idiopathic pulmonary haemosiderosis (IPH)

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BMJ Case Reports 2010; doi:10.1136/bcr.06.2009.1969

Rare disease

A female soccer player with recurrent haemoptysis and iron deficiency anaemia: idiopathic pulmonary haemosiderosis (IPH)—case report and literature review Roland Schroers1, Francesco Bonella2, Martin Tötsch3, Ulrich Costabel2

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Author Affiliations

Correspondence to Roland Schroers, [email protected], Ulrich Costabel, [email protected] Published 18 January 2010

Summary A 19-year-old woman presented with repeated episodes of haemoptysis and shortness of breath. Blood tests revealed iron deficiency anaemia and chest imaging studies showed bilateral lung opacities. In further laboratory tests and technical examination including bronchoalveolar lavage and transbronchial lung biopsy, pulmonary embolism, cardiac disease, and pulmonary vasculitis due to autoimmune disease were ruled out. Finally, a diagnosis of idiopathic pulmonary haemosiderosis (IPH) was made in January 2008. The patient was treated with prednisone, azathioprine, and oral iron supplementation. Subsequently, the patient’s condition and haemoglobin value improved notably. In May 2009, the patient was in full disease remission including a normal blood count and normal iron parameters. IPH is a rare cause of diffuse alveolar haemorrhage of unknown origin. It occurs most frequently in children and adolescents and typically presents with recurrent haemoptysis due to alveolar bleeding. However, pulmonary signs and symptoms often are obscure in children. In these cases iron deficiency anaemia is the prominent clinical finding. The purpose of this case report is to increase awareness of IPH as a possible cause of recurrent haemoptysis and anaemia.

Background Idiopathic pulmonary haemosiderosis (IPH) is a rare cause of diffuse alveolar haemorrhage of unknown origin. It occurs most frequently in children and adolescents and typically presents with recurrent haemoptysis due to alveolar bleeding. However, pulmonary signs and symptoms often are obscure in children. In these cases iron deficiency anaemia is the prominent clinical finding. The purpose of this case report is to increase awareness of IPH as a possible cause of recurrent haemoptysis and anaemia. Furthermore, this presentation should remind the reader of the differential diagnoses of alveolar haemorrhages.

Case presentation A 19-year-old woman was referred to our hospital after she had consulted her general physician because of repeated episodes of haemoptysis. Her past medical history was unremarkable; she attended high school and regularly played soccer. In December 2007, she had experienced a 7 day period of cough and haemoptysis with spots of bright red blood. She complained of no other symptoms and haemoptysis resolved within days. Four weeks later, she experienced increasing shortness of breath on exertion and fatigue along with recurrent haemoptysis. At that time, blood tests revealed anaemia (haemoglobin 96 g/l), and chest radiographs showed bilateral lung opacities.

Investigations Upon admission, we saw a female adolescent complaining of dyspnoea while walking and with pronounced skin pallor but otherwise inconspicuous physical status. Haematological tests showed a normocytic anaemia (haemoglobin 87g/l, mean corpuscular volume (MCV) 85 fl); leucocyte and platelet counts were normal. The reticulocyte count was 1.5%. Serum ferritin concentration was normal (72.3 ng/ml, normal range (NR) 34–210 ng/ml); however, serum iron concentration (15 µg/dl, NR 28–140 µg/dl) and transferrin saturation (3%; NR 16–45%) were notably decreased. In agreement with a diagnosis of iron deficiency anaemia, the concentration of the soluble transferrin receptor was increased (3.6 mg/l, NR 0.83–1.76mg/l). C reactive protein, lactic dehydrogenase, bilirubin, vitamin B12, and folate values were normal, as were tests for blood coagulation, kidney, and liver function. Furthermore, laboratories for autoimmune disease including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), rheumatoid factor, anti-CCP-antibodies, complement factors (C3/C4), and tests for anti-phospholipids, anti-basement membrane, and transglutaminase autoantibodies did not show any abnormalities. Computed tomography scanning demonstrated diffuse ground glass opacification of both lungs, accentuated in the lower parts. Diffuse alveolar bleeding was suspected and a bronchoscopy was performed. In bronchoalveolar lavage (BAL) and transbronchial biopsies abundant haemosiderin laden alveolar macrophages were noticed (fig 1). However, no

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signs of inflammation or vasculitis were seen and microbiological tests were negative for various microbes including mycobacteria, chlamydia, and mycoplasma. Lung perfusion scintigraphy and echocardiography revealed normal results. Lung function tests showed moderate restriction, and diffusion capacity as determined by carbon monoxide (CO) transfer was normal. In summary, a diagnosis of IPH was made.

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Figure 1 Lung biopsy combination of alveolar haemorrhage and accumulation of haemosiderin laden macrophages in a section of a right middle lobe transbronchial forceps biopsy (left panel: period acid-Schiff (PAS) staining; right panel, Prussian-blue staining). Proliferation of pneumocytes (type II) is non-specific. Recurrent bleeding results in accumulation of haemosiderin in vessel walls, alveolar septa and interstitial macrophages.

Differential diagnosis Pulmonary vasculitis and capillaritis Autoimmune disease, such as lupus erythematosus, Wegener’s granulomatosis, or Goodpasture’s syndrome Pulmonary embolism Mitral stenosis Chronic left heart failure Pulmonary hypertension.

Treatment The patient was treated with prednisone (40 mg daily), azathioprine (150 mg daily), and oral iron substitution.

Outcome and follow-up Subsequently, the patient’s condition improved notably and to date she has not complained of any further bleedings. Starting in August 2008, the prednisone dosage was reduced stepwise down to 5 mg maintenance. In May 2009, the patient was in full remission, and blood count as well as iron parameters were normal.

Discussion IPH, also known as Ceelen’s disease, is a chronic disease characterised by recurrent episodes of diffuse alveolar haemorrhage. 1 IPH typically presents in children and young adults with the triad of haemoptysis, pulmonary infiltrates, and anaemia. The pathogenesis remains largely unknown. Although coexistence of IPH and gluten enteropathy points to an immunological process, BAL, lung biopsy, and laboratory tests characteristically are without evidence of pulmonary vasculitis/capillaritis or autoimmune disease, such as lupus erythematosus, Wegener’s granulomatosis, or Goodpasture’s syndrome. 2 In addition, cardiopulmonary examination is unremarkable regarding haemodynamic disorders responsible for alveolar haemorrhage—for example, pulmonary embolism, mitral stenosis, chronic left heart failure or pulmonary hypertension. 1 As observed in our case, many patients with IPH have moderate to severe anaemia. Following pulmonary haemorrhage, alveolar macrophages phagocytose erythrocytes and accumulate haemosiderin iron, which is not available for haemoglobin synthesis. Accordingly, IPH patients develop iron deficiency anaemia as indicated by decreased bone marrow haemosiderin and increased soluble transferrin receptor values. Serum ferritin values often are misleadingly normal or elevated. 1 Since anaemia owing to repeated occult alveolar haemorrhages can be the only clinical sign, awareness of IPH should help to facilitate its diagnosis. Since Ceelen’s disease (IPH) is a rare disease, there is no standard treatment proven in well controlled clinical trials. In patients with concomitant coeliac disease, a gluten-free diet can result in clinical remission. 1 For the other patients, glucocorticoids and immunosuppressive agents are commonly used. 1 , 3 The use of systemic glucocorticoids for IPH resulted from the hypothesis of an immune pathogenesis. Although data are sparse, case reports and case series imply that systemic glucocorticoids reduce the morbidity and mortality of acute episodes of alveolar haemorrhage. In addition, patients with recurrent IPH episodes respond


favourably to chronic oral glucocorticoids, with decreased frequency of alveolar haemorrhages and a reduction of fibrotic changes. For example, in a series of 23 children with IPH, low dose prednisone was associated with improved survival compared to historical controls. 4 An immunosuppressive drug such as azathioprine may be added to systemic glucocorticoids in patients who have severe initial disease or have recurrent episodes of alveolar haemorrhage. 5 However, evidence supporting the efficacy of this approach is limited. 1 , 3 , 5 , 6 Recurrent alveolar haemorrhage may eventually result in pulmonary fibrosis and respiratory failure. Due to great variation of clinical courses and lack of large patient series, the overall prognosis of IPH remains difficult to assess in individual patients. 3 , 6

Learning points Idiopathic pulmonary haemosiderosis (IPH) is a rare disease characterised by recurrent episodes of diffuse alveolar haemorrhage. The diagnosis of IPH should be considered in children and young adults presenting with the triad of haemoptysis, pulmonary infiltrates, and anaemia. Differential diagnoses of IPH include pulmonary vasculitis/capillaritis and autoimmune disease, such as lupus erythematosus, Wegener’s granulomatosis, or Goodpasture’s syndrome. Cardiopulmonary disease such as pulmonary embolism, mitral stenosis, chronic left heart failure or pulmonary hypertension must be ruled out. There is no standard treatment for IPH; however, corticosteroids and immunosuppressive drugs may improve symptoms and survival.

Footnotes Competing interests: None. Patient consent: Patient/guardian consent was obtained for publication.

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Ziesche R, Costabel U, Guzman J, et al. Cytologic and immunocytologic findings in bronchoalveolar lavage as a contribution to the differential diagnosis of chronic lung hemorrhage. Pneumologie 1990; (Suppl 1): 299–300. [Medline]

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Kiper N, GocmenA, Ozcelik U, et al. Long-term clinical course of patients with idiopathic pulmonary hemosiderosis (1979–1994): prolonged survival with low-dose corticosteroid therapy. Pediatr Pulmonol 1999; : 180. [CrossRef] [Medline] [Web of Science]

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Airaghi L, Ciceri L, Giannini S, et al. Idiopathic pulmonary hemosiderosis in an adult. Favourable response to azathioprine. Monaldi Arch Chest Dis 2001; : 211. [Medline]

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Ioachimescu OC, Sieber S, Kotch A. Idiopathic pulmonary haemosiderosis revisited. Eur Respir J 2004; : 162–70. [Abstract/FREE Full text]
