Approach to Neonates and Young Infants with Fever without a Source Who Are at Risk for Severe Bacterial Infection

Introduction Among neonates and infants <3 months of age with fever without a source (FWS), 5% to 15% of cases are patients with fever caused by a serious bacterial infection (SBI). To favour the differentiation between low- and high-risk infants, several algorithms based on analytical and clinical parameters have been developed. The aim of this review is to describe the management of young infants with FWS and to discuss the impact of recent knowledge regarding FWS management on clinical practice. Materials and Methods PubMed was used to search for all of the studies published over the last 35 years using the keywords: "fever without source" or "fever of unknown origin" or "meningitis" or "sepsis" or "urinary tract infection" and "neonate" or "newborn" or "infant <90 days of life" or "infant <3 months". Results and Discussion The selection of neonates and young infants who are <3 months old with FWS who are at risk for SBI remains a problem without a definitive solution. The old Rochester criteria remain effective for identifying young infants between 29 and 60 days old who do not have severe bacterial infections (SBIs). However, the addition of laboratory tests such as C-reactive protein (CRP) and procalcitonin (PCT) can significantly improve the identification of children with SBI. The approach in evaluating neonates is significantly more complicated, as their risk of SBIs, including bacteremia and meningitis, remains relevant and none of the suggested approaches can reduce the risk of dramatic mistakes. In both groups, the best antibiotic must be carefully selected considering the clinical findings, the laboratory data, the changing epidemiology, and increasing antibiotic resistance of the most common infectious bacteria.

[1]  O. Ramilo,et al.  Accuracy of the Urinalysis for Urinary Tract Infections in Febrile Infants 60 Days and Younger , 2018, Pediatrics.

[2]  A. Berger,et al.  Diagnostic accuracy of the ROCHE Septifast PCR system for the rapid detection of blood pathogens in neonatal sepsis—A prospective clinical trial , 2017, PloS one.

[3]  S. Brkić,et al.  Use of presepsin and procalcitonin for prediction of SeptiFast results in critically ill patients☆ , 2017, Journal of critical care.

[4]  F. Balamuth,et al.  Lumbar Puncture for All Febrile Infants 29-56 Days Old: A Retrospective Cohort Reassessment Study. , 2017, The Journal of pediatrics.

[5]  A. Saitoh,et al.  Human parechovirus type 3 infection: An emerging infection in neonates and young infants. , 2017, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[6]  A. van der Ende,et al.  Listeria monocytogenes meningitis in the Netherlands, 1985–2014: A nationwide surveillance study , 2017, The Journal of infection.

[7]  Thomas A. Hooven,et al.  Pneumonia , 2017, Seminars in Fetal and Neonatal Medicine.

[8]  R. McCulloh,et al.  Facing the ongoing challenge of the febrile young infant , 2017, Critical Care.

[9]  P. Montaldo,et al.  Presepsin for the detection of early-onset sepsis in preterm newborns , 2017, Pediatric Research.

[10]  S. Chawla,et al.  Enhanced Identification of Group B Streptococcus and Escherichia Coli in Young Infants with Meningitis Using the Biofire Filmarray Meningitis/Encephalitis Panel , 2017, The Pediatric infectious disease journal.

[11]  M. Monuteaux,et al.  Urine Concentration and Pyuria for Identifying UTI in Infants , 2016, Pediatrics.

[12]  J. R. Contreras,et al.  Lack of Accuracy of Biomarkers and Physical Examination to Detect Bacterial Infection in Febrile Infants , 2016, Pediatric emergency care.

[13]  F. Strle,et al.  Narrowing of the Diagnostic Gap of Acute Gastroenteritis in Children 0–6 Years of Age Using a Combination of Classical and Molecular Techniques, Delivers Challenges in Syndromic Approach Diagnostics , 2016, The Pediatric infectious disease journal.

[14]  O. Ramilo,et al.  Association of RNA Biosignatures With Bacterial Infections in Febrile Infants Aged 60 Days or Younger. , 2016, JAMA.

[15]  A. Gervaix,et al.  Validation of the “Step-by-Step” Approach in the Management of Young Febrile Infants , 2016, Pediatrics.

[16]  A. Mencacci,et al.  Diagnostic accuracy of presepsin (sCD14-ST) and procalcitonin for prediction of bacteraemia and bacterial DNAaemia in patients with suspected sepsis. , 2016, Journal of medical microbiology.

[17]  R. Jhaveri,et al.  Evaluation and Management of Febrile Children: A Review. , 2016, JAMA pediatrics.

[18]  S. Y. Kim,et al.  Can absence of pyuria exclude urinary tract infection in febrile infants? About 2011 AAP guidelines on UTI , 2016, Pediatrics international : official journal of the Japan Pediatric Society.

[19]  J. Vila,et al.  Development of a new protocol for rapid bacterial identification and susceptibility testing directly from urine samples. , 2016, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[20]  V. Cheng,et al.  Clinical Evaluation of the New High-Throughput Luminex NxTAG Respiratory Pathogen Panel Assay for Multiplex Respiratory Pathogen Detection , 2016, Journal of Clinical Microbiology.

[21]  Kyrie L Shomaker,et al.  A Meta-analysis of the Rates of Listeria monocytogenes and Enterococcus in Febrile Infants. , 2016, Hospital pediatrics.

[22]  R. Jhaveri,et al.  Reductions in neonatal listeriosis: "Collateral benefit" of Group B streptococcal prophylaxis? , 2016, The Journal of infection.

[23]  F. Mosca,et al.  Presepsin (Soluble CD14 Subtype): Reference Ranges of a New Sepsis Marker in Term and Preterm Neonates , 2015, PloS one.

[24]  Joel S. Tieder,et al.  Association between Clinical Outcomes and Hospital Guidelines for Cerebrospinal Fluid Testing in Febrile Infants Aged 29-56 Days. , 2015, The Journal of pediatrics.

[25]  H. Wong,et al.  Interleukin-27: a novel biomarker in predicting bacterial infection among the critically ill , 2015, Critical Care.

[26]  S. Esposito,et al.  Direct and indirect effects of the 13-valent pneumococcal conjugate vaccine administered to infants and young children. , 2015, Future microbiology.

[27]  S. Mintegi,et al.  A Prospective Multicenter Study of Leukopenia in Infants Younger Than Ninety Days With Fever Without Source , 2015, The Pediatric infectious disease journal.

[28]  J. Lohr,et al.  Pediatric Fever of Unknown Origin. , 2015, Pediatrics in review.

[29]  D. Kimberlin,et al.  Neonatal Herpes Simplex Virus Infection. , 2015, Infectious disease clinics of North America.

[30]  Samir S. Shah,et al.  Association of clinical practice guidelines with emergency department management of febrile infants ≤56 days of age. , 2015, Journal of hospital medicine.

[31]  C. Asche,et al.  Epidemiology of Bacteremia in Previously Healthy Febrile Infants: A Follow-up Study. , 2015, Hospital pediatrics.

[32]  M. Blennow,et al.  Intrapartum GBS screening and antibiotic prophylaxis: a European consensus conference , 2015, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[33]  S. Esposito,et al.  Prospective evaluation of rhinovirus infection in healthy young children. , 2015, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[34]  E. Burdino,et al.  Etiological diagnosis of bloodstream infections through a multiplex real-time polymerase chain reaction test in pediatric patients: a case series from a tertiary Italian hospital , 2015, Infectious diseases.

[35]  A. Kimia,et al.  The effect of traumatic lumbar puncture on hospitalization rate for febrile infants 28 to 60 days of age. , 2015, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[36]  C. Dani,et al.  Presepsin for the Detection of Late-Onset Sepsis in Preterm Newborns , 2015, Pediatrics.

[37]  M. Loeffelholz,et al.  Duration of Rhinovirus Shedding in the Upper Respiratory Tract in the First Year of Life , 2014, Pediatrics.

[38]  S. Aronoff,et al.  Use of serum procalcitonin in evaluation of febrile infants: a meta-analysis of 2317 patients. , 2014, The Journal of emergency medicine.

[39]  Samir S. Shah,et al.  Variation in Care of the Febrile Young Infant <90 Days in US Pediatric Emergency Departments , 2014, Pediatrics.

[40]  H. Wong,et al.  Biomarkers of sepsis and their potential value in diagnosis, prognosis and treatment , 2014, Expert review of clinical immunology.

[41]  A. Ohlsson,et al.  Intrapartum antibiotics for known maternal Group B streptococcal colonization. , 2014, The Cochrane database of systematic reviews.

[42]  A. Herz,et al.  The Changing Epidemiology of Serious Bacterial Infections in Young Infants , 2014, The Pediatric infectious disease journal.

[43]  J. Craig,et al.  Parental perspectives on evaluation and management of fever in young infants: an interview study , 2014, Archives of Disease in Childhood.

[44]  L. Coin,et al.  Diagnosis of childhood tuberculosis and host RNA expression in Africa. , 2014, The New England journal of medicine.

[45]  M. Waseem,et al.  Can a Simple Urinalysis Predict the Causative Agent and the Antibiotic Sensitivities? , 2014, Pediatric emergency care.

[46]  S. Reif,et al.  Diagnostic markers of serious bacterial infections in febrile infants younger than 90 days old , 2014, Pediatrics international : official journal of the Japan Pediatric Society.

[47]  E. Alpern,et al.  Management of Febrile Neonates in US Pediatric Emergency Departments , 2014, Pediatrics.

[48]  Michael Levin,et al.  Detection of Tuberculosis in HIV-Infected and -Uninfected African Adults Using Whole Blood RNA Expression Signatures: A Case-Control Study , 2013, PLoS medicine.

[49]  G. Mengozzi,et al.  Diagnostic and prognostic value of presepsin in the management of sepsis in the emergency department: a multicenter prospective study , 2013, Critical Care.

[50]  Colin G Fink,et al.  Transcriptomic Profiling in Childhood H1N1/09 Influenza Reveals Reduced Expression of Protein Synthesis Genes , 2013, The Journal of infectious diseases.

[51]  S. Crosby,et al.  Gene expression profiles in febrile children with defined viral and bacterial infection , 2013, Proceedings of the National Academy of Sciences.

[52]  S. Mintegi,et al.  Accuracy of a sequential approach to identify young febrile infants at low risk for invasive bacterial infection , 2013, Emergency Medicine Journal.

[53]  A. Gervaix,et al.  Association of Procalcitonin With Acute Pyelonephritis and Renal Scars in Pediatric UTI , 2013, Pediatrics.

[54]  S. Mintegi,et al.  Diagnostic Performance of the Lab-score in Predicting Severe and Invasive Bacterial Infections in Well-appearing Young Febrile Infants , 2012, The Pediatric infectious disease journal.

[55]  S. Mintegi,et al.  Diagnostic Value of Procalcitonin in Well-Appearing Young Febrile Infants , 2012, Pediatrics.

[56]  H. Wong,et al.  Interleukin-27 is a novel candidate diagnostic biomarker for bacterial infection in critically ill children , 2012, Critical Care.

[57]  Lucy Savitz,et al.  Costs and Infant Outcomes After Implementation of a Care Process Model for Febrile Infants , 2012, Pediatrics.

[58]  Virginia Pascual,et al.  Host Immune Transcriptional Profiles Reflect the Variability in Clinical Disease Manifestations in Patients with Staphylococcus aureus Infections , 2012, PloS one.

[59]  A. Tsertsvadze,et al.  Diagnosis and management of febrile infants (0-3 months). , 2012, Evidence report/technology assessment.

[60]  S. Ralston,et al.  Occult serious bacterial infection in infants younger than 60 to 90 days with bronchiolitis: a systematic review. , 2011, Archives of pediatrics & adolescent medicine.

[61]  L. Putignani,et al.  Multiplex PCR Allows Rapid and Accurate Diagnosis of Bloodstream Infections in Newborns and Children with Suspected Sepsis , 2011, Journal of Clinical Microbiology.

[62]  A. Schuchat,et al.  Prevention of perinatal group B streptococcal disease. Revised guidelines from CDC. , 2010, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[63]  R. Jhaveri,et al.  Changing Epidemiology of Serious Bacterial Infections in Febrile Infants without Localizing Signs , 2010, PloS one.

[64]  S. Schrag,et al.  Group B streptococcal disease in infants: progress in prevention and continued challenges. , 2010, Clinics in perinatology.

[65]  A. Gervaix,et al.  Validation of a laboratory risk index score for the identification of severe bacterial infection in children with fever without source , 2010, Archives of Disease in Childhood.

[66]  L. Carin,et al.  Gene expression signatures diagnose influenza and other symptomatic respiratory viral infections in humans. , 2009, Cell host & microbe.

[67]  P. Dayan,et al.  Influenza Virus Infection and the Risk of Serious Bacterial Infections in Young Febrile Infants , 2009, Pediatrics.

[68]  Virginia Pascual,et al.  Enhanced Monocyte Response and Decreased Central Memory T Cells in Children with Invasive Staphylococcus aureus Infections , 2009, PloS one.

[69]  A. Gervaix,et al.  The Search for Adenovirus 14 in Children in Houston, Texas , 2008, The Pediatric infectious disease journal.

[70]  M. Plebani,et al.  Procalcitonin and C-Reactive Protein as Diagnostic Markers of Severe Bacterial Infections in Febrile Infants and Children in the Emergency Department , 2007, The Pediatric infectious disease journal.

[71]  J. Banchereau,et al.  Gene expression patterns in blood leukocytes discriminate patients with acute infections. , 2007, Blood.

[72]  P. Lebon,et al.  Serum procalcitonin and other biologic markers to distinguish between bacterial and aseptic meningitis. , 2006, The Journal of pediatrics.

[73]  V. Fowler,et al.  Neonatal Meningitis: What Is the Correlation Among Cerebrospinal Fluid Cultures, Blood Cultures, and Cerebrospinal Fluid Parameters? , 2006, Pediatrics.

[74]  A. Spitzer,et al.  Empiric Use of Ampicillin and Cefotaxime, Compared With Ampicillin and Gentamicin, for Neonates at Risk for Sepsis Is Associated With an Increased Risk of Neonatal Death , 2006, Pediatrics.

[75]  G. Garra,et al.  Reappraisal of criteria used to predict serious bacterial illness in febrile infants less than 8 weeks of age. , 2005, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[76]  Nathan Kuppermann,et al.  Risk of serious bacterial infection in young febrile infants with respiratory syncytial virus infections. , 2004, Pediatrics.

[77]  C. Byington,et al.  Serious bacterial infections in febrile infants 1 to 90 days old with and without viral infections. , 2004, Pediatrics.

[78]  T. Newman,et al.  Management and outcomes of care of fever in early infancy. , 2004, JAMA.

[79]  L. Baraff Editorial: Clinical policy for children younger than three years presenting to the emergency department with fever. , 2003, Annals of emergency medicine.

[80]  C. Cubells,et al.  Procalcitonin in pediatric emergency departments for the early diagnosis of invasive bacterial infections in febrile infants: results of a multicenter study and utility of a rapid qualitative test for this marker , 2003 .

[81]  Tiffany S. Glasgow,et al.  Serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens. , 2003, Pediatrics.

[82]  D. Relman New technologies, human-microbe interactions, and the search for previously unrecognized pathogens. , 2002, The Journal of infectious diseases.

[83]  J. Coste,et al.  Procalcitonin in children admitted to hospital with community acquired pneumonia , 2001, Archives of disease in childhood.

[84]  S. Suter,et al.  Procalcitonin, IL-6, IL-8, IL-1 receptor antagonist and C-reactive protein as identificators of serious bacterial infections in children with fever without localising signs , 2001, European Journal of Pediatrics.

[85]  R. Bolte,et al.  Applying Outpatient Protocols in Febrile Infants 1-28 Days of Age: Can the Threshold Be Lowered? , 2000, Clinical pediatrics.

[86]  M. Baker,et al.  Evaluation and management of infants with fever. , 1999, Pediatric clinics of North America.

[87]  J. Coste,et al.  Comparison of procalcitonin with C-reactive protein, interleukin 6 and interferon-alpha for differentiation of bacterial vs. viral infections. , 1999, The Pediatric infectious disease journal.

[88]  L. Bell,et al.  Unpredictability of serious bacterial illness in febrile infants from birth to 1 month of age. , 1999, Archives of pediatrics & adolescent medicine.

[89]  J. Avner,et al.  The efficacy of routine outpatient management without antibiotics of fever in selected infants. , 1999, Pediatrics.

[90]  R. Evans Complications of lumbar puncture. , 1998, Neurologic clinics.

[91]  J. Bartfield,et al.  Neonatal fever: utility of the Rochester criteria in determining low risk for serious bacterial infections. , 1997, The American journal of emergency medicine.

[92]  D. Korones,et al.  Febrile infants at low risk for serious bacterial infection--an appraisal of the Rochester criteria and implications for management. Febrile Infant Collaborative Study Group. , 1994, Pediatrics.

[93]  Peiris Js,et al.  Outpatient management of fever in selected infants. , 1994 .

[94]  Louis M. Bell,et al.  Outpatient management without antibiotics of fever in selected infants. , 1993, The New England journal of medicine.

[95]  W. Bonadio,et al.  Efficacy of a Protocol to Distinguish Risk of Serious Bacterial Infection in the Outpatient Evaluation of Febrile Young Infants , 1993, Clinical pediatrics.

[96]  D. Schriger,et al.  Practice guideline for the management of infants and children 0 to 36 months of age with fever without source. Agency for Health Care Policy and Research. , 1993, Annals of emergency medicine.

[97]  K. Powell Evaluation and management of febrile infants younger than 60 days of age , 1990, The Pediatric infectious disease journal.

[98]  R. Dagan,et al.  Ambulatory care of febrile infants younger than 2 months of age classified as being at low risk for having serious bacterial infections. , 1988, The Journal of pediatrics.

[99]  C B Hall,et al.  Identification of infants unlikely to have serious bacterial infection although hospitalized for suspected sepsis. , 1985, The Journal of pediatrics.

[100]  N. Team Fever in under 5s: assessment and initial management , 2019 .

[101]  O. Megged Bacteremic vs nonbacteremic urinary tract infection in children☆,☆☆ , 2017, The American journal of emergency medicine.

[102]  J. Bouyer,et al.  Use of Procalcitonin Assays to Predict Serious Bacterial Infection in Young Febrile Infants. , 2016, JAMA pediatrics.

[103]  S. Schrag,et al.  Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. , 2010, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[104]  Acepclinicalpoliciescommittee Clinical policy for children younger than three years presenting to the emergency department with fever. , 2003, Annals of emergency medicine.

[105]  J. Peiris,et al.  Outpatient management of fever in selected infants. , 1994, New England Journal of Medicine.

[106]  G. Fleisher,et al.  Outpatient treatment of febrile infants 28 to 89 days of age with intramuscular administration of ceftriaxone. , 1992, The Journal of pediatrics.

[107]  A. MacGowan,et al.  Listeriosis--the therapeutic options. , 1990, The Journal of antimicrobial chemotherapy.