PCA volume 12 number 3/2

Idiopathic Pulmonary Hemosiderosis: Two different presentations, One way to diagnose

W. Kampman¹, A.L.T. van Overbeek&endash;van Gils², P.J.C. van der Straaten¹

¹Reinier de Graaf Ziekenhuis, Delft
²Scheperziekenhuis, Emmen

Introduction
Unlike diseases of the airways, interstitial lung diseases in childhood are exceedingly rare and create a diagnostic challenge because clinical presentation and radiographic features are very aspecific. One of the diseases of the mentioned group, idiopathic pulmonary hemosiderosis (IPH), may present with acute or recurrent respiratory symptoms, along with iron deficiency anemia, with or without hemoptysis, like we will describe in the first case report. In the second case report we describe a case with a misleading presentation of iron deficiency anemia, supposed hematemesis and occult blood in feces.

Case report 1
A five-year-old girl was admitted to our hospital in 1999 for the first time, because of anemia. She was the first-born of a twin, born by Caesarian section at 38 weeks gestational age. Her birth weight was 2500 g (P10). In the beginning of 1999 adenotonsillectomy was performed, because of recurrent upper respiratory tract infections. This did not lead to the expected improvement, however, and a low hemoglobin level of 3.4 mmol/l was found. Physical examination revealed a child with extreme pallor, normal respiratory rate, a normal precordium, with a grade 2/6 systolic ejection murmur, normal pulmonary auscultation, no distension or tenderness of the abdomen. Liver and spleen were not enlarged. Laboratory findings showed a severe microcytic anemia with hemoglobin of 3.4 mmol/l, MCV 62, reticulocytes 42 promille, consistent with iron deficient anemia, but because the child was well fed the possibility of transient erythroblastopenia of childhood (TEC) already in remission was also considered. The patient received an erythrocyte transfusion One year later we saw her again with anemia. She was very tired and suffering from a cold with cough. Just a few months earlier she had been treated for pneumonia. At this time the mother informed us that the child was coughing some blood. Again severe microcytic anemia was found, at first with a normal iron status, but three months later there was iron deficiency again: (Fe 3 mmol/l, saturation 3%, ferritin 123 mg/l). No signs of bleeding in the tractus digestivus (occult blood on feces: neg., Meckelscan: neg.) or in the tractus urogenitalis (normal urine specimen) were observed.
Because of the history of coughing blood we considered the probability of pulmonary hemosiderosis. A CT scan of the thorax showed areas with interlobular subpleural lines (interstitial deposits) diffusely over both lungs. Suspicion of pulmonary hemosiderosis increased and a bronchoalveolar lavage (BAL) was performed. In the lavage fluid hemosiderin was found in the macrophages. Therapy with prednisolone (2 mg/kg/day) was initiated. After 9 weeks of treatment she developed a Cushing syndrome, therefore doses have been reduced by half. At this moment prednisolone is given once every two days. To date no relapses of pulmonary hemorrhage have occurred.

Case report 2
AA one-and-a-half year-old previously healthy boy was admitted to our hospital because of increasing fatigue and pallor since 3 weeks. Moreover, small amounts of bright red blood were seen once in his vomit. He was born prematurely and was small for gestational age at 35 2/7 weeks and a birth weight of 1495 g (P3). He received a blood transfusion at the age of 3 weeks because of a low hemoglobin level. On physical examination, he presented with extreme pallor, with normal respiratory rate, a hyperdynamic precordium, with a grade 3/6 systolic ejection murmur, no distention nor tenderness of the abdomen. Liver and spleen were not enlarged. His weight and length were normal for his age (0 SD). Examination of skin and extremities revealed no abnormalities. Laboratory findings revealed a severe anemia with a hemoglobin level of 1.8 mmol/l and a MCV of 68 fl. An extended work-up was performed. Iron status showed Fe 1 mmol/l, TBC 76 mmol/l, saturation 1 %, transferrin 4.0 g/l. No abnormalities indicating hemolysis, (chronic) infection, malignancies including myeloproliferative disorders, marrow dysfunction, hemoglobinopathies or coagulation disorders were found. This led to the conclusion of severe iron deficiency anemia, most likely due to blood loss. Because of the finding of positive occult blood in feces and the history of hematemesis, the gastro-intestinal tract was extensively examined. Colonoscopy, gastroscopy, Sellink enteroclysis, Meckelscan, duodenal biopsy, cultures of stool, sputum, viral serology, IgE and RAST revealed no anomalies. Remarkable was, however, the amount of blood present in the endotracheal tube during extubation following the gastroscopy, which could not be explained by the uncomplicated, non-traumatic intubation. One day after the gastroscopy, the patient started coughing and developed fever; chest roentgenogram showed an infiltrate and treatment with antibiotics was initiated. However, lung abnormalities became more obvious during the following week: chest roentgenograms revealed diffuse parenchymal infiltrates associated with an interstitial pattern predominantly in the right lung base. In the mean time, the patient needed several blood transfusions.
The possibility of pulmonary hemosiderosis was raised, based both on clinical as on radiographic findings, although gastric aspirates for macrophages containing hemosiderin remained negative. In addition, bronchoscopy with BAL was performed. Macrophages in the BAL fluid were indeed laden with hemosiderin. Diagnostic tests for autoimmune disease and precipitins for cow-milk remained negative. In this way idiopathic pulmonary hemosiderosis was diagnosed.
Initial therapy with prednisone appeared to be insufficient and chloroquine was added. After two episodes of trying to stop the prednisone, recurrence of pulmonary hemorrhage occurred. Four years after the initial presentation, the patient was finally able to stop using prednisone. Several months later chloroquine was also discontinued and ever since the boy is in remission.

Comment
IPH is a rare disorder with an estimated incidence of 0.24 - 1.23 per million in selected populations. It is characterized by recurrent or chronic diffuse alveolar hemorrhage and accumulation of hemosiderin in the lungs. The erythrocytes are broken down by macrophages. The iron is stored in the macrophages and will not be available for re-use. The anemia caused by blood loss is enforced by the iron deficiency and presents itself as a microcytic anemia.
The diagnosis of IPH is usually made by a triad of hemoptysis, diffuse parenchymal infiltrates on chest radiographs and iron deficiency anemia. The delay in diagnosis is often prolonged after the initial diagnosis of microcytic anemia, followed by establishment of the iron status. In the absence of pulmonary problems low iron status indicates nutritional iron deficiency. In IPH iron deficiency is not a constant finding and is not absolutely required for diagnosing IPH; microcytic anemia with normal iron status is not only seen in thalassemia, but may also be seen in IPH. The diagnosis can be confirmed by demonstration of hemosiderin-laden macrophages in gastric aspirates or BAL. Biopsy is not essential for diagnosis if BAL results are typical.¹ CT appearances of pediatric interstitial lung disease have been described only in small series. In IPH CT appearances (the presence of ground glass opacification and nodules) using thin-section CT seem to be relatively specific. More definitive categorization of the histopathology and increased accuracy of thin-section CT are required.²
The cause of IPH is unknown, but a number of studies have suggested that it may be immunologic (Heiner syndrome; associations with immune diseases and connective tissue diseases).³ Familial cases described suggest possible genetic susceptibility to an environmental⁴ or to a toxic factor such as to environmental hydrophilic fungi, as Stachybotrys chartarum.⁵
The clinical course of IPH is exceedingly variable. Death may occur suddenly from acute pulmonary hemorrhage or after progressive interstitial fibrosis, which is enforced by the toxic effect of accumulation of iron in the lungs, resulting in (chronic) respiratory insufficiency. The presence of anti-neutrophil cytoplasm antibodies (ANCA) at the initial assessment is thought to be a sign of poor prognosis for pulmonary progression. The presence of other antibodies seems to be the key predictor for development of an immune disorder.
Many studies have shown that IPH has a poor prognosis, with a mean survival of 2.5 years after diagnosis. However, prolonged survival seems to be possible for children. Early active and extended courses of immunosuppressive therapy may improve the prognosis in IPH.⁶ The first treatment recommended is corticosteroid therapy. Hydrochloroquine is currently being tested as a first and second line treatment besides corticosteroids. Other immunomodulators such as azathioprine and cyclophosphamide have also been used with variable success. Recent studies suggest that early aggressive treatment with immunosuppressiva may improve the prognosis in IPH.

The natural clinical presentation of our first patient eventually led to the diagnosis of IPH; it was not until respiratory symptoms and hemoptysis appeared that the suspicion of IPH raised. (We did not exclude tuberculosis, which should also be considered in the presence of mentioned symptoms.) Although TEC is a disease more frequent and more likely in the general pediatric department, the diagnosis of IPH must be considered if severe anemia appears to be microcytic with reticulocytosis and can not be explained by nutritional iron deficiency. In our second patient the initial presentation with iron deficiency anemia, hematemesis and occult blood in feces was somewhat misleading; this was the result of swallowing blood originating from the airways. The diagnosis of IPH could still be made relatively early in the clinical course. First we excluded chronic blood loss from the tractus digestivus (like observed in infectious enteritis, inflammatory bowel disease, polyps, Meckel diverticulum or cow milk allergy) as a cause of the anemia as well as other possible causes of microcytic anemia with iron deficiency; chronic infection, sideroblastic anemia and hemoglobinopathies. Eventually, strong suspicion of IPH rose due to the onset of pulmonary infiltrates.

To avoid any delay in diagnosis, clinical practitioners should be aware of its occurrence, though rare. In the presence of a severe microcytic anemia, the amount of reticulocytes should be established. IPH should be considered as differential diagnosis of severe microcytic anemia with reticulocytosis, with or without iron deficiency, even if hemoptysis or other respiratory symptoms are not (yet) present.

References

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