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Clinical Investigations: DIFFUSE LUNG DISEASE |

Prognosis in Pediatric Idiopathic Pulmonary Hemosiderosis* FREE TO VIEW

Muhammad M. Saeed, MD; Marlyn S. Woo, MD; Eithne F. MacLaughlin, MD; Monique F. Margetis, MD; Thomas G. Keens, MD, FCCP
Author and Funding Information

*From the Division of Pediatric Pulmonology, Childrens Hospital Los Angeles, and the University of Southern California School of Medicine, Los Angeles, CA.

Correspondence to: Marlyn S. Woo, MD, Division of Pediatric Pulmonology, Childrens Hospital Los Angeles, 4650 Sunset Blvd, Mail Stop #83, Los Angeles, CA 90027; e-mail: mwoo@chla.usc.edu



Chest. 1999;116(3):721-725. doi:10.1378/chest.116.3.721
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Study objectives: Previously, IPH patients have been reported to have an average survival of 2.5 years. However, at our institution, many IPH patients have survived longer than that. Therefore, we conducted this study to determine the clinical course and current mortality of pediatric IPH patients treated with immunosuppressants.

Design: Retrospective chart review.

Setting: Children’s hospital.

Participants: Seventeen patients in whom IPH was diagnosed between 1972 and 1998.

Measurements and results: Mean age at diagnosis was 4.5 ± 3.5 years, and 12 patients were female. At diagnosis, all patients had anemia and pulmonary infiltrates; 85% had hypoxemia, 65% had hemoptysis, and 70% had fever. The diagnosis was made by open lung biopsy in 13 patients (76%), hemosiderin-laden macrophages in BAL fluid in 1 patient (6%), hemosiderin-laden macrophages in gastric aspirate in 2 patients (12%), or by clinical presentation alone in 1 patient (6%). The mean duration of follow-up for all patients was 3.6 ± 3.4 years (range, 0.7 to 10.2). Initial treatment consisted of prednisone only in 14 patients (82%), and prednisone and hydroxychloroquine in two patients (12%). Thirteen patients (76%) required long-term corticosteroids because of recurrent hemoptysis. Eight patients (47%) required other immunosuppressants (hydroxychloroquine or azathioprine) in addition to prednisone to control their hemoptysis. One patient who was not treated with prednisone remained asymptomatic for 1.8 years. Three patients (17%) died of acute massive pulmonary hemorrhage (4.1 ± 5.0 years postdiagnosis).

Conclusion: Five-year survival for IPH patients in our study was 86% (by Kaplan-Meier method). We conclude that these IPH patients who received long-term treatment had a better outcome than those previously reported who were not treated with extended courses of immunosuppressive therapy. We speculate that long-term immunosuppression therapy may improve the prognosis in IPH.

Idiopathic pulmonary hemosiderosis (IPH) is a disorder of unknown etiology that is characterized by recurrent or chronic hemorrhage and accumulation of hemosiderin in the lungs. Clinically, it manifests as a triad of hemoptysis, diffuse parenchymal infiltrates on chest radiographs, and iron deficiency anemia. This condition was first described by Virchow in 1864 as “brown lung induration.”1 In 1931, Ceelen reported the clinical picture of IPH in two children. The first antemortem diagnosis of IPH was reported by Waldenström in 1944.1Since then, multiple cases have been reported, but IPH is still a rare disorder with an estimated incidence of 0.242and 1.233cases per million in selected populations. The clinical course of IPH is exceedingly variable, and most of the patients continue to have episodes of pulmonary hemorrhage despite therapy. Death may occur suddenly from acute pulmonary hemorrhage or after progressive pulmonary insufficiency resulting in chronic respiratory failure. Although its etiology remains unknown, IPH is considered to be an immune-mediated disease.45 Corticosteroids have been used in the treatment of IPH, and they have been thought to decrease the frequency of hemorrhage.68 However, other studies suggest that they do not have any effect on the course or prognosis of this disease.4,6,9Other immune modulators have also been used with variable success, including hydroxychloroquine,1011 azathioprine,1213 and cyclophosphamide.14 To determine the prognosis in children with IPH who were treated with prednisone and other immunosuppressants, we reviewed the clinical courses in patients with IPH who were treated at Childrens Hospital Los Angeles.

The medical charts of all the patients who had a diagnosis of IPH and received medical care at Childrens Hospital Los Angles from January 1972 to March 1998 were reviewed. The diagnosis of IPH was established by evidence of recurrent pulmonary hemorrhage (hemoptysis, infiltrates on chest radiograph, presence of hemosiderin-laden macrophages in BAL or in gastric aspirates, or typical microscopic findings in lung biopsy), hypochromic microcytic anemia, and the absence of other diseases that can result in pulmonary hemorrhage. All patients underwent either a lung biopsy or an extensive diagnostic evaluation to exclude secondary causes of pulmonary hemorrhage, including vasculitides, rheumatologic diseases, immune deficiency, and glomerulonephritis. The following data were collected: age at diagnosis, sex, clinical presentation, method of diagnosis, treatment, and clinical course during subsequent follow-up. All patients received long-term follow-up at our institution and did not develop any evidence of extrapulmonary disease. When available, autopsy reports were reviewed to determine the cause of death. All clinical parameters are reported as mean ± SD. The survival rate was calculated by the Kaplan-Meier method.

Diagnosis

Seventeen patients were diagnosed with IPH at Childrens Hospital Los Angeles from 1972 to 1998. The mean age at diagnosis was 4.5 ± 3.5 years (range, 7.8 months to 14 years). There were 12 girls and 5 boys (2.4:1). Clinical findings on initial presentation are summarized in Table 1 . All 17 patients were found to have cough, anemia, and pulmonary infiltrates on chest radiographs. Fever, low oxygen saturation (Spo2 < 95%), respiratory distress, and digital clubbing were found less frequently. Recurrent hemoptysis was the only presenting complaint in one patient. Although pallor was the chief complaint in three patients (17%), all patients were invariably found to have hypochromic, microcytic anemia on initial presentation. The mean hemoglobin on initial presentation was 7.9 ± 3.0 g/dL (range, 1.8 to 11.2 g/dL). Six of the patients required blood transfusions to manage severe anemia. One patient (case 2) presented with congestive heart failure secondary to severe anemia (hemoglobin level, 1.8 g/dL). Three patients had eosinophilia. Milk precipitins were measured in 12 patients, and they were elevated in three patients (two of them also had eosinophilia). One patient had a very high response to peanuts on radioallergosorbent testing, with no elevated milk precipitins.

The diagnosis of IPH was made by lung biopsy in 13 patients. The findings of all lung biopsies were consistent with recurrent hemorrhages without evidence of vasculitis or infections. Four patients also had biopsy evidence of interstitial fibrosis. No other pathology or disease was found on these biopsies. In three patients, the diagnosis was made by typical clinical manifestations and the presence of hemosiderin-laden macrophages in either BAL fluid (one patient) or in gastric aspirates (two patients). In one patient whose family had refused lung biopsy, the diagnosis was made by clinical presentation and by laboratory tests that failed to reveal any other possible cause of pulmonary hemorrhage. BAL was performed in 10 patients (60%), and all were found to have significant numbers of hemosiderin-laden macrophages without evidence of infection or aspiration.

Clinical Course

After diagnosis, 14 patients (82%) were initially treated with prednisone (2 mg/kg/d) alone, two patients (12%) were treated with prednisone (2 mg/kg/d) and hydroxychloroquine (200 mg qd), and one patient (6%) did not receive any medications. This latter patient had initially presented in congestive heart failure secondary to severe anemia, was given a blood transfusion, and remained asymptomatic (without any treatment) for 1.2 years, after which she was discharged from follow-up. Eight of 15 patients (53%) continued to have bleeding episodes, and were treated with additional medications: azathioprine (four patients), hydroxychloroquine (three patients), or both azathioprine and hydroxychloroquine (one patient). Important data about the diagnosis, clinical presentation, diagnosis, treatment, and follow-up are summarized in Table 2 .

Only two patients have been successfully weaned off immunosuppressive therapy. These two patients (cases 10 and 13) were relatively young (mean age, 1.6 years) and had strongly positive milk precipitins. These two patients were treated with prednisone and a milk-free diet. One of them was successfully weaned off prednisone within 1 month and remained asymptomatic, except for a single episode of pulmonary hemorrhage after consuming a milk-based food. The other patient was treated with prednisone for 8 months and was then successfully weaned off. For about 3 years, he has not had any episodes of pulmonary hemorrhage. In two other patients (cases 11 and 12), after the addition of azathioprine, it was possible to gradually stop prednisone, and the patients remained asymptomatic with azathioprine alone. The response to the therapy was assessed by the absence of signs and symptoms of pulmonary hemorrhage (absence of cough, hemoptysis, respiratory distress, and pneumonia), as well as laboratory measures (serial measurements of hemoglobin levels and reticulocyte counts) and serial chest radiographs. Currently, among patients who are still receiving their treatment at Childrens Hospital Los Angeles, two patients are being treated with prednisone alone, two with azathioprine alone, three with prednisone and azathioprine, and one with prednisone and hydroxychloroquine. One patient is being treated with a milk-free diet without any medications. One patient, who was initially found to have restrictive lung disease, was treated with prednisone and hydroxychloroquine; serial pulmonary function studies showed a gradual improvement in total lung capacity with IPH therapy. Patients who were on prednisone had well known side effects including cushingoid features, weight gain, growth retardation, and (rarely) cataracts. Hydroxychloroquine was not associated with any side effects. Patients taking azathioprine were very closely monitored for its side effects (including hepatotoxicity and bone marrow suppression); only one patient had mild, transient elevation in hepatic transaminases, which reversed when the dose was decreased.

Three patients (17%) have died. All three patients were female, and all of them had an initial hemoglobin level of < 6.5 g/dL (5.6 ± 1 g/dL), which was significantly lower than the hemoglobin level in IPH patients who survived (8.4 ± 3.3 g/dL; p < 0.02). Two of the three patients who died had a very high reticulocyte count (27 and 24%, respectively). Case 1 initially presented in January 1975 with hemoptysis, pulmonary infiltrates, and anemia. IPH was diagnosed by an open lung biopsy, and the patient was treated with prednisone. However, she continued to have episodes of pulmonary hemorrhage, requiring five hospital admissions within 7 months. She finally died of massive pulmonary hemorrhage. Case 3 was treated with prednisone, hydroxychloroquine, and azathioprine. She was followed up for 9.9 years, after which she died of massive hemoptysis. This latter patient was poorly compliant with the medical treatment and frequently did not take her medication, which might have played a role in her death. Case 4 was treated with prednisone after diagnosis. However, she also continued to have episodes of pulmonary hemorrhage, so hydroxychloroquine was added to her treatment regimen. She died of massive pulmonary hemorrhage 1.8 years after diagnosis. The causes of death were confirmed by autopsy in two cases. In the third patient, the family refused autopsy. The mean duration of follow-up for all patients was 3.6 ± 3.4 years (range, 0.7 to 10.2 years). Using the Kaplan-Meier method of survival analysis, the 5-year survival for IPH patients in this series was 86%.

We found that 5-year survival of patients with IPH at our institution was 86%. This survival rate is significantly higher than the rates reported in previous studies.56,15 However, most of our patients were treated with immunosuppressants, and long-term therapy with immunosuppressants was not instituted in many of the previous studies. Soergel and Sommers4 reported an average survival of 2.5 years after the onset of symptoms in 112 patients with IPH in 1962, although in about half the patients, the diagnosis was made after death. Among their 68 patients in whom the diagnosis was made during life, only 28 patients were treated with corticosteroids.4 The authors concluded that the short-term use of corticosteroids during bleeding episodes speeds recovery, and perhaps it improves the immediate prognosis. However, it did not seem to alter the long-term course or prognosis of the disease. In 1983, Chryssanthopoulos et al15 reported on 30 children who were observed for an average of 5.1 years. In the 18 children who died (60%), the mean survival was only 2.8 years (range, 3 months to 10.5 years). In that study, 6 patients were treated with intermittent steroid therapy, 20 were treated with continuous steroid therapy, and 4 patients did not receive steroid therapy.15 None of the patients were treated with azathioprine. The authors concluded that the available therapeutic modalities (including corticosteroids) did not provide a better outcome for IPH. Kjellman et al2 reviewed 10 cases of IPH in Swedish children. In their study group, all patients received corticosteroids, and three patients also received azathioprine.2They noticed that symptoms and chest radiograph changes seemed to improve during immunosuppressive therapy. Ohga and colleagues3 reported a 5-year mean survival rate of 67.1%, but no details about treatment were provided. Hence, while some studies showed that corticosteroids might be helpful in the short-term control of symptoms, their role in the long-term management has remained controversial. Published experience with other immunosuppressants has been very limited and is confined to case reports. Because of the rarity and extremely variable clinical course of IPH, there have been no randomized clinical trials to assess the efficacy of different therapeutic modalities.

In our study, there were two patients who did not require long-term immunosuppression, and who may have a lower morbidity. These two patients who fit into the description of Heiner’s syndrome,1 were relatively young at diagnosis, and had evidence of allergy to milk protein. They remained well after restricting the milk proteins, and were eventually weaned off corticosteroids. Hence, they might have a better prognosis than patients with IPH with no evidence of milk-protein allergy, and they may not need long-term immunosuppression. We decided to include these patients in our review, as the diagnosis of Heiner’s syndrome as a separate entity remains controversial. The role of milk-precipitins in the causation of pulmonary hemosiderosis is unclear.

In our study, the patients who died had more severe anemia than the patients who survived. In the study by Chryssanthopoulos et al,15 the serum hemoglobin was almost identical in patients who survived and in those who died (mean hemoglobin, 6.4 vs 5.8 g/dL). Ohga and colleagues3 did not find any difference between the groups of patients who died or survived in terms of the number of blood transfusions.

To the best of our knowledge, our study has shown the highest survival in the literature. We believe that this better overall survival may be due to a more aggressive use of immunosuppressants. However, our study is a retrospective review and hence does not permit us to compare individual therapies or to evaluate the efficacies of individual therapies. In addition, our study does not have adequate data to support one therapy in favor of other therapies. We speculate that aggressive treatment with corticosteroids and other immunosuppressants may improve the longevity in IPH patients.

Abbreviation: IPH = idiopathic pulmonary hemosiderosis

Table Graphic Jump Location
Table 1. Initial Clinical Presentation
* 

Spo2 = oxygen saturation.

Table Graphic Jump Location
Table 2. Important Data for Patients With IPH*
* 

aza = azathioprine; CHF = congestive heart failure; Dx = diagnosis; F/U = follow-up; GA = gastric aspirate; HLM = hemosiderin-laden macrophage; HXC = hydroxychloroquine; MA = evidence of milk protein allergy; MFD = milk-free diet; pred = prednisone; F = female; M = male.

Heiner, DC (1990) Pulmonary hemosiderosis. Chernick, V Kendig, EL, Jr eds.Disorders of the respiratory tract in children,498-509 WB Saunders. Philadelphia, PA:
 
Kjellman, B, Elinder, G, Garwicz, S, et al Idiopathic pulmonary hemosiderosis in Swedish children.Acta Pediatr Scand1984;73,584-588. [CrossRef]
 
Ohga, S, Takahashi, K, Miyazaki, S, et al Idiopathic pulmonary haemosiderosis in Japan: 39 possible cases from a survey questionnaire [letter].Eur J Pediatr1995;154,994-995. [PubMed]
 
Soergel, KH, Sommers, SC Idiopathic pulmonary hemosiderosis and related syndromes.Am J Med1962;32,499-511
 
Gonzalez-Crussi, F, Hull, MT, Grosefeld, JL Idiopathic pulmonary hemosiderosis: evidence of capillary basement membrane abnormality.Am Rev Respir Dis1976;114,689-698. [PubMed]
 
Matsaniotis, N, Karpouzas, J, Apostolopoulou, E, et al Idiopathic pulmonary hemosiderosis in children.Arch Dis Child1968;43,307-309. [PubMed]
 
Beckerman, RC, Taussig, LM, Pinnas, JL Familial idiopathic pulmonary hemosiderosis.Am J Dis Child1979;133,113-118
 
Gilman, PA, Zinkham, WH Severe idiopathic pulmonary hemosiderosis in the absence of clinical or radiologic evidence of pulmonary disease.J Pediatr1969;75,118-121. [PubMed]
 
Boat, TF Idiopathic pulmonary hemosiderosis. Chernick, V Boat, T eds.Kendig’s disorders of the respiratory tract in children1998,628-629 WB Saunders. Philadelphia, PA:
 
Bush, A, Sheppard, MN, Warner, JO Chloroquine in idiopathic pulmonary hemosiderosis.Arch Dis Child1992;67,625-627. [PubMed]
 
Zaki, M, Al Saleh, Q, Al Mutari, G Effectiveness of chloroquine therapy in idiopathic pulmonary hemosiderosis.Pediatr Pulmonol1995;20,120-126
 
Byrd, RB, Gracey, DR Immunosuppressive treatment of idiopathic pulmonary hemosiderosis.JAMA1973;226,458-459. [PubMed]
 
Rossi, GA, Balzano, E, Battistini, E Long-term prednisone and azathioprine treatment of a patient with idiopathic pulmonary hemosiderosis.Pediatr Pulmonol1992;13,176-180. [PubMed]
 
Colombo, JR, Stolz, SM Treatment of life-threatening primary pulmonary hemosiderosis with cyclophosphamide.Chest1992;102,959-960. [PubMed]
 
Chryssanthopoulos, C, Cassimos, C, Panagiotidou, C Prognostic criteria in idiopathic pulmonary hemosiderosis in children.Eur J Pediatr1983;140,123-125. [PubMed]
 

Figures

Tables

Table Graphic Jump Location
Table 1. Initial Clinical Presentation
* 

Spo2 = oxygen saturation.

Table Graphic Jump Location
Table 2. Important Data for Patients With IPH*
* 

aza = azathioprine; CHF = congestive heart failure; Dx = diagnosis; F/U = follow-up; GA = gastric aspirate; HLM = hemosiderin-laden macrophage; HXC = hydroxychloroquine; MA = evidence of milk protein allergy; MFD = milk-free diet; pred = prednisone; F = female; M = male.

References

Heiner, DC (1990) Pulmonary hemosiderosis. Chernick, V Kendig, EL, Jr eds.Disorders of the respiratory tract in children,498-509 WB Saunders. Philadelphia, PA:
 
Kjellman, B, Elinder, G, Garwicz, S, et al Idiopathic pulmonary hemosiderosis in Swedish children.Acta Pediatr Scand1984;73,584-588. [CrossRef]
 
Ohga, S, Takahashi, K, Miyazaki, S, et al Idiopathic pulmonary haemosiderosis in Japan: 39 possible cases from a survey questionnaire [letter].Eur J Pediatr1995;154,994-995. [PubMed]
 
Soergel, KH, Sommers, SC Idiopathic pulmonary hemosiderosis and related syndromes.Am J Med1962;32,499-511
 
Gonzalez-Crussi, F, Hull, MT, Grosefeld, JL Idiopathic pulmonary hemosiderosis: evidence of capillary basement membrane abnormality.Am Rev Respir Dis1976;114,689-698. [PubMed]
 
Matsaniotis, N, Karpouzas, J, Apostolopoulou, E, et al Idiopathic pulmonary hemosiderosis in children.Arch Dis Child1968;43,307-309. [PubMed]
 
Beckerman, RC, Taussig, LM, Pinnas, JL Familial idiopathic pulmonary hemosiderosis.Am J Dis Child1979;133,113-118
 
Gilman, PA, Zinkham, WH Severe idiopathic pulmonary hemosiderosis in the absence of clinical or radiologic evidence of pulmonary disease.J Pediatr1969;75,118-121. [PubMed]
 
Boat, TF Idiopathic pulmonary hemosiderosis. Chernick, V Boat, T eds.Kendig’s disorders of the respiratory tract in children1998,628-629 WB Saunders. Philadelphia, PA:
 
Bush, A, Sheppard, MN, Warner, JO Chloroquine in idiopathic pulmonary hemosiderosis.Arch Dis Child1992;67,625-627. [PubMed]
 
Zaki, M, Al Saleh, Q, Al Mutari, G Effectiveness of chloroquine therapy in idiopathic pulmonary hemosiderosis.Pediatr Pulmonol1995;20,120-126
 
Byrd, RB, Gracey, DR Immunosuppressive treatment of idiopathic pulmonary hemosiderosis.JAMA1973;226,458-459. [PubMed]
 
Rossi, GA, Balzano, E, Battistini, E Long-term prednisone and azathioprine treatment of a patient with idiopathic pulmonary hemosiderosis.Pediatr Pulmonol1992;13,176-180. [PubMed]
 
Colombo, JR, Stolz, SM Treatment of life-threatening primary pulmonary hemosiderosis with cyclophosphamide.Chest1992;102,959-960. [PubMed]
 
Chryssanthopoulos, C, Cassimos, C, Panagiotidou, C Prognostic criteria in idiopathic pulmonary hemosiderosis in children.Eur J Pediatr1983;140,123-125. [PubMed]
 
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