What are the causes and diagnostic approaches for Fever of Unknown Origin (FUO) in Pediatrics?

From the Guidelines

Fever of unknown origin (FUO) in pediatrics requires a systematic diagnostic approach, prioritizing the identification of underlying infections, autoimmune disorders, and malignancies, while also considering less common causes such as periodic fever syndromes and drug reactions. The diagnostic approach should be guided by the patient's age, clinical presentation, and risk factors for serious bacterial infections (SBI) 1. Initial evaluation should include a complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, blood cultures, urinalysis, and chest radiography.

Key Considerations

• The definition of fever varies between studies, but a commonly used definition is a rectal temperature of greater than or equal to 38.0 C (100.4 F), documented in the clinical setting or at home within the past 24 hours 1.
• The risk of SBI by age has been reported as 13% in neonates (aged 3 to 28 days), 9% in infants aged 29 to 56 days, and 7% in infants aged 90 days or younger 1.
• Urinary tract infections (UTIs) are a common cause of FUO in febrile infants and young children, with a prevalence of approximately 5% in this age group 1.

Diagnostic Approach

• Initial evaluation should include a thorough history and physical examination, as well as laboratory tests such as complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, C-reactive protein, blood cultures, urinalysis, and chest radiography.
• If these tests are inconclusive after 7-10 days of persistent fever, further investigation is warranted, including second-line testing such as tuberculin skin testing, serologic studies for viral infections (EBV, CMV, HIV), autoimmune markers (ANA, RF), and imaging studies such as abdominal ultrasound or CT scan 1.
• Empiric antipyretic therapy with acetaminophen (10-15 mg/kg every 4-6 hours, maximum 5 doses/day) or ibuprofen (5-10 mg/kg every 6-8 hours) can be used for symptomatic relief while investigating the cause.

Management

• Management should focus on identifying and treating the underlying cause of FUO, rather than simply controlling the fever.
• Hospitalization may be necessary for severely ill children or those with concerning features such as lethargy, poor feeding, or signs of sepsis.
• A multidisciplinary approach involving infectious disease specialists, rheumatologists, and hematologist-oncologists is often beneficial in challenging cases 1.

From the Research

Causes of Fever of Unknown Origin (FUO) in Pediatrics

• Infectious diseases, such as salmonellosis, tuberculosis, malaria, and rickettsial diseases, are common causes of FUO in children 2
• Connective tissue disorders, including juvenile rheumatic arthritis, are also frequently associated with FUO 2
• Malignancy is another significant cause of FUO in children, accounting for a substantial proportion of cases 2, 3
• Other rare diseases and uncommon manifestations of common diseases can also lead to FUO 4

Diagnostic Approaches for FUO in Pediatrics

• A thorough history and physical examination are essential in diagnosing FUO, with attention to details such as age, history of contact, exposure to wild animals, and medications 2
• Initial investigations should include complete blood count, blood smear examination, and level of acute phase reactants 2
• Radiological imaging, such as PET/CT, can be a useful aid in diagnosing FUO, particularly in identifying the underlying cause 5
• A four-stage investigative protocol for FUO has been proposed, which includes a systematic review of epidemiological information, medical history, physical examination, laboratory analysis, and adequate invasive procedures 3
• Trials of antimicrobial agents should be avoided, as they can obscure the diagnosis of the disease in FUO 2