Original Research

INTERSTITIAL LUNG DISEASE

A Kindred of Children With Interstitial

Lung Disease*
Heather Thomas, MD; Kimberly A. Risma, MD, PhD; T. Brent Graham, MD;
Alan S. Brody, MD; Gail H. Deutsch, MD; Lisa R. Young, MD; and
Patricia M. Joseph, MD, FCCP

Background: Childhood interstitial lung disease (ILD) is a spectrum of diseases including many
different rare lung conditions. We present a family with an unusual presentation of ILD in
association with rheumatologic and immunologic abnormalities.
Methods: Eight children with a common father were evaluated for evidence of lung disease in
association with rheumatologic findings. All underwent routine history and physical examination,
hematologic evaluation, and chest radiography and/or CT scan of the chest. Seven children
underwent a more extensive immunologic evaluation. Those who were able underwent pulmo-
nary function testing, and four children underwent lung biopsy.
Results: Six of eight children with a common father were found to have radiographic findings
consistent with ILD. These children also had evidence of autoimmune disease with joint
symptoms, alopecia, rheumatoid factor production, and hypergammaglobulinemia. Open-lung
biopsy in four children revealed a spectrum of pulmonary lymphoid proliferations ranging from
reactive lymphoid hyperplasia to lymphoid interstitial pneumonia.
Conclusion: The findings of ILD and autoimmunity in a kindred of children suggest a novel
genetic disorder of autosomal dominant pattern and variable penetrance. Although the precise
pathogenesis remains unclear, these cases provide valuable insight into childhood ILD.
(CHEST 2007; 132:221230)
Key words: autoimmune diseases; interstitial lung disease; pediatrics; pulmonary fibrosis
Abbreviations: ABCA3 adenosine triphosphate-binding cassette A-3; ANA anti-nuclear antibody;
EBV Epstein-Barr virus; ESR erythrocyte sedimentation rate; HHV human herpes virus; ILD interstitial lung
disease; LIP lymphocytic interstitial pneumonia; NK natural killer; PCR polymerase chain reaction;
PFT pulmonary function test; RF rheumatoid factor; SFTPB surfactant protein B; SFTPC surfactant protein
C; VATS video-assisted thorascopic surgery

C hildhood interstitial lung disease (ILD) is a

broad category that includes many rare lung
conditions. Rather than a discrete entity, perhaps it
*From Cincinnati Childrens Hospital Medical Center, University
of Cincinnati, Cincinnati, OH.
This work was performed at Cincinnati Childrens Hospital
Medical Center.
The authors have no actual or potential conflict of interests to
disclose.
Manauscript received October 11, 2006; revision accepted March
26, 2007.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Patricia Joseph, MD, FCCP, University of
Cincinnati, 231 Albert Sabin Way, Cincinnati, OH 45267-0564;
e-mail: patricia.joseph@uc.edu
DOI: 10.1378/chest.06-2476
should be considered a clinical syndrome character-
ized by tachypnea, crackles, hypoxemia and/or dif-
fuse infiltrates.1 With an estimated prevalence of
3.6 cases per million, ILD in children is extremely
rare, and disease pathogenesis and natural history
are poorly understood.2
The international consensus statement defining
pathologic, radiologic, and clinical manifestations of
idiopathic interstitial pneumonias in adults is largely
not applicable to children.3,4 While the majority of
cases of ILD are idiopathic, ILD can occur in
association with other systemic disorders. ILD asso-
ciated with rheumatologic diseases and environmen-
tal exposures, such as hypersensitivity pneumonitis,
can overlap between adults and children. More than
50% of adults with systemic lupus erythematosus,

www.chestjournal.org CHEST / 132 / 1 / JULY, 2007 221

approximately 50% with rheumatoid arthritis, 70%
with scleroderma, and 5 to 40% with polymyositis-
dermatomyositis have pulmonary involvement at di-
agnosis.5,6 Most of the information about the preva-
lence of ILD in association with rheumatologic
diseases in children is derived from case reports.79
Certain forms of ILD are heritable, including
those that occur in conjunction with known Mende-
lian disorders (ie, Hermansky-Pudlak syndrome, tu-
berous sclerosis, Niemann-Pick disease).10 Recently,
specific mutations in genes for surfactant protein B
(SFTPB) and surfactant protein C (SFTPC) and
adenosine triphosphate-binding cassette A-3
(ABCA3) gene have been described. These defects
cause a disease spectrum from early neonatal death
(SFTPB) to a highly variable presentation in adults
and children (SFTPC).1113 Hereditary idiopathic
pulmonary fibrosis has been identified in family
cohorts, in whom a genetic basis has yet to be
identified.14,15 We present a kindred of children with
lung disease associated with rheumatologic and im-
munologic abnormalities. Because of the heritable
pattern, this family provides opportunity for insights
into mechanisms of ILD pathogenesis.
Materials and Methods
Identification of Patients
The proband, a 10-year-old, African-American girl (patient C),
presented to rheumatology clinic with alopecia, joint pain, and
eczema. Symptoms of dyspnea with minimal exertion, chest
tightness, and intermittent cough prompted a chest CT scan and
then pulmonary consultation. Case histories are outlined in the
Appendix with patients labeled A through H. Two family mem-
bers (patients D and G) were subsequently evaluated for similar
symptoms. The remaining siblings were later evaluated, although
symptoms were mild or absent. All studies were performed as
part of clinical care so institutional board approval was not
obtained.
Pulmonary Function Testing
Patients, if able, performed spirometry and plethysmography.
Results were expressed as a percentage of predicted normal
values derived from American Thoracic Society recommenda-
tions.16,17
Bronchoscopy
Four patients (patients A, C, D, and G) underwent flexible
bronchoscopy with BAL under general anesthesia. Samples were
submitted for microbiology and cytologic evaluation.
Chest CT Scan
High-resolution imaging was performed during inspiration and
expiration. Older patients (patients A, B, C, D, and E) underwent
imaging during voluntary breath holding, and younger patients
(patient F, G, and H) with a controlled ventilation technique.18
222
Laboratory Studies
Studies were performed in the clinical laboratory at Cincinnati
Childrens Hospital Medical Center. The lymphocyte subpopu-
lation analysis used an automated flow analysis methodology.
Lung Biopsy
Lung biopsy was performed in four patients using a minimally
invasive thoracoscopic technique under general anesthesia with-
out need for single-lung ventilation, as previously described.19,20
Tissue specimens were processed according to a consensus
protocol for handling lung biopsy tissue.21
Results
The patients studied share a complex family
grouping (Fig 1). Details of the case histories are
outlined in the Appendix and summarized in Table
1. Patient C is the proband. All three mothers are
asymptomatic. The father has declined evaluation
but has overlapping symptoms including alopecia,
eczema, and possible exercise limitation. His eight
children have varying clinical presentations. Five
children (patients A, B, E, F, and H) were evaluated
for lung disease due to the findings in their siblings.
Evaluation of patient H was limited due to his young
age and lack of symptoms. Four children (patients A,
C, D, and G) were symptomatic at their initial
evaluation. Six children had decreased weight for
height ratio (patients A, B, C, D, E, and G). Two
were hospitalized as infants for failure to thrive
(patients C and G) and had tachypnea, hypoxemia,
and crackles on initial pulmonary evaluation. None
had significant environmental exposures or travel.
Tables 2 and 3 summarize the immunologic labo-
ratory findings in patients A through G. All had
normal electrolytes and renal and liver function (not
shown), but five patients (patients C, D, E, F, and G)
had mild microcytic anemia. WBC counts and abso-
lute lymphocyte and neutrophil counts were normal
but sedimentation rates (ESRs) were elevated. Ig
studies revealed elevated IgG and IgA in the older
children (patients A, B, C, and D). Rheumatoid
factor (RF) was elevated in patients B, C, D, and G.
Anti-nuclear antibody (ANA) was positive in three
patients (patients B, C, and E); specific autoantibod-
ies were negative. Follow-up evaluation of the
youngest, patient G, by 18 months of age revealed
dramatically elevated IgG (1,900 mg/dL; normal, 400
to 1,250 mg/dL) and positive RF [896 U/mL] and
ANA (1:1,280) not seen at the initial evaluation.
Serum electrophoresis did not show monoclonal
gammopathy. Diphtheria and pneumococcal titers
were positive.
Four children (patients C, E, F, and G) were
tested and had negative HIV titers. There was no
Original Research
 Figure 1. Depiction of family tree. Letters identify individual patients as presented in the text. Solid
arrow indicates the proband. Shaded boxes correspond to specified symptoms.

evidence for acute or chronic/active Epstein-Barr
virus (EBV); all children except for one had evidence
of remote EBV infection with seroconversion (posi-
tive IgG against viral capsid antigen and EBV nu-
clear antigen, and absent IgM against viral capsid
antigen). Patient E had no evidence of EBV expo-
sure based on serologic testing 3 months prior to the
abnormal CT scan finding.
Lymphocyte subpopulation analysis revealed ex-
panded B-cell percentages in all except patient F,
who was unaffected (Table 3). In addition, all af-
fected children except patients A and G had low
CD8 percentages as well. By 2 years of age, however,
the latter child (patient G) had acquired a low CD8
percentage also (10%, not shown). Patients A, C, D,
and G had normal T-cell proliferation to mitogens.
Patients A and G underwent natural killer (NK) cell
function testing that was normal.
The four oldest children (patients A, B, C, and D)
underwent pulmonary function tests (PFTs). Pa-
tients C and D had obstructive ventilatory defects,
while patients A and B had no obstruction or restric-
tion. All four children had a significant diffusion
defect (Table 4). CT scan abnormalities varied. Five
had diffuse ground-glass opacities (patients B, C, D,
E, and G), four had cystic changes (patients B, C, D,
and G), and two had tree-in-bud changes (patients B
and C). Patient A had multiple noncalcified nodules
without ground-glass opacities, tree-in-bud changes
or cystic changes (Fig 2). Two children (patients F
and H) had normal chest CT scans. Results of
SFTPB, SFTPC, and ABCA3 mutational analyses
were negative in patients C and G.
Four children (patients A, C, D, and G) under-
went video-assisted thorascopic surgical (VATS) lung
biopsy. Histology demonstrated a variable lympho-
cytic proliferation (Fig 3). The biopsy of patient C
revealed marked lymphocytic infiltrate with reactive

Table 1Clinical Information on Individual Patients*

Patient Age at Onset of Symptoms First Symptoms Joint Involvement Skin Involvement Biopsy (Age)

A 3 mo Eczema Knee arthralgia Eczema, alopecia, conjunctivitis Yes (16 yr)

B Infancy Eczema None Eczema, conjunctivitis No
C 1 yr FTT, eczema Knees, ankle, wrist arthritis Eczema, alopecia Yes (8 yr)
D 3 yr Alopecia, eczema Knee arthralgia Eczema, alopecia Yes (8 yr)
E 5 yr Eczema, alopecia None Eczema No
F None None None None No
G 3 mo Dyspnea, cough None None Yes (13 mo)
H None None None None No
*FTT failure to thrive.

www.chestjournal.org CHEST / 132 / 1 / JULY, 2007 223

 Table 2Laboratory Data

Patients

Variables A B C D E F G

Cytopenia None None Anemia Anemia Anemia Anemia Anemia

ESR (010 mm/h) 22* 20* 85* 64* 31* 37* 31*
IgG, mg/dL 2,270* 2,000* 2,330* 2,300* 1,353 571 1,130
Range 6331,522 5841,509 6381,453 5981,379 4821,520 4311,406 4001,250
IgA, mg/dL 264 374* 396* 443* 164* 77 69
Range 68378 45234 45234 33200 25152 22157 14105
IgM, mg/dL 96 199 302* 193 144 111 195*
Range 60263 49230 49230 46197 41186 45190 41164
IgE, KU/L 855 162 26 1,507* 65 12 13
Normal 114 304 328 248 192 128 53
RF (019 U/mL) 20 402* 1,480* 117* 20 20 26
ANA Negative 1:1280* 1:640* Negative 1:160* Negative Negative
*Abnormal values.

follicles extending into the interstitium. Immunohis-
tochemistry established that the interstitial lympho-
cytic population was predominantly T-cells admixed
with few small B-cells. The histology of patient G
revealed severe follicular bronchiolitis with focal
extension into the interstitium. In situ hybridization
for EBV in both patients was negative. Biopsies of
patients A and D demonstrated chronic bronchiolitis
with follicular hyperplasia; a lung nodule from
patient A was a large intraparenchymal lymph node
with lymphoid hyperplasia. Polymerase chain reac-
tion (PCR) for EBV, human herpes virus (HHV)-6,
adenovirus, influenza, parainfluenza, and respiratory
syncytial virus was performed on the lung biopsies
for patients A, C, and D. PCR results for EBV and
HHV-6 were positive in patient A, and parainfluenza
virus type 1 was positive in patient D.
Discussion
We have identified a family with a common father
and symptoms of alopecia, eczema, and joint pain in
association with ILD. The severity of lung disease
was variable and independent of age. The affected
children have CT scan evidence of ILD and diffusion
defect on PFTs (if able). Surfactant studies and lung
histology do not suggest SFTPB, SFTPC, or ABCA3
genes mutations as an etiology in this family. Immu-
nologic evaluation revealed evidence of B-cell dys-
regulation characterized by expanded numbers of
B-cells, hypergammaglobulinemia, and significant
auto-antibody production.
It is important to note that the proband presented
with rheumatologic and pulmonary symptoms, but
many siblings had evidence of ILD in the absence of
overt pulmonary symptoms. This illustrates the need
for careful evaluation for pulmonary disorders in
children with rheumatologic diseases. In such pa-
tients, pulmonary symptoms may be masked by
overlapping rheumatologic symptoms such as exer-
cise limitations secondary to joint inflammation.
Standard radiographic and pulmonary function
studies may not yield classic findings of ILD. In our
cohort, no restrictive lung defect was noted, but two

Table 3Lymphocyte Subpopulation Analysis

Patients

Variables A B C D E F G

Mature T-cells CD3, % 57 56 48* 54* 52* 66 43*

Range 5278 5578 5578 5578 5578 4376 5077
T-helper cells CD4, % 32 40 34 42 42 48 28*
Range 2548 2753 2753 2753 2753 2348 3358
T-suppressor cells CD8, % 25 15* 14* 11* 10* 15 14
Range 935 1934 1934 1934 1934 1433 1326
B-cells CD19, % 31* 38* 39* 38* 45* 30 53*
Range 824 1031 1031 1031 1031 1444 1335
NK cells CD16, % 9 6 12 7 2* 3* 3
Range 627 426 426 426 426 423 213
*Abnormal values.

224 Original Research

 Table 4 PFT Results*

Patients

Variables A B C D

FEV1, % predicted 86/89 90/93 74/89 79/50

FVC, % predicted 84/83 99/95 76/97 90/65
FEV1/FVC, % 89/92 79/84 85/81 77/67
Total lung capacity, % predicted 78/88 89/79 86/94 85/78
Functional residual capacity, % predicted 79/106 107/83 107/108 114/113
Residual volume, % predicted 73/105 75/51 116/95 89/130
Adjusted diffusion capacity of the lung for 61/61 80/74 53/51 75/75
carbon monoxide, % predicted
*Data are presented as % of predicted at the initial visit/% of predicted at 6-month follow-up visit.
Abnormal values.

children (patients C and D) had an obstructive
ventilatory defect, and two children (patients A and
B) had normal spirometry. All four children had a
diffusion defect (adjusted diffusion capacity of the
lung for carbon monoxide 80%). Adults at presen-
tation with rheumatoid arthritis showed 37% with an
obstructive defect, 8.6% with a restrictive defect, and
6.5% with a mixed defect.22 Copley et al23 reported
that ILD was identified on CT scan 66% of the time
vs only 45% on chest radiography (p 0.025).
Therefore, it may be more appropriate to consider a
chest CT scan early in children with suspected ILD.

Figure 2. CT scan images. The letter in the upper left corner of each image indicates the patient. Top
left, patient A: Noncalcified nodules (arrows) without evidence of interstitial changes. Top middle,
patient B: Tree-in-bud opacities, seen here as diffuse, fine, small nodules present throughout the
periphery, and a bleb (arrow); ground-glass opacities are not shown in this image. Top right, patient
C-1: Diffuse cystic changes. Center left, patient C-2: Subpleural interstitial thickening with some cystic
changes, with a few ground-glass opacities. Center middle, patient D-1: An area of cystic changes
(arrow). Center right, patient D-2: Ground-glass opacities (arrows). Bottom left, patient E-1: Areas of
patchy ground-glass opacities in midlung fields. Bottom middle, patient E-2: Diffuse ground-glass
opacities in lung bases. Bottom right, patient G: Ground-glass opacities, some confluent, with a large
cyst and areas of small cystic changes.

www.chestjournal.org CHEST / 132 / 1 / JULY, 2007 225

 Figure 3. Lung biopsy hematoxylin-eosin sections from patient C (top left, A, and top right, B) and
patient G (bottom left, C, and bottom right, D) [top left, A: original 4; top right, B: original 20;
bottom left, C: original 4; bottom right, D: original 20]. Histology showed a prominent lymphocytic
infiltrate with reactive follicles (arrows) that extend into the interstitium. Immunohistochemistry
demonstrated that the interstitial lymphocytes were predominantly T-cells, plasma cells, and histiocytes
with few small B lymphocytes (not shown). In situ hybridization for EBV was negative. This is indicative
of LIP.

With the exception of genetic mutations of surfactant
metabolism, lung biopsy remains the gold standard
for laboratory confirmation of ILD in children.24
VATS is the preferred approach because it provides
decreased morbidity with adequate tissue sam-
ples.19,20,25
In our patients, lung biopsies revealed a spectrum
of reactive lymphoid hyperplasia in the lung with
overlapping histologic patterns, including follicular
bronchiolitis and lymphocytic interstitial pneumonia
(LIP).26 Chest CT scans that show areas of ground-
glass attenuation, poorly defined centrilobular nod-
ules, and subpleural small nodules support these
diagnoses.27 Patterns of follicular bronchiolitis and
LIP are suggestive of several etiologies including,
but not limited to viruses (ie, EBV, HIV, and
HHV-6), autoimmune diseases, and congenital im-
munodeficiency.28 In our cohort, the children who
underwent lung biopsy were HIV negative, and
findings for EBV in the lung were negative in
biopsies in three patients. All but one child had
serologic evidence of remote EBV without evidence
of a symptomatic illness. One child (patient A) had a
positive EBV and HHV-6 PCR in his lung biopsy,
and another (patient D) had parainfluenza type 1.
Because these biopsies were performed at a time
when the patients were at their clinical baseline
without evidence of acute infection, the significance
of these findings is unknown.
LIP has been described in a variety of autoim-
mune disorders, primarily in adults.29 Although clin-
ical findings such as elevated RF levels and variable
ANA suggest an autoimmune etiology in this family,
the clinical symptoms of these patients are not
consistent with Sjogren syndrome, Hashimoto dis-
ease, myasthenia gravis, or systemic lupus erythem-
atosus, and specific autoantibodies for these diseases
are negative. Two children have joint symptoms of
arthralgia and one has arthritis, but the remainder
have no evidence for juvenile rheumatoid arthritis.
There is also no evidence for primary immune
deficiency such as common variable immune defi-
ciency, which can be associated with LIP, since
B-cell, T-cell, and NK-cell function is intact and
there is no history of recurrent infections other than
pneumonia in the affected children. In our kin-
dred, B-cell percentages were expanded in all af-
fected children except patient F, who appears unaf-
fected. This suggests a correlation between B-cell
expansion and lung disease. In the youngest child,
B-cell expansion preceded the appearance of ele-
vated IgG and RF. Expanded B-cell numbers pre-

226 Original Research

ceding hypergammaglobulinemia suggests that B-
cell activation is a precursor for abnormal plasma cell
activity. The mechanism for chronic B-cell expan-
sion/activation is unclear, but possibilities include
the following: (1) ongoing stimulation from activated
T-cells and/or persistent antigenic stimulus, as may
occur in genetic disorders of NK or T-cell deficiency,
chronic viral infections such as HIV, or autoimmune
disorders; (2) autonomous B-cell activation and dif-
ferentiation in the absence of typical T-cell or anti-
gen stimulation; or (3) failure of appropriate B-cell
death following removal of antigenic stimulus, such
as occurs in disorders of apoptosis as described
below.
In one case series of individuals with LIP, 80% of
cases were found to have polyclonal hypergamma-
globulinemia.30 Hypergammaglobulinemia is noted
in many immune system disorders including viral
infections such as HIV and autoimmune diseases
such as Sjogren syndrome, juvenile rheumatoid ar-
thritis, and autoimmune hepatitis, all of which are
associated with abnormal B-cell activation and/or
differentiation.3134 It is also reported in cases of
lymphoproliferative diseases such as autoimmune
lymphoproliferative syndrome, a defect of lympho-
cyte apoptosis caused by gene defects in the Fas
gene.35 Other atypical cellular proliferative disorders
such as Rosai Dorfman and Castleman disease
present with hypergammaglobulinemia.36 Histologic
features similar to LIP are described in multicentric
Castleman disease, with or without association to
viral infections such as HIV.37,38 Importantly, the
clinical, histologic, and laboratory features of these
children do not meet criteria for any of these specific
disorders of cellular proliferation.
In review of the literature, we identified three
similar reports of families with pediatric ILD. Child-
hood onset of pulmonary fibrosis associated with LIP
is reported in two siblings but without associated
evidence of collagen vascular disease.39 One sibling
had progressive fibrosis and death within 4 years of
diagnosis; the second has survived 10 years with
minimal symptoms. In a second family, six children
with one father presented with pulmonary fibrosis.7
The father and several children of this cohort also
had arthritis and autoantibodies. In a third kindred,
multiple family members presented with autoim-
mune features, arthritis, and pulmonary fibrosis.8
The proband was a school-age child with arthritis,
hypergammaglobulinemia, and evidence of B-cell
activation similar to the features described here.
In our cohort, the pattern of inheritance appears
autosomal dominant, with variable severity of disease
between the children, suggesting incomplete pen-
etrance. Specifically, the lung disease in patient G is
far more severe than his elder siblings based on CT
www.chestjournal.org
evidence, hypoxemia, and exercise limitation. Poten-
tial explanations include the following: (1) disease
progression halts at some time point; (2) different
family members have milder disease at onset; (3)
differences reflect variable genetic penetrance; (4)
modifier genes may influence disease severity; or (5)
confounding factors, (eg, malnutrition, aspiration,
infection, or environmental exposures) may influ-
ence disease severity. Further efforts are underway
to identify the genetic defect. The progression of
disease is undetermined. The periodic evaluation of
the children by immune, radiographic, and pulmo-
nary function measures will provide a unique oppor-
tunity to follow disease progression.
In summary, we present a family with apparent
autosomal dominant pattern of ILD associated with
rheumatologic symptoms of alopecia, joint symp-
toms, and eczema, and evidence of B-cell activation.
This family highlights the importance of careful
evaluation for subclinical pulmonary disease in chil-
dren with rheumatologic disorders. Further investi-
gation into the genetic etiology underlying the lung
disease in this family may yield insights into the
pathogenesis of pediatric ILD and disorders of lym-
phocyte proliferation.
Appendix
None of the parents have been formally evaluated. All three
mothers deny respiratory or rheumatologic symptoms. The fa-
ther, who has declined formal medical evaluation, only admits
alopecia and eczema. He denies overt rheumatologic or respira-
tory symptoms, but family members suggest that he has limited
exercise tolerance with dyspnea on exertion. All of his known
children have been evaluated and are presented here (Fig 1).
Case studies are presented by age, with patient C being the
proband. None of the patients report significant environmental
exposures or travel.
Patient A
Patient A, a 15.5-year-old, African-American boy with no
significant medical history came to medical attention due to his
half-siblings illness. He reported alopecia totalis, eczema, con-
junctivitis, and dyspnea with minimal exertion but denied joint
pain. On examination, he was not tachypneic (20 breaths/min) or
hypoxic (oxygen saturation 98% on room air). Weight was 44.7 kg
(10th percentile), and height was 162.1 cm (25th percentile).
Physical examination revealed bald patches on his head and an
eczematous rash on his elbows. His conjunctiva were erythema-
tous and inflamed with a blue rim around the iris. His lungs were
clear to auscultation bilaterally without crackles, wheezes, or
rhonchi.
PFTs revealed normal spirometry and lung volumes with a
mild diffusion defect (Table 4). Chest CT scan showing multiple
noncalcified nodules in every lobe of the lung without interstitial
changes (Fig 2) was unchanged 6 months later. ESR, IgG, and
IgE were elevated, but RF was within normal limits (Table 2).
Lymphocyte subpopulation analysis revealed an expanded B-cell
line (Table 3). Flexible bronchoscopy revealed normal anatomy
CHEST / 132 / 1 / JULY, 2007 227
and negative bacterial, viral, and fungal culture results. The
patient underwent VATS lung biopsy. Pathology examination
revealed chronic bronchiolitis with follicular hyperplasia (Fig 3).
PCR findings on the lung biopsy for EBV and HHV-6 were
positive.
Patient B
Patient B, a 10-year-old, African-American girl with no signif-
icant previous medical history came to medical attention due to
her half-siblings illness. Her history was significant for alopecia,
eczema, and conjunctivitis. She had dyspnea with maximal
exertion but was not tachypneic (24 breaths/min) or hypoxic
(oxygen saturation 98% on room air). Weight was 32.9 kg (50th
percentile), and height was 147.4 cm (97th percentile). Her
conjunctiva were erythematous bilaterally. Her lungs were clear
to auscultation bilaterally without crackles, wheezes, or rhonchi.
PFTs revealed normal spirometry and lung volumes with
borderline diffusion abnormality initially (Table 4) and were not
changed at 6 months. Her chest CT scan showed ground-glass
opacities, blebs, and tree-in-bud opacities (Fig 2) and remained
unchanged at 6 months. ESR, IgG, IgA, and RF were elevated
(Table 2). Her lymphocyte subpopulation analysis revealed an
expanded B-cell line (Table 3).
Patient C
The proband, a 10-year-old, African-American girl with a
medical history significant for asthma and failure to thrive as an
infant presented to rheumatology clinic at 8 years of age with
joint pain, hair loss, and eczema. She was thought clinically to
have juvenile rheumatoid arthritis. However, her dramatically
elevated RF (Table 2) and chest CT scan findings (Fig 2) were
not consistent with typical juvenile rheumatoid arthritis. Chest
CT scan showed ground-glass opacities with subpleural cystic
changes (Fig 2; the first study used helical techniques with 5-mm
contiguous images and inspiratory high-resolution images).
She was referred for pulmonary evaluation, where she reported
dyspnea on exertion, chest tightness, and intermittent cough. She
was tachypneic (44 breaths/min) and mildly hypoxic (oxygen
saturation 94% on room air). Her weight of 22.6 kg (10th
percentile) was low in comparison to her height (130 cm, 50th
percentile). Pertinent findings on physical examination included
low lung volumes to percussion, bibasilar crackles, 3 clubbing,
hair loss, and an eczematous rash. A PFT revealed a nonspecific
ventilatory defect with a moderate diffusion defect (Table 4).
Chest CT scan showed diffuse subpleural cystic lesions and
tree-in-bud changes (Fig 2). Initial laboratory evaluation (elec-
trolytes, liver function tests, CBC with differential) was normal.
Her ESR and C-reactive protein were elevated, as were Igs
(Table 2). Her B-cell line was hyperexpanded (Table 3). Flexible
bronchoscopy revealed normal bronchial anatomy and negative
culture findings (bacterial, viral, and fungal). There were 40%
lipid-laden macrophages present in BAL fluid, but there was no
significant gastroesophageal reflux by pH probe. Echocardiogram
was normal. Tissue from VATS lung biopsy was consistent with
LIP (Fig 3). Treatment with oral steroids improved the extrapul-
monary symptoms (ie, joint pain) and the PFT results improved
mildly (Table 4), but the chest CT scan showed progression of
disease.
Patient D
Patient D, 9-year-old, African-American boy with no significant
medical history came to medical attention for symptoms similar
to his older sibling: alopecia, eczema, joint pain, and dyspnea with
228
activity. He was not tachypneic (22 breaths/min) or hypoxic
(oxygen saturation 96% on room air). He was reportedly always
small and thin, but weight was 24.1 kg (50th percentile) and
height was 129.5 cm (75th percentile). Physical findings included
complete loss of hair including eyebrows, an eczematous rash,
and mild clubbing. A lung examination was normal.
PFTs revealed a mild obstructive defect (Table 4). Chest CT
scan showed cystic changes with ground-glass opacities (Fig 2).
Laboratory evaluation revealed a microcytic anemia, elevated RF,
and elevated IgG and IgA (Table 2). Lymphocyte subpopulation
analysis revealed an expanded B-cell line with suppressed T-
suppressor cells (Table 3).
One year after initial evaluation, a dry cough and dyspnea with
activity developed. His weight had only increased by 1 lb. He had
new crackles on physical examination. PFTs showed a mild
obstructive defect with a mild diffusion abnormality (Table 4).
Repeat chest CT scan showed no radiographic evidence of
disease progression. Flexible bronchoscopy revealed normal
anatomy and negative bacterial, viral, and fungal culture results.
VATS lung biopsy demonstrated a chronic bronchiolitis with
follicular hyperplasia (Fig 3). Results by PCR on the lung tissue
were positive for parainfluenza 1.
Patient E
Patient E, a 6-year-old, African-American girl with no signifi-
cant medical history came to medical attention due to her
siblings illness. She had alopecia and eczema without joint pain.
She was not tachypneic (28 breaths/min) or hypoxic (oxygen
saturation 100% on room air). Weight was 18.3 kg (50th percen-
tile), and height was 115.8 cm (75th percentile). Pertinent
physical findings included patchy hair loss on her temples and an
eczematous rash. Lung examination was normal.
She was unable to perform PFTs. Chest CT scan showed
diffuse ground-glass opacities without cystic changes (Fig 2).
Laboratory evaluation revealed a microcytic anemia, elevated
ESR, and elevated IgA. RF was within normal limits (Table 2).
Lymphocyte subpopulation analysis revealed an expanded B-cell
line with a suppressed T-suppressor cell line (Table 3). She
remains asymptomatic and unable to perform PFTs.
Patient F
Patient F, a 4-year-old, African American girl with no signifi-
cant medical history came to medical attention due to her
siblings illness. She denied alopecia, eczema, joint pain, dyspnea,
cough, or wheeze. She was not tachypneic (20 breaths/min) or
hypoxic (oxygen saturation 100% on room air). Weight was 14.6
kg (50th percentile), and height was 96.3 cm (75th percentile).
Physical examination was normal. She was unable to perform
PFTs. Her chest CT scan was normal. Laboratory evaluation
revealed an elevated ESR. Her RF and lymphocyte subpopula-
tion analysis were within normal limits (Tables 2, 3).
Patient G
Patient G is a 16-month-old, African-American boy with a
history of failure to thrive and recurrent pneumonia. He was
hospitalized three times for bronchiolitis/pneumonia in the first
6 months of life. He had mild alopecia and eczema without joint
symptoms. His persistent symptoms and his siblings illness
prompted pulmonary evaluation. He was tachypneic (56 breaths/
min) and hypoxic (oxygen saturation 93% on room air). Weight
was 6.58 kg ( 3rd percentile), and height was 67.5 cm (50th
percentile). Physical examination demonstrated mild clubbing, an
eczematous rash, and hair loss on his scalp. He had subcostal and
substernal retractions. His lungs were coarse to auscultation with
poor aeration at the bases.
Original Research
 Infant PFTs showed a ventilatory defect based on forced flows
from tidal breathing (maximal flow at functional residual capacity,
50%; tidal volume, 77%). Forced flows were not obtained due to
tachypnea. Chest radiography showed minimal changes, but CT
scan showed ground-glass opacities with cystic changes more
prominent in the lower lobes (Fig 2; the first study used helical
techniques during quiet respirations in both decubitus positions,
1.25-mm sections at 15-mm intervals). Laboratory evaluation
revealed elevated ESR, IgG, IgM, and RF (Table 2). Lymphocyte
subpopulation analysis revealed an expanded B-cell line (Table
3). Flexible bronchoscopy was unremarkable, and culture find-
ings were negative. A pH probe showed no significant reflux. Due
to the severity of disease and lack of diagnosis, the patient
underwent VATS lung biopsy. The pathologic diagnosis revealed
severe follicular bronchiolitis with extension into the interstitium
in a LIP-like pattern. Approximately 1 year after presentation, the
patient had inadequate weight gain and remained tachypneic and
hypoxic. He underwent a 6-week trial of azithromycin without
improvement. Subsequent chest CT scan showed worsening
disease.
Patient H
Patient H is a 3-month-old, African American boy who was
born during the evaluation of his siblings. He did not have
alopecia, eczema, or joint pain. He had appropriate weight gain.
Physical examination was unremarkable. The mother reports no
symptoms in him similar to her affected children. His chest CT
scan showed no evidence of ILD. Because of his young age and
normal clinical examination, extensive laboratory evaluation has
not yet been performed.
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Original Research