Sunday, October 1, 2017

Serious Bacterial Infections in the Febrile Infant

Image Credit: Pixabay
Authors: Kaycie Corburn, MD; Jacqueline Shibata, MD; Lee Grodin, MD; Raymond Beyda, MD
Edited by: Jay Khadpe, MD FAAEM; Michael C. Bond, MD FAAEM
Originally Published: Common Sense September/October 2015

Pediatric fever, especially in infants, is often a challenging and nerve-racking presentation to evaluate in the ED. The prevalence of serious bacterial infections (SBI) in young infants range from 8-20%.[1] There is no clear cut consensus on how to work-up these patients in the ED.[2] As a result, many infants are subjected to invasive, unnecessary, and costly procedures or needlessly treated with empiric antibiotics and hospitalizations. In this edition of the Resident Journal Review, we review the literature on this topic in an effort to give more clarity on how to approach the febrile infant.

Aronson P, et al. Variation in care of the febrile young infant <90 days in U.S. pediatric emergency departments. Pediatrics. 2014;134(4),667-677.
This study describes the variation in ED testing, treatment, hospitalization rates, and outcomes of febrile young infants <90 days old.

This is a retrospective cohort study using the Pediatric Health Information System (PHIS) database. Between July 2011 and June 2013, infants <90 days of age were eligible for inclusion if they had an admission or discharge diagnosis of fever. Infants with complex or chronic diseases as well as those transferred were excluded. Over the study period, 37,907 infants at 37 participating sites met the inclusion criteria. After exclusions, the final cohort consisted of 35,070 infants of which 22.0% were <28 days of age, 42.9% were 29-56 days of age, and 35.1% were 57-89 days of age.

The proportion of infants undergoing blood, urine, and CSF testing along with hospitalization rates was inversely proportional to age. The overall SBI rate was 8.4%, with higher rates among infants <28 days old. For all groups, 5.3% had a urinary tract infection (UTI), 2.4% had bacteremia or sepsis, and 0.3% had meningitis. In total, six infants died.

Testing, treatment, and hospitalization rates varied widely between institutions with hospitalization rates ranging from 3% to 65% in patients 57-89 days old. All 37 hospitals were ranked into tertiles (low, moderate, or high) based on utilization of resources. High utilization hospitals remained consistent across age groups. For example, 12 out of 37 hospitals remained in the same utilization tertile for all three age groups. Patient outcomes were similar despite the varying levels of utilization.

Since variation in care did not seem to result in worse patient outcomes, targeting some care variations may represent an opportunity to better direct resources in the management of febrile infants. For example, nearly two-thirds of the study patients received ampicillin as part of their empiric antibiotic regimen despite the facts that Listeria is an uncommon cause of meningitis and bacteremia beyond the first month of life and that there is significant resistance to ampicillin.[3]

Overall, this study found that for patients <28 days of age, lower hospitalization rates lead to higher three-day revisits and later hospitalizations. However, for patients 29-56 days of age, hospitalization rates were not associated with higher three -day revisit rates or later hospitalization rates. Although more studies are needed for neonates <28 days of age, hospitalization rates for children >28 days of age may be able to be lowered without risk to the patient. More research is needed to address these possible areas for improved resource management.

Huppler et. al. Performance of low-risk criteria in the evaluation of young infants with fever: Review of the literature. Pediatrics. 2010;125:228-233.
Neonates are more vulnerable to infection due to immature immune systems. In the 1980s and 1990s investigators developed and validated criteria to identify low-risk febrile infants who may not need empiric antibiotics and hospitalization as was recommended prior to 1985. Identifying such infants could decrease nosocomial infections, adverse reactions to medications, bacterial resistance, and reduce costs to families and the health care system.

In this review, the authors evaluated how well low-risk criteria for SBIs in febrile infants performed in prospective studies in which antibiotics were withheld compared to prospective and retrospective studies in which they were empirically administered. Studies of infants >90 days age, with specific infections, or with additional risk factors were excluded. The authors identified 21 studies of infants with fever, SBIs, and low-risk criteria. They found that in prospective studies in which antibiotics were initially withheld from patients who met low-risk criteria (n=870), only six patients (0.67%) became culture positive for SBI and all did well when treated with antibiotics. The relative risk (RR) of an SBI in high-risk versus low-risk patients was found to be 30.5 (95% CI: 7-68). The authors concluded that the low-risk criteria allows 30% of young febrile infants to be observed, thus avoiding complications from empiric treatment. Of note, the rate of SBIs in this low-risk cohort was significantly lower than the rate in all the other studies (2.7%, p=.01). They hypothesized that when withholding antibiotics, practitioners are more likely to collect samples carefully and do a meticulous physical exam. A weakness of this review is that there was variation in the low-risk criteria used and the age groups of the patients included (although all were <60 days old in the prospective withholding antibiotics group). Also due to design, long term outcomes were not evaluated.

Wolff, M. et al. Serious bacterial infection in recently immunized young febrile infants. Academic EM. 2009;16:1284-1289.
Because of the risk of SBIs, many infants undergo invasive procedures during the evaluation of fever. Up to 29% of infants have fever after receiving routine 2-month vaccines which results in a two- to seven-fold increase in medical utilization, procedures, and prescription of antibiotics. Realizing this, these investigators examined the prevalence of SBIs in well-appearing patients presenting with fever after recent immunization. This retrospective review examined 2,247 infants aged 6-12 weeks presenting to an urban academic pediatric ED between 2000-2007 with a temperature greater than 38C˚ (100.4F˚) as measured at home, in a clinic, or in the ED. Exclusion criteria included gestational age less than 32 weeks, chronic illness, surgery in the last week, concurrent antibiotic use, or focal infection other than otitis media. Only infants with blood and urine cultures were included. Of the 1,978 infants with fever, 213 (10.8%) received an immunization within three days prior to the encounter. Recently immunized (RI) patients had a RR of definite SBI compared to non-recently immunized (NRI) patients of 0.41 (95% CI=0.19-0.9) with a prevalence of 3.7% (95% CI=6.8-9.2) compared to 8.5% in the NRI group. All of the infections in the RI group were UTIs. Of RI patients, 73.7% received immunizations within the last 24 hours and had a SBI prevalence of 0.6% and RR of 0.09 (CI 0.01-0.6) compared to the NRI group. Because there are risks associated with the procedures of a sepsis work-up, hospitalization, and empiric antibiotic treatment, a modified work-up may be appropriate for febrile infants presenting to the ED within 24 hours of vaccination.

Limitations of this study include its retrospective design and associated biases, lack of patient outcomes, small sample size, and analysis of single-center information. However, the results suggest that for well-appearing young infants presenting within 24 hours post-immunization, a careful exam and urine testing may be appropriate management.

Krief WL, Levine DA, Platt SL, et al. Influenza virus infection and the risk of serious bacterial infections in young febrile infants. Pediatrics. 2009;1:30-39.
Influenza is a common cause of fever occurring with predictable seasonal variation which complicates the evaluation of febrile infants during flu season. Detecting influenza infection may assist in predicting risk for SBIs, and guide risk stratification and management.

In this multi-center, prospective, cross-sectional study the authors determined the risk of SBI in febrile infants younger than 60 days who tested positive for influenza compared to those who tested negative. SBI was defined as either a UTI, bacteremia, enteritis, or bacterial meningitis. They enrolled 1,091 patients from five pediatric EDs. Of the 844 who were tested for influenza, 123 tested positive and 721 negative. Patients were excluded if they received antibiotics within 48 hours of presentation or consent was not obtained. Of patients with known influenza status and for whom culture results of blood, urine, cerebrospinal fluid, and stool were available, the overall SBI rate along with the rates for UTI, bacteremia, meningitis, and enteritis were calculated. Of influenza positive patients, 2.5% (0.5-7.2% 95% CI) had SBIs, all attributable to UTIs, compared with 13.3% (10.9-16.1%) in the influenza negative group yielding a relative risk for overall SBI of 0.19 (0.06-0.59 95% CI). Of the 721 influenza negative infants there was a 2.2% rate of bacteremia (1.3-3.6% 95% CI), a 0.9% rate of meningitis (0.3-1.9% 95% CI), and a 1.7% rate of enteritis (0.3-8.9% 95% CI). The UTI rate for influenza positive patients was 2.4% (0.5-6.9% 95% CI) compared to 10.8% (8.6-13.3% 95% CI) in influenza negative patients with a relative risk of 0.23 (0.07-0.70 95% CI). However, there was insufficient power in the study to detect a statistically significant difference in risk of bacteremia, enteritis, or meningitis. This study suggests that, for febrile infants, a positive influenza test is associated with a decreased risk of UTI and overall SBI. However, SBI due to UTI is still of a high enough prevalence in influenza positive infants (2.4%) to warrant serious consideration in the febrile infant.

Sakran W, Makary H, Colodner R, et al. Acute otitis media in infants less than three months of age: Clinical presentation, etiology and concomitant diseases. International Journal of Pediatric Otorhinolaryngology. 2006;70:613-617.
Acute otitis media (AOM) is a common cause of fever in infants <3 months old. Although usually occurring in isolation, it can be associated with other SBIs including UTI, bacteremia, meningitis, or pneumonia.

The authors of this study examined the incidence of these infections in a cohort of infants <3 months diagnosed with first episode of AOM. 66% percent of these patients were febrile but none were toxic in appearance. White blood cell counts along with blood, urine, and cerebrospinal fluid cultures were obtained prior to antibiotic administration. Pathogen type was examined by culture, frequency, and drug susceptibility. Of the 68 patients with AOM enrolled, 17 were less than 28 days old. Of the 68, 14 had other associated infections, including bronchiolitis in seven, UTI in six, and conjunctivitis in one. No bacteremia or meningitis cases were reported in this cohort. The study suggests that in infants <3 months with AOM, there is a low risk of bacteremia and meningitis while UTI and bronchiolitis were present in 8.8% and 10.4% of the patients, respectively. However, the small numbers in this study make it difficult to draw significant conclusions.

Bonsu BK, Harper MB. Identifying febrile young infants with bacteremia: Is the peripheral white blood cell count an accurate screen? Annals of Emergency Medicine. 2003;42(2),216-225.
Realizing that over 95% of physicians obtain a peripheral white blood cell count (WBC) to screen for sepsis in febrile infants, the authors of this study investigated whether leukocytosis is a reliable sign of sepsis in infants.

This was a retrospective study of infants aged 0 to 89 days without history leukemia and a ED triage temperature ≥ 38 C from 1992-1999. The authors calculated the predictive value of a WBC. In the 3961 eligible cases, both CBC and blood cultures were obtained in 3810 patients. The rate of bacteremia for these patients was 1%. Despite attempting to find several different values that may be appropriate levels of WBC to predict bacteremia, the authors could not determine any WBC value to be a reliable predictor for sepsis. The mean peripheral WBC for patients with bacteremia (13.9K) was not statistically different from those without bacteremia (10.9K).

This publication agrees with several other studies that have suggested the WBC is not helpful to predict SBIs in infants.[5,6] The authors consequently encourage physicians to add blood cultures as a routine component of the evaluation of febrile infants.

S Vaillantcourt, et al. Repeated emergency department visits among children admitted with meningitis or septicemia: A population-based study. Annals of Emergency Medicine. 2014;65:625-632.

This study investigated cases of children diagnosed with meningitis or septicemia after a previous ED evaluation and discharge in Ontario, Canada.

Of 521 children aged 30 days to five years with eligibility for the study, 114 (21.9%) were discharged from an ED within five days prior to their diagnosis. Eleven children were discharged with an unrelated diagnosis and were excluded. Also excluded were children hospitalized for fewer than four days who were being observed for suspected meningitis or septicemia. This left 99 children who had been discharged with diagnoses of fever (most common), otitis media, upper respiratory infection, viral infection, gastroenteritis, UTI, or seizure five days prior to admission for meningitis or septicemia.

Between those children admitted after their first visit to the ED and those admitted later, there was no statistically significant difference in length of stay, intensive care unit admission, or 30-day mortality. Two main explanations were suggested. The first was that the patients were not toxic enough during their initial presentation to warrant admission and had less virulent infections or better immune system competency. The second possibility was that those who had been initially discharged had not yet developed meningitis or septicemia.

As mentioned in the subsequent article by Green et al., “Sick Kids Look Sick,” it seems that the physicians in Ontario are practicing safe, effective medicine.[6] Various prediction algorithms and decision aid tools have come up short over the years. However it seems that a physician’s medical evaluation and judgment may provide the best care for the child with infection.

Despite fears that young infants presenting with fevers will have an SBI, invasive, expensive, and often traumatic evaluations may not be necessary for all of these patients. If a work-up is pursued, data from the cohort of over 35,000 infants suggests that standardized sepsis algorithms dictating management of these patients are unnecessary while taking an individualized approach to each febrile infant is appropriate. In fact, it may be prudent to do less for infants who are deemed low risk for an SBI.

Small prospective studies have shown that it is reasonable to use validated low risk criteria to support withholding empiric antibiotics until cultures prove an SBI is present. Other retrospective studies imply that recent immunization, confirmed influenza or RSV, or well-appearing infants with AOM may have a lower relative risk of concomitant meningitis or bacteremia. Given the small sample sizes and the retrospective designs of most studies, caution must still be taken with these conclusions. Using clinical judgment rather than the shotgun sepsis approach may be acceptable for treatment of these febrile infants as many of the tests used, such as WBC, and antibiotics given, such as ampicillin, may not be helpful. A thorough physical exam, urine studies, monitoring, and even close follow-up may be all that is warranted and may help physicians live up to the doctrine, “Primum non nocere” — first do no harm.


1. Schwartz S, Raveh D, Toker O, Segal G, Godovitch N, Schlesinger Y. A week-by-week analysis of the low-risk criteria for serious bacterial infection in febrile neonates. Arch Dis Child. 2009;94(4):287–292.

2. American College of Emergency Physicians Clinical Policies Committee; American College of Emergency Physicians Clinical Policies Subcommittee on Pediatric Fever. Clinical policy for children younger than three years presenting to the emergency department with fever. Ann Emerg Med. 2003;42(4):530-545.

3. Brown JC, Burns JL, Cummings P. Ampicillin use in infant fever: a systematic review. Arch Pediatr Adolesc Med. 2002;156(1):27-32.

4. Lin DS, Huang SH, Lin CC, et al. Urinary tract infections in febrile infants younger than eight weeks of age. Pediatrics. 2000;105:E20.

5. Bonsu BK, Harper MB. Utility of the peripheral blood white blood cell count for identifying sick young infants who need lumbar puncture. Ann Emerg Med. 2003;41:206-214.

6. Green SM et al. Sick Kids Look Sick. Annals of Emergency Medicine. 2015;65(6),633-665.

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