Large multicenter study quantifies the flu season challenge to young transplant recipients.

Solid organ transplant (SOT) recipients are at higher risk of severe outcomes from influenza infection, due to both underlying comorbidities and the need for immunosuppression.

Adult studies have demonstrated this higher risk of morbidity and mortality, but pediatric populations have been understudied. Pediatric infectious disease physician Daniel Dulek, M.D., at Monroe Carell Jr. Children’s Hospital at Vanderbilt, led research on 10 years of data on influenza-associated hospital events (IAHEs) to understand the scope of influenza in pediatric SOT recipients.

“Previous studies have been small and have not had sufficient numbers of patients included to adequately define flu incidences,” Dulek said. “We wanted more tangible evidence to help physicians encourage vaccination, to guide clinical trials of newer regimens and dose formulations of flu vaccine, and to inform the use of early antiviral therapy for some of these kids.”

His study is the first to comprehensively define the incidence of and selected risk factors, including demographic characteristics, for IAHE in pediatric SOT recipients.

IAHE Defined

Dulek and his team used the Pediatric Health Information System and Scientific Registry of Transplant Recipients databases to determine the incidence of influenza-associated hospital encounters (IAHEs) in solid organ transplant recipients under age 18 who received transplants between 2006 and 2015. They tracked data over the three years following transplantation of a kidney, the most common, followed by liver, heart, lung and intestine transplants.

A single influenza-association hospital encounter was defined as a visit to the hospital where the transplantation took place, whether through an ED visit or an inpatient stay, and during which a diagnosis of influenza was made. An IAHE was classified as severe if the patient spent any time in the ICU or died in the hospital.

Rates and Severity

Of the 7,997 SOT recipients studied in the cohort, 511 experienced 573 episodes of IAHE over the three years, with 64 having severe IAHE. In 36 cases, the patient required mechanical ventilation, two patients had extracorporeal membrane oxygenation, and four died.  Accounting for competing risks, the overall cumulative three-year incidence of IAHE in the cohort was 7.3 percent, with a one-year IAHE incidence of 2.7 percent.

“These findings highlight the significant impact that influenza has on pediatric SOT recipients,” Dulek said. “They do not even capture episodes of influenza that do not require hospital evaluation or admission, nor did the study assess long-term impact of influenza on respiratory status or organ graft function.”

Parsing Subgroup Hazards

“We have known that lymphopenia, diabetes, recent transplantation and steroid therapy are associated with higher risks in adults, and that influenza vaccination and early antiviral therapy mitigate disease severity,” Dulek said. “In our pediatric study, we also found that age at transplant, race/ethnicity and organ type were all associated with risk for IAHE and severe IAHE.”

“In our pediatric study, we also found that age at transplant, race/ethnicity and organ type were all associated with risk for IAHE and severe IAHE.”

Age was a significant factor, with older children having fewer overall and fewer severe IAHEs. Further, the risk of IAHE was higher in non-Hispanic Black and Hispanic patients than in white patients.

Variations in incidence and severity among type of organ reached significance along some parameters, with kidney transplant recipients having the highest chance of having an IAHE. While heart and intestinal transplant recipients were not the most vulnerable to IAHE, when infected, their illnesses were the most severe.

Another sub-analysis looked at outcomes for those who received lymphocyte-depleting agents or IL-2 receptor antagonists at transplantation, with no associated hazard of either IAHE or severe IAHE found.

Vaccination and Anti-Virals

“Our study suggests a higher incidence of moderate to severe influenza illness in pediatric SOT transplants than has been  previously reported,” Dulek said. “We need to be particularly vigilant about improving messaging to parents of these vulnerable young people on getting vaccinated and avoiding influenza infection.”

 “Our study suggests a higher incidence of moderate to severe influenza illness in pediatric SOT transplants than has been  previously reported.”

Future Probes

Next steps for Dulek’s work include determining the impact of influenza antiviral use on patient outcome and probing the longer-term impact of influenza on transplant outcomes.

“Our finding that only 43.7 percent of those who had severe IAHEs received early antiviral therapy, compared with 57.4 percent of those with non-severe IAHE indicates a potential opportunity for improved influenza care,” he said.

Additional questions remain, he said, including whether a severe case of influenza raises the risk for other adverse outcomes related to transplant, like rejection.

“This work and these future objectives are in line with the strong history of  research we at Vanderbilt have done, and continue to do, in respiratory virus surveillance and pathogenesis, from influenza to RSV to COVID.”

About the Expert

Daniel E. Dulek, M.D.

Daniel E. Dulek, M.D., is an assistant professor of pediatrics and director of clinical services in pediatric infectious disease at Vanderbilt University Medical Center. He also serves as the medical director of the Peter F. Wright Immunocompromised Host Infectious Diseases Service at Monroe Carell Jr. Children’s Hospital at Vanderbilt. His research is focused on the epidemiology, treatment, and diagnosis of infections in transplant patients, with a special interest in immunogenetic prediction of infection risk.