Fever in a Neonate

Etiology

The etiology of early-onset neonatal sepsis is predominantly caused by Group Beta Streptococcal (GBS) infection followed by Escherichia coli.  Risk factors are maternal Group B streptococcal colonization, chorioamnionitis, premature or prolonged (greater than 18 hours) rupture of membranes, and preterm birth (less than 37 weeks).

The etiology of late-onset neonatal sepsis includes pathogens such as Group B strep, E. coli, Coagulase-negative Staphylococci, Staphylococcus aureus, Klebsiella pneumonia, Enterococci (more common in preterm infants), Pseudomonas, and Candida albicans. Risk factors for late-onset neonatal sepsis are prematurity, low birth weight, prolonged indwelling catheter use, invasive procedures, ventilator-associated pneumonia, and prolonged antibiotic usage.[1]

Epidemiology

WHO statistics cite over one million neonatal deaths around the world each year result from neonatal sepsis/pneumonia making it the leading cause of infant mortality. According to the Centers for Disease Control and Prevention (CDC), the estimated incidence of early-onset neonatal sepsis in the United States is 0.77 to 1 per 1000 live births. With the establishment of guidelines for universal screening and treatment of maternal GBS colonization, the incidence of early-onset sepsis in full-term infants has decreased to 0.3 to 0.4/1000 live births. However, the incidence of late-onset sepsis remained the same (0.4/1000). [2]

Pathophysiology

The activation of the pattern recognition receptors (PRR) like extracellular, toll-like receptors (TLRs), and intracellular NOD-like receptors (NLR) and RIG-like receptors (RLR) helps in recognition of a pathogen by the local immunity.  Gram-positive, gram-negative sepsis activates TLR2 and TLR4, respectively; whereas, the double-stranded virus activates TLR3. They start an immune response by producing pro-inflammatory cytokines which cause endothelial activation and damage-causing SIRS, sepsis, and death. Premature neonates show dysregulation complement system making them susceptible to severe sepsis.[1]

Toxicokinetics

Host defense proteins like opsonin (CRP), haptoglobin, lactoferrin, serum amyloid A and procalcitonin provide additional protection. Septic neonates have decreased the production of Interleukins (IL-1beta, TNF-alpha, IEN-gamma, and IL-12). The quantitative and qualitative deficits in neutrophils, neutrophil depletion of bone marrow, and decreased deformability and delayed apoptosis play a significant role in neonatal sepsis-causing endothelial damage, disseminated intravascular coagulation (DIC), and multi-organ failure.[3]

History and Physical

Neonatal sepsis has a varied presentation. The neonate could have hypo or hyperthermia, irritability or lethargy, apnea or tachypnea, bradycardia or tachycardia, poor feeding, excessive sleepiness, or being fussy. Necrotizing enterocolitis (NEC), ventilator-associated pneumonia, urinary tract infection are common in premature infants. The physical examination could be normal or may reveal signs that are suggestive of neonatal sepsis.

A careful history is very important. History should include both maternal and infant risk factors. Maternal risk factors are lack of or delayed prenatal care, maternal GBS colonization, intrapartum antibiotic use, maternal medical history including diabetes, hypertension, thyroid disease, and maternal drug abuse. Infant risk factors are prematurity, low birth weight, post-neonatal course, detailed history of NICU stay, prolonged rupture of membranes, and sick contacts.[4]

Evaluation

The initial workup of neonates with suspected sepsis should include complete blood count with differential (CBC-diff), chemistry panel, and cultures of the blood, urine, and cerebrospinal fluid (CSF). C- Reactive Protein (CRP) and procalcitonin can be used in conjugation with other factors as a risk stratification to identify infants at risk for serious bacterial infection. Based on the presentation, one could also include a Respiratory Pathogen panel or tests for RSV, influenza, gastrointestinal (GI) pathogens, and possibly a chest x-ray. Rochester criteria, Philadelphia criteria, and Boston criteria all recommend full septic workup in infants less than 28 days of age presenting with fever regardless of other risk factors.[5]

After the wide use of the streptococcal vaccination, the prevalence of bacteremia in febrile infants has decreased. Gomez et al. validated the “Step by Step” approach,[6] which showed that risk stratification is a workable strategy to identify low-risk infants with fever. Infants with fever at high risk for serious bacterial infection may demonstrate evidence of leukocytes in the urine, and elevated procalcitonin (greater than 0.5 Ng/ml), CRP (greater than 20 mg/L) and ANC (greater than 10,000/mm3). Wallace and Brown et al.  showed that the frequency of bacterial meningitis with urinary tract infection (UTI) is minimal.[7] Greenhow et al. concluded that 24% of well-appearing neonates with fever despite having no laboratory studies done and none of them had delayed bacteremia or meningitis.[8] Recently some centers are using the CSF molecular testing which has a turn around time of two hours to aid in the evaluation and management of febrile neonates, especially during the enteroviral season. This test is also useful if the CSF is contaminated with blood, to differentiate between bacterial and viral pathogens.

Treatment / Management

The ill-appearing neonate requires a full septic work and broad-spectrum antibiotic coverage with ampicillin and cefotaxime, the combination of which covers 100% of early neonatal infections and 93% of late-onset bacteremia. Gentamicin and penicillin can cover 94% of early infections.[9] Cefotaxime does not treat some Escherichia coli, Pseudomonas, Enterococci, Acinetobacter, and Listeria monocytogenes. Use of Cefotaxime in the NICU can cause outbreaks of drug-resistant nosocomial infections, which is a serious concern in many centers. Pediatric Infectious diseases specialists consider empiric treatment of neonatal herpes with Intravenous Acyclovir if the CSF has an elevated red cell count or in any ill-looking neonate with suspected herpes.[10] We admit and empirically treat ill-looking infants and infants with risk factors while waiting for the cultures.(B2)

Fluid resuscitation is different to treat septic shock. In term neonate, the fluid bolus is 20 ml/kg as rapidly as possible up to 60 ml/kg, whereas in the preterm neonate the fluid bolus comprises 10 ml/kg in 30-60 minutes and repeat if needed and then vasopressor support for the fluid refractory shock with dopamine and dobutamine. For catecholamine-resistant shock consider milrinone for a shock with poor LV function and normal blood pressure, nitrous oxide for low blood pressure and poor RV function,  vasopressin, or terlipressin and Inotropes for warm shock and low blood pressure and consider ECMO if the child develops persistent fetal circulation.

Based on the laboratory data, you can risk stratifying the well-looking febrile infants greater than 21 days of age with no risk factors and with no source of invasive infection into high risk, medium risk, and low risk.  You can safely observe low-risk infants at home or in the hospital without empiric treatment, meanwhile, high-risk infants are observed and treated in the hospital. You also can observe medium-risk infants in the hospital or at home before treating them empirically.[11] If in doubt admit them to the pediatric unit for observation while waiting for the culture results.[12](B2)

Differential Diagnosis

One can consider the following differential diagnoses:

• Hypoglycemia
• Congenital heart disease
• Inborn errors of metabolism.
• Congenital adrenal insufficiency
• Congenital hypothyroidism
• Neglect/abuse

Prognosis

Prognosis is excellent if treated early in full-term neonates. The prognosis is different in premature and very premature infants.