Discussion
There is no consensus in terms of the evaluation and management of
children with IPH.12,15 To the best of our knowledge,
this study is one of the largest with a long follow-up period, which
demonstrated that the presence of hypoxia at diagnosis could be an
independent risk factor for recurrent episodes. Moreover, our study is
the first to indicate that prognosis might be poor in patients with ANA
positivity at the time of diagnosis.
Only one recent study has attempted to identify predictors for
recurrence episodes in patients with IPH.16 However,
the focus of this study was not to predict patients with recurrence
episodes, and only 10 patients with recurrence episodes were evaluated
and its follow-up period was shorter than the present study. Their
results suggested that bilirubin levels were significantly higher in
children with recurrence episodes. The results of our study, on the
other hand, revealed that patients presenting with hypoxia or requiring
transfusion at the time of diagnosis had significantly more recurrence
episodes. Moreover, multivariate regression analysis demonstrated that
hypoxia was an independent risk factor in predicting recurrence
episodes. To the best of our knowledge, our study is the first to
indicate that the presence of hypoxia at initial presentation is an
independent risk factor for recurrent IPH episodes. Another significant
result of our study was that important factors such as age at the onset
of symptoms, length of delay in diagnosis, clinical features, physical
examination findings, and laboratory results were not helpful in
predicting recurrence episodes. This study provides valuable information
to physicians that may guide the management of treatment for patients
who present with hypoxia.
IPH may occur at any age but it is more frequently reported in children
between the ages of 1 and 7 years, similar to the results of present
study.17,18 The results of our study revealed that the
symptom onset age was 3 months for the youngest, and 15 years of age for
the oldest patient. This result demonstrates the fact that IPH can be
seen in all age groups and physicians should be careful not to focus on
younger patients only.
Consanguinity was present in 48% of the patients in our study. This
rate proves to be more than the double the rate of consanguinity in
Turkey (20%).19 Furthermore, a sibling one of our
patient’s died with similar symptoms. Our result, in line with those of
previous studies, indicates that genetics might play a role in the
underlying mechanisms of IPH.20-23
Studies in the literature reported varying results regarding the
presenting symptoms of the disease24-26. In our study,
the most common presenting features at onset were anemia, cough,
dyspnea, and hemoptysis. In their study, Tayard et al. also reported
that anemia and dyspnea were the most common
symptoms.20 In the study conducted by Zhang et al.,
however, cough and hemoptysis were the predominant symptoms, and dyspnea
was observed in 15% of the patients.16
Although hemoptysis is one of the components of the classic triad of the
disease, it only occurs in around half of all patients at initial
presentation.16,20 Yet it has been reported that
hemoptysis was seen in almost all adult patients during the course of
the disease.3 The results of studies conducted by
French and Chinese researchers revealed that hemoptysis was observed in
around half of all patients, as was the case in our
study.16,20 In spite of the fact that opinions
suggesting that hemoptysis might go unnoticed due to sputum swallowing
in young children,27 no evident hemoptysis was
observed in 39% of patients covered by our study with a long follow-up
period. It should be remembered that evident hemoptysis might never
emerge in a substantial part of patients, including during the course of
the disease.
Studies thus far have reported delays in diagnosis to range between 1
and 6.3 years.20,28 In our study, evidence of
remarkable delay in diagnosis was observed in some patients. Two of the
most significant reasons for this situation are the absence of the known
classic triad in half of all patients and the low level of awareness of
pediatricians about this disease. Further, the three centers in which
our study was conducted were reference centers in metropolitans. It
takes time for patients, to access such centers, and a significant
portion of the patients lose time because they receive treatment having
been pre-diagnosed as having iron deficiency anemia and pneumonia. In
order to prevent delays in diagnosis, particularly in patients with no
classic triad symptoms, awareness about the disease should be increased
and physicians should adopt a high level of suspicion to this end.
Multiple theories have been proposed regarding the potential underlying
pathophysiology of the disease.7,10,29 Even though
some evidence has been reported in the literature regarding the
relationship between IPH and autoimmune diseases, this association still
remains controversial.20,30,31 Previous studies
speculated that more than one-quarter of patients developed an immune
disorder later in follow-up.30 At least one antibody
was found to be positive in 35% of patients covered by our study but
accompanying autoimmune diseases were observed in very few patients. In
long-term follow-ups, however, four patients were observed to have
accompanying autoimmune diseases.
It has been strongly suggested that there is a relationship between
celiac disease and IPH. Researchers believe that an immunologic
pathogenesis underlies this combination, which has yet to be
clarified.32-34 The results of our study revealed that
celiac antibody positivity was 30%, even though only one patient was
diagnosed as having celiac disease upon further investigation. Also,
celiac antibody positivity disappeared in one other patient. The high
celiac autoantibody positivity in our patients increases the possibility
that IPH may be within the spectrum of autoimmune diseases. Also, it is
important to keep in mind that antibody results could change over time.
Our present study provides support for importance of BAL in diagnosis of
IPH; six patients had negative results in gastric aspirate, although
their hemosiderin-laden macrophages in BAL were positive. Furthermore,
we are not able to evaluate the trigger effects of infectious agents in
the exacerbation of IPH because of limited microbiologic records.
However, some of our patients clearly stated that attacks were triggered
by infection, indicating that further research is required especially to
elucidate on the role of influenza in triggering attacks.
Our study also aimed to predict the treatment responses of patients.
Transfusion history, presence of hypoxia, ANA positivity, and elevated
transaminases enzymes at presentation were associated with poor
treatment response. The limited number of studies in the literature
investigating the possible factors affecting prognosis at the time of
diagnosis yielded different results. A study conducted in Greece in 1983
reported poorer prognoses for young male children.35In another study conducted in Japan in 1995, on the other hand, the
authors argued that prognosis might be poorer in patients with fever,
leukocytosis, hepatomegaly, and splenomegaly.16 In a
study conducted in India, the authors associated hemoptysis and high
bilirubin at diagnosis with poor prognosis.36 A
previous study of 15 patients indicated that the presence of ANCA was
associated with poor prognosis in IPH.30 Blanco et al.
proposed that ANCA positivity might have been associated with poor
prognosis their study conducted with four patients with IPH with no
systemic or renal disease .37 Interestingly, our
results revealed that the patient group with ANA positivity had poorer
prognoses. To our knowledge, this association has never been reported in
the literature. Prognostic value of autoantibodies was evaluated in many
studies; presence of ANA was associated with a more severe disease in
certain connective tissue disorders38. Our result on
prognosis evaluation may be random due to the fact that the number of
patients per group was limited, but it might also be related to the
possibility of accompanying autoimmune events that could have affected
prognosis that have yet to be identified in the ANA- positive group. Our
study underlined this relationship but in order to clarify this
relationship, further larger and prospective studies are needed.
There are no prospective studies on the management of IPH in children
for which most of the evidence is delivered from observational
studies.12 It was seen that the second treatment of
choice following steroids was hydroxychloroquine, and inhaler steroid
treatment was used in one-third of the patients. It was also observed
that steroid treatment was generally well tolerated by the patients and
adverse effects that led to steroid discontinuation were quite few. It
was, however, seen that the patients often went through relapse episodes
during the downgrading or discontinuation of steroid treatment. Such
episodes were most commonly observed 6 months following steroid
discontinuation, but there was a case of recurrence after 30 months. It
is therefore important to closely follow-up patients even if they have
no symptoms after steroid discontinuation.
One of the main limitations of our study is its retrospective design.
However, the study data were enhanced by contacting the patients to
collect their current data and long-term prognoses. Another limitation
was that patients from different centers were included in the study and
there were interdepartmental differences in follow-up protocols.
Further, there have been changes in examinations in patient assessment
and treatment management because the study covered a period of 40 years.
In conclusion, our study offers significant results to the literature
because it has a large population and covers a long period of follow-up.
The results of our study demonstrated that the presence of hypoxia at
diagnosis could be an independent risk factor for recurrent episodes.
This information may guide physicians in the planning treatment
strategies for patients who present with hypoxia. Further, our study is
the first to indicate that prognosis might be poor in patients with ANA
positivity at the time of diagnosis but this result needs to be
clarified by further studies.