Fever of Unknown Origin in Pediatric Age

Fever of unknown origin (FUO) in children can be a challenging diagnostic dilemma for healthcare professionals. Unlike in adults, where FUO is defined as a temperature greater than 38.3°C (101°F) lasting for more than three weeks with no identifiable cause after three outpatient visits or three days of inpatient investigation, the definition in pediatrics varies slightly. In children, FUO is typically defined as a fever greater than 38.3°C (101°F) lasting for more than one week with no apparent source after appropriate outpatient evaluation.

Epidemiology and Etiology

The incidence of FUO in children ranges from 0.5% to 3% of hospitalized patients. The etiology of FUO in children is diverse and can vary based on age, geographic location, and underlying medical conditions. In general, the most common causes of FUO in children can be categorized as follows:

Infectious Diseases: This is the most common cause of FUO in children, accounting for approximately 30-50% of cases. Viral infections (such as Epstein-Barr virus, cytomegalovirus, and human immunodeficiency virus), bacterial infections (such as endocarditis, osteomyelitis, and tuberculosis), and parasitic infections (such as malaria and toxoplasmosis) are among the possible infectious etiologies.
Autoimmune and Rheumatologic Disorders: These account for approximately 10-20% of FUO cases in children. Examples include juvenile idiopathic arthritis, systemic lupus erythematosus, and vasculitides.
Malignancies: Malignancies, such as leukemia, lymphoma, and solid tumors, can present with FUO and account for approximately 5-10% of cases.
Miscellaneous Causes: Other potential causes include inflammatory bowel diseases, granulomatous diseases (such as sarcoidosis), factitious fever, and hereditary autoinflammatory disorders.

It is important to note that the etiology of FUO can vary based on age. For instance, in neonates and young infants, infectious causes are more common, while in older children, autoimmune and rheumatologic disorders become more prevalent.

Clinical Evaluation

The evaluation of a child with FUO requires a comprehensive and systematic approach. The initial assessment should include a detailed medical history, thorough physical examination, and appropriate laboratory investigations.

Medical History

A detailed medical history is crucial in identifying potential causes of FUO. The following aspects should be explored:

Onset, duration, and pattern of fever (continuous, intermittent, or periodic)
Associated symptoms (e.g., rash, joint pain, weight loss, night sweats, fatigue)
Recent travel history, environmental exposures, or animal contacts
Immunization status
Family history of autoimmune or rheumatologic disorders
Previous hospitalizations or surgical procedures
Medication history, including complementary and alternative medicines

Physical Examination

A thorough physical examination should be performed, with particular attention paid to the following:

Vital signs, including temperature pattern
Lymphadenopathy
Skin rashes or lesions
Musculoskeletal system (joint swelling or tenderness)
Abdominal examination (hepatosplenomegaly, masses, or tenderness)
Neurological examination

Laboratory Investigations

Initial laboratory investigations should include:

Complete blood count with differential
Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
Comprehensive metabolic panel
Urinalysis
Blood cultures (if bacteremia is suspected)

Additional tests may be ordered based on the suspected etiology, such as:

Serological tests for viral, bacterial, or parasitic infections
Autoimmune and rheumatologic workup (e.g., antinuclear antibodies, rheumatoid factor)
Imaging studies (e.g., chest X-ray, computed tomography, or magnetic resonance imaging)
Bone marrow aspiration and biopsy (if malignancy is suspected)

Diagnostic Approach

The diagnostic approach to FUO in children involves a stepwise process of clinical observation, laboratory testing, and targeted investigations based on the suspected etiology.

Initial Evaluation

The initial evaluation should focus on identifying potential infectious causes, as these are the most common etiologies of FUO in children. This includes a thorough history, physical examination, and baseline laboratory investigations, as mentioned earlier.

If an infectious cause is suspected, appropriate diagnostic tests (e.g., blood cultures, serological testing, imaging studies) should be performed. In some cases, empiric antimicrobial therapy may be initiated while awaiting test results.

Evaluation for Noninfectious Causes

If the initial evaluation does not reveal an infectious cause, further investigations should be directed toward noninfectious etiologies, such as autoimmune or rheumatologic disorders and malignancies.

For autoimmune or rheumatologic disorders, a comprehensive rheumatologic workup, including antinuclear antibodies, rheumatoid factor, and other disease-specific tests, may be warranted. Imaging studies (e.g., ultrasound, computed tomography, or magnetic resonance imaging) may also be helpful in identifying potential sources of inflammation or organ involvement.

If malignancy is suspected, a bone marrow aspiration and biopsy should be considered, along with appropriate imaging studies to identify potential masses or lymphadenopathy.

Empiric Treatment and Therapeutic Trials

In some cases, particularly when the diagnostic evaluation is inconclusive, empiric treatment or therapeutic trials may be considered. This approach involves initiating targeted therapy and observing the patient's response.

For example, in cases where tuberculosis is suspected but not confirmed, a trial of anti-tuberculosis therapy may be initiated, with close monitoring for clinical improvement or resolution of fever. Similarly, in cases where an autoinflammatory disorder is suspected, a trial of corticosteroids or other immunomodulatory agents may be considered.

It is important to note that empiric treatment or therapeutic trials should be undertaken with caution and under close medical supervision, as they carry potential risks and may delay definitive diagnosis and treatment.

Management

The management of FUO in children is guided by the underlying etiology and may involve a multidisciplinary approach involving pediatricians, infectious disease specialists, rheumatologists, and other relevant specialists.

Antimicrobial Therapy

If an infectious cause is identified, appropriate antimicrobial therapy should be initiated promptly, based on the specific pathogen and antimicrobial susceptibility patterns. In some cases, prolonged courses of antimicrobial therapy may be required, particularly for conditions like endocarditis or osteomyelitis.

Immunomodulatory and Anti-inflammatory Therapy

For autoimmune or rheumatologic disorders, immunomodulatory agents, such as corticosteroids, disease-modifying antirheumatic drugs (DMARDs), or biologic agents, may be prescribed to control inflammation and manage the underlying condition.

Antineoplastic Therapy

If a malignancy is identified as the cause of FUO, appropriate antineoplastic therapy, such as chemotherapy, radiation therapy, or targeted therapies, may be initiated. Close collaboration with pediatric oncologists and hematologists is essential for effective management.

Supportive Care

Regardless of the underlying etiology, supportive care measures are crucial in the management of FUO in children. These may include:

Antipyretic medications (e.g., acetaminophen, ibuprofen) to control fever and associated symptoms
Adequate hydration and nutritional support
Pain management, if necessary
Monitoring for and addressing potential complications (e.g., electrolyte imbalances, organ dysfunction)

Prognosis and Follow-up

The prognosis of FUO in children is highly dependent on the underlying etiology and the promptness of diagnosis and treatment. In general, infectious causes and some autoimmune disorders have a better prognosis when treated appropriately, while malignancies and certain rheumatologic diseases may have a more guarded prognosis.

Regular follow-up and monitoring are essential to assess treatment response, identify potential complications, and adjust management strategies as needed. Multidisciplinary care involving pediatricians, specialists, and allied health professionals (e.g., physiotherapists, dietitians) may be necessary for comprehensive management and rehabilitation.

Prevention

Prevention strategies for FUO in children primarily focus on reducing the risk of infectious diseases through appropriate immunizations, practicing good hygiene, and avoiding potential sources of exposure (e.g., animal contacts, travel to endemic areas).

For autoimmune and rheumatologic disorders, early recognition and prompt treatment may help prevent or mitigate the development of FUO and associated complications. Regular medical follow-up and adherence to prescribed treatment regimens are important preventive measures.