Fever In A Neonate


Article Author:
Usha Avva


Article Editor:
Scarlet Benson


Editors In Chief:
Ann Anderson Berry
Mark Hudak
Sumesh Parat


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
6/18/2019 3:10:52 AM

Introduction

The World Health Organization categorizes neonatal sepsis into early and late based on the age of onset. Early neonatal sepsis affects infants less than 72 hours of age; whereas, we see late-onset infections in infants older than 72 hours to 28 days of age. Early recognition and treatment are necessary to decrease the significant morbidity and mortality in this age group.[1]

Etiology

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

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 the neonatal sepsis/pneumonia making it the leading cause of infant mortality, whereas pre-term infants are more at risk for neonatal sepsis in the United States. 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.[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 proinflammatory 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 pro calcitonin 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 their decreased deformability and delayed apoptosis play a significant role in neonatal sepsis-causing endothelial damage, 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) is common in premature nfants. The physical examination could be noncontributory or could show an ill-looking infant with abnormal or unstable vital signs.

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, neonatal course, a detailed history of NICU stay, prolonged ruptur of membranes, sick contacts and detailed feeding history.[4]

Evaluation

Initial workup of neonates with suspected sepsis should include CBC, chemistry panel, and cultures of the blood, urine and cerebrospinal fluid (CSF)  We use a microscopic analysis of urine, CRP, and pro-calcitonin in the risk stratification process to identify infants at low 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 a full septic work up 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 pro-calcitonin (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 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 specialist 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.

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 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 old 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 stratify 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]

Differential Diagnosis

One can consider the following differential diagnoses. They are

  • 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.

Pearls and Other Issues

 

 

 

Enhancing Healthcare Team Outcomes

The outcome of well looking febrile infants is excellent with a care coordination between the emergency medicine providers and hospitalist service. Early recognition is the most important factor in decreasing the morbidity and mortality in neonatal sepsis. The septic premature infants require a dedicated team and cooperation among various specialists like the neonatologist, pediatric infectious disease specialists, intensivist and with specialized centers to provide ECMO for the optimum outcome. Take the help of the pharmacists and infectious disease specialists in choosing and in calculating the doses for the of empiric antibiotics in premature and full-term infants both in early onset and late onset neonatal sepsis.

The management of well looking previously healthy febrile infants from age 7-90 days is changing from the traditional teaching.  Infants from 7 to 28 days of age received full septic work up in 58% of the cases. That number dropped to 25% in infants aged 29 days-60 days, further dropped to 5% in infants aged 61 days to 90 days.[8] Evidence Level 2.

The modified Philadelphia criteria has high sensitivity and low specificity when applied to the febrile infants in this age of the improved vaccination as opposed to the age before Hemophilus influenza and streptococcal vaccination than the Rochester criteria. Evidence Level 2[13]


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Fever In A Neonate - Questions

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A 3-week-old infant is brought in with a fever, poor feeding, and irritability. Physical exam shows temperature 39.4 C and right otitis media with a bulging tympanic membrane. The rest of the exam is normal. Appropriate labs are obtained. What antibiotic is the best treatment in this scenario?



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Which of the following is not a risk factor of the early neonatal sepsis?



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A 9-day-old female twin born via c-section to G2 P2 mother due to the nonprogression of labor at 35 weeks of gestation came to the emergency department with fussiness and decreased oral intake. The baby was discharged from the newborn nursery on day 5. The baby received phototherapy for hyperbilirubinemia for 24 hours prior to discharge. Mom is group B Streptococcus (GBS) positive. What is the risk factor for late-onset sepsis in the baby?



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Which of the following is not a risk factor for late neonatal sepsis?



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Fever In A Neonate - References

References

Qazi SA,Stoll BJ, Neonatal sepsis: a major global public health challenge. The Pediatric infectious disease journal. 2009 Jan     [PubMed]
Aronson PL,Wang ME,Shapiro ED,Shah SS,DePorre AG,McCulloh RJ,Pruitt CM,Desai S,Nigrovic LE,Marble RD,Leazer RC,Rooholamini SN,Sartori LF,Balamuth F,Woll C,Neuman MI, Risk Stratification of Febrile Infants ≤60 Days Old Without Routine Lumbar Puncture. Pediatrics. 2018 Dec     [PubMed]
Shah BA,Padbury JF, Neonatal sepsis: an old problem with new insights. Virulence. 2014 Jan 1     [PubMed]
Simonsen KA,Anderson-Berry AL,Delair SF,Davies HD, Early-onset neonatal sepsis. Clinical microbiology reviews. 2014 Jan     [PubMed]
Laptook AR,Bell EF,Shankaran S,Boghossian NS,Wyckoff MH,Kandefer S,Walsh M,Saha S,Higgins R, Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants. The Journal of pediatrics. 2018 Jan     [PubMed]
Aronson PL,McCulloh RJ,Tieder JS,Nigrovic LE,Leazer RC,Alpern ER,Feldman EA,Balamuth F,Browning WL,Neuman MI, Application of the Rochester Criteria to Identify Febrile Infants With Bacteremia and Meningitis. Pediatric emergency care. 2019 Jan     [PubMed]
Gomez B,Mintegi S,Bressan S,Da Dalt L,Gervaix A,Lacroix L, Validation of the "Step-by-Step" Approach in the Management of Young Febrile Infants. Pediatrics. 2016 Aug     [PubMed]
Wallace SS,Brown DN,Cruz AT, Prevalence of Concomitant Acute Bacterial Meningitis in Neonates with Febrile Urinary Tract Infection: A Retrospective Cross-Sectional Study. The Journal of pediatrics. 2017 May     [PubMed]
Greenhow TL,Hung YY,Pantell RH, Management and Outcomes of Previously Healthy, Full-Term, Febrile Infants Ages 7 to 90 Days. Pediatrics. 2016 Dec     [PubMed]
Puopolo KM,Eichenwald EC, No change in the incidence of ampicillin-resistant, neonatal, early-onset sepsis over 18 years. Pediatrics. 2010 May     [PubMed]
Muller-Pebody B,Johnson AP,Heath PT,Gilbert RE,Henderson KL,Sharland M, Empirical treatment of neonatal sepsis: are the current guidelines adequate? Archives of disease in childhood. Fetal and neonatal edition. 2011 Jan     [PubMed]
Hyde TB,Hilger TM,Reingold A,Farley MM,O'Brien KL,Schuchat A, Trends in incidence and antimicrobial resistance of early-onset sepsis: population-based surveillance in San Francisco and Atlanta. Pediatrics. 2002 Oct     [PubMed]
Madhi F,Jung C,Timsit S,Levy C,Biscardi S,Lorrot M,Grimprel E,Hees L,Craiu I,Galerne A,Dubos F,Cixous E,Hentgen V,Béchet S,Bonacorsi S,Cohen R, Febrile urinary-tract infection due to extended-spectrum beta-lactamase-producing Enterobacteriaceae in children: A French prospective multicenter study. PloS one. 2018     [PubMed]

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