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Ilene Claudius, MD and Mizuho Spangler, DO

Updates on fever work-up in infants of differing ages.

Pearls:

  • Fever even in a well appearing child can be very concerning because 42% of infants less than 90 days old with bacteremia or bacterial meningitis will not look ill at their first visit to medical contact.

  • Even after meeting “low-risk” laboratory criteria, children less than 28 days of age have high rates of serious bacterial infections(SBI) and merit admission on antibiotics.

  • Well appearing, vaccinated febrile children 3-36 months of age do not need blood cultures or a Complete Blood Count(CBC) for evaluation but urine testing may be indicated depending on other risk factors.

  • Fever as a chief complaint is different in the Emergency Department(ED) from the primary care provider’s office. The patients presenting to the ED are more likely to have a Serious Bacterial Infection(SBI). The perspective presented in this discussion is from a pediatric ED provider.

Fever in a child less than 28 days old

  • The risk of SBI in these patients is somewhere between 12-20%  with the youngest neonates having rates as high as 26 to 31%. Guidelines by institutions uniformly recommend a full workup including CBC, blood culture, UA, urine culture, lumbar puncture, CSF culture, admission, and antibiotics. This comes from the fact that those that are “low-risk” by the typical criteria still have SBI rates from 3.5 to 6%.

  • Pathogens: E. coli is more common than Group B Strep(GBS) now that mothers are better treated for GBS and after those two, Staphylococcus Aureus is probably the next most common. Streptococcus Pneumoniae is now much less common and accounts for only 3% of bacteremia in the 1-3 week old group. Herpetic disease accounts for only 0.3% of fever but has such significant sequelae that it cannot be ignored.

  • For antimicrobials typically providers are using ampicillin plus either an aminoglycoside or a third-generation cephalosporin. Ceftriaxone is not recommended as there is a black box warning for children less than 28 days of age because of the risk of hyperbilirubinemia.

*Editor’s note: The black box warning for Ceftriaxone is for its use with calcium containing fluids in neonates given a risk of cardio/pulmonary calcium precipitation. There is also a warning against using ceftriaxone in hyperbilirubinemic neonates for risk of displacement of bilirubin from albumin and subsequent encephalopathy. More details from the FDA can be found in the package insert.

Aminoglycosides can be used for rule out sepsis with the reminder that they do not penetrate the CSF so if meningitis is suspected a cephalosporin should be used.

Fever in a child one to three months of age

  • Practice is more variable in this age group. Not all practice guidelines recommend CSF testing in this age group (when deemed “low-risk” by blood and urine studies) and not all guidelines recommend antibiotic use. Claudius is on the conservative side and does CSF studies on all these patients.

*Editor’s note: The variability of clinical practice in outpatients is demonstrated in this article in JAMA that also supports Dr. Claudius assertion that patients who present to pediatricians may be managed differently than those who present  to the ED.

Pantell et. al. Management and outcomes of care of fever in early infancy. JAMA. 2004 Mar 10;291(10):1203-12. Free Full Text

  • Risk of bacteremia in this group is less than 2% when well-appearing and 10-11% if ill-appearing. UTI is the most common SBI in this age group with 8% of febrile patients in this age having a UTI. Of those with UTI nearly 3% will have concomitant bacteremia whether they were febrile or not. Finding UTI as a source does not reduce the risk of meningitis.

  • To decide who can go home from the ED Claudius uses the Philadelphia criteria. These criteria require a lumbar puncture and are very sensitive but not very specific which leads to not missing cases at the expense of overtreatment.

    • Philadelphia Criteria

    • Patients: 28 to 56 days old who are well-appearing  with a temperature at or above 38.2.

    • Criteria for low risk: White blood cell count less than 15,000, Band to neutrophil ratio of less than .2, CSF with less than 8 white cells per mm3, Urinalysis with less than 10 white cells per high power field.

    • Sensitivity: 98 to 100%.

    • Specificity 26 to 42%.

*Editor’s note: Beyond the above listed criteria Urine and CSF gram stain were included as were chest X-ray or stool white count if clinically indicated. A current review of fever in infants less than 90 days of age with more details on the criteria can be found here:

Biondi EA, Byington CL. Evaluation and Management of Febrile, Well-appearing Young Infants. Infect Dis Clin North Am. 2015 Sep;29(3):575-85. PMID: 26188607

  • Many providers also use the Rochester Criteria which does not require CSF testing but can only be applied to a more strictly defined population of healthy term infants. It was originally studies on infants less than 60 days of age. Many protocols use a “modified Rochester criteria”.

Fever in infants 3-36 months of age

  • Workup is generally not needed in this age group for well appearing patient with fever aside from testing for urinary tract infections. UTI is common in this age group especially in children with higher fever, prolonged fevers and Caucasians. Bacteremia is rare in well appearing children in this age group. “Occult” bacteremia, that is bacteremia in well appearing children, is present at a rate of about 0.17 to 0.36%.

  • Much of the drop in bacteremia rates is related to pneumococcal vaccination. PCV13 is the current vaccine and cover somewhere between 60 and 74% of the serotypes that cause invasive pneumococcal disease. After the infant series, 93 to 94% of kids will have antibodies to the vast majority of serotypes in the vaccine. A few serotypes do not respond as well and 19A is a major cause of invasive disease for which the immunogenicity is only 82%

  • In unvaccinated children, the rate of bacteremia is harder to know but it is still rare with less than half of one percent in communities where there is 80% vaccination rates. This data is from the era of PCV7 and we currently cover six more serotypes of pneumococcus with PCV13.

  • When a child has had a single dose of pneumococcal vaccine it is also hard to know what the risk is. For PCV7, the immunogenicity was about 70% after one dose of the vaccination and about 95% after two doses of the vaccination. Claudius assumes the immunogenicity of PCV13 is similar and if a kid looks really well and has gotten one dose of the vaccine, that their risk of occult bacteremia is reasonably low.

  • CBCs and Blood cultures are likely not needed and rates of false positive blood cultures are high. 63 to 88% of blood cultures that are positive are false-positive, so there is downside in following up a false-positive culture for a patient whose a priori risk of bacteremia was incredibly low.

  • In the pre-PCV era,  a white blood cell count greater than 15,000 was used to predict bacteremia. Now the sensitivity of a white blood cell count above 15,000 for bacteremia is about 50 to 60 percent and the specificity is in the range of 53 to 80%. A white cell count of greater than 15,000 predicts bacteremia in 1.5 to 3.2%. A higher cutoff of 25,000 and a temperature greater than 39 degrees celsius is more specific and the the serious bacterial infection rate is 39%.

Other testing and new testing

  • CRP and procalcitonin are used by some but do not have high sensitivity to adequately rule out SBI. On the horizon are PCR for bacterial ribosomal subunit and leukocyte RNA biosignatures which may lead to rapid and more accurate results than current testing.