Introduction
Childhood interstitial lung disease (chILD), also referred to as diffuse
lung disease (DLD), is a heterogenous group of disorders with
overlapping clinical, radiographic, and pathologic characteristics.
While chILD is considered rare, the incidence and prevalence are not
well established.1 Over the past 30 years, the scope
of the field has expanded through recognition of specific disease
entities. For example, surfactant protein B deficiency was first
described in the early 1990’s,2 with reports ofSFTPC and ABCA3 mutations as causes of chILD in 2001 and
2005, respectively,3; 4 followed by the definite
description of Neuroendocrine cell Hyperplasia of Infancy (NEHI) in
2005.5 After development of consensus terminology and
lung biopsy classification, the first clinical practice guideline was
published in 2013.6-8 Further advances in molecular
genetics and imaging technology have subsequently modified the
diagnostic approach, though limited data are available on the clinical
utility of genetic testing for chILD.
In 2012, a revision to the International Classification of Diseases
(ICD) Ninth Revision added codes for several chILD disorders under an
umbrella diagnosis of “Other alveolar and parietoalveolar
pneumonopathy”, which included code for surfactant mutations of the
lung, NEHI, and other interstitial lung diseases of
childhood.9 The currently utilized tenth revision of
ICD codes expanded the codes for systemic disease associated with
pulmonary manifestations10. Billing codes have not
previously been utilized as a case ascertainment method for research in
chILD.
In this study, we sought to evaluate recent practices at a tertiary care
medical center to better understand chILD prevalence, care patterns,
healthcare utilization, and outcomes. We identified diagnostic
challenges and found substantial inpatient and multidisciplinary
outpatient care utilization. By highlighting the scope of this patient
population and associated care needs, this knowledge can be leveraged to
inform healthcare delivery in the future.
Methods
Study population
A single-center, retrospective cohort study of patients receiving care
at the Children’s Hospital of Philadelphia (CHOP) was performed. This
study was granted exempt approval with waiver of informed consent from
the CHOP Institutional Review Board (IRB 19-016269). Patients were
identified based on a query of selected ICD-10 billing codes
(Supplemental Table 1 ) relevant for chILD/DLD. Medical records
were then reviewed for patients who had either outpatient or inpatient
pulmonary encounters between January 1, 2019, and December 31, 2021,
curating cases for inclusion after chart review to confirm ILD/DLD
diagnosis. Data collection included EMR data through September 28, 2022,
allowing time for diagnostic testing and clinical follow up after
initial evaluations.
Study design and data collection
Outpatient and inpatient encounters, medication exposure data, and
procedural history were obtained via electronic medical record (EMR)
reports developed for this study. Supplemental chart review was
performed, focused on assessment of diagnostic testing performed outside
of CHOP and characterization of disease severity and outcomes. Study
data were collected and managed using Research Electronic Data Capture
electronic data capture tools hosted at CHOP.11; 12Disease categories or classification were designated by the study team
based on the aggregate of available clinical data, genetic testing,
imaging, and lung biopsy reports in the EMR.
Statistical analysis
We analyzed EMR data based on lifetime to date and the time period
between 2019-2021. Descriptive statistics were utilized, with reporting
of means and standard deviations (SD) for continuous variables and
frequencies and percentages for categorical variables.
Results
Patient demographics and clinical characteristics
Through ICD-10 billing diagnoses, a total of 306 patients were
identified as receiving care during this 3-year period. Demographic
characteristics are summarized in Table 1 . A slight majority
(55%) of patients were male, and 77.1% were born as a result of
full-term (≥ 37 weeks) pregnancies. More than half (56.2%) of the
cohort identified as white race and two-thirds (66.7%) had private
insurance, in comparison to white race for 53.3% and private insurance
for 52.4% among all patients seen with outpatient encounters in the
Division of Pulmonary and Sleep at CHOP during the same time period. For
those patients with a documented age of onset of respiratory symptoms
(n=231), 40.7% had respiratory symptom onset in the first two years of
life, with 30.3% developing symptoms before six months of age. The
onset of respiratory symptoms was not documented in the EMR for 24.5%
of the cohort. Overall, 70 (22.9%) patients were referred for a second
opinion after seeing a pulmonologist at another institution.
Distribution of ILD diagnoses
DLD associated with oncologic disorders was the most common diagnostic
category, accounting for 65 (21.2%) cases (Table 2 ). We also
identified cases of bronchiolitis obliterans (n=31, 10.1%), DLD
associated with connective tissue diseases (n=29, 9.5%), NEHI (n=28,
9.2%), environmental/toxic related lung injury (n=27, 8.8%), and
alveolar hemorrhage disorders (n=23, 7.5%). Surfactant metabolic
dysfunction was responsible for 19 cases (6.2%), while 15 cases (4.9%)
had DLD associated with immune-related disorders. There were multiple
other diagnoses for which three or fewer patients were identified
(Supplemental Table 2 ). For 32 cases (10.5% of the cohort), a
definitive diagnosis or classification could not be assigned based on
EMR data. The overall cohort mean age at time of diagnosis was 7.3 years
(SD 6 years).
Diagnostic testing and monitoring
Almost all patients (92.2%) had chest computed tomography (CT) scans,
with 220 (71.9%) patients having at least one chest CT between
2019-2021. Flexible bronchoscopy was performed in 97 (31.7%) patients
ever in their lifetime, with procedures in 73 (23.9%) patients during
the recent 3-year period. Echocardiography was performed in 195 patients
(63.7%) ever in their lifetime and half (n=153, 50%) of patients
during the 3-year period, with a mean of 2.1 (SD 2.7) procedures per
patient per year.
Lung tissue sampling was performed in 110 (35.9%) patients in a variety
of contexts (Figure 1A ), with 72 (65.5%) patients having the
procedure at our center at a mean age of 7.6 years (SD 6.3 years).
Fifty-two (72.2%) patients had a wedge biopsy. In addition, there were
13 transbronchial biopsies, six lung nodule biopsies, three
endobronchial ultrasound with transbronchial needle aspiration
procedures, two lobectomies, two bronchial biopsies, two core needle
biopsies, and one endobronchial mass excisional biopsy. Of the 23
patients identified with alveolar hemorrhage, most (n=20, 87%)
underwent lung biopsy, resulting in histologic diagnosis of capillaritis
in 50%. Over half (52.6%) of patients ultimately diagnosed
with surfactant metabolic dysfunction underwent lung biopsy. Notably, 45
(40.1%) patients had a lung biopsy performed at an outside institution;
seven of these patients subsequently had a lung biopsy repeated at our
center.
In total, 149 (48.7%) patients underwent genetic testing relevant for
their lung disease evaluation (Figure 1B ), and 38 (25.5%) of
tested patients had a diagnosis established by genetic testing
(Figure 2). Alterations in genes impacting surfactant
metabolism dysfunction accounted for 50% of positive results. CHOP
providers ordered the testing for 22 (57.9%) of positive results.
The 76-gene CHOP Comprehensive
Pulmonary-Vascular Panel was performed for 41 cases and yielded positive
results in four cases. Two patients were found to be compound
heterozygous for variants in ABCA3 , one patient was found to be
heterozygous for a de novo pathogenic variant in SFTPC ,
and one patient was heterozygous for a pathogenic deletion within
chromosome 14q12, which includes the NKX2.1 gene. CHOP providers
ordered other respiratory relevant genetic analyses in 61 patients,
including single gene testing/targeted variant testing and targeted
pulmonary gene panels for 47 patients, 14 of which resulted in a
molecular diagnosis. Chromosomal microarray analyses were performed in
21 patients, all of which were non-diagnostic. Respiratory-relevant
genetic testing was performed prior to referral to our center in 41
patients, with molecular diagnosis established by single gene
testing/targeted variant testing and targeted pulmonary gene panels for
14 (37.8%) of 37 patients.
Whole exome sequencing (WES) was performed in 58 (38.9%) patients, was
ordered by CHOP providers in 42 (72.4%) instances and was diagnostic
for six (10.3%) patients. Positive findings resulted in diagnoses of
CHOPS syndrome (n=2), ataxia telangiectasia (n=2), lysosomal storage
disease (n=1), and one diagnosis of an immune-related disorder
(STAT1 gain-of-function variant). Two of the patients diagnosed
through WES also had non-diagnostic targeted pulmonary gene panels,
including one patient with CHOPS syndrome and one with lysosomal storage
disease (GM1 gangliosidosis).
In examining the diagnostic categories of patients who underwent genetic
testing within the overall cohort, NEHI made up the largest group (n=21,
14.1%), followed by those with ILD not otherwise specified (NOS) (n=19,
12.8%), surfactant metabolic dysfunction (n=18, 12.1%), DLD associated
with connective tissue disorders (n=16, 10.7%), and bronchiolitis
obliterans (n=14, 9.4%). Patients with surfactant metabolic dysfunction
and those ILD NOS were among those most likely to have undergone genetic
testing (94.7% and 82.6%, respectively, Figure 1B ).
Both genetic testing and lung biopsy were performed in 63 (20.6%)
unique patients. Those with alveolar hemorrhage disorders were the
largest subgroup (n=12, 19.0%), followed by nine (14.3%) patients with
DLD associated with connective tissue disease and seven (11.1%)
patients with surfactant metabolic dysfunction. We analyzed the time
order of testing for the 20 patients who had the CHOP Comprehensive
Pulmonary-Vascular Panel and lung biopsy performed, as we could confirm
the order timing within our institution. Eleven patients had lung biopsy
performed prior to genetic testing, while eight had genetic testing
performed first. One patient had lung biopsy performed on the same day
that genetic testing was initiated. Ultimately, six patients who had a
lung biopsy later had a genetic diagnosis established.
Outpatient care utilization
Within this cohort, nearly all patients (96.1%) received outpatient
pulmonary care at our center. A mean of 2.8 (SD 2.6) outpatient
pulmonary visits per patient per year occurred between 2019-2021.
Cardiology, endocrinology, and gastroenterology were other highly
utilized medical subspecialties (Figure 3 ). At our center, more
patients had encounters with nutrition and physical therapy than with
speech and language pathology or occupational therapy.
Hospitalizations
We quantified the hospitalization events using EMR data for hospital
days at CHOP both for lifetime to date and for the 3-year period from
2019-2021. In their lifetime, 246 (80.4%) patients had ever been
hospitalized at CHOP, while nearly half (n=138, 45.1%) had ever been
hospitalized in an intensive care unit (ICU). Between 2019-2021, 176
(57.5%) patients were hospitalized, with a mean of 42.1 (SD 80.6)
hospital days and 3.1 (SD 3.5) hospitalizations per hospitalized
patient. ICU admission occurred in 82 patients, reflecting 26.8% of all
chILD patients and 46.6% of the hospitalized chILD patients, and
accounting for a mean of 38.4 (SD 93.2) ICU days and 1.8 (SD 1.9) ICU
hospitalizations per ICU hospitalized patient. When considering
hospitalization burden across the entire cohort, the mean number of
hospitalization events per patient was 1.8 (SD 3.0) during this 3-year
period, with 0.5 (SD 1.3) ICU hospitalization events per patient.
In examining hospitalization data based on diagnostic category from
2019-2021, the largest group of hospitalized patients was DLD associated
with oncologic disorders (n=34, 19.3%). Other groups of patients who
accounted for the most hospitalizations were patients with
environmental/toxic related lung disease (n=26, 14.8%), bronchiolitis
obliterans (n=16, 9.1%), alveolar hemorrhage disorders (n=16, 9.1%),
and DLD associated with connective tissue disease (n=19, 10.8%). Within
each of these disease categories, most patients were hospitalized at
least once in their lifetime (Figure 4A ). Between 2019-2021,
the percentage of ICU hospitalization by disease category was greatest
for patients with surfactant metabolic dysfunction (42.1%), alveolar
hemorrhage disorders (30.4%), and DLD associated with oncologic
disorders (27.7%) (Figure 4B ).
Medication utilization
Medication exposure most relevant for treatment of chILD/DLD was
examined. Due to the EMR driven, retrospective methodology of our study,
medication exposure was defined as documentation of an inpatient order
or presence of medication on the medication list associated with an
outpatient encounter. In examining lifetime exposure, 78% of patients
had some form of oral and/or intravenous corticosteroid ever prescribed,
and 57% were prescribed intravenous corticosteroids
(methylprednisolone). Between the years of 2019 and 2021, 10.5% of
patients were prescribed intravenous corticosteroids, while 29.4% had
oral and/or intravenous corticosteroids prescribed.
Hydroxychloroquine was prescribed for 10.5% (n=32) of the overall
cohort across their lifetime, with 7.8% (n=24) of the cohort receiving
hydroxychloroquine between 2019 and 2021 at a mean age of 10.6 years (SD
6.4) at the time of the first prescription. The most frequent underlying
diagnoses for patients prescribed hydroxychloroquine were surfactant
metabolic dysfunction (n=11, 45.8%) and DLD associated with connective
tissue disease (n=7, 29.2%). Pirfenidone was prescribed for eight
(2.6%) patients, including three with DLD associated with oncologic
disease, two with DLD associated with connective tissue disease, and one
each with bronchiolitis obliterans, surfactant metabolic dysfunction,
and fibrotic lung disease of unknown etiology.
Respiratory support and Outcomes
In the overall cohort, 32.7% had ever required chronic home
supplemental oxygen, 12.4% had ever received chronic non-invasive
respiratory support, and 4.6% underwent tracheostomy for chronic
invasive respiratory support. The mean age at time of tracheostomy
placement was 4.8 (SD 6.1) years. Chronic supplemental oxygen use was
prevalent in patients with NEHI, accounting for 24% of the group with
home supplemental oxygen use in general.
Of the 306 patients seen between 2019-2021, seven (2.2%) patients had
died as of January 1, 2022, including four with DLD associated with
oncologic disorders, one with DLD associated with connective tissue
disease (juvenile dermatomyositis with pulmonary involvement), one with
surfactant metabolic dysfunction (SFTPC ), and one with DLD
associated with immune-related disorders (severe combined
immunodeficiency disease). Five deaths were to due respiratory failure,
while in two patients cause of death was not documented. Pulmonary
fibrosis was associated with mortality in four patients, including the
one with connective tissue disease (juvenile dermatomyositis), one with
ILD due to SFTPC , and two with prior history of oncologic
disease. Further, thirteen patients underwent lung transplantation
including four patients with surfactant metabolic dysfunction, three
with DLD associated with oncologic disorders, two with vascular disease
not otherwise specified, and one each with alveolar capillary dysplasia,
bronchiolitis obliterans, pulmonary capillary hemangiomatosis, and ILD
of unknown etiology. The four patients with surfactant metabolic
dysfunction who underwent lung transplant included two patients
heterozygous for variants in ABCA3 , and two patients with
surfactant protein C associated ILD. Two other patients were listed for
lung transplant, and one was awaiting combined heart/lung transplant.