Approach to fever without focus in an infant

1. Introduction and Definitions

Fever is one of the most common reasons for pediatric emergency visits. Fever Without Focus (FWF), also known as Fever Without a Source (FWS), is defined as an acute febrile illness (rectal temperature $\ge$ 38°C or 100.4°F) in a child younger than 36 months of age in whom the etiology of the fever is not apparent after a careful history and physical examination.

The primary clinical challenge in managing FWF is distinguishing the vast majority of infants with self-limiting viral infections from the minority with Serious Bacterial Infections (SBI) or Invasive Bacterial Infections (IBI).

• SBI includes urinary tract infection (UTI), bacteremia, and meningitis.
• IBI specifically refers to bacteremia and bacterial meningitis.

Management strategies are strictly age-dependent due to the changing epidemiology of pathogens and the maturity of the host immune system. The age groups are generally stratified into:

1. Neonates: <28 days (or <1 month)
2. Young Infants: 29–90 days (1–3 months)
3. Older Infants/Toddlers: 3–36 months.

2. Epidemiology and Etiology

2.1. Prevalence of SBI

• Neonates (<28 days): The risk of SBI is highest in this group (7–13%), necessitating aggressive management. Bacteremia occurs in 1–2% and meningitis in 0.2–0.5%.
• Young Infants (29–90 days): Risk decreases but remains significant. UTI is the most common SBI (5–13%).
• Older Infants (3–36 months): With the advent of conjugate vaccines (Hib and Pneumococcal), the rate of occult bacteremia has dropped to <1% in fully immunized children.

2.2. Common Pathogens

• Bacteria:
  • Escherichia coli is the most common pathogen overall (especially for UTI and bacteremia).
  • Group B Streptococcus (GBS) remains a major concern in neonates.
  • Listeria monocytogenes (rare, but relevant in neonates).
  • Streptococcus pneumoniae and Neisseria meningitidis (less common in immunized populations but critical in unimmunized infants).
• Viruses: The majority of FWF cases are viral. Common agents include Enterovirus, Respiratory Syncytial Virus (RSV), Influenza, Human Parechovirus, and Adenovirus. Herpes Simplex Virus (HSV) must be considered in neonates.

3. Initial Clinical Evaluation

3.1. History

A detailed history helps identify potential sources or high-risk features:

• Fever history: Duration, method of measurement, maximum temperature.
• Perinatal history: Maternal fever, GBS status, rupture of membranes, prematurity.
• Symptoms: Changes in feeding, crying pattern, activity, vomiting, diarrhea, or respiratory symptoms.
• Sick contacts: Household illnesses.
• Immunization status: Particularly Hib and Pneumococcal vaccines.

3.2. Physical Examination

The goal is to identify a focus of infection (e.g., otitis media, soft tissue infection) or signs of systemic toxicity.

• General Appearance: Assessment of the "toxic" appearance is crucial. Signs include lethargy, poor perfusion, hypoventilation, hyperventilation, or cyanosis.
• Red Flag Signs: In infants, red flags for serious illness include drowsiness, inconsolability, poor peripheral circulation, decreased skin elasticity, hypotension, and petechial rash.
• Vital Signs: Tachycardia, tachypnea, and temperature instability (hypothermia or hyperthermia).

4. Management Protocol by Age Group

The management is stratified by age due to the varying risk of SBI.

4.1. Neonates (0–28 Days)

Fever in a neonate is considered a medical emergency due to the immature immune system and unreliable clinical signs.

Approach:

1. Hospitalization: All febrile neonates should ideally be hospitalized.
2. Full Sepsis Evaluation: This is mandatory and includes:
   • Blood: Complete blood count (CBC), blood culture, inflammatory markers (CRP, Procalcitonin).
   • Urine: Urinalysis and urine culture (obtained by catheterization or suprapubic aspiration, not bag specimen).
   • CSF: Lumbar puncture (LP) for cell count, glucose, protein, Gram stain, and culture.
   • Viral Testing: Consider HSV PCR (if risk factors or vesicles present) and Enterovirus PCR (during season).
   • Chest X-ray: Indicated if respiratory signs are present (tachypnea, desaturation).

Treatment:

• Empiric Antibiotics: Parenteral antibiotics must be started immediately after cultures are obtained.
  • Regimen: Ampicillin (for Listeria and Enterococcus) PLUS Cefotaxime OR Gentamicin/Amikacin (for Gram-negatives like E. coli).
  • Acyclovir: Add high-dose IV acyclovir (60 mg/kg/day) if there is concern for HSV (seizures, vesicles, elevated liver enzymes, maternal history).

4.2. Young Infants (29–60 Days)

This is a "gray zone" where management depends on risk stratification. The goal is to identify "low-risk" infants who may be managed with less invasive testing or outpatient observation.

Step 1: Determine Risk Status Infants are considered High Risk if they appear ill/toxic or have abnormal vital signs. These infants require full sepsis workup, admission, and parenteral antibiotics.

Step 2: Evaluation for Well-Appearing Infants For well-appearing infants, laboratory screening is used to define low risk (e.g., Rochester, Philadelphia, or Boston criteria concepts).

• Mandatory Tests: Urinalysis and Urine culture (UTI is the most common SBI), Blood culture, Inflammatory markers (Procalcitonin, CRP, ANC).
• Lumbar Puncture (LP):
  • 29–60 days: If inflammatory markers (e.g., Procalcitonin >0.5 ng/mL, CRP >20 mg/L, ANC >4000/mm³) are abnormal, LP is recommended.
  • If markers are normal ("Low Risk"), LP may be deferred, and the infant may be observed.

Step 3: Management based on Risk

• Low Risk (Normal labs, well-appearing):
  • Can be managed as outpatients without antibiotics if close follow-up (within 12-24 hours) is ensured.
  • Alternatively, may receive Ceftriaxone (IM/IV) pending cultures, but this requires 24-hour follow-up.
• High Risk (Abnormal labs):
  • Requires LP and hospitalization.
  • Start parenteral antibiotics (e.g., Ceftriaxone or Cefotaxime) pending culture results.

4.3. Older Infants and Toddlers (3–36 Months)

Management depends heavily on immunization status and the severity of fever.

A. Toxic/Ill-Appearing Child:

• Admit to hospital.
• Full septic screen (Blood, Urine, CSF).
• Start parenteral antibiotics (Ceftriaxone/Cefotaxime).

B. Well-Appearing, Fully Immunized:

• Risk: The risk of occult bacteremia is very low (<1%). The primary risk is UTI.
• Urinalysis: Recommended for:
  • Females <24 months.
  • Uncircumcised males <12 months.
  • Circumcised males <6 months.
  • Any child with history of recurrent UTI.
• Blood Tests: CBC and blood culture are not routinely indicated unless fever is prolonged or no focus is found after initial evaluation.
• Chest X-ray: Only if respiratory signs (tachypnea, hypoxia, focal findings) are present.
• Management: If UA is negative, discharge with reassurance and antipyretics. Return if fever persists >48 hours or condition worsens.

C. Well-Appearing, Under-Immunized:

• Risk of occult bacteremia (Pneumococcal/Hib) is higher.
• Evaluation: Consider CBC and Blood Culture.
• Treatment: If WBC >15,000/mm³, consider empiric Ceftriaxone (50 mg/kg) followed by 24-hour outpatient follow-up.

5. Specific Diagnostic Considerations

5.1. Urine Studies

Since UTI is the most common SBI across all age groups, a valid urine specimen is critical.

• Collection: Catheterization or suprapubic aspiration is preferred for culture in infants <2 years. Bag specimens have high contamination rates and should generally be used only for screening (negative urinalysis rules out UTI).
• Urinalysis: Presence of leukocyte esterase, nitrites, or pyuria (>5 WBC/hpf) suggests UTI.

5.2. Inflammatory Markers

Current guidelines emphasize the use of inflammatory markers to stratify risk in the 29–60 day age group.

• Procalcitonin (PCT): High sensitivity for Invasive Bacterial Infection. A value >0.5 ng/mL is considered elevated.
• C-Reactive Protein (CRP): A value >20 mg/L is considered elevated.
• Absolute Neutrophil Count (ANC): >4000–5200/mm³ may indicate higher risk.

5.3. Viral Testing

• Rapid Viral Panels: Testing for RSV, Influenza, or COVID-19 can be useful. A positive viral test reduces (but does not eliminate) the risk of bacteremia or meningitis. However, the risk of UTI remains significant even in infants with viral bronchiolitis. Therefore, urinalysis should still be performed in febrile infants with viral symptoms.

6. Treatment Protocols (Summary)

Note: Doses: Ampicillin 100-200 mg/kg/day; Cefotaxime 150-200 mg/kg/day; Ceftriaxone 50-75 mg/kg/day (100 mg/kg for meningitis).

7. Discharge and Follow-up

For infants managed as outpatients, strict discharge criteria must be met:

1. Reliability: Parents must be reliable and able to return immediately if the child worsens.
2. Access: Access to a telephone and transportation.
3. Follow-up: Guaranteed follow-up within 12–24 hours (re-evaluation).

If cultures (blood/urine/CSF) become positive:

• Blood: Patient must be recalled immediately for admission and parenteral antibiotics.
• Urine: If the child is well, oral antibiotics may be initiated based on sensitivity. If ill, admit for parenteral therapy.