PULMONARY BLEEDING IN INFANTS AND CHILDREN
Andrew A. Colin, MD
Division of Pediatric Pulmonology, Miller School of Medicine, University of Miami, Miami, FL
Andrew A. Colin, MD
Division of Pediatric Pulmonology
Miller School of Medicine, University of Miami
1580 NW 10th Avenue, Room 125
Miami, FL 33136
Telephone: (305) 243-3176
Fax: (305)243-1262
E-mail: acolin@med.miami.edu
This discussion focuses on diffuse alveolar hemorrhage (DAH). This paper is not intended to be
a comprehensive review of the subject as previously undertaken by Godfrey1 and Nusslein2, but
rather to highlight some recently presented novel aspects on this difficult topic, such as Acute
Idiopathic Pulmonary Hemorrhage of Infancy (AIPH), a recent classification of DAH, and novel
therapeutic methods using bronchoscopy.
CLINICAL PRESENTATION:
The typical presentation of DAH is the triad: hemoptysis, anemia and diffuse alveolar infiltrates,
but the three elements rarely coexist. While in infants, who will be separately discussed below,
overt hemorrhage from the airway is the common presentation; a fall in hematocrit (typically
hypochromic, microcytic anemia) associated with respiratory disease is the hallmark of
pulmonary bleeding.
The onset of symptoms is variable: a fulminant onset with acute hemoptysis is occasionally
fatal; however, most cases have an insidious presentation with anemia, pallor, weakness and
poor weight gain. Some patients vomit swallowed blood and do not have hemoptysis.
The physical examination is non-specific and ranges from dyspnea, with crackles and
wheezing to the physical findings associated with pulmonary hypertension or frank respiratory
failure. Fever and chest pain are sometimes associated with the bleeding episode, and may be
the markers for a recurrent bleed.
LABS:
Pulmonary function testing in age appropriate children is non-specific, but diffusion studies
(DLCO) may result unexpectedly high because of the rapid uptake of the tracer gas by
hemoglobin in the alveolar spaces.
Radiographic changes are non-specific as well, and range from minimal infiltrates to massive
parenchymal involvement, The fleeting nature of the infiltrates may be a telltale sign. In patients
with small frequent episodes of bleeding the radiographs may reflect chronic diffuse interstitial
involvement and may change only minimally with an acute episode of bleeding. CT scan
appears to offer no better specificity than the chest radiograph, though MRI of the lung may
prove more useful in defining the presence of blood, showing decreased signal on the T2weighted images
INCIDENCE:
The incidence of pulmonary bleeding in childhood is low; hence there is little systematic
information on bleeding in children. The incidence estimate in Sweden is 0.24 cases per million
and a higher rate of 1.23 cases per million is reported from Japan.
CAUSES OF HEMOSIDEROSIS:
Because of the low incidence of DAH, little systematic information on causes of lung bleeding in
childhood, and essentially none of large scale, is available. In one 10 year review from a large
referral center, 228 children and young adults were reported: Cystic fibrosis (CF) represented
65%, Congenital heart disease 16%. The remaining 19% were infections (other than CF),
neoplasms (2.6%), and other causes.3
Classification: As above, many of the cases occur in the context of cystic fibrosis or lung
infections; predominantly tuberculosis. The remaining cases of “Idiopathic Pulmonary
Hemosiderosis” were traditionally viewed as a wastebasket of many conditions, which were
variable in nature and overall poorly understood. A recent review4 offers a systematic approach
to classification of DAH emphasizing the distinction between disorders without pulmonary
capillaritis; this group is broken down to those with noncardiovascular causes and
cardiovascular cause. The other group includes the disorders with pulmonary capillaritis
which typically carry a more ominous prognosis. Included in the latter group are Idiopathic
pulmonary capillaritis, Wegener’s granulomatosis, Microscopic polyangiitis, Systemic lupus
erythematosus, Goodpasture’s syndrome, Antiphospholipid antibody syndrome, HenochSchonlein purpura, IgA nephropathy, Polyarteritis nodosa, Behcet syndrome, Cryoglobulinemia,
Drug-induced capillaritis, and Idiopathic pulmonary–renal syndrome
ACUTE IDIOPATHIC PULMONARY HEMORRHAGE OF INFANCY (AIPH)
Infantile airway bleeding is an uncommon occurrence but has periodically emerged in clusters;
historically in Greece, and more recently in Cleveland and Massachusetts. This entity was
recognized by the Centers for Disease Control (CDC) as unique and earned its definition in a
publication in 2001: a clinically confirmed case is an illness in a previously healthy infant aged
<1 year, with a gestational age >32 weeks, and no history of neonatal medical problems that
could cause pulmonary hemorrhage. In addition, the cases are characterized by abrupt onset of
overt bleeding or frank evidence of blood in the airway, a severe presentation leading to acute
respiratory distress or failure, and diffuse pulmonary infiltrates on chest radiograph.
In the mid 90s a series of 30 cases of AIPH was reported from Cleveland.5 Of these 77% were
from the same geographic area and were African-American, with male predominance (77%),
73% required respiratory support, and 5 (16%) of them died. While the numbers were small it
appears that corticosteroid administration had a protective role. Most infants were placed on
corticosteroid therapy, 3/5 infants who died had not received steroids or stopped them soon
after discharge, and 2/25 who survived did not receive steroids. An initial association of this
cluster of AIPH was made to Stachybotrys chartarum, a mold that may be found in waterdamaged homes. Ultimately, this association has not been confirmed.
AIPH in five infants in the Boston area were reported in 2004.6 No mortality was reported. The
cause was assumed to be related to an underlying susceptibility to bleed, and von Willebrand
Disease (VWD) was ultimately diagnosed in 3 of the infants. Such underlying vulnerability was
thought to be precipitated by injury to the lungs, possibly a viral infection, but this was not
substantiated.
THE ROLE OF BRONCHOSCOPY IN AIRWAY AND PULMONARY BLEEDING
Diagnostic: Flexible bronchoscopy is key in the initial diagnosis of DAH, in particular in cases
who do not present with overt airway bleeding. In such cases bronchoalveolar lavage (BAL)
results in persistently blood-tinged return fluid.7 Repeat bronchoscopy has been proposed by
the Cleveland group5 for therapeutic decision-making and long term follow-up. A scoring system
for hemosiderin-laden macrophages was developed by them to allow comparison between
repeated procedures through the long term follow-up.
Therapeutic: Medical treatment of hemosiderosis is beyond the scope of this presentation.
However, the use of bronchoscopy both flexible and rigid to control bleeding is common in the
adult literature, but barely addressed in pediatrics. The previously cited review on diffuse
alveolar hemorrhage in children4 does not list bronchoscopy related interventions to control
bleeding. The largest report on a series of 14 patients with acute life-threatening pulmonary
hemorrhage lists use of CO2 laser bronchoscopy, Nd-YAG laser bronchoscopy, endoscopic
balloon occlusion of a lobe or main bronchus, topical airway vasoconstrictors and endoscopic
tumor excision.8 An exciting innovation in the bronchoscopic interventions to control airway
bleeding has recently emerged with the successful intrapulmonary instillation of activated
recombinant factor VII (rFVIIa) to control DAH in a series of adult patients.9 Similarly, tranexamic
acid, a synthetic anti-fibrinolytic agent has been reported in a series of 6 patients.10 The use of
both agents is an extension of previous experience with their systemic administration to treat
patients with recalcitrant pulmonary bleeding. Colin et al11 have recently reported Heslet et al’s9
protocol to instill rFVIIa to control an unremitting diffuse pulmonary hemorrhage of 4 weeks
duration, as an intervention of last resort for a 16 year old patient with acute myelogenous
leukemia. The hemorrhage was visualized during the procedure and its resolution following the
treatment was immediate, unequivocal, and definitive. The remarkable ease and efficacy of this
intervention makes it attractive for treatment of pulmonary hemorrhage in both adults and
children.
PROGNOSIS:
There is little information about long term outcome of pulmonary hemosiderosis. Most
informative are studies by Saeed12 and Le Clainche13 that suggest that the overall prognosis
may not be favorable in the “idiopathic” cases. Thus, these cases require careful follow-up and
appropriate treatment that most often consists of corticosteroids and immunosuppressive
therapies. The Saeed paper12 emphasizes the beneficial long-term impact of
immunosuppression therapy on the prognosis of DAH. Some cases with DAH may declare
themselves in later life as having well-defined connective tissue or granulomatous diseases.
While the infant population with AIPH discussed above likely reflects a different subclass within
the “Idiopathic” group, individuals with recurrent bleeding and mortality have been reported.
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