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746 SECTION 12: Pediatrics autonomic events.30 In rats, a depression of ventilation in response to lipopolysaccharide might explain why infection can serve as an environmental stressor causing apnea during the vulnerable period of infancy.31 CLINICAL FEATURES AND MANAGEMENT Generally, SIDS victims present in one of two ways: not amenable to resuscitation or potentially responsive to resuscitation measures. Infants with rigor mortis, livedo reticularis, pH <6, and a significantly reduced core temperature in the absence of a history of environmen tal hypothermia should not be resuscitated. However, the warm infant with apnea and no pulse may benefit from attempts at resuscitation. Regardless of the presentation of SIDS, obtain a thorough history and perform a complete physical examination. Important questions include complete description of the circumstances, caretakers, recent illness, prenatal and birth history, maternal and family history of miscarriages or other infant deaths, and family history of metabolic disease. For epidemiologic information, documentation of sleep position, sleep location, when and by whom the infant was last seen alive, when and in what position the infant was found, and whether or not bed sharing was involved is helpful to the coroner. Examination of the infant may be unrevealing or may show subtle but relevant signs of trauma, such as facial bruising, petechiae, blood in the nose or the mouth, or a torn frenulum, that raise suspicion of inflicted trauma. Rectal temperature and presence of rigor mortis or lividity will help the coroner in deter mining an approximate time of death. The management of a nonresuscitative SIDS infant and interactions with the infant’s family is emotionally challenging for many provid ers. One major responsibility of the physician is to notify, counsel, and educate the family. Frequently, the family wants to spend time with the deceased infant. In general, the infant’s body should not be manipu lated or photographed after death has been declared unless permis sion is granted by the coroner. If the family wants a hand or footprint, inkless pads must be used, and this must be documented in the medical record. Do not remove any lines or tubes placed during attempted resuscitation. If the presence of tubing is disconcerting to the family, tubes may be cut at the skin to appear less obvious. Unless directed otherwise by the coroner, the family can hold the deceased infant in a private set ting but one that allows discreet monitoring of the family. In most jurisdictions, victims of sudden and unexplained deaths must be reported as soon as possible to the coroner’s office. Treating physicians should complete a form reporting the death, but do not sign the official death certificate, as the cause of death will not be evident until the coroner’s investigation is finished. SIDS is technically a postmortem diagnosis, and sudden unexpected infant death is a more appropriate term for an ED record (although not included in the 10th revision of the International Classification of Diseases). If blood samples were drawn, put the samples on hold in the laboratory for later access by the coroner. Once death has been pronounced, the physician does not have jurisdiction to perform postmortem sampling or radiography unless directed to do so by the coroner.

vision of the International Classification of Diseases). If blood samples were drawn, put the samples on hold in the laboratory for later access by the coroner. Once death has been pronounced, the physician does not have jurisdiction to perform postmortem sampling or radiography unless directed to do so by the coroner. Cardiac dysfunction related to prolonged QT interval or Wolff- Parkinson-White syndrome has been reported in sudden unexpected infant death, 32 with an accessory atrioventricular pathway found in 20% of “SIDS” cases on autopsy. Up to 35% have an abnormal result on postmortem cardiac channel testing. 33 If a cardiac anomaly, particularly a channelopathy is found, testing of family members may be lifesaving, and this is one concrete example to offer families to underscore the importance of an autopsy. A home scene investigation is often conducted. Some jurisdictions have infant death teams that fully evaluate the circumstances surrounding the unexpected death of young infants. If the physician believes the infant is a victim of SIDS, the family should be so advised but told that the final confirmation awaits the autopsy report. Involving the primary care provider, who may follow up on the autopsy and remain in contact with the family, is of paramount importance. The hospital chaplain or social worker may provide additional support, and a chaplain consult may be especially needed in cases in which the laws regarding autopsy before burial are at odds with the family’s religious doctrine. For infants requiring a perimortem baptism, this is ideally done by a chaplain but can be performed by a medical provider if no chaplain is available. Some states also require notification of organ procurement agencies. When interviewed, one of the recurring themes voiced by mothers of SIDS victims is a sense of self-blame. 34 Eliminating interactions that exacerbate this sentiment, while preserving the need for a thorough investigation, is an important tenet in SIDS care. Most communities have organizations for parents of SIDS victims, and information about these organizations can be obtained from First Candle (1-800-221-SIDS, www.firstcandle.org). REFERENCES The complete reference list is available online at www.TintinalliEM.com. Fever and Serious Bacterial Illness in Infants and Children David M. Rodriguez Jo-Ann O. Nesiama Vincent J. Wang INTRODUCTION AND EPIDEMIOLOGY Fever is the most common chief complaint of children presenting to the ED, accounting for approximately 30% of pediatric outpatient visits. It is critical to differentiate mildly ill from seriously ill children with fever, especially in the neonate and infant. This challenge is compounded by the nonspecific symptoms and lack of a focus of infection in most children with fever. Many factors influence evaluation and management, including clinical assessment, physical examination findings, patient age, immunization status, and height of the fever. This chapter focuses on the management of a neonate, infant, or child with acute fever at risk for serious bacterial illness, because morbidity and mortality are high if serious bacterial illness is missed or not prop erly treated. Neonates, defined as infants <1 month old, are at highest risk. Infants between 1 and 2 months of age are also at risk due to relative immunosuppression. The significance of age groups is discussed in the subsequent sections.  FEVER Any elevation in temperature above normal is commonly considered a fever. A cutoff temperature formally defining fever is not universally accepted. In infants, the threshold for relative concern has traditionally been 38°C (100.4°F). In the neonate or infant <2 to 3 months of age, temperature <36°C (96.8°F) is equally concerning.

on in temperature above normal is commonly considered a fever. A cutoff temperature formally defining fever is not universally accepted. In infants, the threshold for relative concern has traditionally been 38°C (100.4°F). In the neonate or infant <2 to 3 months of age, temperature <36°C (96.8°F) is equally concerning. Historically, occult bacteremia criteria used 39°C (102.2°F) in those 3 to 36 months in age, and a temperature >41°C (105.8°F) was considered to confer increased risk for serious bacterial infection. In children >36 months old, sources of serious bacterial infection can be reliably ascertained by specific signs or symptoms. In infants and younger children, or children with developmental delay, who have limited ability to demonstrate specific signs and symptoms, the cause of fever may be difficult to determine, and more testing is often necessary. Axillary temperatures are 0.6°C (1°F) lower than oral tempera tures, which are 0.6°C (1°F) lower than rectal temperatures. Tempera tures taken with infrared thermometers are of variable reliability and reproducibility. 1,2 Fever is treated with acetaminophen or ibuprofen. The dosage of acetaminophen is 15 milligrams/kg/dose PO or PR (maximum daily dose, 80 milligrams/kg) every 4 to 6 hours, up to five times per day. CHAPTER Tintinalli_Sec12_p0669-0996.indd 746 8/2/19 7:50 PM

ermometers are of variable reliability and reproducibility. 1,2 Fever is treated with acetaminophen or ibuprofen. The dosage of acetaminophen is 15 milligrams/kg/dose PO or PR (maximum daily dose, 80 milligrams/kg) every 4 to 6 hours, up to five times per day. CHAPTER Tintinalli_Sec12_p0669-0996.indd 746 8/2/19 7:50 PM CHAPTER 119:  Fever and Serious Bac terial Illness in Infants and Childr en      747 Acetaminophen may also be given IV with dosages, intervals, and maximum daily dose differing by age. The dosage of ibuprofen is 10 milligrams/kg/dose (maximum daily dose, 40 milligrams/kg) every 6 to 8 hours. Ibuprofen can be given to children older than 6 months of age.  SERIOUS BACTERIAL ILLNESS Infants ≤3 months of age, and especially neonates, are relatively immunodeficient. Neonates and young infants demonstrate decreased opsonin activity, decreased macrophage and neutrophil function, and bone marrow insufficiency. 3 Infants and children demonstrate a poor immunoglobulin G antibody response to encapsulated bacteria until 24 months of age. Immune development is a continuum and improves as the child matures. Therefore, the age of the patient and the virulence of the bacteria are considerations for the evaluation of fever in children and the identification of serious bacterial illness. The most common manifestations of serious bacterial illness in children include urinary tract infection (UTI), bacteremia and sepsis, pneumonia, and meningitis. Of note, the following discussion applies primarily to developed countries. Urinary Tract Infection Overall, the most common serious bacterial illness is UTI with or without pyelonephritis. The incidence among young children <24 months of age presenting to EDs with fever and no obvious source of infection is between 3% and 8%. In the first 2 months of life, the incidence of UTI is even higher; in a recent study, UTI was found in 11% of infants who presented to the ED with fever and 7.6% among those with a history of parent-reported fever, but no fever on arrival to the ED. 4 Because UTIs may not produce symptoms other than fever, routinely obtain a urinalysis and culture in the evalua tion of the febrile neonate or infant without other source . Additional details regarding the epidemiology, risk factors, testing, and treatment of UTI can be found in Chapter 135, “Urinary Tract Infection in Infants and Children. ” One study reported that 13% of infants (15 of 117 infants) <3 months of age with a febrile UTI admitted to the hospital had a sterile pleocytosis of the cerebrospinal fluid thought to be due to systemic release of inflammatory mediators or low bacterial virulence in the subarachnoid space. A report by the Pediatric Emergency Medicine Research Collaborative Committee in 2011 showed similar findings. 6 However, another study did not replicate these findings.7 Less than 1% of febrile infants with UTI will have bacterial meningitis, but concomitant infection of the urine and cerebrospinal fluid has been reported. Bacteremia and Sepsis Most studies of febrile infants ≤3 months old cite a bacteremia/sepsis incidence of 1% to 3%. 4,9 The most common causes of bacteremia in this age group are Escherichia coli, group B Streptococcus, and Listeria monocytogenes. Ill-appearing neonates or those identified as high risk because of laboratory testing have an inci dence of serious bacterial illness of 13% to 21%.10 Overall, however, viral infections are the most frequent cause of fever in infants. Many studies have shown that infants with viral illnesses are less likely to have serious bacterial infections. 10-12 Most studies of bacteremia/sepsis also cite an incidence of 2% to 3% in febrile infants 3 to 36 months of age.

21%.10 Overall, however, viral infections are the most frequent cause of fever in infants. Many studies have shown that infants with viral illnesses are less likely to have serious bacterial infections. 10-12 Most studies of bacteremia/sepsis also cite an incidence of 2% to 3% in febrile infants 3 to 36 months of age. Prior to the widespread use of heptavalent pneumococcal conjugate vaccine in 2000, a temperature of ≥39°C (102.2°F), WBC >15,000/mm 3, and absolute neutrophil count >10,000/mm3 were independent predictors of occult bacteremia in febrile infants and children between 3 and 36 months old. 13 The presence of any of these factors increased the incidence of bacteremia to 8% to 17%. Administration of the Haemophilus influenzae type b vaccine and the pneumococcal conjugate vaccines (currently in use in the United States is the 13-valent pneumococcal conjugate vaccine) has decreased the occult bacteremia rate of febrile children 3 to 36 months of age to 0.5% to 0.7%. 14-17 The incidence of serious bacterial illness in children 2 to 6 months old who were incompletely or not immunized decreased because the widespread use of the vaccines resulted in herd immunity. In 2009, a decavalent pneumococcal conjugate vaccine was released in Europe, and in 2010, the 13-valent pneumococcal conjugate vaccine was introduced in the United States. Both of these are expected to further decrease the incidence of invasive pneumococcal disease. The Centers for Disease Control and Prevention reports a 90% reduction in inva sive infections from Streptococcus pneumoniae in children <5 years old when comparing 2016 with 1998 data in the United States. 18 Given these declines and the fact that 80% of pneumococcal bacteremia resolves spontaneously, the traditional standards for routine evaluation of the febrile infant 3 to 36 months old have changed. Guidelines now recom mend urine testing only (at the discretion of the treating provider); routine WBC count and chest radiography are not indicated, and the use of routine antibiotics is discouraged. Pneumonia and Sinusitis Pneumonia and sinusitis are common bacterial infections of childhood, frequently associated with or following upper respiratory tract symptoms (see Chapter 123, “Nose and Sinus Disorders in Infants and Children”; Chapter 124, “Mouth and Throat Disorders in Infants and Children”; and Chapter 128, “Pneumonia in Infants and Children”). Pneumonia occurs in all age groups, with the most common causative agents being the same as those for bacteremia or meningitis in each age group. The incidence of pneumococcal pneu monia in all ages has decreased since the introduction of the pneumo coccal conjugate vaccines. 19-21 Sinusitis is uncommon in children <3 years of age because sinus formation is incomplete. Plain chest radiographs remain the gold standard for diagnosis of pneumonia. In neonates and young infants, routine chest radiographs are not necessary unless the patient has specific physical examination findings suggestive of pneumonia, such as respiratory distress, rales, grunting, significant tachypnea, or hypoxemia. 20,22,23 In older children with chronic medical problems, such as cystic fibrosis, congenital heart disease, chronic lung disease, or malignancy, consider pneumonia in the differential diagnosis of fever and upper respiratory tract symp toms, even if there are no signs of lower tract infection. In one study performed before the widespread use of the pneumococcal conjugate vaccine, a WBC count of 20,000/mm 3 was associated with occult pneumonia in 19% of patients without focal findings. 24 Without predisposing conditions or abnormal test results, the decision to obtain a chest radiograph can otherwise be made clinically. Pneumonia in a febrile but otherwise asymptomatic child is unlikely.

accine, a WBC count of 20,000/mm 3 was associated with occult pneumonia in 19% of patients without focal findings. 24 Without predisposing conditions or abnormal test results, the decision to obtain a chest radiograph can otherwise be made clinically. Pneumonia in a febrile but otherwise asymptomatic child is unlikely. Meningitis In developed countries, most studies of febrile infants <3 months old cite a bacterial meningitis incidence of 1%. The most common organisms are the same as those for bacteremia/sepsis: E. coli, group B streptococci, and L. monocytogenes. For children >3 months old, the most common organisms are S. pneumoniae, Neisseria meningitidis, and Staphylococcus aureus, with a lower incidence of S. pneumoniae meningitis since routine vaccinations with the conjugate vaccines. Outside of North America, the epidemiology of meningitis is more complex, depending on the region of the world in which the patient has been living or traveling. N. meningitidis and Mycobacterium tuberculosis are the more common causes. Although N. meningitidis rarely occurs in North America, incidence may be higher elsewhere, especially in the “meningitis belt” of sub-Saharan Africa. In patients with symptoms of meningitis and recent travel to Africa, meningococcal meningitis should be considered as a diagnosis . Treatment is similar to other causes of bacterial meningitis. Tuberculosis meningitis is discussed in Chapter 174, “Central Nervous System and Spinal Infections. ” The diagnosis of meningitis is made by cerebrospinal fluid analysis (see later section, “Procedures in Children: Lumbar Puncture”). It is often difficult to distinguish between viral and bacterial meningitis because there is a wide overlap in cerebrospinal fluid and peripheral blood findings. Because of the serious morbidity of missed meningitis, administer appropriate antibiotics in the ED and admit any ill-appearing patient or any patient <2 months old with any degree of cerebrospinal fluid pleocytosis. Infants with aseptic meningitis generally should be hospitalized and ensured adequate long-term follow-up because they are at greater risk for dehydration and subsequent neurologic and learning disabilities. For older children with cerebrospinal fluid pleocytosis and likelihood of viral meningitis, if the child is to be discharged from the ED, it is wise to administer a long-acting parenteral antibiotic (ceftriaxone, 100 milligrams/kg IM or IV) and ensure follow-up in 24 hours. Chapter 120, “Meningitis in Infants and Children, ” describes the diagnosis and treatment of meningitis in infants and children in more detail. Tintinalli_Sec12_p0669-0996.indd 747 8/2/19 7:50 PM

o administer a long-acting parenteral antibiotic (ceftriaxone, 100 milligrams/kg IM or IV) and ensure follow-up in 24 hours. Chapter 120, “Meningitis in Infants and Children, ” describes the diagnosis and treatment of meningitis in infants and children in more detail. Tintinalli_Sec12_p0669-0996.indd 747 8/2/19 7:50 PM 748 SECTION 12: Pediatrics TABLE 119-1 Suggested Guidelines for the Evaluation and Management of Neonates, Infants, and Children With Fever Who Are Well Appearing, Have Had All Relevant Immunizations, and Have No Clinical Source for Fever Age Group Evaluation Treatment and Disposition Neonate, 0–28 d * of age, ≥38 °C (100.4°F) SBI incidence of ill appearing: 13%–21%; if not ill appearing: <10% CBC and blood culture and Urinalysis and urine culture and CSF cell count, Gram stain, and culture. Chest radiograph is optional, if no respiratory symptoms. Stool culture if diarrhea is present. Admit and treat with: Parenteral antibiotic therapy with ampicillin, 50 milligrams/kg, and either cefotaxime, 50 milligrams/kg, or gentamicin, 2.5 milligrams/kg. Do not give ceftriaxone to infants <1 month old because it may displace bilirubin and worsen hyperbilirubinemia. Infant 29–56 d * of age, ≥38.2 °C (100.8°F) (Philadelphia Protocol) SBI incidence of ill appearing: 13%–21%; if not ill appearing: <5% Same as for neonates. Discharge if: WBC ≤15,000/mm 3 and ≥5000/mm 3 and <20% band forms. Urinalysis negative. CSF WBC <10 cells/mm3. Negative chest radiograph or fecal leukocytes if applicable. Admit if: Any of above criteria is not met, and treat with parenteral ceftriaxone, 50 milligrams/kg with normal CSF, 100 milligrams/kg with signs of meningitis. Infants 57 d to 6 mo* of age, ≥38 °C (100.4°F) Non-UTI SBI incidence is estimated to be negligible. UTI is 3%–8%. Urinalysis and urine culture alone. For conservative management, treat infants 57–90 d using Philadelphia Protocol above. Discharge if negative. Treat for UTI with oral antibiotics as outpatient (see Table 135-6). Admit and treat with parenteral ceftriaxone if patient fails conser vative criteria for discharge. Infants 57 d to 6 mo * of age ≥39 °C (102.2°F) SBI incidence is estimated as <1%; non-UTI SBI incidence is estimated to be negligible. UTI is 3%–8%. Urinalysis and urine culture alone. Urinalysis and urine culture in addition to CBC and blood culture. Discharge if negative. Treat for UTI as above. If WBC ≥15,000/mm 3, consider treatment with ceftriaxone, 50 milligrams/kg IV/IM, and follow-up in 24 h. If WBC ≥20,000/mm 3, consider chest radiograph and CSF testing.† Infants/children 6–36 mo of age Non-UTI SBI incidence is <0.4% UTI in girls ≤8% UTI in boys (<12 mo) ≤2% Uncircumcised boys (1–2 y) remains 2% Urinalysis and urine culture. Girls 6–24 mo Boys 6–12 mo Uncircumcised boys 12–24 mo Discharge if negative. Treat for UTI as above as outpatient. Children >36 mo and older No workup is routinely necessary. Discharge and treat with antipyretics: acetaminophen, 15 milligrams/kg PO/PR every 4 h, or ibuprofen, 10 milligrams/kg PO every 6 h as needed. Abbreviations: CSF = cerebrospinal fluid; SBI = serious bacterial illness; UTI = urinary tract infection. *For preterm infants, count age by estimated postconception date and not by actual delivery date for the first 90 days of life. †Meningismus is difficult to discern in infants <6 months of age, and especially in infants <2 months of age, and its absence does not exclude meningitis. Because of the declining prevalence of meningitis in the United States as infants age, we recommend routine CSF testing in infants <2 months of age, but selective CSF testing in infants 2 to 6 months of age.

fants <6 months of age, and especially in infants <2 months of age, and its absence does not exclude meningitis. Because of the declining prevalence of meningitis in the United States as infants age, we recommend routine CSF testing in infants <2 months of age, but selective CSF testing in infants 2 to 6 months of age. Peripheral WBC count (whether elevated or low) does not predict the risk for meningitis, and the decision to perform a lumbar puncture should be made independently of the peripheral WBC count. 26-28 Reproduced with permission from Tenenbein M, Macias CG, Sharieff GQ, Yamamoto LG, & Schafermeyer RW (Eds). Strange and Schafermeyer’s Pediatric Emergency Medicine, 5 ed. McGraw-Hill, Inc. © 2019. Table 59-1, Pg 389. GENERAL TREATMENT AND DISPOSITION PRINCIPLES FOR FEVER BASED ON AGE The clinical challenge is to distinguish the cause of fever: a benign viral infection, serious bacterial illness, or a noninfectious illness. Most fevers are due to viral infections, but bacterial infections are not infrequent. The significance of fever depends on multiple factors. If the physical examination identifies the source of infection, evaluation, testing, and treatment are dictated by the presumptive diagnosis. If the physical examination does not identify a source of infection causing fever, decision making is based first on age and then by height of fever. There are no absolute rules in the evaluation and management of fever, but the guidelines in Table 119-1 are suggested for the management of neonates, infants, and children who are well appearing, have had all relevant immunizations, and have no obvious cause for the fever. Again, this discussion should be applied judiciously to nondeveloped countries or patients recently emigrated from nondeveloped countries, because the epidemiology of fever may be more diverse in international settings and is beyond the scope of this chapter. Detailed discussion of evidence-based information is provided later in the section, “Decision Rules for Assessment of Fever in Neonates and Infants <3 Months Old. ” Any ill-appearing infant or child should have a complete sepsis evalua tion performed and should be admitted for parenteral antibiotic therapy. FEVER EVALUATION IN NEONATES AND INFANTS ≤3 MONTHS OLD In infants <3 months of age, review the birth history, including the length of the gestation, the use of peripartum antibiotics in the mother or infant during labor or delivery, and the presence of neonatal complications, such as fever, tachypnea, or jaundice. Signs and symptoms of serious bacterial illness are typically nonspecific in this age group. For example, vomiting and diarrhea accompany many problems, including gastroenteritis, otitis media, UTI, and meningitis. Alternatively, crying may be either a manifestation of serious bacterial illness or a benign condition of infancy (colic or hunger). Tintinalli_Sec12_p0669-0996.indd 748 8/2/19 7:50 PM

is age group. For example, vomiting and diarrhea accompany many problems, including gastroenteritis, otitis media, UTI, and meningitis. Alternatively, crying may be either a manifestation of serious bacterial illness or a benign condition of infancy (colic or hunger). Tintinalli_Sec12_p0669-0996.indd 748 8/2/19 7:50 PM CHAPTER 119:  Fever and Serious Bac terial Illness in Infants and Childr en      749 TABLE 119-2 Comparison of Low-Risk Rochester Criteria, Philadelphia Protocol, and Boston Criteria for Assessment of Fever in Well-Appearing Neonates and Infants * Low-Risk Criteria for Serious Bacterial Infection* Rochester Criteria Philadelphia Protocol Boston Criteria Fever T ≥38°C (100.4°F) T ≥38.2°C (100.8°F) T ≥38°C (100.4°F) Age ≤60 d 29–56 d 28–89 d Past medical history Term infant ≥37 wk gestation No immunodeficiency syndrome No immunizations within 48 h No perinatal or postnatal antibiotics   No recent antibiotics No treatment for jaundice No chronic illnesses or admissions Not hospitalized longer than mother Physical examination Well appearing Unremarkable examination Same Same Laboratory values Blood count WBC ≥5000/mm 3, ≤15,000/mm 3 WBC ≤15,000/mm 3 WBC ≤20,000/mm 3 Absolute band count ≤1500/mm 3 Band-to-neutrophil ratio ≤0.2 Urinalysis WBC ≤10 per high-power field WBC ≤10 per high-power field WBC ≤10 per high-power field Stool WBC ≤5 per high-power field — — Lumbar puncture and cerebrospinal fluid findings None WBC ≤8 per high-power field WBC ≤10 per high-power field Negative Gram stain Chest radiograph None Negative Negative if obtained Comments Excluded lumbar puncture, so number of missed meningitis cases is unknown. UTIs missed in those with negative urinalysis. The least sensitive of the low-risk criteria. Sensitivity of low-risk criteria for SBI 98%; specificity 44%; PPV 14%; NPV 99.7% 5% of low-risk neonates and infants had SBI (8 bacteremia, 8 UTI, 10 bacterial gastroen teritis); 96% sensitive to ceftriaxone Abbreviations: NPV = negative predictive value; PPV = positive predictive value; SBI = serious bacterial illness; T = temperature; UTI = urinary tract infection. *Any single deviation from the criteria is interpreted as failure of low-risk criteria. Undress infants completely. Assess age-appropriate normal vital signs. Tachypnea or hypoxemia may be a clue to lower respiratory tract infection. Inconsolable crying or increased irritability when handled is frequently seen in infants with meningitis. Although fullness of the anterior fontanelle may be noted in some infants with meningitis, other signs of meningeal irritation, such as nuchal rigidity, are usually absent. Perform a head-to-toe evaluation to identify a focus of infection, such as an inflamed tympanic membrane or evidence of cellulitis. Treatment of neonates and infants <3 months old with a focal source for fever is controversial. In a small study of tympanocentesis-confirmed acute otitis media, there were no cases of bacteremia or meningitis, but UTI was found in 9%. 29 The sample size of this study was not adequate to determine that blood testing or lumbar puncture was not necessary. A recent study in Europe 29 that used a step-by-step approach in the evaluation of febrile infants without a source of fever identified a population of infants at low risk for serious bacterial illness that could be managed on an outpatient basis without the use of antibiotics or lumbar puncture. This study used physical appearance (well-appearing or not), age (cutoff of 21 days), urinalysis, and biomarkers in a stepwise fashion to identify these infants. The low-risk group of infants still had a rate of missed serious bacterial illness of 0.7%.

utpatient basis without the use of antibiotics or lumbar puncture. This study used physical appearance (well-appearing or not), age (cutoff of 21 days), urinalysis, and biomarkers in a stepwise fashion to identify these infants. The low-risk group of infants still had a rate of missed serious bacterial illness of 0.7%. Therefore, even with an identified source, laboratory testing, close monitoring, and follow-up, especially in children <3 months old, are recommended to detect occult infection.  DECISION RULES FOR ASSESSMENT OF FEVER IN NEONATES AND INFANTS <3 MONTHS OLD Clinical assessment of the severity of illness in neonates and young infants is difficult. The three most commonly applied outpatient criteria for the management of fever in well-appearing neonates and young infants are the Rochester Criteria, the Philadelphia Protocol, and the Boston Criteria (Table 119-2). All three have limitations for clinical decision making. A comparison of these decision rules is dif ficult because of differences in inclusion criteria, laboratory testing, and clinical implications for decision making. In addition, the routine administration of antibiotics to pregnant women who test positive for group B Streptococcus on vaginal cultures and improved immuniza tion practices have decreased the incidence of serious bacterial illness, making it difficult to extrapolate these three decision rules to current practice. The Rochester Criteria state that in well-appearing neonates and infants ≤60 days old, without prior or peripartum illness and with a normal CBC, a negative urinalysis and negative chest radiograph (if indicated) are sufficient to exclude serious bacterial illness. 30 However, the Rochester Criteria miss 1% of patients with serious bacterial illness and do not include lumbar puncture as one of the diagnostic tests. The Rochester Criteria are the least sensitive of the three guidelines. In the largest validation study of the Rochester Criteria, the cohort of 1057 patients included 511 who met low-risk criteria (Table 119-2). Five patients, or 1% of patients identified as low risk, had serious bacterial illness that was missed. Lumbar puncture was not included in the rules, so the criteria do not provide the ability to exclude meningitis. Of note, the incidence of meningitis was 0.3% of the entire cohort of 1057 patients, which is lower than the 1% meningitis incidence cited in most other studies. In summary, the Rochester Criteria miss 1% of patients with serious bacterial illness and do not exclude meningitis. The Philadelphia Protocol (Table 119-2) includes the results of lumbar puncture in clinical decision making and includes young infants age 29 to 56 days old. 31 The sensitivity of the low-risk criteria for excluding serious bacterial illness (neonatal bacteremia, UTI, or meningitis) is 98%; specificity is 44%; positive predictive value is 14%; and negative predictive value is 99.7%. The temperature criterion for fever was 38.2°C (100.8°F), not 38°C (100.4°F). The incidence of meningitis in this cohort was 1.2%. Using the Philadelphia Protocol, all patients with meningitis were identified. One of 288 patients, who had otherwise met low-risk criteria, was identified by an elevated cerebrospinal fluid WBC alone. In addition, all cases of bacteremia and UTI were identified by the Philadelphia Protocol. Tintinalli_Sec12_p0669-0996.indd 749 8/2/19 7:50 PM

rotocol, all patients with meningitis were identified. One of 288 patients, who had otherwise met low-risk criteria, was identified by an elevated cerebrospinal fluid WBC alone. In addition, all cases of bacteremia and UTI were identified by the Philadelphia Protocol. Tintinalli_Sec12_p0669-0996.indd 749 8/2/19 7:50 PM 750 SECTION 12: Pediatrics The Boston Criteria (Table 119-2) attempted to identify young infants at lower risk of serious bacterial illness and safely treat them as outpatients with empiric ceftriaxone. 32 The Boston Criteria included infants 28 to 89 days of age and accepted a peripheral WBC up to 20,000/mm 3 as normal. Lumbar puncture was performed in all patients, and all patients with meningitis were excluded. In those who met lowrisk criteria, <1% of patients had a missed serious bacterial illness, and none had complications after empiric treatment with ceftriaxone. By using the Boston Criteria, a greater number of patients are discharged. Subsequent studies applying the Rochester, Philadelphia, and Boston decision rules missed serious bacterial illness in neonates 0 to 30 days old. 33,34 The safest course for 0- to 30-day-old infants is sepsis testing, admission, and empiric antibiotic treatment (Table 119-1). The recognition of occult serious bacterial illness in well-appearing neonates and infants <3 months of age is difficult. No single clinical variable or diagnostic test can correctly or reliably identify it in this age group. In addition, as noted earlier with the Rochester, Philadelphia, and Boston decision rules, these rules differ in their inclusion criteria. Combinations of variables can be helpful. A study from Boston chose statistically significant cutoff points for predictive variables for SBI. 35 In order of greatest statistical significance for prediction were positive urinalysis, WBC >20,000/mm3, temperature >39.6°C (103.3°F), WBC <4100/mm3, and age <13 days old. No variable or cutoff point was 100% sensitive or specific, and the number of meningitis cases was too small to lead to the inclusion of results of lumbar puncture in the decision rule. This study challenges the previous study protocols by introducing clinical and diagnostic test variables that were determined to be statistically significant. Although this is not standard of care, this added information may help determine different thresholds for fever evaluation in the neonate or for admission and antibiotic therapy.  TREATMENT, DISPOSITION, AND FOLLOW-UP FOR FEVER IN NEONATES AND INFANTS ≤3 MONTHS OLD There is no community standard of practice regarding the need for hospitalization of infants 3 months of age and younger. Some physi cians hospitalize all febrile infants <3 months old, and others hospitalize selectively. Some have attributed this difference in management to a difference in bias, with physicians in private practice having a bias toward wellness (the infant is basically healthy) and emergency physicians having a bias toward illness (worst-case scenario approach). 36 Because the differentiation between sick and well infants <28 days of age is dif ficult, with varying reports of missed serious bacterial illness, all febrile infants <28 days of age should have sepsis evaluations, including CBC, blood culture, urinalysis, urine culture, cerebrospinal fluid cell count, Gram stain and culture, and admission for parenteral antibiotics. Infants who are ill appearing or fail to meet the low-risk criteria (Table 119-2) should be admitted and administered parenteral antibiotics.

ave sepsis evaluations, including CBC, blood culture, urinalysis, urine culture, cerebrospinal fluid cell count, Gram stain and culture, and admission for parenteral antibiotics. Infants who are ill appearing or fail to meet the low-risk criteria (Table 119-2) should be admitted and administered parenteral antibiotics. Ampicillin (50 milligrams/kg/dose every 8 hours) and cefotaxime (50 milligrams/kg/ dose every 8 hours) is a common antibiotic regimen (or ampicillin and gentamicin, 2.5 milligrams/kg/dose), but choose antibiotics based on regional susceptibility patterns for group B Streptococcus, E. coli, and L. monocytogenes. Do not give ceftriaxone to infants <1 month old because it may displace bilirubin and worsen hyperbilirubinemia . The decision to discharge a febrile infant home must be made after careful clinical and appropriate laboratory assessment and after ensur ing the reliability of follow-up. Utilization of the Rochester Criteria, the Philadelphia Protocol, or the Boston Criteria may be considered. No missed cases of meningitis have been described with the Philadelphia Protocol and the Boston Criteria. The Philadelphia Protocol is recom mended due to its high sensitivity. If low-risk criteria are met for the Philadelphia Protocol, the patient may be discharged home without antibiotic administration, with evalu ation in 24 hours. Additional factors for outpatient management are a reliable caretaker with a telephone and an infant who can maintain hydration. Any child who is ill appearing should be admitted and given parenteral antibiotics, regardless of the age. Utilization of the data from viral testing may also influence the deci sion to discharge to home or admit for observation. In a large, multicenter, retrospective study, Schnadower et al 37 proposed that febrile infants 29 to 60 days old who demonstrate evidence of UTI, but meet low-risk criteria, may be safely discharged with anti biotic therapy. Significant adverse events, such as meningitis and sepsis, requiring critical care intervention occurred in 2.8% of patients. Bacte remia occurred in 6.5% of patients. Low-risk criteria for both adverse events and bacteremia were lack of ill appearance in the ED and lack of high-risk past medical history. Additional low-risk criteria for bactere mia included peripheral band count of <1250 cells/mm 3 and peripheral neutrophil count of ≥1500 cells/mm 3.37 Antibiotics are administered for clinically evident bacterial disease, such as pneumonia, meningitis, otitis media, cellulitis, and septic arthritis. Specific management is outlined in Chapter 121, “Ear and Mastoid Disorders in Infants and Children”; Chapter 128, “Pneumonia in Infants and Children”; and Chapter 142, “Rashes in Infants and Children. ”  SPECIAL SITUATIONS: NEONATES AND INFANTS <3 MONTHS OLD WITH FEVER AND RECOGNIZABLE VIRAL ILLNESS Many studies have shown that infants with bronchiolitis may still have a serious bacterial illness, although the risk of serious bacterial illness is significantly lower in febrile infants with bronchiolitis compared to febrile infants without bronchiolitis. 10,11,38-41 ED evaluation should therefore also include a minimum of a urinalysis and urine culture in patients with bronchiolitis. Consider urinalysis, urine culture, CBC, and blood culture in patients with suspected or proven enterovirus or parainfluenza infection.  SERUM BIOMARKERS Although the serum WBC count, absolute neutrophil count, and bandto-neutrophil ratio remain the standard biomarkers for serious bacte rial illness in young infants (see previous section on decision rules), the value of several other potential biomarkers deserves mention. C-reactive protein has been widely studied, but recent studies suggest that procalcitonin may be better.

and bandto-neutrophil ratio remain the standard biomarkers for serious bacte rial illness in young infants (see previous section on decision rules), the value of several other potential biomarkers deserves mention. C-reactive protein has been widely studied, but recent studies suggest that procalcitonin may be better. Procalcitonin is emerging as the best biomarker currently available to detect bacterial infections in febrile children, including in infants with fever without a source. 42-46 However, these studies have used varying cutoff levels. In addition, procalcito nin is not widely available, particularly within the United States. An approach combining clinical decision and serum biomarkers, as in the study by Gomez et al, 28 may be the best approach to the evaluation of these infants. FEVER EVALUATION IN INFANTS 3 TO 36 MONTHS OLD  CLINICAL FEATURES Clinical assessment is more reliable for older infants and young children than for young infants. Viral illnesses, including respiratory infections and gastroenteritis, account for most febrile illnesses and usually have system-specific symptoms, such as vomiting, diarrhea, rhinorrhea, cough, or rash. Characteristics to note are willingness of patients to make eye contact, playfulness and positive response to interactions, negative response to noxious stimuli, alertness, and ease of consolation. Toxic infants will not respond appropriately. Otitis media is usually caused by S. pneumoniae or nontypeable H. influenzae. Although pneumonia is commonly viral, it is difficult to distinguish bacterial from viral causes. In older infants or young chil dren with UTI, fever is usually the only presenting sign, but a history of foul-smelling urine or crying with urination may be noted. Cellulitis is clinically apparent. Abscess may be associated with these patients as well. Bacterial pharyngitis is unlikely under the age of 3 years. Nuchal rigidity and Kernig or Brudzinski signs may be absent in children with meningitis even up to the age of 2 years old . A bulging fontanelle, vomiting, irritability that increases when the infant is held, inconsolability, or a complex febrile seizure may be the only signs sug gestive of meningitis. Infants with aseptic meningitis generally should be hospitalized and provided with long-term follow-up because they are at greater risk for dehydration and subsequent neurologic and learning disabilities. Tintinalli_Sec12_p0669-0996.indd 750 8/2/19 7:50 PM

ebrile seizure may be the only signs sug gestive of meningitis. Infants with aseptic meningitis generally should be hospitalized and provided with long-term follow-up because they are at greater risk for dehydration and subsequent neurologic and learning disabilities. Tintinalli_Sec12_p0669-0996.indd 750 8/2/19 7:50 PM CHAPTER 119:  Fever and Serious Bac terial Illness in Infants and Childr en      751 Petechiae noted on physical examination are concerning for infection by N. meningitidis. However, most children with fever and petechiae will have a viral cause, such as adenovirus, whereas purpura fulminans (see Chapter 142, “Rashes in Infants and Children”), hypotension, lethargy, and meningismus predict meningococcemia. For the well-appearing child with fever and petechiae, there are no good predictors for serious bacterial illness. Time may be the best diagnostic test, with a brief observation period or admission warranted for cases that are indeterminate.  DIAGNOSIS The American Academy of Pediatrics practice guidelines that advocate testing for UTI in children 2 months to 2 years of age may be broken down into guidelines for girls and boys. 9 Ill appearance and history of UTI exclude patients from these guidelines. For girls, testing should be done if they have two or more of the following risk factors: (1) white race; (2) age <12 months; (3) temperature ≥39°C (102.2°F); (4) fever ≥2 days; and (5) absence of another source of infection. Uncircum cised boys should be tested if no apparent focus of infection is present. Circumcised boys should be tested if two or more of the following risk factors exist: (1) nonblack race; (2) temperature ≥39°C (102.2°F); (3) fever >24 hours; and (4) absence of another source of infection. Many would advocate that empiric blood testing and treatment for these patients is no longer necessary. Although reports of decreased bacteremia incidence have been published, as of this writing, no studies to determine predictors of bacteremia, outcome of empiric antibiotic use, reduction of complications, or outcome of nontreatment protocols have been published since the introduction of the pneumococcal conjugate vaccines. In addition, no practice parameters have established a cur rent standard of care, and the American Academy of Pediatrics has not renewed its practice guideline since 1993. The physician is therefore left with evidence of decreased incidence of bacteremia, but no studies or practice parameters supporting a selective testing or nontesting protocol. Given the decrease in invasive pneumococcal disease 14,18,47,48 and the limited predictive value of an elevated WBC for bacteremia, 14,49,50 three options exist. The first option is following the previous practice param eters and obtaining a CBC and blood culture on all children between 3 and 36 months old with a fever >39°C (102.2°F), and then treating with ceftriaxone only if the WBC is >15,000/mm 3.51 Because of the low posi tive predictive value of an elevated WBC, the second option is obtaining a blood culture and waiting for results before beginning empiric treatment. The third option is to assume that the incidence of pneumococcal disease has decreased so substantially that laboratory evaluation in a well-appearing child is unnecessary, so discharge with primary care follow-up is reasonable. Variants on the first and second options may be to evaluate children between 2 and 6 months of age because these children have not received the first three vaccine series.  TREATMENT, DISPOSITION, AND FOLLOW-UP IN INFANTS 3 TO 36 MONTHS OLD Any child who appears ill or toxic, is unable to maintain oral hydration, or has inadequate follow-up after discharge should be admitted for IV hydration and/or parenteral antibiotic therapy.

children have not received the first three vaccine series.  TREATMENT, DISPOSITION, AND FOLLOW-UP IN INFANTS 3 TO 36 MONTHS OLD Any child who appears ill or toxic, is unable to maintain oral hydration, or has inadequate follow-up after discharge should be admitted for IV hydration and/or parenteral antibiotic therapy. Choices for antibiotics depend on the organism and the regional susceptibilities. For recognized bacterial infections, use appropriate antibiotics based on the type of infection and regional and national standards. Treatment with high-dose amoxicillin (30 milligrams/kg/dose given three times daily, to a maximum adult dose) is recommended for otitis media, pneumonia, and sinusitis. Alternatives include amoxicillin/clavulanic acid, basing the dosing on high-dose amoxicillin, or azithromycin (10 to 12 milligrams/kg on day one (max 500 mg/dose) followed by 5 to 6 milligrams/kg once daily on days 2 to 5) for penicillin-allergic patients. Patients with cellulitis should be treated with appropriate anti streptococcal and antistaphylococcal antibiotic therapy (Chapter 142, “Rashes in Infants and Children”). Cephalexin (20 to 25 milligrams/ kg per dose four times a day for 10 days) or amoxicillin/clavulanic acid (22.5 milligrams/kg/d per dose twice daily) are appropriate choices. Given the increase in methicillin-resistant S. aureus, consider using an antibiotic regimen effective against this organism: clindamycin (10 milligrams/kg per dose three times a day for 10 days) or a combination of cephalexin and trimethoprim-sulfamethoxazole (trimethoprim, 4 mil ligrams/kg per dose twice a day for 10 days). The choice of antibiotic therapy for UTIs should be based on regional antibiotic susceptibility testing. Table 135-6 lists common treatment options. Approximately 80% of patients with S. pneumoniae bacteremia will have spontaneous resolution, but in 20% of patients, complications will arise, such as meningitis, pneumonia, or sinusitis. Each of these factors may be considered if occult bacteremia is suspected. If treatment is indicated, obtain a blood culture before administration of ceftriaxone at a single dose of 50 milligrams/kg. Ceftriaxone reduces the risk of complications from bacteremia. 32,52,53 While reducing the incidence of infectious sequelae, the difficulty with empiric antibiotic treatment arises when the blood culture returns as positive but no cerebrospinal fluid studies were sent.  POSITIVE BLOOD CULTURES IN CHILDREN 3 TO 36 MONTHS OLD Recall all children with positive blood cultures. In the case of positive S. pneumoniae cultures, if the child is receiving appropriate antibiotics, is clinically well, and is afebrile, the child should complete the course of therapy. If the child is afebrile and clinically well but not receiving anti biotics, opinions differ regarding the need for additional blood cultures and antibiotic therapy. In general, neither is necessary unless the child has developed a specific focus of infection. The febrile child with a positive blood culture should receive evalu ation (repeat blood culture, CBC, and consider urinalysis and lumbar puncture). For the persistently febrile patient who is well appearing and has a normal evaluation, admission is usual, although empiric treatment with ceftriaxone and follow-up as an outpatient may be considered. For any patient who is ill appearing, obtain the sepsis evaluation and admit for parenteral antibiotics. Likewise, children who are thought to be at risk for serious bacterial illness and do not have reliable follow-up or the ability to return to the hospital should also be admitted for inpa tient management. Children with cultures positive for N. meningitidis or methicillinresistant S. aureus should be admitted for parenteral antibiotic therapy.

e thought to be at risk for serious bacterial illness and do not have reliable follow-up or the ability to return to the hospital should also be admitted for inpa tient management. Children with cultures positive for N. meningitidis or methicillinresistant S. aureus should be admitted for parenteral antibiotic therapy. For organisms other than S. pneumoniae, N. meningitidis, or methicillinresistant S. aureus, more conservative management may be warranted. FEVER IN CHILDREN >36 MONTHS OLD Children >36 months old are easier to evaluate, and their complaints are usually more specific. Children with infections such as UTI, meningitis, pneumonia, pharyngitis, and otitis media are more likely to complain of symptoms typical for these diagnoses. Pharyngitis due to group A Streptococcus becomes more common in this age group, especially in the school-aged child (Chapter 124, “Mouth and Throat Disorders in Infants and Children”). However, infectious mononucleosis also becomes more prevalent in this age group and may mimic the signs and symptoms of group A streptococcal pharyngitis. Treatment for group A streptococcal infection is amoxicillin (25 milligrams/kg twice daily for 10 days), penicillin G benzathine (50,000 units/kg IM single dose, up to 900,000 units IM for older pediatric patients), or azithromycin (10 to 12 milligrams/kg on day one (max 500 mg/dose) followed by 5 to 6 milligrams/kg once daily on days 2 to 5) for penicillin-allergic patients. Kawasaki’s disease (see Chapter 129, “Congenital and Acquired Pediatric Heart Disease”) is the most common cause of acquired cardiac disease in children and typically presents in children <5 years of age. Patients usually have high fevers for 5 days, strawberry-appearing tongue, conjunctivitis and iritis, red mucous membranes in the mouth and dry cracked lips, and swollen lymph nodes. Peeling of the skin in the hands, feet, and genital area may also occur in the later phases. Variants of Kawasaki’s disease also occur, with fewer of these classic signs. Untreated patients with Kawasaki’s disease may develop life-threatening coronary aneurysms. Treatment for Kawasaki’s disease involves aspirin and IV immunoglobulin. PROCEDURES IN CHILDREN: LUMBAR PUNCTURE The usual goal of lumbar puncture in children is to obtain cerebrospinal fluid to test for markers of infection. Measuring opening pressure is not necessary, and therefore, the procedure is straightforward. Tintinalli_Sec12_p0669-0996.indd 751 8/2/19 7:50 PM