Fever Without Localizing Signs

Children <3 Months

The risk of SBI varies with age. Although longitudinal studies have shown that only 1%–2% of children are brought to medical attention for fever during the first 3 months of life, a greater proportion of febrile infants have SBIs than older children. Risk is greatest during the immediate neonatal period and through the first month of life (and is heightened in the infant born prematurely).

In a prospective study conducted at the University of Rochester, researchers identified factors associated with a low risk of SBI in febrile infants <3 months. Among 233 infants who were born at term with no perinatal complications or underlying diseases who had not received antibiotics and who were hospitalized for fever and possible septicemia, 144 (62%) were considered unlikely to have an SBI and fulfilled all of the following criteria: no clinical evidence of infection of the ear, skin, bones, or joints; white blood cell (WBC) count between 5000 and 15,000/μL; <1500 band cells/μL; and normal urinalysis results. Only 1 (0.7%) of the 144 infants had an SBI (i.e., Salmonella gastroenteritis), and none had bacteremia. In contrast, among the 89 infants who did not meet these criteria, 22 (25%) had an SBI ( P < .0001) and 9 (10%) had bacteremia ( P < .0005).

Many studies largely have corroborated the results of the Rochester study. ^{, ,} Although investigators have used slightly different criteria to define young febrile infants at low risk of SBI (and some investigators excluded children <1 month), all found that the risk of a serious bacterial illness in the group defined as being at low risk is, indeed, very low. Approximately 10% of these infants have UTI, largely due to E. coli , and 10% with UTI (1% overall) have concomitant bacteremia or meningitis. ^{, ,}

In a meta-analysis of studies of febrile children <3 months, the risks of “serious bacterial illness,” bacteremia, and meningitis were 24.3%, 12.8%, and 3.9%, respectively, in “high-risk” infants and 2.6%, 1.3%, and 0.6%, respectively, in “low-risk” infants. The negative predictive value for serious bacterial illnesses of infants fulfilling low-risk criteria ranged from 95% to 99% (and was 99% for bacteremia and 99.5% for meningitis). Although the risk of SBI among febrile infants <3 months of age with no apparent focus of infection is high, clinical and laboratory assessment can identify infants who are at very low risk (slightly more than 50%).

An observational study of more than 3000 infants <3 months of age with a fever >38°C treated by practitioners and reported as part of the Pediatric Research in Office Settings Network found that 64% were not hospitalized. ^, Practitioners individualized management and relied on clinical judgment; guidelines were followed in only 42% of episodes. ^{, ,} Outcomes of the children were excellent. If the guidelines had been followed, outcomes would not have improved, but there would have been substantially more laboratory tests performed and more hospitalizations.

The risk of serious bacterial illness in very young infants fell with the marked reduction in early-onset group B streptococcal (GBS) infections because of the effectiveness of intrapartum antimicrobial prophylaxis for pregnant women with GBS colonization. Intrapartum chemoprophylaxis, however, has not altered the incidence of late-onset GBS infection. While Listeria monocytogenes was historically of concern for causing neonatal meningitis, data suggest that widespread GBS prophylaxis likely led to a “collateral benefit” of a dramatic reduction in neonatal listeriosis. In febrile children <3 months of age who have an identified viral infection such as influenza, respiratory syncytial virus (RSV), or enteroviruses, the risk of a SBI other than a UTI falls to almost zero. ^, There is controversy about the significance of the detection of rhinovirus in febrile infants given the widespread use of sensitive molecular assays and the prolonged (several weeks) detection of virus. Data from one study suggest that in febrile infants <28 days of age in whom rhinovirus is detected, the risks for UTI or bacteremia or meningitis are unchanged. However, in infants 29–90 days, those with rhinovirus have a lower risk of bacteremia or meningitis, suggesting that rhinovirus might have been the cause of the fever. Considering newer epidemiologic data, The American Academy of Pediatrics updated guidance in 2021 for the management of well-appearing infants 22- to 28-days old and 29- to 60-days old, identifying opportunities for less testing (e.g., lumbar puncture) and treatment, and fewer hospitalizations than in the 8- to 21-day-old group.