Background

The fever without a source (FWS) evaluation in children, 3–36 months of age with a temperature ≥39 °C, has a long history that starts prior to routine Haemophilus influenzae type b (Hib) and the conjugated pneumococcal vaccination. Back in the 1980s, occult bacteremia was common with a prevalence estimated at 3–12% of well‐appearing children with FWS.^1,2 The concern was progression of occult bacteremia to serious bacterial infections (SBI) such as pneumonia, septic arthritis, cellulitis, sepsis, or meningitis. Hib is a very invasive bacterium, with a 12 times higher likelihood of causing meningitis than Streptococcus pneumoniae when bacteremia is present.³ This led to the routine FWS work‐up for well‐appearing children, 3–36 months, with fever ≥39 °C and no source on physical examination. This evaluation included a complete blood count (CBC) and differential, and if elevated, a blood culture was sent, and antibiotics were administered. If the white blood cell (WBC) count was ≥20,000 a chest X‐ray was performed.² Since the introduction of the Hib vaccination in 1987, the rate invasive H. influenzae infections has decreased to the point of near elimination of the disease.⁴ The rate of occult bacteremia for FWS children after widespread Hib vaccination was then estimated at 1.9%, with the majority being due to S. pneumoniae.^5,6 In 2000, the first conjugated pneumococcal vaccine was introduced, and the rate of bacteremia in FWS children declined markedly to 0.25% in 2009.⁷ Because the rate of occult bacteremia is so low, routine FWS evaluations are no longer recommended in fully vaccinated children.⁸ Now, in the well‐appearing, vaccinated child with FWS one must evaluate them for their risk for urinary tract infection (UTI) and occult pneumonia. Exceptions are children who are un‐ or under‐vaccinated, who warrant assessment for occult bacteremia in addition to UTI and occult pneumonia. Also, children with FWS for ≥5 days warrant an evaluation for possible Kawasaki Syndrome, and in fever present for ≥7 days without a source, a fever of unknown origin evaluation should be performed.

In the child that is under‐immunized due to age (2–6 months), it appears that risk for S. pneumoniae and H. influenzae bacteremia is not significantly increased and remarkably low at <1%. This low rate of bacteremia is likely due to maternal antibodies and herd immunity. Traditionally, the practice of drawing a CBC was performed while holding the blood culture and if WBC was >15,000 then sending the blood culture. One reason this was performed was the high rate of contamination of the blood culture, the ratio of blood culture contaminants is 7.6–1 for detecting one positive blood culture.⁷ Now that inflammatory markers are available in a timely fashion, C‐reactive protein (CRP) or procalcitonin may be helpful in detecting the child with possible bacteremia. In a systematic review and meta‐analysis of over 7000 children with FWS, a procalcitonin >0.5 ng/mL was found to have a sensitivity of 82% and specificity of 86% for detecting invasive bacterial infection.⁹ Procalcitonin has been found to be more sensitive and specific than CRP or WBC count.¹⁰ In the older under‐ or un‐vaccinated child (6–36 months) the rate of bacteremia was found to be low but up to 1.4%. Given the low rate of bacteremia in the under‐ or un‐vaccinated child, inflammatory markers can be helpful to detect children at risk for SBI, and one must weigh the risk and benefits of workup on this population.

Most children with FWS that are well‐appearing, have a self‐limited viral illness.¹¹ UTIs are the most common occult bacterial infection in children presenting with FWS with a prevalence rate that differs by age, race, sex, and circumcision status.¹² The estimated prevalence of UTI for girls with FWS in the first year of life is between 5.7% and 8.5%, then declines to 2.1% between 12 and 24 months of age. The rate of UTI in febrile, uncircumcised boys 6–12 months of age is similar to girls, with a prevalence of 7.3%.¹³ This is in stark contrast to circumcised boys, aged 6–12 months, where the prevalence of UTI is 0.3%; with an even lower estimate after 1 year. Given the relatively high prevalence of UTI as a source of FWS, current recommendations are to obtain a urinalysis and (if urinalysis is positive) urine culture, on all girls, age <24 months, uncircumcised boys <12 months of age, and circumcised boys <6 months.¹⁴

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