Evaluation

Fever Without Apparent Source in Infants and Young Children

Editors: Ann M. Dietrich MD, FAAP, FACEP; Zbigniew Fedorowicz PhD, MSc, DPH, BDS, LDSRCS; Scott A. Barron MD, FAAP

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Background Information

Description

  • Fever without apparent source describes an acute febrile illness in infants and young children who appear well after a thorough history and physical exam.
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Also Called

  • Fever without source
  • Fever without localizing signs
  • Fever without focus
  • Unexplained fever
  • Undifferentiated fever

Definitions

  • Fever is defines as a rectal temperature ≥ 38 degrees C (100.4 degrees F) documented in a clinical setting or at home within the past 24 hours.
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  • Serious bacterial illness (SBI) is a common term for a heterogeneous group of serious illnesses.
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    • Historically, the term has included serious illnesses that present with fever without apparent source, such as urinary tract infection, bacteremia, and bacterial meningitis, plus other clinically obvious infections, such as cellulitis, viral or bacterial pneumonia, and bacterial gastroenteritis.
    • The American Academy of Pediatrics recommends retiring the term and instead addressing bacterial meningitis, bacteremia, and urinary tract infection separately.
  • Invasive bacterial infection (IBI) often refers to infections such as bacterial meningitis and bacteremia.
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Incidence/Prevalence

  • Fever is the most common chief concern in children presenting to an emergency department, and accounts for reported 15% of visits in children < 15 years old.
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  • About 20% of children with fever are reported to have no identified source of infection after a thorough history and physical exam.
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Etiology and Pathogenesis

Causes in Infants < 3 Months Old

  • Infection is the most common cause of fever without a source in younger infants. The infection is most often a self-limiting viral illness.
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  • The reported estimated incidence of serious bacterial infection (SBI) in febrile infants < 3 months old is 9%-14%. The most common SBI is urinary tract infection (UTI). Bacteremia and bacterial meningitis are less common than UTI.
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  • STUDY SUMMARY
    UTI is more common than bacteremia and meningitis among infants < 3 months old presenting with first episode of serious bacterial illness
    COHORT STUDY: Pediatr Infect Dis J 2014 Jun;33(6):595

  • STUDY SUMMARY
    rates of sepsis or bacteremia appear low in preterm and full term infants presenting to emergency department with fever
    COHORT STUDY: Pediatrics 2024 Apr 1;153(4)

Causes in Children Aged 3-36 Months Old

  • A self-limiting viral infection is the most common cause of fever in children aged 3-36 years.
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  • Urinary tract infection (UTI) is the most common serious bacterial infection in vaccinated children.
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  • The prevalence of UTI as a cause of fever without apparent source varies. As many as 17% of cases of fever without apparent source among White female children < 2 years old are reportedly due to UTI. Circumcised boys aged 29-60 days have a reported likelihood of UTI of < 1 %.
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  • Universal vaccination for Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae have resulted in the disappearance of occult bacteremia as a cause of fever without apparent source, and a dramatic reduction in bacterial meningitis in children < 5 years old.
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  • Infection with Neisseria meningitidis is at historically low levels.
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  • STUDY SUMMARY
    incidence of occult bacteremia appears low in febrile children aged 2-36 months since introduction of routine pneumococcal vaccination
    BEFORE AND AFTER STUDY: Arch Dis Child 2009 Feb;94(2):144BEFORE AND AFTER STUDY: Int J Environ Res Public Health 2016 Jul 19;13(7):doi:10.3390/ijerph13070723COHORT STUDY: Acad Emerg Med 2009 Mar;16(3):220

Pathogenesis

  • Vertebrates maintain temperature through physiologic and behavioral mechanisms.
    • Thermosensitive cells in the anterior hypothalamus monitor blood temperature and regulate body temperature to maintain a central set point.
    • Physiologic mechanisms are the primary means of maintaining body temperature.
      • When blood temperature is below the set point, brown fat catabolism and shivering both increase heat production, and peripheral vasoconstriction increases heat retention.
      • When blood temperature is above the set point, heat is lost through perspiration and vasodilation helps further release heat.
    • Behavioral mechanisms are secondary to physiologic mechanisms and include adjusting clothing, consuming hot or warm liquids, and adjusting body position.
    • PubMed27894446Pediatric clinics of North AmericaPediatr Clin North Am20170201641205-230205Reference - Pediatr Clin North Am 2017 Feb;64(1):205
  • Molecular mechanisms that regulate the set point are not fully understood.
    • The upregulation of the set point results in fever and is mediated by endogenous pyrogenic cytokines.
    • Cytokines are released in response to an inflammatory processes, such as that triggered by microbial invasion. Cytokines that are significantly involved in fever include interleukins 1 and 6 and tumor necrosis factor-alpha.
    • Pyrogenic cytokines stimulate production of prostaglandin E2, which acts on the hypothalamus to increase the central set point.
    • Most antipyretics, including nonsteroidal anti-inflammatory drugs and acetaminophen, reduce fever by inhibiting production of prostaglandin E.
    • PubMed27894446Pediatric clinics of North AmericaPediatr Clin North Am20170201641205-230205Reference - Pediatr Clin North Am 2017 Feb;64(1):205
  • Although metabolically costly, fever has been maintained as a basic host defense mechanism for hundreds of millions of years of natural selection.
    • The effects of fever may be multifactorial.
    • The proposed mechanisms for the efficacy of higher temperatures include:
      • Inhibited growth of some microorganisms
      • Improved immune function, such as increased:
        • Polymorphonuclear neutrophil (PMN) efficiency (in vitro, PMNs move toward, phagocytose, and kill pathogens more quickly at higher temperatures)
        • T-helper lymphocytes adherence
        • Immunoglobulin production
        • Tumor necrosis factor-alpha cytotoxicity
    • PubMed27894446Pediatric clinics of North AmericaPediatr Clin North Am20170201641205-230205Reference - Pediatr Clin North Am 2017 Feb;64(1):205
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