Fever of Unknown Origin: Clinical Case and Viva Q&A

Clinical Case of Fever of Unknown Origin in Children

A 6-year-old boy is brought to the pediatric clinic by his parents with complaints of persistent fever for the past 3 weeks. The fever has been intermittent, ranging from 38.5°C to 39.5°C, typically higher in the evenings. The child has experienced occasional chills but no rigors.

History

• No specific pattern to the fever
• No recent travel history
• No known exposure to infectious diseases
• Up-to-date on vaccinations
• No pets at home
• No history of recurrent infections

Associated Symptoms

• Mild fatigue and decreased appetite
• No weight loss
• No night sweats
• No rash or joint pain
• No abdominal pain or changes in bowel habits
• No respiratory or urinary symptoms

Physical Examination

• Temperature: 38.7°C
• Heart Rate: 110 bpm
• Respiratory Rate: 22/min
• Blood Pressure: 100/60 mmHg
• Weight: 20 kg (slight decrease from last visit 2 months ago)
• General: Alert, mildly pale, no apparent distress
• HEENT: No pharyngeal erythema, no lymphadenopathy
• Chest: Clear breath sounds bilaterally, no murmurs
• Abdomen: Soft, non-tender, no hepatosplenomegaly
• Skin: No rashes or lesions
• Musculoskeletal: No joint swelling or tenderness
• Neurological: Grossly intact

Initial Laboratory Results

• WBC: 7,500/μL (slightly elevated neutrophils)
• Hemoglobin: 11.2 g/dL
• Platelets: 280,000/μL
• ESR: 55 mm/hr
• CRP: 3.5 mg/dL
• Urinalysis: Normal
• Blood and urine cultures: Pending

Assessment

The patient presents with classic features of fever of unknown origin in the pediatric population: fever >38.3°C (101°F) of at least 8 days duration, with no apparent diagnosis despite initial outpatient or hospital evaluation. The normal physical examination and nonspecific laboratory findings necessitate further investigation.

Plan

1. Admit for further evaluation and management
2. Complete blood count with differential, comprehensive metabolic panel
3. Blood cultures (aerobic and anaerobic)
4. Chest X-ray
5. Abdominal ultrasound
6. Consider testing for EBV, CMV, and other viral etiologies
7. If fever persists, consider advanced imaging (CT or MRI) and rheumatologic workup
8. Consult infectious disease and rheumatology specialists as needed

This case highlights the challenge of diagnosing FUO in children and the need for a systematic approach to evaluation.

Clinical Presentations

Varieties of Clinical Presentations in Pediatric FUO

1. Classic FUO with Nonspecific Symptoms

   • Persistent fever (>38.3°C) for ≥8 days
   • Fatigue and decreased activity
   • Mild appetite loss
   • No localizing signs

2. FUO with Predominant Gastrointestinal Symptoms

   • Fever accompanied by abdominal pain
   • Changes in bowel habits (diarrhea or constipation)
   • Possible nausea or vomiting
   • May suggest inflammatory bowel disease or abdominal abscess

3. FUO with Musculoskeletal Manifestations

   • Fever with joint pain or swelling
   • Morning stiffness
   • Muscle aches
   • May indicate juvenile idiopathic arthritis or other rheumatologic conditions

4. FUO with Recurrent Episodes

   • Periodic fever syndromes
   • Episodes of high fever alternating with periods of normal temperature
   • May be accompanied by rash, joint pain, or abdominal pain
   • Examples include PFAPA syndrome, Familial Mediterranean Fever

5. FUO with Respiratory Focus

   • Fever with subtle respiratory symptoms
   • Mild cough or tachypnea
   • Normal or near-normal chest examination
   • May indicate occult pneumonia or tuberculosis

6. FUO with Hematologic Abnormalities

   • Fever with pallor or easy bruising
   • Lymphadenopathy or hepatosplenomegaly
   • Abnormal blood counts
   • May suggest leukemia or lymphoma

7. FUO with Neurological Symptoms

   • Fever with headache, neck stiffness, or altered mental status
   • Subtle neurological deficits
   • May indicate central nervous system infection or autoimmune encephalitis

8. FUO in Immunocompromised Children

   • Fever in a child with known immunodeficiency or on immunosuppressive therapy
   • May have subtle or atypical presentations of common infections
   • Higher risk of opportunistic infections

9. FUO with Dermatological Manifestations

   • Fever accompanied by rash or skin lesions
   • Rash may be subtle or transient
   • May suggest viral exanthems, Kawasaki disease, or systemic juvenile idiopathic arthritis

10. FUO with Occult Dental or ENT Focus

    • Fever without apparent source
    • Subtle signs of dental abscess or sinusitis
    • May require specialized ENT examination or imaging to diagnose

Viva Questions and Answers

1. Q: How is Fever of Unknown Origin (FUO) defined in pediatrics?

   A: In pediatrics, FUO is typically defined as a fever >38.3°C (101°F) lasting for at least 8 days with no apparent diagnosis despite initial outpatient or hospital evaluation. This definition helps distinguish FUO from more common acute febrile illnesses in children.

2. Q: What are the major categories of causes for FUO in children?

   A: The major categories include: 1. Infections (e.g., occult bacterial infections, viral infections, parasitic diseases) 2. Rheumatologic/autoimmune disorders (e.g., juvenile idiopathic arthritis, systemic lupus erythematosus) 3. Malignancies (e.g., leukemia, lymphoma) 4. Miscellaneous (e.g., drug fever, factitious fever) 5. Undiagnosed (a significant proportion of cases may remain undiagnosed)

3. Q: How does the etiology of FUO differ between developed and developing countries?

   A: In developed countries, infections account for about 30-40% of FUO cases, with autoimmune diseases and malignancies being significant causes. In developing countries, infections are more predominant, accounting for up to 60% of cases, with tuberculosis being a common etiology. Malaria, enteric fever, and visceral leishmaniasis are also more common in developing regions.

4. Q: What are some key components of the initial evaluation of a child with FUO?

   A: Key components include: 1. Detailed history (including travel, animal exposures, medications) 2. Thorough physical examination (repeated over time) 3. Complete blood count with differential 4. Inflammatory markers (ESR, CRP) 5. Blood and urine cultures 6. Chest X-ray 7. Abdominal ultrasound 8. Tuberculin skin test or interferon-gamma release assay

5. Q: How does age affect the differential diagnosis of FUO in children?

   A: Age significantly influences the differential diagnosis: - Neonates: Bacterial infections are more common (e.g., sepsis, UTI) - Infants and toddlers: Viral infections and occult bacterial infections are frequent - School-age children: Autoimmune diseases become more prevalent - Adolescents: Malignancies and inflammatory bowel disease should be considered

6. Q: What is the role of imaging studies in the evaluation of FUO?

   A: Imaging studies play a crucial role: 1. Chest X-ray: To detect occult pneumonia or hilar lymphadenopathy 2. Abdominal ultrasound: To evaluate for abscesses, lymphadenopathy, or organomegaly 3. CT or MRI: For detailed evaluation of specific areas based on clinical suspicion 4. Nuclear medicine studies (e.g., PET-CT): Can be helpful in localizing inflammatory foci 5. Echocardiogram: To evaluate for endocarditis or myocarditis

7. Q: Describe the approach to antibiotic use in a child with FUO.

   A: The approach to antibiotic use in FUO should be cautious: 1. Avoid empiric antibiotics unless there's strong suspicion of a bacterial infection 2. If antibiotics are started, they should be broad-spectrum and based on likely pathogens 3. Reassess the need for antibiotics frequently 4. Consider discontinuing antibiotics if there's no clinical improvement and cultures remain negative 5. Specific antibiotic therapy should be guided by identified pathogens and susceptibilities

8. Q: What are some important infectious causes of FUO in children that might be missed on initial evaluation?

   A: Important infectious causes that might be missed include: 1. Occult osteomyelitis 2. Bartonellosis (cat-scratch disease) 3. Tuberculosis 4. Epstein-Barr virus infection 5. Cytomegalovirus infection 6. Brucellosis 7. Q fever 8. Parasitic infections (e.g., toxoplasmosis, visceral leishmaniasis) 9. Infective endocarditis 10. Occult dental abscesses

9. Q: How does juvenile idiopathic arthritis (JIA) present as a cause of FUO?

   A: JIA, particularly systemic JIA, can present as FUO: 1. High spiking fevers, often with a characteristic double quotidian pattern 2. Evanescent salmon-pink rash 3. Arthritis may not be evident initially 4. Hepatosplenomegaly and lymphadenopathy may be present 5. Elevated inflammatory markers (ESR, CRP) 6. Anemia and thrombocytosis are common 7. Ferritin levels are often markedly elevated

10. Q: What malignancies should be considered in a child with FUO?

    A: Malignancies to consider include: 1. Leukemia (particularly acute lymphoblastic leukemia) 2. Lymphoma (both Hodgkin and non-Hodgkin) 3. Neuroblastoma 4. Wilms tumor 5. Hepatoblastoma 6. Langerhans cell histiocytosis 7. Hemophagocytic lymphohistiocytosis (which may be associated with malignancies)

11. Q: Describe the characteristics of periodic fever syndromes.

    A: Periodic fever syndromes are characterized by: 1. Recurrent episodes of fever with symptom-free intervals 2. Often have a genetic basis 3. May be accompanied by specific symptoms during episodes (e.g., abdominal pain, rash) 4. Examples include Familial Mediterranean Fever, TRAPS, HIDS, and PFAPA syndrome 5. Diagnosis often based on clinical criteria and genetic testing 6. Treatment may involve anti-inflammatory medications or targeted therapies

12. Q: How does factitious fever present, and how is it diagnosed?

    A: Factitious fever, also known as Munchausen syndrome by proxy when induced by a caregiver, can present as: 1. Inconsistent fever patterns 2. Lack of associated symptoms or signs of illness 3. Normal laboratory findings despite reported high fevers 4. Fever that doesn't respond to antipyretics 5. Diagnosis involves: - Careful observation in a controlled setting - Use of tamper-proof electronic thermometers - Separation from the suspected inducing caregiver - Psychological evaluation of the child and family 6. It's a diagnosis of exclusion and requires a multidisciplinary approach

13. Q: What is the role of bone marrow examination in the evaluation of FUO?

    A: Bone marrow examination in FUO: 1. Not routinely performed in initial evaluation 2. Considered when there are hematologic abnormalities or strong suspicion of malignancy 3. Can diagnose leukemia, lymphoma, and metastatic solid tumors 4. May reveal hemophagocytosis in HLH 5. Can identify some infections (e.g., leishmaniasis, tuberculosis) 6. Usually includes aspiration and biopsy 7. Timing is crucial - often reserved for cases where diagnosis remains elusive after initial workup

14. Q: How does Kawasaki disease present as a cause of FUO?

    A: Kawasaki disease can present as FUO with: 1. Fever lasting ≥5 days, often high and unremitting 2. Incomplete cases may not show all classic criteria initially 3. Other features developing over time: - Bilateral non-exudative conjunctivitis - Oral mucous membrane changes - Peripheral extremity changes - Polymorphous rash - Cervical lymphadenopathy 4. Elevated inflammatory markers (ESR, CRP) 5. Thrombocytosis in the second week of illness 6. Potential for coronary artery aneurysms, necessitating early diagnosis and treatment

15. Q: What is the utility of serial C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) measurements in FUO?

    A: Serial CRP and ESR measurements in FUO: 1. Help track the inflammatory process over time 2. CRP rises and falls more quickly than ESR, reflecting acute changes 3. Persistently elevated levels suggest ongoing inflammation 4. Decreasing levels may indicate response to treatment 5. Normal levels don't exclude serious pathology (e.g., can be normal in malignancies) 6. Very high levels may suggest bacterial infection or autoimmune disease 7. Useful in monitoring response to empiric treatments 8. Should be interpreted in conjunction with clinical findings and other tests

16. Q: Describe the approach to a child with FUO and recent travel history.

    A: Approach to FUO with recent travel history: 1. Detailed travel history (locations, activities, exposures) 2. Consider region-specific infections: - Malaria in endemic areas - Dengue in tropical regions - Typhoid fever in areas with poor sanitation 3. Evaluate for parasitic infections (e.g., schistosomiasis, visceral leishmaniasis) 4. Consider post-travel vaccinations and prophylaxis 5. Consult infectious disease specialists 6. Specific tests based on exposures: - Thick and thin blood smears for malaria - Serologies for arboviruses - Stool studies for parasites 7. Consider prolonged incubation periods of some travel-related infections 8. Assess for non-infectious travel-related causes (e.g., venous thromboembolism)

17. Q: What is the role of procalcitonin in the evaluation of FUO?

    A: Procalcitonin in FUO evaluation: 1. More specific for bacterial infections than CRP or ESR 2. Can help differentiate bacterial from viral infections 3. May be elevated in some non-infectious inflammatory conditions 4. Useful in deciding whether to initiate or continue antibiotics 5. Serial measurements can guide antibiotic duration 6. Normal levels don't completely exclude bacterial infection 7. Interpretation should consider the clinical context 8. May be less reliable in certain conditions (e.g., malaria, fungal infections) 9. Not a standalone test but part of a comprehensive evaluation

18. Q: How does central nervous system (CNS) vasculitis present as a cause of FUO?

    A: CNS vasculitis presenting as FUO: 1. Fever may be the initial or predominant symptom 2. Neurological symptoms may be subtle or fluctuating: - Headache - Cognitive changes - Focal neurological deficits 3. Can be primary CNS vasculitis or secondary to systemic diseases 4. Laboratory findings often nonspecific (elevated ESR/CRP) 5. CSF analysis may show mild pleocytosis and elevated protein 6. Neuroimaging (MRI) may show ischemic lesions or vessel wall enhancement 7. Cerebral angiography may demonstrate vascular abnormalities 8. Brain biopsy may be necessary for definitive diagnosis 9. High index of suspicion needed as presentation can be insidious

19. Q: What is the approach to fever in a neutropenic child?

    A: Approach to fever in a neutropenic child: 1. Consider as medical emergency due to high risk of severe infection 2. Define as single temperature ≥38.3°C or ≥38.0°C for ≥1 hour 3. Immediate evaluation: - Thorough physical exam, including mucous membranes and catheter sites - Blood cultures (peripheral and central line if present) - Complete blood count, renal and liver function tests - Chest X-ray if respiratory symptoms present 4. Empiric broad-spectrum antibiotics within 60 minutes of presentation 5. Consider antifungal therapy if fever persists >4-7 days 6. G-CSF may be used to shorten duration of neutropenia 7. Isolation precautions as appropriate 8. Serial monitoring of clinical status and laboratory parameters 9. Tailor antibiotics based on culture results and clinical course

20. Q: How does hemophagocytic lymphohistiocytosis (HLH) present in the context of FUO?

    A: HLH presenting as FUO: 1. Persistent high fever unresponsive to antibiotics 2. Hepatosplenomegaly 3. Cytopenias (affecting ≥2 cell lines) 4. Hyperferritinemia (often >10,000 ng/mL) 5. Hypertriglyceridemia and/or hypofibrinogenemia 6. Hemophagocytosis in bone marrow, spleen, or lymph nodes 7. Low or absent NK cell activity 8. Elevated soluble CD25 (IL-2 receptor) 9. Can be primary (genetic) or secondary (triggered by infections, malignancies, rheumatologic disorders) 10. Neurological symptoms may be present 11. Rapid deterioration possible, requiring high index of suspicion and prompt treatment

21. Q: What is the role of positron emission tomography (PET) in evaluating FUO?

    A: Role of PET in FUO evaluation: 1. Can detect areas of increased metabolic activity suggestive of inflammation or malignancy 2. Particularly useful when conventional imaging is negative 3. Can guide biopsy of suspicious lesions 4. Helpful in detecting occult infections, vasculitis, and malignancies 5. May reveal multifocal disease not apparent on other imaging modalities 6. Can be combined with CT (PET-CT) for better anatomical localization 7. Higher sensitivity compared to gallium scans 8. Limitations include: - Exposure to radiation (consideration in children) - False positives (e.g., brown fat, muscle uptake) - Cost and availability 9. Interpretation requires correlation with clinical and laboratory findings

22. Q: How does drug-induced fever present, and what is the approach to diagnosis?

    A: Drug-induced fever: 1. Can occur with any medication, but some are more commonly implicated (e.g., antibiotics, anticonvulsants) 2. Usually occurs within 7-10 days of starting the medication 3. Fever patterns can vary (continuous, remittent, or periodic) 4. May be accompanied by rash (especially in drug hypersensitivity syndromes) 5. Diagnosis approach: - Detailed medication history, including over-the-counter and herbal remedies - Temporal relationship between drug initiation and fever onset - Exclusion of other causes of fever - Consider drug levels if applicable - Look for other signs of drug reaction (eosinophilia, liver function abnormalities) 6. Diagnostic challenge: fever resolution typically occurs within 48-72 hours of drug discontinuation 7. Re-challenge is generally not recommended due to risk of severe reactions

23. Q: What is the significance of ferritin levels in the evaluation of FUO?

    A: Significance of ferritin levels in FUO: 1. Acute phase reactant, elevated in various inflammatory conditions 2. Extremely high levels (>10,000 ng/mL) suggest: - Hemophagocytic lymphohistiocytosis (HLH) - Adult-onset Still's disease (systemic JIA in children) - Severe sepsis 3. Moderately elevated levels seen in: - Infections - Malignancies - Autoimmune diseases 4. Can help differentiate between infectious and non-infectious causes 5. Serial measurements useful in monitoring disease activity 6. Interpretation should consider: - Iron status (can be elevated in iron overload conditions) - Liver function (ferritin is produced by the liver) 7. Normal levels don't exclude significant pathology 8. Part of the diagnostic criteria for HLH 9. Can guide further diagnostic testing (e.g., bone marrow examination in very high levels)

24. Q: How does inflammatory bowel disease (IBD) present as a cause of FUO in children?

    A: IBD presenting as FUO in children: 1. Fever may precede gastrointestinal symptoms 2. Associated symptoms may be subtle: - Mild abdominal pain - Weight loss or poor growth - Fatigue - Extraintestinal manifestations (e.g., arthritis, skin lesions) 3. Laboratory findings: - Anemia (often microcytic) - Elevated inflammatory markers (ESR, CRP) - Hypoalbuminemia - Elevated fecal calprotectin 4. Crohn's disease more likely than ulcerative colitis to present as FUO 5. Diagnosis may require: - Endoscopy and biopsy - Imaging studies (MR enterography, capsule endoscopy) 6. Consider in adolescents with unexplained fever and weight loss 7. Family history may be relevant 8. Early involvement of gastroenterology for suspected cases

25. Q: What is the approach to fever in a child with a central venous catheter?

    A: Approach to fever in a child with a central venous catheter: 1. Consider catheter-related bloodstream infection as a primary cause 2. Obtain blood cultures: - From all catheter lumens - Peripheral blood culture 3. Evaluate catheter exit site for signs of infection 4. Consider catheter-sparing antibiotic treatment initially: - Broad-spectrum coverage including gram-positive and gram-negative organisms - Consider local antibiotic resistance patterns 5. Assess need for catheter removal based on: - Patient's clinical status - Organism identified (e.g., S. aureus, Candida spp. often require removal) - Persistence of positive cultures despite appropriate antibiotics 6. Use differential time to positivity of central vs. peripheral cultures to aid diagnosis 7. Consider echocardiography to evaluate for endocarditis in persistent bacteremia 8. Antibiotic lock therapy may be considered for salvaging the catheter in some cases 9. Duration of antibiotics typically 10-14 days, longer if complicated

26. Q: How does one approach the diagnosis of tuberculous disease in a child with FUO?

    A: Approach to diagnosing tuberculosis in FUO: 1. Consider in all cases, especially in endemic areas or with relevant exposures 2. Detailed history: - TB contacts - Travel to endemic areas - BCG vaccination status 3. Physical examination: - Lymphadenopathy (especially cervical) - Respiratory findings may be subtle or absent 4. Tuberculin skin test (TST) or Interferon-Gamma Release Assay (IGRA) - False negatives possible in severe disease or malnutrition 5. Chest X-ray: - May show hilar lymphadenopathy, infiltrates, or miliary pattern 6. Microbiological confirmation: - Sputum (induced sputum in younger children) - Gastric aspirates in infants - Consider bronchoalveolar lavage 7. Molecular tests (e.g., Xpert MTB/RIF) for rapid detection 8. Culture remains gold standard but takes several weeks 9. Consider extrapulmonary TB: - CNS (lumbar puncture) - Abdominal (ultrasound, ascitic fluid analysis) - Bone/joint involvement 10. Empiric treatment may be necessary if high suspicion despite negative initial tests