coronary occlusion. Coronary artery bypass surgery was performed without any complications. At the time of catheterization, he had normal ventricular size and function, and no evidence of valvular abnormalities. Other medical comorbidities were arterial hypertension and peptic ulcer disease.
The patient had smoked for approximately 20 years (1 pack of cigarettes per day on average) and had quit 22 years before diagnosis of the acute coronary syndrome. No other occupational or environmental noxious exposures were identified. He denied any history of HIV exposure, and the results of a recent enzyme-linked immunosorbent assay had been negative. His family history was consistent only for myocardial infarction (both parents, at a young age).
A chest radiograph showed persistent left lower lobe infiltrates (for approximately 4 months), and the results of blood tests consisted of a normal CBC count, normal metabolic panel, normal urinary sediment level, and normal coagulation studies (ie, prothrombin time and activated thromboplastin time). Tests for the presence of antineutrophil cytoplasmic antiglomerular basement membrane, antiphospholipid, and antinuclear antibodies were all negative. A previous bronchoscopy, which had been performed to evaluate the patient's hemoptysis 3 months before the current presentation, showed no endobronchial source of bleeding and no intraluminal abnormalities. A repeat echocardiogram showed normal left ventricular contractility, severe mitral regurgitation, with mild mitral annulus calcification, and a mildly dilated left atrium. No vegetation was seen on a transesophageal echocardiogram.
The chest radiograph and CT scan at presentation are shown in Figures 1 and 2, respectively. A diagnostic procedure was performed.
[FIGURES 1-2 OMITTED]
What is your diagnosis?
Diagnosis: Idiopathic pulmonary hemosiderosis, adult-type
The term hemosiderosis derives from the Greek hemo (blood) and sideros (iron), and is characterized by the focal or generalized accumulation of iron in the form of hemosiderin. Hemosiderin is an intracellular storage form of iron, which appears as yellow-brown granules, containing ferric hydroxides, polysaccharides, and proteins. Hemosiderin contains > 33% iron by weight and stains blue with the Perls' Prussian stain.
Pulmonary hemosiderosis is the clinical and functional consequence of iron overload of the lungs. The main iron sources in the lungs are as follows: from the RBC metabolism during episodes of alveolar hemorrhage (90% of the eases), circulatory (where it is bound to transferrin or lactoferrin) or inhalatory (from cigarette smoke or metallic dusts). The alveolar macrophages convert the hemoglobin iron into hemosiderin within 36 to 72 h and become hemosiderin-laden macrophages (ie, siderophages). Within the pulmonary macrophages, iron is removed from hemoglobin in an essential step (mediated by hemeoxygenase), which is subject to a complex regulation. The capacity of alveolar macrophages to metabolize iron is easily exhaustible, and the presence of free iron in the alveoli can cause local injury and fibrosis. Iron exerts a toxic effect, partially through its capacity to produce highly reactive hydroxyl radicals from less toxic oxygen superoxide and hydrogen peroxide, which in turn will cause lipid layer peroxidation, protein and carbohydrate degradation, and subsequent fibrogenesis.
Idiopathic pulmonary hemosiderosis (IPH), which is a rare condition of unknown cause and balanced gender distribution, was first described in 1864 by Virchow as "brown lung induration" in an adult. Later, in 1931, Ceelen described the first autopsy findings in two children. Approximately 80% of cases occur in children, while adult cases either begin in childhood and are followed into adulthood or (rarer) are primary adult-onset IPH. In a seminal review published in 1962 by Soergel and Sommers, 21 of 112 patients (18.7%) were at least 16 years old at disease onset. Among adult-onset cases, the usual age of presentation is in the fourth or fifth decade of life. On this basis, the current patient is unusual in first presenting in the eighth decade. Whether adult-onset IPH is the same as pediatric-onset IPH remains unclear. Familial clustering has been described, suggesting a possible genetic or environmental contribution.
The pathogenesis of IPH remains unknown. Pathogenic theories are based on a postulated primary disruption of the alveolar-endothelial membrane of yet unclear etiology. Based on the demonstration of plasma-circulating immune complexes and the presence on electron microscopy of questionable alveolar membrane deposits, an autoimmune pathogenesis seems to be logical. In support of this theory is the excellent response of patients with acute exacerbations of IPH to corticosteroids; furthermore, about a quarter of the patients who survive for > 10 years with the disease subsequently develop some form of autoimmune disease. Several children with IPH have had detectable levels of plasma antibodies (ie, precipitins and IgE) against cow milk, which has led to the hypothesis of a systemic allergic or hypersensitivity reaction to milk components (Heiner syndrome). Several authors have identified patients with coexistent pulmonary hemosiderosis and celiac sprue who seemed to achieve complete clinical remission (regarding both pulmonary and gastroenterology symptoms) after the institution of a gluten-free diet. Several reports of an infantile bland alveolar hemorrhage similar to IPH suggested a link with environmental exposures to fungi (ie, Stachybotrys atra) in water-damaged houses. Therefore, infectious and mycotoxigenic pathogenetic mechanisms have been postulated to be involved in IPH, mimicking a well-known animal (equine) condition called stachybotryomycotoxicosis.
The clinical presentation of IPH varies widely from acute, fulminant forms with massive hemoptysis, to a more subacute presentation that is characterized by cough, dyspnea, repetitive hemoptysis, fatigue, and/or asymptomatic anemia. As in the current patient, individuals may experience both subacute and fulminant phases during the clinical course of the disease. In adults, the respiratory symptoms tend to be more pronounced, while in children failure to thrive and anemia (and less often, hemoptysis) may be the presenting findings.
The laboratory investigation of IPH may reveal variable degrees of anemia, and should exclude quantitative or qualitative platelet defects, liver or kidney disease, coagulopathies, and inflammatory syndromes. The sideropenic microcytic anemia is the consequence of recurrent intraalveolar bleeding. Bone marrow biopsy specimens typically show hyperplastic erythropoiesis and low intramedullary iron stores. Sputum cytologic examination may provide clues of intraalveolar bleeding (erythrocytes and hemosiderin-laden macrophages) by staining with hematoxylin-eosin and Perls' Prussian blue (Fig 3, left, A, and right, B, respectively). As expected, BAL fluid from involved areas has a higher diagnostic yield. The predominant cellular types found in BAL fluid are alveolar macrophages, some of which are filled with hemosiderin (siderophages) and intact erythrocytes.
Pulmonary function tests in patients with IPH show restrictive ventilatory defects of variable severity, which are related to the degree of interstitial fibrosis. Though rarely performed in acutely ill patients, the diffusing capacity of the lung for carbon monoxide may be elevated during disease exacerbations, as a manifestation of alveolar hemorrhage, with high CO uptake by the intraalveolar erythrocytes.
Radiographic features of IPH vary by the clinical phase and are not pathognomonic. During exacerbations, the chest radiograph shows diffuse alveolar infiltrates, predominantly in the lower lung fields (Fig 1), with corresponding ground-glass attenuation seen on high-resolution CT scans (Fig 2). The initial alveolar infiltrates tend to resorb over time, and an interstitial fine reticulomicronodular pattern of opacities may occur in the same areas, with variable degrees of fibrosis. Honeycombing is rare.
Pulmonary hemorrhage may be an isolated phenomenon or may be associated with extrapulmonary involvement. As such, the differential diagnosis of IPH includes various systemic illnesses that are associated with alveolar hemorrhage (Table 1). Specifically, one must exclude glomerulonephritis (ie, proteinuria, hematuria, and erythrocyte casts), systemic vasculitis, and underlying connective tissue diseases. Other immune derangements that should be considered are direct antibody-mediated injury (eg, Goodpasture syndrome), immune complex deposition (eg, systemic lupus erythematosus), neutrophil activation by antineutrophil cytoplasmic antibodies (eg, Wegener granulomatosis and microscopic polyangiitis), and an association with antiphospholipid antibodies (ie, antiphospholipid syndrome).
In addition to light microscopy, biopsy specimens from IPH patients should be submitted for immunofluorescence or immunohistochemistry stains to evaluate for Ig and immune complex depositions. Biopsy specimens should be carefully examined for features of granulomatous disease, as seen in fungal, mycobacterial, or other infections, sarcoidosis, berylliosis, or Wegener granulomatosis. The diagnosis of IPH requires the exclusion of vasculitis (as seen in Wegener granulomatosis), Churg-Strauss syndrome, microscopic polyangiitis, and immune complex deposition disorders. The iron stains, such as Perls' Prussian blue stain, typically show numerous siderophages in alveolar and distal airways, as is the case in patients with other diseases that are characterized by alveolar hemorrhage.
As the diagnosis of IPH is largely exclusionary, transbronchial lung biopsy from areas of ground-glass attenuation is generally the initial diagnostic procedure performed. Larger samples can be obtained by video-assisted thoracoscopic surgery or open-lung biopsy with a much higher yield. The laboratory investigation findings for antinuclear antibodies, anti-double-stranded DNA, antiglomerular basement membrane antibodies, antiphospholipid antibodies, antineutrophil cytoplasmic antibodies (both perinuclear and cytoplasmic variants), IgG and IgE cow's milk antibodies, and rheumatoid factor are generally negative. Also, patients can be tested for celiac sprue with plasma antigliadin and antireticulin antibodies, although the lack of GI symptoms makes this diagnosis unlikely.
Hemosiderosis due to various heart conditions deserves particular attention here, especially as our patient presented with severe mitral regurgitation. The pulmonary parenchymal manifestations of cardiac disorders are the consequence of either elevated postcapillary pressures (eg, mitral stenosis or congestive heart failure), or abnormal blood flow (eg, mitral regurgitation). Typical radiographic findings in mitral stenosis are as follows: cephalization of pulmonary vasculature; interstitial or alveolar edema; alveolar opacities representing diffuse alveolar hemorrhage; and, in patients with longstanding disease, secondary pulmonary hemosiderosis and/or diffuse pulmonary ossification. In patients with mitral regurgitation, the clinical picture depends on the acuity of onset of the valvulopathy. In acute-onset mitral regurgitation (eg, due to endocarditis, trauma, dysfunction related to ischemia, infarction, or rupture of the chordae tendinae), the abrupt occurrence of symmetrical pulmonary edema is typical. In contrast, in patients with chronic valvular disease (eg, myxomatous degeneration, rheumatic fever, mitral annulus calcification, annulus dilatation secondary to left ventricular cavity enlargement, and periprosthetic valve leak), a more insidious disease is usual, with progressive eccentric left ventricular hypertrophy, and, ultimately, enlargement and failure. Asymmetric right-upper lobe pulmonary edema due a regurgitant jet toward the pulmonary veins has been described in approximately 10% of cases. Because our patient showed no evidence of asymmetric pulmonary edema and episodes of hemoptysis antedated the development of mitral insufficiency, we considered that valvular disease was unlikely to be the cause of pulmonary hemosiderosis.
IPH should also be differentiated from pneumoconiosis siderotica, a form of pneumoeoniosis that is due to the presence of environmental iron dust, which is usually clinically significant only when combined with silica exposure (silicosiderosis). In our patient, there was no history of any environmental exposure except tobacco smoking (which was insufficient to cause hemosiderosis).
The current approach to managing IPH is based on relatively small case series and anecdotal reports. Splenectomy has been tried, without significant success. Before the era of assays for antiglomerular basement membrane antibodies or antineutrophil cytoplasmic antibodies, plasmapheresis had been tried with variable results. The appeal of plasmapheresis has been based on the clinical similarity of IPH to Goodpasture syndrome, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune pulmonary capillaritis. Indeed, in our patient, before the serologic results were available, plasmapheresis was undertaken, although it would be unfair to attribute any therapeutic response to plasma exchange, as corticosteroids in large doses were also administered.
Based on the notion that IPH is an autoimmune disease, and the good response in the face of new alveolar hemorrhage episodes, corticosteroids have become the mainstay of therapy. Other immunosuppressive agents (eg, azathioprine, hydroxychloroquine, cyclophosphamide, and methotrexate) have been tried as corticosteroid-adjunctive or steroid-sparing therapy, with variable results. In acute exacerbations of IPH, therapy with prednisone is usually started at a dose of 1 mg/kg/d (or equivalent) and is titrated to a maintenance dose of 10 to 15 mg/d. In some patients, IPH will recur immediately after the discontinuation of corticosteroid therapy, and most patients will actually continue to receive prednisone after 2 years of treatment. An azathioprine-prednisone combination seems to be one of the most popular therapeutic regimens. Anecdotal reports of lung transplantation in two cases of IPH have been published, unfortunately with poor outcomes, including recurrence.
The most frequent causes of death in patients with IPH are acute respiratory failure accompanying massive alveolar hemorrhage and chronic respiratory failure with cor pulmonale due to severe pulmonary fibrosis. Although older series had presented IPH as a grave condition, more recent reports have described better outcomes, probably due to more sustained immunosuppressive therapy, improved diagnostic evaluation, and better access to health care. In general, children and adolescents have a more severe course and prognosis, while adults have milder symptoms and a more favorable prognosis.
Our patient underwent bronchoscopy acutely, which showed blood in small amounts in the upper and lower lobe bronchi, without any significant intraluminal lesions. BAL confirmed the progressively bloodier return of the saline solution aliquots, while the transbronchial biopsy specimens showed minimal intraalveolar hemorrhage and mild lymphocytic infiltration of the interstitium. An open-lung biopsy was performed from the left lower lobe and lingula, and showed bland alveolar hemorrhage, mild lymphocytic interstitial and alveolar infiltrates, and fibrosis. Because there was no evidence of malignancy, vaseulitis, or granulomatous, immunologic, or infectious processes, the diagnosis of IPH was rendered. The patients was started on therapy with prednisone, 40 mg/d, followed by plasmapheresis and then therapy with azathioprine, 100 mg/d, for maintenance therapy, although the patient continued to experience multiple IPH exacerbations with frequent hemoptysis. Higher doses of corticosteroids (ie, > 50 mg/d) seemed to be more effective than small doses in preventing new flare-ups. The patient survived for 7 years after the acute presentation described here, after which he experienced sudden death, presumably due to an arrhythmia.
IPH is a rare interstitial lung disease of unknown etiology, which can be included in the orphan lung diseases. A primary pediatric form (most of the cases) and a primary adult form (very rare) have been described. Symptoms of cough, hemoptysis, and dyspnea, new or recurrent multilobar pulmonary infiltrates, and anemia suggest a diagnosis of diffuse alveolar hemorrhage. Sputum and/or BAL fluid examination show numerous hemosiderin-laden macrophages (siderophages), while the lung biopsy specimen generally confirms a bland alveolar hemorrhage, variable degrees of interstitial fibrosis, and the presence of intraalveolar and interstitial siderophages. The immunosuppressive agents, including corticosteroids, represent the backbone of therapy of both acute exacerbations and remission periods. With the advent of more effective immunosuppressive agents, improved long-term disease-free survival has been described.
1. IPH is a diagnosis of exclusion; lung biopsy is required in all instances when there is no procedural contraindication. Studies such as antinuclear, antineutrophil cytoplasm and antiglomerular basement membrane antibodies are important diagnostic tools in differentiating it from other conditions.
2. IPH characteristically presents in childhood or early adulthood (> 80% cases); very rarely it may be diagnosed at onset in the 6th or 7th decade of life.
3. Severe, longstanding mitral regurgitation and mitral stenosis may account for cases of secondary pulmonary hemosiderosis. In the case of mitral regurgitation, Doppler echocardiogram can illustrate the asymmetrical regurgitant flow from the left atrium into the right upper (and rarely, left upper) lobe vessels, with subsequent more severe hemosiderotic changes in the respective areas.
4. Corticosteroids and/or other immunosuppressants (eg, hydroxychloroquine, methotrexate, and azathioprine) seem to influence favorably the long-term outcome of patients with IPH.
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* From the Departments of Pulmonary, Allergy, and Critical Care (Drs. Ioachimescu and Stoller) and Pathology (Dr. Farver), Cleveland Clinic Foundation, Cleveland, OH.
Manuscript received October 5, 2004; revision accepted October 28, 2004.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).
Correspondence to: Octavian C. Ioachimescu, MD, 9500 Euclid Ave A90, Cleveland OH 44195; e-mail: email@example.com
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