DISCUSSION:
This U.S. National Registry for
ChILD provides a large cohort of subjects poised to support a broad
scope of ongoing and future studies. In contrast to prior publications
from the chILDRN, the scope of the Registry differs in that
ascertainment is prospective, does not require lung biopsy, and does not
require definitive diagnosis prior to enrollment, thus including the
full spectrum of chILD cases. IRB reliance and data sharing provide
robust infrastructure and feasibility for future detailed analyses of
specific disease subtypes and planning for clinical trials.
International registries for rare lung diseases in children have
developed in recent years, enabling cohort identification and providing
valuable data including disease prevalence, morbidity, and healthcare
utilization in certain countries1-3. While here we
report the largest prospective cohort to date in the U.S., the study was
not designed to capture incidence or prevalence data for patients in a
controlled manner. Approximately two-thirds of subjects have been
enrolled from five centers. Because study enrollment is currently
dependent on the availability of internal resources to screen and
identify eligible subjects, administer informed consent, and enter study
data, we cannot conclude whether the distribution of subjects reflects
disease prevalence at U.S. centers based on regional population,
referral patterns, or other factors. The participating sites were
self-selected and represent an extensive but incomplete geographic
distribution, with fewer centers from the southern and western U.S. The
distribution of race and ethnicity as reported in the Registry is
similar to the 2020 U.S. Census Data, though direct comparison is
limited as the Registry allows for selection of “unknown or not
reported” for both race and ethnicity.19 Additional
centers have subsequently indicated interest to join the Registry, and
the goal is to further expand participation. Interestingly, our cohort
recruitment occurred primarily in the outpatient pediatric pulmonology
setting at most sites, with fewer subjects than expected with infant
disorders, likely reflecting limited enrollment through neonatal or
pediatric intensive care units. This primarily outpatient enrollment
pattern may also have resulted in an underestimation of mortality. While
the chILDRN has always been a multidisciplinary network from its
inception, we think it will be important to continue to expand registry
enrollment referrals from neonatologists, critical care physicians,
geneticists, radiologists, and pathologists, as well as other
subspecialists such as rheumatologists, immunologists, and oncologists,
who see substantial numbers of infants and children with or at-risk for
chILD.
For the U.S. Registry, subjects could be enrolled with clinically
suspected chILD without a specific diagnosis, whether due to ongoing
clinical evaluations or currently unclassifiable findings. This subgroup
reflects an important clinical and scientific challenge and an
opportunity to improve care for children with diffuse lung disease.
While prior studies have classified subjects by specific diagnosis or
diagnosis category, this registry additionally invited designation of
the suspected underlying disease process(es) (e.g., interstitial
fibrosis, airway disease, immune-mediated), enabling a framework for
therapy and research in the absence of specific diagnosis. While
advances in defining the molecular basis of chILD hold great promise for
precision medicine, we also anticipate that approaches which focus on
the common biologic processes involved in chILD will continue to be
useful for future clinical trials.20,21
The utilization of lung biopsy and genetic testing varied for different
types of disorders, reflecting evolving understanding of the
pathophysiology and genetic mechanisms of different diseases.
Importantly, the accessibility of different genetic testing options has
changed considerably over the more than 20-year period during which
these children were diagnosed and enrolled, and practice patterns of
genetic testing continue to change rapidly. More than one-half of
Registry subjects have had some type of genetic testing, including
single gene testing, gene panels, karyotype analysis, chromosomal
microarray, exome, or genome sequencing. Our current data do not capture
clinical rationale for selected genetic testing, including impacts of
insurance approval, turn-around-time, or patient/family preferences,
which are all important areas for future study. Many sites found it
challenging to locate genetic testing results in the electronic medical
record, as results may come from clinical laboratories outside the
site’s hospital system. Further, we found variable accuracy of the
genetic information entered by sites such as incorrect data
transcription or misinterpretation of the clinical implication of the
genetic testing results. A future direction for the registry will be to
utilize a genetic counselor or clinical geneticist to review the primary
documentation of genetic testing results to enable collection of more
detailed genetic testing results and facilitate central
reclassification, when appropriate. These expanded workflows will become
increasingly important as we anticipate that the increased use of exome
and genome sequencing will lead to identification of new chILD disorders
and could avoid the need for lung biopsy for some children.
Through ongoing longitudinal data collection, the U.S. National Registry
for ChILD provides exciting opportunities for future clinical research.
Additional studies are already underway to evaluate radiologic, genetic,
and histopathologic disease features and correlations. As participating
centers proceed with longitudinal data collection, the Registry will
enable future analysis of natural history, treatment approaches, and
outcome measures in chILD. The Registry will also facilitate clinical
trials through identification of cohorts of subjects with specific
diagnoses or disease processes. Further, evaluation of quality of life,
comorbidities, and clinical practice patterns will be important to
optimize supportive care for affected children and their families.
Alignment with recent international efforts1-3 will
expand these opportunities. As information about chILD disorders
continues to grow through clinical, translational, and basic science
research as well as efforts to expand the U.S. National Registry
enrollment, we look forward to ongoing collaboration with the global
pulmonary scientific community to better understand these rare diseases
and improve the care of affected children and their families.