A Look at the Potential of Precision Medicine for Pediatric Respiratory Diseases

A session presented at this year’s American Thoracic Society (ATS) virtual conference focused on the feasibility and potential for precision medicine in pediatric respiratory diseases, emphasizing progress made via genome-wide association studies (GWAS). However, several barriers remain when it comes to cost and early screening initiatives.

For childhood asthma in particular, Anke H Maitland-van der Zee, PharmD, PhD, a professor of precision medicine at the Academic Medical Center in Amsterdam, the Netherlands, outlined recent research attempting to identify adolescents who would most benefit from either personalized care (genotype-directed prescribing) vs standard care. In the study discussed, all participants were between ages 12 and 18.

Patients that were genotyped received montelukast while those undergoing standard care received a long-acting beta agonist (LABA). Analyses showed patients who received individualized care had a better quality of life, which was a score of 0.16 on the pediatric quality of life questionnaire. “It has to be emphasized that the clinical threshold was 0.25, so it's lower than that, but after 12 months [genotyped patients] seem to be a little bit better off,” Maitland-van der Zee said.

In patients carrying homozygous variants, this effect was more pronounced, marking a sign “it’s probably useful to determine this treatment according to [patients’] genotype,” she noted. A similar trial that will include children ages 6 to 18 aims to provide a clearer answer to this question and is slated to take place in the coming years.

In addition to GWAS, another route for potential precision medicine in this population could involve using exhaled breath to assess volatile organic compounds in patients’ lungs. One study on this subject showed “that if you use a cluster approach, it is possible to identify 5 different clusters of pediatric asthma patients by looking at their exhaled breath.”

Comparing the clinical characteristics of these patients revealed differences in age group, amount of asthma control, and quality of life. “Exhaled breath tells you something about the inflammatory phenotype or the asthma phenotype in patients,” Maitland-van der Zee explained.

Similarly, researchers in the United Kingdom, by looking at exhaled breath, were able to develop a sensor technology to identify patients that were or were not negative for a skin prick test—a test that checks for immediate allergic reactions to different substances. These results again illustrated the use of exhaled breath to help phenotype patients.

According to Maitland-van der Zee, future priorities in this area include better phenotyping of patients—potentially by combining biomarkers—identifying treatable traits and non-invasive biomarkers, and facilitating early detection. New developments in e-health may also help providers measure these factors remotely.

Following talks on the promise of precision medicine in this field, Ann Chen Wu, MD, MOH, an associate professor in the department of population medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, laid out some of the cost effectiveness and ethical issues linked to precision medicine. Chen is also the director of the Center for Healthcare Research in Pediatrics and Precision Medicine Translational Research Center at Harvard Medical School.

A joint statement issued by ATS and the National Heart, Lung, and Blood Institute several years ago concluded “precision medicine had more value in lung diseases because of the introduction of biologics,” Chen explained. Currently, newer biologics are directed towards 10% to 15% of patients with severe, persistent asthma among those with asthma.

However, biologics can cost between $30,000 and $40,000 per patient and have to be administered in a hospital setting. But the use of precision medicine in this field “could help allocate use of biologics to those who need it and would benefit from it the most,” Chen said.

Although precision medicine holds potential, a lack of data on minority populations with respiratory diseases precludes ensuring it is generalizable to diverse real-life populations. “Addressing questions about the impact of genetic factors on therapeutic drug response in globally diverse populations is essential for making precision medicine socially and scientifically precise,” she said.

In addition, no studies currently exist that focus exclusively on cost effectiveness of precision medicine for lung diseases. Using a general example of genomic sequencing in newborns, Chen detailed the unintended positive and negative consequences of genomic testing, including:

• Diagnoses in children could lead to family member diagnoses
• Earlier medical diagnoses and treatment could lead to better outcomes
• Whole genome sequencing could lead to increased health-care expenditures without substantial clinical benefits, as inconclusive results may lead to additional testing and a “diagnostic odyssey”

Notably, “systematic reviews of psychological outcomes of single gene and multi-gene testing suggests that the test disclosure does not cause depression or anxiety, as some people have worried,” she said.

Given all the potential benefits and costs, better assessments of the value of genomic sequencing for newborns are warranted. But this will require a very large sample size, a long time horizon, and will be expensive.

As observational data and computational modeling approaches provide an alternative to such studies, Chen and other researchers developed a model to estimate the cost effectiveness of integrating various genomic sequencing strategies into clinical care.

One version of the model focused on pediatric cancer and included a panel of 11 genes. It showed that “among children with the cancer risk variant found on newborn screening, subsequent surveillance and care would reduce cancer deaths before age 20 by half, as compared with no screening or usual care.”

Chen continued “we calculated that universal screening would cost $244,000 per life year gained at a cost of $55 per test. We concluded that population-based genetic testing of newborns can reduce mortality associated with pediatric cancers and could potentially be cost effective as sequencing costs decline.”

If cost effectiveness is determined for lung diseases, policy makers and insurers can decide whether to cover the cost of the test, while as new findings of genetic variants or genes are found, their interpretation can change. “For example, one variant that was thought to be associated with a disease could have a new benign interpretation,” Chen said. This scenario poses another challenge as it is still unknown, ethnically, how much time should be allocated to communicate updated information to patients or whose job it is to inform patients of these changes in interpretation.

“Precision medicine for pediatric lung disease has great potential, but we have a long way to go,” Chen concluded. “Assessing cost effectiveness, generalizability to diverse populations, and the ethical considerations will increase likelihood of translation to clinical practice.”