(Chest. 1999;116:721-725.)
© 1999
American College of Chest Physicians
Prognosis in Pediatric Idiopathic Pulmonary Hemosiderosis*
Muhammad M. Saeed, MD;
Marlyn S. Woo, MD;
Eithne F. MacLaughlin, MD;
Monique F. Margetis, MD and
Thomas G. Keens, MD, FCCP
*
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{at}chla.usc.edu
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Abstract
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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.
Key Words: idiopathic pulmonary hemosiderosis • immunosuppression • pediatric • prognosis
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Introduction
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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
1944.1
Since then, multiple cases have been reported, but
IPH is still a rare disorder with an estimated incidence of
0.242
and 1.233
cases 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.4
5
Corticosteroids have been used in the treatment of IPH, and they have
been thought to decrease the frequency of hemorrhage.6
7
8
However, other studies suggest that they do not have any effect on the
course or prognosis of this disease.4
6
9
Other immune
modulators have also been used with variable success, including
hydroxychloroquine,10
11
azathioprine,12
13
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.
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Materials and Methods
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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.
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Results
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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%.
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Discussion
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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.5
6
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.2
They 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.
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Footnotes
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Abbreviation: IPH = idiopathic pulmonary
hemosiderosis
Received for publication December 9, 1998.
Accepted for publication April 22, 1999.
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References
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Boat, TF (1998) Idiopathic pulmonary hemosiderosis. Chernick, V Boat, T eds. Kendig's disorders of the respiratory tract in children ,628-629 WB Saunders Philadelphia, PA.
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Zaki, M, Al Saleh, Q, Al Mutari, G (1995) Effectiveness of chloroquine therapy in idiopathic pulmonary hemosiderosis. Pediatr Pulmonol 20,120-126
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Byrd, RB, Gracey, DR (1973) Immunosuppressive treatment of idiopathic pulmonary hemosiderosis. JAMA 226,458-459[CrossRef][ISI][Medline]
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Rossi, GA, Balzano, E, Battistini, E (1992) Long-term prednisone and azathioprine treatment of a patient with idiopathic pulmonary hemosiderosis. Pediatr Pulmonol 13,176-180[ISI][Medline]
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Colombo, JR, Stolz, SM (1992) Treatment of life-threatening primary pulmonary hemosiderosis with cyclophosphamide. Chest 102,959-960[Abstract/Free Full Text]
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Chryssanthopoulos, C, Cassimos, C, Panagiotidou, C (1983) Prognostic criteria in idiopathic pulmonary hemosiderosis in children. Eur J Pediatr 140,123-125[CrossRef][ISI][Medline]
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TOP
Abstract
Introduction
