Overview
Definition:
Fever of unknown origin (FUO) in children is defined as a fever of at least two weeks' duration, with a temperature of ≥38.3°C (101°F) on several occasions, and in which no specific diagnosis has been established after one week of conventional inpatient investigation, or three outpatient visits or three days of inpatient investigation.
Epidemiology:
FUO constitutes 3-5% of all pediatric consultations for fever
In school-age children, infectious causes are most common (40-50%), followed by rheumatologic (10-20%), oncologic (5-10%), miscellaneous (10-20%), and undiagnosed (10-20%) causes
The etiology varies with geographic location and endemic diseases.
Clinical Significance:
FUO in children can represent a wide spectrum of serious underlying conditions, ranging from common infections to rare autoimmune diseases or malignancies
A systematic, staged approach is crucial for timely diagnosis, appropriate management, and prevention of potential long-term sequelae, making it a high-yield topic for pediatric residents preparing for DNB and NEET SS examinations.
Clinical Presentation
Symptoms:
Persistent or recurrent fever ≥38.3°C
Malaise and fatigue
Weight loss
Poor appetite
Night sweats
Localizing symptoms such as sore throat, cough, abdominal pain, joint pain, or rash may or may not be present
Duration of fever typically exceeding 14 days.
Signs:
Fever noted on examination
Pallor
Lymphadenopathy
Hepatosplenomegaly
Joint effusions or tenderness
Skin lesions (rash, petechiae)
Ocular inflammation (uveitis)
Oral ulcers
Pharyngeal erythema
Cardiac murmurs
Signs of meningeal irritation
Signs of dehydration.
Diagnostic Criteria:
The classic definition of FUO requires a temperature of ≥38.3°C on several occasions, duration of fever >3 weeks, and failure to diagnose after 1 week of inpatient or 3 outpatient evaluations
Modified criteria in children often use a shorter duration (e.g., 7-14 days) depending on the context and severity of illness.
Diagnostic Approach
History Taking:
Detailed fever pattern (intermittent, continuous, relapsing)
Associated symptoms (respiratory, GI, GU, musculoskeletal, neurological)
Recent travel history
Exposure to sick contacts or animals
Immunization status
History of congenital anomalies
Medications (recent antibiotics, immunosuppressants)
Family history of autoimmune diseases or malignancies
Nutritional status
Daycare or school attendance
Any red flags: high persistent fever, severe constitutional symptoms, abnormal physical findings, neutropenia, elevated ESR/CRP, abnormal imaging findings.
Physical Examination:
Comprehensive head-to-toe examination
Careful palpation for lymphadenopathy (size, location, consistency)
Assessment of liver and spleen size
Examination of joints for swelling, tenderness, and range of motion
Thorough skin examination for rashes, petechiae, or purpura
Ophthalmoscopic examination for uveitis or fundal lesions
Oral cavity examination for ulcers or pharyngitis
Cardiovascular and respiratory system examination
Neurological assessment for meningeal signs.
Investigations:
Initial investigations: Complete blood count (CBC) with differential, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), urinalysis, urine culture, blood cultures (at least two sets from different sites, ideally during fever spikes), chest X-ray
Further investigations based on clinical suspicion: Serological tests for common viral and bacterial infections (EBV, CMV, HIV, mycoplasma, Bartonella, Lyme disease)
Autoimmune markers (ANA, rheumatoid factor)
Imaging: Ultrasound abdomen (hepatosplenomegaly, lymph nodes), Echocardiogram (endocarditis), CT scan (abscess, malignancy, lymph nodes), MRI (CNS involvement, osteomyelitis)
Specific tests: Tuberculin skin test (TST) or Interferon-gamma release assay (IGRA) for tuberculosis
bone marrow examination (leukemia, lymphoma, disseminated infection)
biopsies of lymph nodes or liver if indicated.
Differential Diagnosis:
Infectious causes: Bacterial (TB, brucellosis, osteomyelitis, endocarditis, abscesses), Viral (EBV, CMV, adenovirus, influenza, HIV), Fungal, Parasitic
Inflammatory/Rheumatologic causes: Juvenile idiopathic arthritis (JIA), Systemic lupus erythematosus (SLE), Kawasaki disease, Henoch-Schonlein purpura, Still's disease
Malignancies: Leukemia, Lymphoma, Neuroblastoma, Wilms tumor
Other causes: Inflammatory bowel disease, Familial Mediterranean fever, Drug fever, Factitious fever, Periodic fever syndromes.
Management
Initial Management:
Hospitalization may be required for severely ill children or if a serious underlying condition is suspected
Supportive care including antipyretics (paracetamol, ibuprofen) for comfort
Fluid management to prevent dehydration
Nutritional support if appetite is poor.
Medical Management:
Treatment is directed at the underlying cause once diagnosed
Antibiotics for bacterial infections
Antivirals for specific viral infections
Anti-inflammatory agents (NSAIDs, corticosteroids) for rheumatologic conditions
Chemotherapy for malignancies
Empiric treatment is generally avoided unless a specific life-threatening infection is strongly suspected and awaiting confirmation, balancing risks and benefits.
Surgical Management:
Surgical intervention is rarely the primary management for FUO but may be required for complications such as abscess drainage, tumor resection, or management of specific rheumatologic complications like joint debridement.
Supportive Care:
Close monitoring of vital signs, fluid balance, and clinical status
Pain management
Psychological support for the child and family
Education regarding the diagnostic process and potential outcomes.
Complications
Early Complications:
Sepsis, organ damage (e.g., kidney, liver, CNS), dehydration, electrolyte imbalances, myocarditis, respiratory distress, bone or joint destruction, complications from uncontrolled malignancy or autoimmune disease.
Late Complications:
Chronic organ dysfunction, growth and developmental delays, secondary infections, long-term effects of treatment (e.g., chemotherapy, immunosuppressants), psychological sequelae.
Prevention Strategies:
Prompt and thorough diagnostic workup
Early recognition of red flags
Adherence to treatment protocols
Regular follow-up to monitor for treatment efficacy and late complications
Maintaining adequate hydration and nutrition.
Prognosis
Factors Affecting Prognosis:
The underlying etiology is the primary determinant of prognosis
Infectious causes generally have good prognosis with appropriate treatment
Malignancies and severe autoimmune diseases carry a poorer prognosis
Delays in diagnosis and treatment can significantly worsen outcomes
Age and general health status of the child are also important.
Outcomes:
The majority of FUO cases in children are due to infectious etiologies and have a good prognosis
Rheumatic diseases have variable outcomes depending on the specific condition
Malignancies require aggressive treatment and have a prognosis dependent on the type and stage of cancer
A small percentage of cases remain undiagnosed but often resolve spontaneously
however, vigilance is required.
Follow Up:
Children diagnosed with FUO require regular follow-up to monitor for resolution of fever, recovery from the underlying condition, assess for treatment side effects, and screen for long-term sequelae
The frequency and duration of follow-up depend on the specific diagnosis.
Key Points
Exam Focus:
Remember the definition of FUO and the timeframes
Differentiate between common pediatric FUO etiologies (infection, rheumatologic, oncologic)
Recognize key red flags in history and examination
Understand the stepwise diagnostic approach, starting with basic investigations.
Clinical Pearls:
Always consider TB and occult abscesses in prolonged fevers, especially in endemic areas
Do not underestimate the importance of a thorough travel and exposure history
Serial physical examinations are critical as findings can evolve
Blood cultures should be drawn when the child is febrile.
Common Mistakes:
Prematurely starting broad-spectrum antibiotics without adequate workup can mask diagnoses and lead to resistance
Failing to consider less common but serious causes like malignancy or autoimmune disease
Inadequate follow-up of patients with unexplained fevers
Over-reliance on advanced imaging without a clear clinical indication.