OVERVIEW

What is fever of unknown origin in children?

It refers to prolonged fever (daily elevated body temperature) in children that persists after comprehensive inpatient evaluation without an identifiable cause. Different institutions have varying definitions for pediatric fever of unknown origin.

Some institutions adopt the adult definition: documented temperature >38.3°C on multiple occasions, lasting ≥3 weeks, with no diagnosis after 1 week of inpatient investigation.

Considering pediatric characteristics, UpToDate defines it as: temperature >38.3°C on multiple occasions lasting ≥8 days, remaining undiagnosed after complete outpatient or inpatient evaluation.

Zhu Futang's Practical Pediatrics defines it as: fever (continuous or intermittent) persisting >3 weeks without diagnosis after physical examination and routine tests.

Is fever of unknown origin common in children?

No.

While fever is a frequent chief complaint in pediatric visits, most cases resolve before diagnosis or develop additional symptoms facilitating identification.

Thus, true fever of unknown origin is uncommon. Due to definition discrepancies, its exact incidence remains unclear.

SYMPTOMS

What are the common manifestations of fever of unknown origin in children?

Prolonged elevated body temperature is the primary manifestation. "Prolonged" refers to a duration of illness exceeding 3 weeks.

The normal body temperature range is 36–37°C (set point). Factors such as activity, eating, crying, or clothing may raise a healthy child's temperature to 37.5°C, but it returns to normal once these factors are removed.

Fever of unknown origin can present with different temperature patterns, which may aid diagnosis:

• Continuous fever (sustained fever): Persists for 24 hours with minimal fluctuation (≤0.6°C).
• Remittent fever: Temperature fluctuates by 2–3°C over 24 hours but never returns to normal.
• Intermittent fever: Fever subsides to normal for at least 24 hours before recurring.
• Biphasic fever: Two fever peaks within 24 hours.
• Irregular fever: No discernible pattern. Children’s fevers often lack clear regularity compared to adults.

What are the associated manifestations of fever of unknown origin in children?

• Malnutrition: Due to increased metabolic demands, children may exhibit weight loss, wasting, or developmental delays.
• Arthritis: Conditions like rheumatic arthritis, rheumatoid arthritis, or joint abscesses may cause joint pain, limited mobility, or deformities.
• Rash: Fever with rash often suggests autoimmune diseases, presenting with varied skin lesions.
• Anemia: Infections or chronic illness may lead to anemia, manifesting as pallor, fatigue, or reduced activity.

CAUSES

What Causes Fever of Unknown Origin in Children?

Over 50% of cases are caused by infectious diseases, including viral, bacterial, fungal, and parasitic infections. Non-infectious causes commonly include tumors, autoimmune diseases, immunodeficiency disorders, and endocrine diseases.

• Systemic infectious diseases:
  • Viral infections: EB virus, cytomegalovirus, adenovirus, hepatitis virus, enterovirus, and arbovirus can cause systemic infections, presenting as persistent fever.
  • Bacterial infections: Mycobacterium tuberculosis, Brucella, Salmonella, and Francisella tularensis. Tuberculosis is transmitted through contact with infected individuals, and children may exhibit persistent low-grade fever and weight loss without prominent cough. Brucellosis is prevalent in pastoral areas and spreads through consuming unpasteurized dairy products. Salmonella can cause typhoid or paratyphoid, with symptoms like persistent fever, abdominal pain, and chills. It spreads via contaminated food, such as raw eggs or poultry. Infected individuals are also sources of transmission. Francisella tularensis can be carried and transmitted by insects like mosquitoes, lice, ticks, fleas, and flies.
  • Other pathogenic infections: Malaria, kala-azar, leptospirosis, schistosomiasis, and fungal infections.
• Localized infectious diseases: Infections confined to specific organs or tissues, but due to children's limited ability to describe symptoms, fever may be the primary manifestation.
  • Bone and joint infections: Osteomyelitis or septic arthritis may present only as fever, possibly accompanied by limited mobility or localized tenderness.
  • Infective endocarditis: May manifest solely as prolonged fever. Echocardiography and blood cultures aid in diagnosis.
  • Liver abscess: May be accompanied by hepatomegaly or abdominal pain, or present only as prolonged fever.
  • Urinary tract infection: May involve pyuria or painful urination, or present only as prolonged fever.
  • Perianal abscess: Physical examination may reveal swelling or ulceration around the anus.
  • Intra-abdominal abscesses: Perinephric, subphrenic, or appendiceal abscesses.
• Connective tissue diseases: The most common non-infectious cause.
  • Includes: Juvenile idiopathic arthritis, systemic lupus erythematosus, polyarteritis nodosa, and Kawasaki disease. May involve other symptoms like rashes or joint pain.
  • Autoimmune antibody testing can provide clues for diagnosis.
• Tumors: Common causes of prolonged fever in children include leukemia and lymphoma, often accompanied by weight loss. Lymphoma may present with localized masses. Other possibilities include neuroblastoma, malignant histiocytosis, Langerhans cell histiocytosis, and sarcomas.
• Other causes: Central thermoregulatory dysfunction, diabetes insipidus, drug fever, summer fever syndrome, inflammatory bowel disease, periodic fever, hyperthyroidism, and immunodeficiency.
• Factitious fever: Elevated temperature due to incorrect measurement methods, without actual fever. May also result from deliberate false measurements by children or caregivers.

Which Children Are More Prone to Fever of Unknown Origin?

Children with immune deficiencies are more susceptible to infections by rare or opportunistic pathogens, leading to prolonged fever. Congenital or active immunodeficiency may involve multiple infections by different pathogens, resulting in persistent fever.

Is Fever of Unknown Origin in Children Contagious?

Not necessarily.

Depending on the pathogen, some diseases are contagious, such as brucellosis, typhoid, malaria, and kala-azar. Non-infectious causes of fever are not contagious.

DIAGNOSIS

How to determine unexplained fever in children?

Symptom assessment: Fever lasting more than 3 weeks without a confirmed diagnosis after physical examination and routine tests.

What tests are performed for unexplained fever in children?

For suspected unexplained fever, hospitalization is usually required for systematic examinations to identify the cause. A thorough physical exam and comprehensive medical history review are conducted. Routine tests include:

• Complete blood count (CBC) + abnormal cell analysis. Microscopic examination to assess morphological changes in red blood cells, white blood cells, and platelets.
• Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) to evaluate the level of inflammatory response.
• Blood culture, urine culture, stool culture, and sputum culture to identify pathogens.
• Urinalysis and urinary tract ultrasound: To check for urinary tract infections.
• Chest X-ray: To detect pneumonia, tuberculosis, or other infections.
• Biochemical tests: To assess liver function, electrolytes, and kidney function.

TREATMENT

Which department should be visited for pediatric fever of unknown origin?

Pediatric internal medicine or fever clinic.

How to treat pediatric fever of unknown origin?

Targeted treatment after identifying the cause.

• If it's an infectious disease: eliminate pathogens and clear the infection site.
• If it's an autoimmune disease: use immunosuppressants to control symptoms.
• If it's a tumor: undergo radiotherapy or chemotherapy.
• If it's drug-induced fever: discontinue all medications.

DIET & LIFESTYLE

What should be noted in diet for children with fever of unknown origin?

Replenish fluids. When dehydrated, body temperature tends to remain elevated.

Protein-rich foods like eggs, lean meat, and fish are recommended as illness causes significant bodily depletion. Starchy foods alone cannot meet the body's needs. High-quality proteins should be provided to satisfy nutritional requirements.

PREVENTION

How to Prevent Fever of Unknown Origin in Children?

Since there are many causes of fever of unknown origin, it cannot be prevented through simple procedures.

If a child develops a fever, promptly record temperature changes and seek help from a professional doctor. Regular treatment can help identify the cause early and shorten the treatment duration.