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.