Fever of Unknown Origin
Fever of unknown origin (FUO) implies
- A febrile illness (38.3°C on multiple occasions)
- Present for >14 days
- No apparent source despite careful history taking, physical exam, and preliminary lab studies
- Etiology has changed as the use of more sensitive tests (e.g., MRI, polymerase chain reaction [PCR] tests) permits earlier detection of many conditions that caused FUO in the past.
- Fever resolves in 40–60% of children without identification of a specific cause.
- FUO in the pediatric population is more often an unusual presentation of a common disease than a common presentation of an unusual disease.
- Common infectious causes
- Respiratory infections (otitis media, mastoiditis, sinusitis, pneumonia, pharyngitis, peritonsillar/retropharyngeal abscess)
- Systemic viral syndrome
- Infectious mononucleosis (Epstein-Barr virus [EBV], cytomegalovirus [CMV])
- Urinary tract infection (UTI)
- Bone or joint infection
- Enteric infection (Salmonella, Yersinia enterocolitica, Yersinia pseudotuberculosis, Campylobacter jejuni)
- Cat-scratch disease
- Less common infectious causes
- Tuberculosis (TB)
- Lyme disease
- Rickettsial disease (Rocky Mountain spotted fever, ehrlichiosis, anaplasmosis)
- CNS infection (bacterial or viral meningoencephalitis, intracranial abscess)
- Dental or periodontal abscess
- Subacute bacterial endocarditis (SBE)
- HIV infection
- Human herpes viruses
- Acute rheumatic fever
- Other infectious causes
- Q fever
- Parvovirus B19
- Endemic fungi (histoplasmosis, blastomycosis, coccidioidomycosis)
- Typhoid (Salmonella spp.)
- Chronic meningococcemia
- Possible noninfectious causes
- Collagen vascular disease (systemic juvenile idiopathic arthritis [JIA], systemic lupus erythematosus, dermatomyositis, sarcoidosis, vasculitis syndrome)
- Kawasaki syndrome
- Inflammatory bowel disease (IBD)
- Drug fever
- Factitious fever or Munchausen syndrome by proxy
- Centrally mediated fever
- Periodic fever syndromes
- Kikuchi-Fujimoto disease (histiocytic necrotizing lymphadenitis)
Approach to the patient
- Phase 1
- Document fever.
- Thorough history and physical exam
- Determine whether constitutional symptoms (e.g., growth failure, developmental arrest) suggest a serious underlying disease.
- Create broad differential diagnosis.
- Begin initial laboratory evaluation while tailoring the cadence of evaluation to patient’s severity of illness.
- Phase 2
- Begin invasive studies to seek rarer forms of fever, such as lymphoma, brucellosis, and SBE, only if clinically indicated.
- Phase 3
- Reexamine patient, consider additional testing, and reconsider causes such as systemic JIA, sarcoidosis, and factitious fever.
- Repeat history and physical exam combined with the results of previous testing should guide the subsequent evaluation.
- Question: Temperatures and how they were measured (tympanic, oral, axillary, rectal)?
- As many as 50% of children referred for evaluation of FUO have multiple unrelated infections, parental misinterpretation of normal temperature variation, or complete absence of fever at time of evaluation.
- Parents are sometimes told to add a 1 to 2°F “correction” onto a temperature measured in the axilla to better approximate the core temperature. Such practices may further cloud the evaluation of the febrile child.
- Question: Ethnicity?
- Significance: Some hereditary periodic fever syndromes have ethnic predilection. Consider familial Mediterranean fever (Armenian, Arab, Turkish, Sephardic Jew), hyper-IgD syndrome (Dutch, French), and tumor necrosis factor receptor–associated periodic fever syndrome (TRAPS) (Irish, Scottish).
- Question: Exposure to animals?
- Household exposures including pets and rodents
- Recreational activities (e.g., hunting)
- Household contacts with occupational exposure to animals
- Consider cat-scratch disease, brucellosis, tularemia, leptospirosis, and lymphocytic choriomeningitis virus (from mice).
- Question: Ingestion of raw meat, fish, or unpasteurized milk?
- Significance: trichinosis, brucellosis, listeriosis, Mycobacteria bovis, salmonellosis, giardiasis, or shiga-toxin producing Escherichia coli
- Question: Travel history, including past residence?
- Significance: malaria, endemic fungi (e.g., coccidioidomycosis in Southwest, blastomycosis in Southeast, histoplasmosis in Midwest), typhoid (Indian subcontinent), TB
- Question: Pica or dirt ingestion?
- Significance: Toxocara canis or Toxoplasma gondii infection
- Question: Change in behavior or activity?
- Significance: brain tumor, TB, EBV, Rocky Mountain spotted fever
- Question: Pattern of fever?
- May correlate with underlying cause. A fever diary kept by the parent or caretaker may provide more objective documentation of the fever pattern than simple recall.
- Need to distinguish continuous fever versus recurrent fever
- Question: Medications (including over-the-counter [OTC] medications and eyedrops)?
- Significance: drug fever, atropine-induced fever, methylphenidate, anticonvulsants, ranitidine, and antibiotics (especially penicillin, cephalosporins, and sulfonamides)
- Question: Well-water ingestion?
- Significance: giardiasis
- Finding: Impaired weight gain or linear growth?
- Significance: collagen vascular disease, malignancy, IBD
- Finding: Toxic appearance?
- Significance: Kawasaki syndrome
- Finding: Conjunctivitis?
- Significance: Kawasaki syndrome (limbic sparing), adenovirus, measles
- Finding: Ophthalmologic exam?
- Significance: Papilledema—consider CNS mass lesion; uveitis—consider TB, systemic lupus erythematosus, Kawasaki syndrome, and sarcoidosis.
- Finding: Sinus tenderness, nasal discharge, or halitosis?
- Significance: sinusitis
- Finding: Pharyngitis?
- Significance: Kawasaki syndrome, EBV, CMV
- Finding: Tachypnea?
- Significance: SBE, pneumonia
- Finding: Rales?
- Significance: histoplasmosis, sarcoidosis, coccidioidomycosis
- Finding: Cardiac murmur, gallop, or friction rub?
- Significance: SBE, acute rheumatic fever, pericarditis
- Finding: Hepatosplenomegaly?
- Significance: hepatitis, EBV, CMV, ehrlichiosis, anaplasmosis
- Finding: Rectal abnormalities?
- Significance: pelvic abscess, IBD
- Finding: Arthritis?
- Significance: JIA, IBD, acute rheumatic fever
- Finding: Bony tenderness?
- Significance: JIA, leukemia, osteomyelitis
Diagnostic Tests and Interpretation
The laboratory evaluation for a child with FUO should be directed toward the most likely diagnostic possibilities. Consider the following initial studies.
- Test: CBC with differential and careful examination of WBC morphology
- Significance: Kawasaki syndrome, cyclic neutropenia, malignancy, ehrlichiosis, anaplasmosis (morulae in WBC cytoplasm), and babesiosis
- Test: ESR, C-reactive protein (CRP), or procalcitonin
- Significance: collagen vascular disease, IBD, occult infection. ESR and CRP are generally normal in drug fever and central fever. Elevated procalcitonin (>0.25 ng/mL) may indicate bacterial infection.
- Test: blood cultures
- Significance: endocarditis, salmonellosis, other bloodstream infections
- Test: urinalysis and urine culture
- Significance: UTI, Kawasaki syndrome (sterile pyuria)
- Test: tuberculin skin test (by purified protein derivative)
- Significance: TB
- Test: stool bacterial culture and examination for ova and parasites
- Significance: Salmonella, Giardia
- Test: specific antibody testing
- Significance: Depending on clinical suspicion, consider the following:
- First line: streptococcal enzyme titers (antistreptolysin O, anti-DNase B); EBV; CMV; cat-scratch disease; Lyme disease; hepatitis A, B, or C; or HIV (by PCR)
- Second line: Rocky Mountain spotted fever; ehrlichiosis/anaplasmosis, toxoplasmosis, brucellosis, Q fever, leptospirosis, tularemia, dengue fever
- Test: viral testing of nasopharyngeal aspirates
- Significance: systemic viral syndrome (adenovirus)
- Test: chest radiograph
- Significance: TB, endemic fungi, pneumonia, malignancy
Additional testing should be guided by history, physical examination, epidemiologic factors, and results of initial testing; indiscriminate use of laboratory testing and imaging is not likely to be helpful.
- Test: evaluation for immune deficiency
- Significance: underlying predisposition
- Test: bone marrow examination and culture
- Significance: Salmonella infection, mycobacteria, histoplasmosis, brucellosis, malignancy
- Test: lumbar puncture
- Significance: CNS infection
- Test: ophthalmology exam
- Significance: Uveitis can be present with Behçet disease, Kawasaki disease, TB, syphilis, sarcoidosis, IBD, or poly- or pauciarticular juvenile arthritis.
- Test: sinus CT
- Significance: sinusitis
- Test: chest radiograph
- Significance: TB, endemic fungi, pneumonia
- Test: chest and/or abdominal CT scan
- Significance: TB, liver abscess, hepatosplenic cat-scratch disease
- Test: pelvic or extremity MRI
- Significance: osteomyelitis, pyomyositis
- Test: gallium or bone scan
- Significance: multifocal osteomyelitis, malignancy
Treatment depends on cause of fever.
Prognosis depends on cause of fever
- Most children with FUO who lack a specific diagnosis fare well with resolution of fever and few or no recurrent episodes.
- Occasionally, evolution or progression of symptoms facilitates diagnosis of a specific condition.
- Chow A, Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr. 2011;7(1):5–10. [PMID:21191771]
- Chusid MJ. Fever of unknown origin in childhood. Pediatr Clin North Am. 2017;64(1):205–230. [PMID:27894446]
- Drenth JPH, van der Meer JWM. Hereditary periodic fever. N Engl J Med. 2001;345(24):1748–1757. [PMID:11742050]
- Gattorno M, Caorsi R, Meini A, et al. Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics. 2009;124(4):e721–e728. [PMID:19786432]
- Jacobs RF, Schutze GE. Bartonella henselae as a cause of prolonged fever and fever of unknown origin in children. Clin Infect Dis. 1998;26(1):80–84. [PMID:9455513]
- Talano JM, Katz BZ. Long-term follow-up of children with fever of unknown origin. Clin Pediatr (Phila). 2000;39(12):715–717. [PMID:11156069]
780.6 Fever, unspecified
R50.9 Fever, unspecified
7520000 Pyrexia of unknown origin (finding)
- Q: Do all of the mentioned tests need to be performed?
- A: A “shotgun” approach to testing is rarely useful in making the diagnosis, and unanticipated abnormalities (e.g., false-positives) may lead to additional invasive tests with potential for harm.
- Q: Is hospitalization required for the diagnosis of FUO?
- A: Many tests, including MRI, can now be performed in the outpatient setting. Hospitalization is not routinely required for diagnosis but should be considered in patients who appear ill, have progression of symptoms, or when the presence of fever needs to be documented.
- Q: How is cat-scratch disease acquired?
- A: Cat-scratch disease, caused by Bartonella henselae, can be acquired through cat (usually kittens or young cats) scratches or licks. Rarely, dogs may transmit the organism. If the family does not own a kitten or young cat, remember to ask about other sources of exposure (e.g., friends, family, school trips).
Samir S. Shah, MD, MSCE
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