Fever Without a Focus in the Neonate and Young Infant

Fever in a neonate (birth to 28 days) or young infant (29 days to 3 months) is considered a medical emergency due to their immature immune systems and higher susceptibility to serious bacterial infections. A fever without a clear source or focus (FWF) in this age group warrants immediate evaluation and empiric antibiotic therapy until a definitive diagnosis is made and the risk of a serious bacterial infection (SBI) is ruled out.

Definition and Epidemiology

Fever is defined as a rectal temperature of ≥38°C (100.4°F) in neonates and young infants. FWF refers to a febrile infant without an apparent source or focus of infection on initial history and physical examination. The incidence of SBI in febrile neonates and young infants ranges from 8% to 12%, with higher rates reported in neonates (<28 days) compared to older infants (29 days to 3 months).

Etiology and Risk Factors

The most common causes of SBI in febrile neonates and young infants include urinary tract infections (UTIs), bacteremia, meningitis, and pneumonia. Other less common but significant causes include osteomyelitis, septic arthritis, and gastrointestinal infections (e.g., enteritis, peritonitis).

Risk factors for SBI in this age group include:

Younger age (neonates at higher risk than older infants)
Prematurity and low birth weight
Prolonged rupture of membranes (>18 hours)
Maternal chorioamnionitis or intrapartum fever
Inadequate intrapartum antibiotic prophylaxis
Perinatal complications (e.g., fetal distress, instrumented delivery)
Underlying medical conditions (e.g., congenital heart disease, immunodeficiency)

Clinical Presentation

The clinical presentation of FWF in neonates and young infants can be nonspecific and subtle, making it challenging to identify the source of infection. Common signs and symptoms may include:

Fever (rectal temperature ≥38°C or 100.4°F)
Irritability or lethargy
Poor feeding or decreased appetite
Vomiting or diarrhea
Respiratory distress or tachypnea
Jaundice or pallor
Abdominal distension or tenderness

It is important to note that some infants may present with hypothermia (low body temperature) rather than fever, which can be a sign of severe illness.

Diagnostic Evaluation

The diagnostic evaluation of FWF in neonates and young infants aims to identify the source of infection, assess the risk of SBI, and guide appropriate management. The following investigations are typically recommended:

History and Physical Examination

A detailed history, including prenatal, perinatal, and postnatal events, should be obtained. A thorough physical examination, with particular attention to vital signs, hydration status, and examination of the skin, eyes, ears, nose, throat, lungs, heart, abdomen, and extremities, is essential.

Laboratory Studies

Complete blood count (CBC): Leukocytosis, leukopenia, or immature neutrophils (bands) may indicate bacterial infection.
C-reactive protein (CRP): Elevated CRP levels can suggest bacterial infection but may be normal in early stages.
Blood culture: Obtained to detect bacteremia and identify the causative organism.
Urinalysis and urine culture: To identify UTIs, which are a common source of SBI in this age group.
Cerebrospinal fluid (CSF) analysis: Lumbar puncture for CSF analysis (cell count, protein, glucose, culture, and other tests) is recommended to rule out meningitis, especially in neonates and infants with concerning clinical or laboratory findings.

Imaging Studies

Chest X-ray: Recommended if respiratory symptoms or signs are present to evaluate for pneumonia.
Abdominal ultrasound or CT scan: May be considered if intra-abdominal pathology is suspected.
Other imaging studies: Such as bone scans or MRI may be indicated if osteomyelitis or septic arthritis is suspected based on physical examination findings or elevated inflammatory markers.

Management

The management of FWF in neonates and young infants involves empiric antibiotic therapy and hospitalization for further evaluation and monitoring.

Empiric Antibiotic Therapy

Empiric broad-spectrum antibiotic therapy should be initiated promptly after obtaining appropriate cultures. The choice of antibiotics depends on the infant's age, risk factors, and local antibiotic resistance patterns. Commonly used regimens include:

Neonates: Ampicillin and an aminoglycoside (e.g., gentamicin) or a third-generation cephalosporin (e.g., cefotaxime) to cover common gram-positive and gram-negative pathogens, as well as Listeria monocytogenes.
Young infants: A third-generation cephalosporin (e.g., ceftriaxone) or a combination of ampicillin and gentamicin may be used.

Antibiotic therapy should be adjusted based on culture results and clinical response.

Hospitalization and Supportive Care

Hospitalization is recommended for close monitoring, supportive care (e.g., intravenous fluids, respiratory support), and further diagnostic evaluation. The duration of hospitalization and antibiotic therapy depends on the clinical course, culture results, and response to treatment.

Follow-up

Infants with FWF should be closely followed after discharge, with prompt re-evaluation if fever persists or new symptoms develop. Appropriate follow-up with the primary care provider or a pediatric infectious disease specialist may be necessary for ongoing management and monitoring.

Prevention

Prevention strategies for FWF in neonates and young infants include:

Appropriate prenatal care and screening for maternal infections
Judicious use of intrapartum antibiotic prophylaxis for Group B Streptococcus colonization or risk factors
Prompt recognition and treatment of maternal chorioamnionitis
Promotion of breastfeeding and good hygiene practices
Timely administration of recommended childhood vaccinations

Risk Stratification and Management Strategies

Due to the potential severity of SBIs in neonates and young infants with FWF, various risk stratification strategies have been developed to guide management decisions. These strategies aim to identify infants at low risk for SBI who may be candidates for outpatient management or shorter courses of antibiotic therapy.

Rochester Criteria

The Rochester Criteria are widely used for risk stratification in febrile infants aged 28 to 89 days. Infants are considered low-risk if they meet the following criteria:

Well-appearing on physical examination
No chronic or underlying medical conditions
No focal signs of infection on examination
Normal white blood cell (WBC) count and differential
Normal urinalysis and urine culture results (if obtained)

Low-risk infants may be candidates for outpatient management with close follow-up or shorter courses of antibiotic therapy.

Boston Criteria

The Boston Criteria are another risk stratification tool used for febrile infants aged 28 to 89 days. Infants are considered low-risk if they meet the following criteria:

Well-appearing on physical examination
No focal signs of infection on examination
WBC count <15 li="">
Absolute band count <1 li="">
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Low-risk infants may be candidates for outpatient management or shorter courses of antibiotic therapy.

Philadelphia Criteria

The Philadelphia Criteria are used for risk stratification in febrile neonates ≤28 days old. Neonates are considered low-risk if they meet the following criteria:

Well-appearing on physical examination
No chronic or underlying medical conditions
No focal signs of infection on examination
Normal WBC count and differential
Normal urinalysis and urine culture results
Normal CSF profile and negative CSF culture

Low-risk neonates may be candidates for outpatient management or shorter courses of antibiotic therapy, although this approach is more controversial given the higher risk of SBIs in this age group.

It is important to note that these risk stratification strategies are not universally accepted, and their use should be guided by local practice patterns, available resources, and close follow-up capabilities.

Complications and Long-term Outcomes

Prompt recognition and treatment of FWF in neonates and young infants are crucial to prevent potential complications and long-term adverse outcomes. Untreated or delayed treatment of SBIs can lead to severe complications, including:

Meningitis: Can result in neurological sequelae, such as hearing loss, developmental delays, seizures, or cognitive impairment.
Sepsis: Can progress to septic shock, multi-organ failure, and potentially death.
Osteomyelitis or septic arthritis: Can lead to permanent joint or bone damage, growth disturbances, or physical disabilities.
Pneumonia: Can cause respiratory distress, hypoxemia, and potential long-term pulmonary complications.

Early recognition, prompt initiation of appropriate antibiotic therapy, and close monitoring are essential to minimize the risk of complications and improve long-term outcomes in neonates and young infants with FWF.