Clinical spectrum of chronic interstitial

lung disease in children

L e l a n d L. Fan, MD, Ann L. W. Mullen, RN, MS, Susan M. Brugman, MD,
S t e p h e n C. Inscore, MD, D a v i d P. Parks, MD, a n d Carl W. White, MD
From the Divisionof Pediatric Pulmonology, Natio~nalJewish Center for Immunology and Respiratory Medicine, Denver, Colorado, the Department of Pediatrics, Universityof Colorado
Health Sciences Center, Denver, and the Department of Pediatrics, Brooke Army Medical
Center, Fort Sam Houston, Texas

To describe the clinical spectrum of interstitial lung disease in children, we reviewed our experience with 48 patients during a 12-year period. Most patients
initially had typical findings of restrictive lung disease and hypoxemia. Growth
failure or pulmonary hypertension or both were found in more than one third.
Specific diagnosis, m a d e in 35 patients (70%), most often required invasive
studies, particularly open lung biopsy. Although the diagnostic yield from open
lung biopsy was high, the diagnosis of many patients remained uncertain. Many
different disorders were encountered. The response to corticosteroids, bronchodilators, and chloroquine was inconsistent. Six patients died, five within 1
year after the initial evaluation. The spectrum of pediatric interstitial lung
disease includes a large, heterogeneous group of rare disorders associated
with high morbidity and mortality rates. (J PEDIATR1992;121:867"72)
Interstitial lung disease refers to a group of chronic pulmonary disorders characterized by derangements of alveolar
walls and loss of alveolar capillary units. Although more
than 100 different disorders have been identified, the
majority of patients have ILD of unknown cause.l The term
"chronic diffuse infiltrative lung disease" has been advocated because involvement of alveolar air spaces is often
present as well. 2 Recognizing its limitations, we will use the
more familiar term, ILD.
Usual interstitial pneumonitis, also known as idiopathic
pulmonary fibrosis and cryptogenic fibrosing alveolitis, is
one of the most common forms of idiopathic ILD in adults.
Another idiopathic disorder is desquamative interstitial
pneumonitis, which is characterized by hyperptasia of alve-

Supported in part (Dr. White) by a Grant-in-Aid and an Established Investigator Award from the American Heart Association
National Center, and National Institutes of Health SCOR I P50
HL 46481-01.
Submitted for publication Dec. 30, 1991; accepted July 28, 1992.
Reprint requests: Leland L. Fan, MD, National Jewish Center for
Immunology and Respiratory Medicine, 1400 Jackson, Denver,
CO 80206.

9/20/41361

olar-lining cells and accumulation of mononuclear cells in

the alveolar spaces. Some investigators believe that DIP and
U1P represent different stages of the same disease process)
Considerable information has accumulated about the pathogenesis of idiopathic pulmonary fibrosis, and there is also
improved understanding of the clinical aspects of this condition in adults. 46
In children, ILD appears to be rare, but our current
knowledge is fragmented. 7, 8 It remains to be determined

DIP
FEV1
FVC
ILD
LIP
UIP

Desquamativeinterstitial pneumonitis
Forcedexpiratory volume in 1 second
Forcedvital capacity
Interstitial lung disease
Lymphocyticinterstitial pneumonitis
Usual interstitial pneumonitis

whether the information gained from adult investigations

can be applied to pediatric ILD. To our knowledge, there
have been no systematic studies of the clinical spectrum of
ILD in children. Therefore we reviewed retrospectively our
experience with pediatric ILD during the past 12 years to
describe ( 1) the clinical findings of children with these disorders, (2) the diagnostic value of routine and invasive tests,

867

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Fan et al.

The Journal o f Pediatrics

December 1992

T a b l e I. Background data on 48 children with ILD

T a b l e II. Presenting symptoms and signs

Patients

Gender
Male
Female
Year of initial evaluation
1980-1983
1984-1987
1988-1991
Age at onset (yr)
<l
1-5
6-10
>10
Duration of symptoms (yr)
<1
1-3
>3
Previous bronchodilator use

Patients

No.

23
25

48
52

9
14
25

19
29
52

22
11
9
6

46
23
19
13

27
8
13
17

56
17
27
35

(3) the variety of diagnoses encountered, (4) therapy, and

(5) outcome.

Symptoms
Cough
Tachypnea
Dyspnea
Cyanosis
Exercise intolerance
Frequent respiratory infection
Retractions
Wheezing
Hemoptysis
Signs
Rales
Tachypnea
Retractions
Weight <5%
Clubbing
Wheezing
Cyanosis
Height <5%
Loud P2
Pc, Pulmonicsecondsound.

No.

37
36
34
32
31
21
20
19
4

77
75
71
67
65
44
42
40
8

29
26
22
17
14
9
9
7
6

60
54
46
35
29
19
19
15
13

METHODS
We reviewed the medical records of patients who had a
discharge diagnosis of ILD, or a related diagnosis such as
DIP, UIP, or lymphocytic interstitial pneumonitis at the
University Hospital, Children's Hospital, and National
Jewish Center for Immunology and Respiratory Medicine,
in Denver, Colo., from 1980 through 1991. To identify additional patients with ILD, we also reviewed the office
records of patients seen by the pediatric pulmonary services
at those institutions during the same period. The catchment
area of our referral hospitals is mainly the Rocky Mountain
region, although a few patients are referred to National
Jewish Center from other parts of the country.
The records of 83 patients were identified in this way.
From this group, we then selected the 48 patients who met
our inclusion and exclusion criteria. The inclusion criteria
were (1) age, 1 month through 18 years, (2) the presence
of rales or tachypnea or the finding of diffuse infiltrates on
roentgenogram of the chest, and (3) persistence of any of
those findings for at least 1 month. The exclusion criteria
were (1) documented endogenous aspiration syndromes,
such as those related to gastroesophageal reflux, swallowing
dysfunction, and tracheoesophageal fistula, because these
conditions commonly cause diffuse infiltrates, (2) bronchopulmonary dysplasia, or (3) known t?nderlying systemic
diseases such as malignancy or immunodefieiency, unless
ILD was the first manifestation of that underlying illness
and the diagnosis was not known at the time of initial evaluation.

Specific details regarding history, physical examination,

initial diagnosis, evaluation, final diagnosis, treatment, and
outcome were recorded on each of the 48 patients and entered into a data base. With regard to treatment, we
attempted to categorize response to drug therapy as positive, indeterminate, or negative. Patients were considered
responsive to specific therapy if they demonstrated any of
the following: improved clinical status, decreased oxygen
requirement, and better pulmonary functions.
RESULTS
Presentation. The background data on the 48 patients are
given in Table I. The larger number of new patients seen in
recent years may.reflect our current interest in and awareness of pediatric ILD more than an increased prevalence of
these conditions. Onset of symptoms occurred most often in
infancy and with decreasing frequency in older age groups.
Although most patients had symptoms for less than 1 year
at the time of initial evaluation, a considerable number had
had symptoms for 1 or more years. Approximately one third
of the patients had been treated with bronchodilators for
suspected reactive airways disease before evaluation.
Most patients had cough, taehypnea, rales, cyanosis, and
exercise intolerance; wheezing was not as prominent a finding (Table II). A considerable number of patients had
growth failure.
Diagnostic evaluation. Chest roentgenograms of all patients showed abnormalities at the time of initial evaluation;

Volume 121
Number 6

Chronic interstitial lung disease

869

%
Pred

FVC

FEV1

FEVI/
FVC

PEF

FEF
25-75

TGV

TLC

Fig. I. Pulmonary function data from forced vital capacity maneuvers and body plethysmography (mean _+ SEM).
%Pred, Percentage of predicted value; PEF, peak expiratory flow; FEF 2~-75,forced expiratory flow at mid phase; TGV,
thoracic gas volume; TLC, total lung capacity.

36 patients had predominantly interstitial infiltrates, 6 had

mixed interstitial and alveolar infiltrates, 4 had predominantly alveolar infiltrates, and 2 had other nonspecific findings such as hyperinflation.
Forced vital capacity maneuvers, performed on 25 patients, suggested a restrictive pattern of lung disease, as
demonstrated by reduced FVC and forced expiratory
volume in 1 second and by a normal FEV1/FVC ratio (Fig.
1). Flow rates were not referenced to specific lung volumes;
therefore it is difficult to determine whether reduced peak
expiratory flow and forced expiratory flow at mid phase
were related to restrictive or obstructive disease. Thoracic
gas volume and total lung capacity, measured in 23 patients,
were within the normal range. Only 1 of 20 patients tested
had more than a 15% increase in FEV~ in response to
inhaled bronchodilators.
Eighty-seven percent (40/46) of the patients tested at the
time of initial evaluation had evidence of hypoxemia as defined by a resting, room air oxygen saturation by pulse oximetry of <90% (normal values in Denver, elevation 1610 m,
92% to 96%) or a resting, room air oxygen tension in arterial blood of <60 mm Hg (normal values in Denver, 65 to
75 mm Hg). Forty-two percent (20/48) of the patients had
evidence of pulmonary hypertension demonstrated by electrocardiogram, echocardiogram, and/or cardiac catheterization.
A specific diagnosis was established by open lung biopsy
in 24 patients, cardiac catheterization in 5, bronchoalveolar lavage in 6, and other laboratory tests in 5. The
diagnostic yield was 80% (24/30) for open lung biopsy, 42%

Table III.Diagnoses
Specific
Environmental disorders
Lymphocyte infiltrative disorders
Pulmonary vascular disease
Infection
Desquamative interstitial pneumonitis
Pulmonary hemosiderosis
Usual interstitial pneumonitis
Pulmonary lymphangiomatosis
Autoimmune-related pulmonary fibrosis
Inflammatory bowel disease-related ILD
Alveolar proteinosis
Suggestive
Lymphocytic interstitial pneumonitis
Epstein-Barr virus
Nonspecific

6
5
5:
4
4
4
2
2
1
1
I
1
1
11
48

(5/12) for cardiac catherization, and 30% (6/20) for bronchoalveolar lavage.
Diagnoses. A specific diagnosis was made in 35 of the 48
patients (Table III). Of the 6 patients with environmental
disorders, 4 had hypersensitivity pneumonitis, 1 had talc
inhalation, and 1 had mineral oil aspiration. Of the 5
patients with lymphocyte infiltrative disorders, 4 had LIP
and 1 had pulmonary lymphoid hyperplasia. 9 Of the 5 with
pulmonary vascular disease, 2 had pulmonary hemangiomatosis, 2 had partial or total anomalous pulmonary venous
return, and 1 had pulmonary vein stenosis. Although the 3
patients with pulmonary venous abnormalities did not have

870

Fan et al.

The Journal of Pediatrics

December 1992

Responsive

[] Indeterminate
60-

%
of
Pts

40-

3/5

[] Unresponsive
12/30

12/31

4 4/"IN

12/31

2/5

20i
I

Steroids

Bronehodilators

Chloro( uine

Fig. 2. Response of patients (Pts) to specific therapy.

typical ILD, they fulfilled entry criteria and were originally

thought to have primary ILD. Of the 4 patients with chronic
lung disease as a result of infection, 2 had adenovirus, 1 had
Myeoplasma pneumoniae, and 1 had influenza B virus. Of
the 4 patients with DIP, 3 had the familial variety, including 2 brothers and a female patient whose uncle had died
of DIP. Three patients had miscellaneous disorders, including 1 with autoimmune-related pulmonary fibrosis, 1 with
ulcerative colitis-related ILD, and 1 with alveolar proteinosis.
Two other patients had suggestive diagnoses. One boy
with suspected LIP did not undergo open lung biopsy, but
he had symptoms identical to those of his twin brother who
had biopsy-proven LIP. Another boy had ILD, with strongly
positive results on serologic study for Epstein-Barr virus,
consistent with recent infection.
In 11 patients, no specific diagnosis was made. Six of
these patients had undergone open lung biopsy, but either
biopsy was nondiagnostic or there was disagreement as to
the specific diagnosis. The diagnosis of UIP was considered
in some of these patients.
The diagnosis at the time of initial evaluation was accurate in only 9 patients. Correct diagnoses included pulmonary hemosiderosis (4 patients), adenovirus infection (1),
hypersensitivity pneumonitis (1), pulmonary hemangiomatosis (1), pulmonary lymphangiomatosis (1), and M. pneumoniae infection (1). All 4 pati~nts with pulmonary hemosiderosis in this study were correctly suspected, on the basis
of typical clinical findings, to have the condition at the time
of initial evaluation.
Therapy. Several forms of therapy were initiated in these
patients. Oxygen therapy was required in 32 patients,

although a beneficial response was difficult to assess retrospectively. Treatment with corticosteroids of at least 1
week's duration was used in 30 patients; dosages, dosing intervals, and duration of treatment were highly variable.
Other agents utilized included bronchodilators in 31 patients, chloroquine or hydroxychloroquine in 5, and other
drugs (azathioprine, cyclophosphamide, etoposide, vinblastine, and methotrexate) in 6. Interferon alfa was used in 3
patients; a positive response was noted in the 2 with pulmonary hemangiomatosis l~ ~ and an indeterminate response
in 1 patient with pulmonary lymphangiomatosis.
Only 40% of patients given corticosteroids responded favorably (Fig. 2). Benefit was noted in the following conditions: LIP or pulmonary lymphoid hyperplasia (3 patients),
hypersensitivity pneumonitis (3), nonspecific (2), ILD with
autoimmune disease (1), UIP (1), pulmonary hemangiomatosis (1), and ILD with ulcerative colitis (1). The limited
number of patients responding to bronchodilators was consistent with the predominantly restrictive pattern of lung
disease found on clinical evaluation and pulmonary function
tests in the majority of patients. Of the 5 patients given
chloroquine or hydroxychloroquine, 2 had a beneficial
response, including 1 with UIP and I with nonspecific ILD.
Three patients, including 2 with DIP and 1 with nonspecific
ILD, did not respond to chloroquine and subsequently died.
Outcome. Forty-four patients have been followed for at
least 1 year after initial evaluation. Three others have been
evaluated within the past year and one was lost to followup. Of those followed at least 1 year, 22 have improved, 12
remain unchanged, 4 are worse, and 6 have died.
Five patients died within the first year after initial evaluation and one 4 years after initial evaluation. Death

Volume 121
Number 6

occurred in all 4 patients with DIP, 1 with total anomalous

venous return, and 1 with nonspecifie ILD. Five of the six
patients died within the first 4 years of life. All died as a result of progressive respiratory failure, although the patient
with anomalous venous return had cardiac failure as well.
DISCUSSION
This study demonstrates that ILD in children comprises
a large, heterogeneous group of rare disorders. Fernald et
al. 12 reported a series of 184 consecutive children with
chronic lung disease referred to a teaching hospital during
a 4-year period; no patient was given a specific diagnosis of
ILD (such as DIP or LIP), although 16 patients were
reported to have "chronic pneumonia without wheezing."
Their report is an indication of the rarity of these disorders.
In 34 children with different types of ILD, Gaultier et al. 13
reported lung function abnormalities (decreases in lung
volume, compliance, arterial oxygen tension, and lung
transfer of carbon monoxide) but did not mention the clinical findings, tests required for diagnosis, response to therapy, or outcome.
The knowledge of specific types of pediatric ILD, such as
DIP, UIP, and LIP, remains very limited. Much of what is
known about DIP in children comes from case reports. 14-24
Stillwell et al. 24 described 14 patients and reviewed an additional 14 cases from the literature. The majority of
patients had the onset of symptoms in infancy and typical
findings of restrictive lung disease. The mortality rate was
39%, with a higher death rate in those patients with onset
in infancy. All four of our patients with DIP were unresponsive to therapy and died, However, 3 of the 4 had the
familial form of DIP, a much more aggressive disease with
a high mortality rate. 14, 15
Most reported patients with UIP or related conditions
have had characteristic findings of reduced lung volumes
and low lung compliance on pulmonary function testing.2s-28 The response to steroids has been generally favorable. The mortality rate, when reported, has ranged from
7% to 50%. In our series, only two patients had biopsyproven UIP; another patient had pulmonary fibrosis related
to an undefined autoimmune disorder. Although all three
patients are currently alive, the response to therapy has been
inconsistent.
Lymphocyte infiltrative disorders, such as LIP or pulmonary lymphoid hyperplasia, can exist as idiopathic, isolated,
and sometimes familial entities,29 but they more commonly
occur with underlying conditions such as immunodeficiency
syndromes, particularly acquired immunodeficiency syndrome, 3~ and autoimmune diseases, such as juvenile rheumatoid arthritis. 31 The five patients with LIP or pulmonary
lymphoid hyperplasia reported in this study did not have
underlying disorders. We excluded six other patients with

Chronic interstitial lung disease

871

LIP from this study because they had immunodeficiencyor

autoimmune disorders. Thus lymphocyte infiltrative disorders appear to be more prevalent in children than other
types of ILD.
In general, our patients did not appear to respond consistently to medical therapy, and the response was not
predicted by the specific entity treated. The response to
treatment in pediatric ILD has been variable; some have
reported favorable responses to steroids 7, 19,25-28,32 and
chloroquine,7,15, 22, 23, 32, 33 and others unfavorable responses, usually with fatal results. 14, 16-18 The reason for
these differences is unclear, but may reflect the heterogeneous nature of the disorders treated. There are no controlled trials for any of these drugs in these diseases, and
therapy remains unproved and empiric.
We recognize the limitations of this retrospective study.
The heterogeneous and rare nature of these disorders, as
well as the variety of diagnostic approaches and prescribed
therapy, made analysis difficult. Nonetheless, this study offers some insights for clinicians encountering a pediatric
patient with persistent rales, tachypnea, hypoxemia, and/or
infiltrates. Our experience suggests that the diagnosis is
usually not apparent at onset, invasive procedures are frequently required, a wide variety of conditions may be discovered, current therapeutic approaches appear to be less
than optimal, and morbidity and mortality rates are
high.
We thank Gary Larsen, MD, Derek Uchida, MD, Steven
Abman, MD, Frank Accurso, MD, and Talmadge King, MD, for
their valuable advice.
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