Differentiating Sepsis From Adverse Events After Immunization in the Neonatal Intensive Care Unit: How Is a Physician to Know?

In this issueof JAMAPediatrics,DeMeoet al1 report on the incidenceofadverseeffectsafter immunizationofextremely lowbirth-weight (ELBW) infants in theneonatal intensivecareunit (NICU). They report that there is an increase in the incidence of sepsis evaluations, respiratory support, and intubation after immunization. The findings of this study confirmwhat anumber of other retrospective studies have found—that ELBW infants appear to have an increase in cardiorespiratory events after vaccination.Themain strengthof this studyandwhatmakes it unique is its large sample size of infants born at less than 28 weeks’ gestation, including those born at the most premature ages (ie, gestational ages [GAs] of 23-24 weeks). This study’s large size further allowed evaluation of single antigen vs combination vaccines, with the authors concluding that therewas no difference in the incidence of adverse events after varying vaccine types. This finding should provide some reassurances to neonatologists and parents. Although this retrospective study clearly reveals an increase inadverseeventsafter immunization,an importantconsideration is that thepostimmunization increasemaynot fully reflect the true incidenceofpostimmunizationadverseevents. Rather, becausephysiciansoftenwait tovaccinate infantsperceived to be at risk for a vaccine-related adverse event until infants arewithout any events for a specified period, the preimmunization rates of adverse events may have been artificially lowbecauseof the selective immunizationof ahealthier population. The rates thereforemay not have been representative of the normal variation with which such events occur in this population. The figure in the article byDeMeoet al supports this bias because it clearly shows that the incidence rates of sepsis evaluations, increased respiratory support, and intubationshadreachedanadirat the timeof immunization.This phenomenon iswell known in vaccine safety studies2,3 as the healthyvaccineeeffect,wherebyvaccination isassociatedwith an apparent greater increase in postimmunization adverse events than would otherwise be expected because of the selective immunizations of a healthier population. With this inmind, the challenge is howphysicians canuse this information in the management of preterm infants after immunization. The findingof increased septic evaluations after immunizations highlights that in preterm infants, physicians have a low threshold for initiating a sepsis evaluation. More than 4 times as many sepsis evaluations were performed in thepostimmunizationperiod (n=1035) than thepreimmunization period (n = 235). Were these additional evaluations needed? Common adverse events of immunizations in ELBW infants, such as fever and increased cardiorespiratory events, are usually transient and non–life-threatening. Perhaps what we need is to alter our response to these adverse events.Asdiscussedabove, infants in the studyhadadecreasing incidence of sepsis evaluations and need for increased respiratory support in the days preceding immunization. What this probably alsomeans is that the infantswere at low risk for sepsis. Infants had no signs or symptoms of sepsis. Infants in the studywere at least 53 days old,making it reasonable to assume that most no longer required a central catheter for nutrition, a leading risk factor for late-onset sepsis in ELBW infants. Given the low prior probability of sepsis,4 the development of nonspecific symptoms after immunizations probably does not alter the posterior probability of sepsis significantly because these symptoms could be attributed to the immunizations themselves. This largestudyraises furtherquestions regarding the typical fever response to immunizations in ELBW infants. This study limited sepsis evaluation analyses to physician responses and did not contain detailed descriptions of the postimmunizationfever response.Atemperature to39°C2days after immunizationmay bemore concerning for sepsis than a temperature of 38°C 6 hours after an immunization. Furthermore, theremaybe somedifferences in responses to the same adverse effect(s), depending on the medical center or physician. Some NICUs routinely prescribe acetaminophen for 24 hours after immunizationswith theperceivedbenefit of eliminating low-grade fevers. Do these NICUs have lower rates of sepsis evaluations after immunizations? Future studies describing information suchas thepercentageof infantswhodeveloped fever, the timing of the fever in relation to the immunization, and themaximumtemperaturewill help physicians discriminate between transient minor adverse effects of immunizations and early signs of sepsis. Of some concernwas this study’s surprising finding of an increased incidenceofpositivebloodculture results after vaccination (5 [2.1%] of 235 positive blood culture results before the immunization period and 39 [3.8%] of 1035 positive blood culture results after the immunization period). Onemight expect that more cultures were performed based on nonspecific symptoms potentially attributable to immunizations, Related article page 740 Opinion