Johns Hopkins All Children’s Study Provides Answers — and New Questions — about Treating a Serious Infection Affecting Mostly Children
Over the last decade, there has been an expanding, national trend in medical education. Increasingly, those who receive their Doctor of Medicine degree (M.D.) are also getting doctorates (Ph.D.s) in research-related fields. The trend has become so strong that, after carrying out a study in 2018 that surveyed M.D./Ph.D. programs, the Association of American Medical Colleges (AAMC) noted that, “M.D./Ph.D.s are conducting research, developing new diagnostics, devices, and treatments, and helping train the next generation of scientists and clinicians.”
Following that study’s completion, AAMC president and CEO Darrell G. Kirch, M.D., said, “Physician-scientists play an essential role in academic medicine through innovative research and discovery, and by linking that new knowledge to clinical applications that can improve patient care and the health of our nation.”
The Johns Hopkins All Children’s Clinical and Translational Research Training (CTRT) Track, which marked its 10th anniversary this year, has played a pivotal role in training the next generation of clinical scientists focused on improving children’s health. In the program, trainees get applied, hands-on experience in designing, implementing, presenting, and publishing a clinical or translational research study, which means moving research from the laboratory to the bedside.
The goal is to mentor resident physicians, fellows and first- and second-year junior faculty on the path to successful independent clinical investigation in clinical and translational research in childhood health and disease.
Building upon the CTRT track, the Center for Pediatric Clinical and Translational Research Training, Education, Engagement and Mentorship in the Johns Hopkins All Children’s Institute for Clinical and Translational Research serves as a resource to those conducting studies and their team members for carrying out “best practices” when conducting clinical research.
John Morrison, M.D., Ph.D., an assistant professor of pediatrics at Johns Hopkins School of Medicine and a pediatric hospitalist in the Department of Medicine at Johns Hopkins All Children’s Hospital, serves as the Center’s director as well as the co-director of the CTRT Track.
“The Center provides new researchers with a complete understanding of the process for opening a scientific research protocol and instructs them on how to best conduct research,” Morrison says. “In addition, they gain a full understanding of the core services we have to support research and learn how and when to engage those services.”
The initiatives and programs developed under the Center include a training module on operationalizing Good Clinical Practice principals in pediatrics; a monthly seminar series in academic medicine that includes multiple topics in clinical and translational research; and a monthly interdisciplinary research forum that brings together fundamental (“basic”) biomedical scientists with clinical/translational researchers, data scientists and clinicians.
Why couple medical care and research?
“New discovery in medicine almost always leads to new questions,“ says Morrison. “Continuously asking the critical questions, persistently pursuing the answers, and relentlessly pursuing ever-better treatments and outcomes for children, are at the core of a pediaric academic medical center like Johns Hopkins All Children‘s, and what propels us forward in research.“
Orbital Cellulitis, Common in Young Children
A Johns Hopkins All Children’s study evaluating treatments for pediatric acute orbital cellulitis published recently in the prestigious journal Pediatrics (October 2021 issue) provides a great example of the impact that the CTRT track has achieved not only for the trainees in the program but for advancing the field of pediatric medicine.
Orbital cellulitis is a bacterial infection that causes fever and swelling around the eyes and eye sockets. In its acute stage, orbital cellulitis can cause vision loss, meningitis and abscesses in the sinuses. If caught early, it can be treated successfully in the hospital with antibiotics. But if the infection progresses, admission to intensive care and surgery to clear the infection may be required.
In addition to treatment with antibiotics, some physicians have used corticosteroids to reduce the inflammation associated with acute orbital cellulitis. However, few studies have evaluated whether steroids are beneficial.
What Did Data from Past Studies Suggest?
Two faculty-mentors in the CTRT Track, Morrison and critical care medicine physician Anthony Sochet, M.D., MHSc, along with Maria Leszczynska, M.D., a 2019 graduate of the Johns Hopkins All Children’s pediatric residency program who was in her second year of residency when the project began, were instrumental in designing and conducting the study that aimed to define the best treatments for acute orbital cellulitis. They started by assessing the current state of the evidence.
“Data from past studies suggested that a combination of antibiotics and corticosteroids may reduce fever, pain, swelling and impaired ocular mobility of children hospitalized with orbital cellulitis,” explains Morrison. “We wanted to determine whether administering corticosteroids along with standard antibiotics made a difference in the length of time that a child was hospitalized (also called “hospital length of stay”). We also wanted to determine whether there was a relationship between the administration of corticosteroids and whether a child underwent surgical interventions, admissions to the pediatric intensive care unit (PICU), or hospital readmissions within 30 days of discharge.”
Previous studies on orbital cellulitis treatment generally included a small number of children and did not compare outcomes between patients who received antibiotics alone and those treated with both antibiotics and corticosteroids.
To achieve their goals for a direct comparison among a large number of children, the researchers used the national Pediatric Health Information System (PHIS) registry database, which included 5,645 children under the age of 18 treated for orbital cellulitis from 2007 to 2018 across 51 children’s hospitals. Among these, 1,347 were treated using both antibiotics and corticosteroids.
What Did the New Data Show?
The researchers found that a greater proportion of patients who were prescribed corticosteroids had more complicated cases, as compared with those who were not prescribed corticosteroids. Many of these complicated cases involved abscesses, which can be dangerous given the location in close proximity to the brain. They also found great variability in the usage of corticosteroids as part of the treatment regimen for orbital cellulitis across hospitals participating nationally in the PHIS registry.
Their analyses revealed no association between corticosteroid administration and hospital length of stay.
“Our study also showed that the prescription of corticosteroids was associated with a greater likelihood of requiring readmission to the hospital or care in the emergency department within 30 days of discharge,” observes Morrison. “What we don’t know is why, since association is not causality. One explanation for our findings is that patients who were prescribed corticosteroids may have been a sicker population at presentation of illness than those who were not prescribed corticosteroids. An alternative explanation is that the corticosteroid therapy itself compromised the effectiveness of antibiotic treatment.”
“One of the proposed benefits of administering corticosteroids is reduced inflammation, which may expedite recovery and hospital discharge,” explains Morrison. “But physicians may hesitate to administer them out of concern for immune suppression, which could inhibit resolution of the infection or lead to infection spreading.”
In order to answer the new questions raised by this research, and determine whether the association between corticosteroids and outcomes is causal or instead represents a “selection bias“ in the treatment of patients with more severe illness, a randomized clinical trial would be necessary. Much like the PHIS registry, this type of clinical trial in children would likely require collaboration across multiple children’s hospitals. Johns Hopkins All Children’s not only participates in the PHIS registry, but also in numerous national clinical trial consortia and cooperative groups. In recent years, Johns Hopkins All Children‘s has also led several multicenter studies nationally or multinationally focused on treatments and outcomes in a variety of pediatric diseases.
Whether it‘s in the journal Pediatrics or other esteemed journals, the hospital continually strives to disseminate the findings of research led at Johns Hopkins All Children’s through impactful publications in the medical and scientific literature, in order to advance knowledge and ultimately improve children’s health far beyond the welcoming doors of our hospital.
In addition to Morrison, Sochet and Leszczynska, Ahh Thy H. Nguyen, MSPH, and Jazmine Mateus, M.P.H., also contributed to designing and carrying out the study.