CHAPTER 167 Pediatric Fever

Transcription

1 CHAPTER 167 Pediatric Fever Nathan W. Mick Fever is the most common chief complaint of pediatric patients presenting to the emergency department (ED), accounting for up to 20% of ED visits. Most cases of fever are viral in origin, are benign in course, and resolve spontaneously. Fever tends to be of a higher clinical importance in younger children as they are immunologically immature and incompletely vaccinated. Management of children presenting to the ED varies dramatically by the age of the child, with the following common, albeit arbitrary, divisions: 0 to 28 days, 1 to 2 months, 2 to 3 months, 3 to 6 months, 6 to 36 months, and 3 years to adulthood. 1 These divisions reflect differing immunologic and vaccination milestones as well as the spectrum of age-specific pathogens. PERSPECTIVE Definitions and Epidemiology Fever is defined as any elevation in body temperature equal to or above 38.0 C and typically is the result of infection. The most reliable method to measure temperature is with a rectal thermometer, particularly in high-risk groups, such as infants 0 to 3 months of age, as axillary, oral, and tympanic thermometers are unreliable in this age group. The rectal route should not be used in patients who are potentially immunocompromised (e.g., children with fever who are receiving cytotoxic chemotherapy) because of the risk of mucosal damage, bacteremia, or transmission of infection. The cutoff for a clinically significant fever (i.e., one that triggers a laboratory evaluation) varies with the age and immunologic status of the child. A rectal temperature of 38.0 C is generally considered to be a clinically significant fever in an infant younger than 3 months, necessitating a thorough laboratory workup, whereas a toddler with a temperature of 39.5 C and an upper respiratory infection may not need any workup beyond a thorough history and physical examination. Fever is to be distinguished from hyperthermia, which is an elevation in the body s temperature set point. Causes of hyperthermia include heatstroke, salicylate ingestion, malignant hyperthermia as a complication of inhalational anesthetics, and elevation in temperature secondary to hypothalamic central nervous system (CNS) damage. The cause of fever varies with the age of the child (Table 167-1). The majority of pediatric fever is due to infections, and most infections are attributable to a viral source. Upper respiratory infections, viral gastroenteritis, croup, bronchiolitis, stomatitis, roseola, infectious mononucleosis, and varicella are all known causes of fever. Most viral illnesses are benign and self-limited, but infection with herpes simplex virus (HSV) or respiratory syncytial virus (RSV), particularly in the first month of life, can lead to significant morbidity and mortality. Bacterial disease is also an important cause of fever in children. Serious bacterial illness (SBI) is typically defined as the presence of pathogenic bacteria in a previously sterile site and includes urinary tract infection (UTI), bacteremia, meningitis, osteomyelitis, bacterial gastroenteritis, bacterial pneumonia, cellulitis, and septic arthritis. Studies have found the risk of SBI in febrile infants younger than 3 months with a temperature above 38.0 C to be between 6 and 10%; children younger than 28 days have the highest incidence. 2 Pathogens change during early infancy, with vertical transmission of organisms such as group B streptococcus, Listeria monocytogenes, and HSV being more common in neonates. By 1 to 2 months of age, organisms such as Streptococcus pneumoniae, Neisseria meningitidis, and urinary pathogens (Escherichia coli or Enterococcus) become more common. In all children younger than 3 months, the urinary tract is the most common site of infection, followed by bacteremia and meningitis. UTIs are more common in white girls compared with other races and are of higher prevalence in patients in whom no source for infection is found and who have higher temperatures (i.e., >39.0 C). 3 Children younger than 3 months may present with an apparent viral syndrome and still harbor serious bacterial illness. Levine and colleagues studied 1248 infants younger than 60 days who had temperatures above 38.0 C. Of these children, 22% were positive for RSV. Although, overall, children with documented RSV had a lower incidence of concomitant SBI than did those without RSV (12.5 vs. 7%), there was no significant difference in rates of SBI in children younger than 28 days (14.2% in RSV-negative neonates vs. 10.1% in RSV-positive infants). Most of the bacterial infections were UTIs. 4 Older children 3 to 36 months of age with recognizable viral syndromes (e.g., croup, bronchiolitis, varicella, stomatitis) have a very low incidence of bacteremia. Greenes and co-workers found that among 1347 patients with temperature above 39.0 C who had a recognizable viral syndrome, the risk of bacteremia was 0.2%. 5 Occult bacteremia describes the presence of pathogenic bacteria in the bloodstream of a well-appearing febrile child in the absence of a focus of infection; it was first described as a clinical entity in the 1970s. 6 The term typically refers to children 3 to 36 months of age who are highly febrile (>39.0 C) but appear well. Before the adoption of the conjugate vaccines against Haemophilus influenzae type b and S. pneumoniae, the incidence of bacteremia in this population was approximately 5%. 7,8 Vaccination has proved remarkably effective, nearly eradicating H. influenzae type b as a significant pathogen and greatly reducing the burden of pneumococcal disease (Fig ) Currently, the rate of occult bacteremia is below 1%, with pathogens such as N. meningitidis becoming proportionally more prevalent. Continued surveillance is ongoing to ensure that there is not a rise in invasive disease 2096

2 Chapter 167 / Pediatric Fever 2097 Table Etiology of Fever in Children AGE BACTERIAL CAUSES VIRAL CAUSES OTHER 0-28 days Group B streptococcus Listeria monocytogenes Escherichia coli Chlamydia trachomatis Neisseria gonorrhoeae 1-3 months Haemophilus influenzae Streptococcus pneumoniae Neisseria meningitidis Escherichia coli 3-36 months Streptococcus pneumoniae Neisseria meningitidis Escherichia coli 3 years to adulthood Streptococcus pneumoniae Neisseria meningitidis Escherichia coli Group A streptococcus Herpes simplex virus Varicella Enteroviruses Respiratory syncytial virus Influenza Varicella Enteroviruses Respiratory syncytial virus Influenza Varicella Enteroviruses Respiratory syncytial virus Influenza Mononucleosis Roseola Adenovirus Norwalk virus Coxsackievirus Varicella Enteroviruses Respiratory syncytial virus Influenza Mononucleosis Roseola Adenovirus Norwalk virus Bundling Environmental Bundling Environmental Leukemia Lymphoma Neuroblastoma Wilms tumor Leukemia Lymphoma Neuroblastoma Wilms tumor Juvenile rheumatoid arthritis Cases/100,000 A Cases/100,000 B Age (months) <2 <5 Age (years) Figure Decline in incidence of occult bacteremia after the introduction of the conjugate vaccine against Haemophilus influenzae (A) and Streptococcus pneumoniae (B). caused by nonvaccine serotypes. Urinary pathogens, occurring in 2% of febrile children younger than 5 years, continue to be an important source of bacterial illness in infants and children. Rates are highest in boys younger than 6 months (2.7%) and girls younger than 12 months (6-8%). 12,13 Bacterial illness in school-age children and adolescents includes focal infections, such as streptococcal pharyngitis, cellulitis, and pneumonia as well as bacteremia and meningitis. N. meningitidis has a bimodal distribution, with the highest incidence in children younger than 12 months (9.2/100,000 population). A second peak occurs during adolescence, when the rate of illness is 1.2/100,000 population, with a significant proportion of cases occurring in college students who reside in a dormitory setting (3.2/100,000 population). 14 Although it is much less common than in viral or bacterial infection, fever can also be a presenting sign of autoimmune diseases, such as juvenile rheumatoid arthritis or Kawasaki disease. CNS lesions such as brain tumors also can infrequently be manifested with fever. DISTINGUISHING PRINCIPLES OF DISEASE Pathophysiology The body s ability to fight infection varies with age. Maternal antibodies confer some protection after birth, but the infant s immune system is initially inadequate, particularly T-cell function and the ability to mount an immunoglobulin G response to infection. The immature neonatal immune system as well as exposure to certain pathogens during the birthing process (e.g., group B streptococcus, Chlamydia trachomatis, Neisseria gonorrhoeae) places the newborn at particular risk for SBI. Young infants are also at risk for disseminated infection as they are unable to mount

3 2098 PART V Special Populations / Section One The Pediatric Patient the immune response needed to prevent a localized infection from spreading. Thus a simple cellulitis, mastitis, omphalitis, or, rarely, gonococcal eye disease can lead to sepsis or focal seeding of the CNS, making aggressive evaluation and treatment of such infections crucial. Immune function improves during the first 2 to 3 months of life, but the risk of SBI does not diminish appreciably until the primary series of vaccinations against H. influenzae type b and pneumococcus is completed (6 months of age). History In dealing with a febrile child, history taking should focus on the length of illness, presence of localizing symptoms, and any pertinent past medical history. In infants younger than 28 days, birth history, particularly the presence of potentially transmittable maternal infection (HSV or group B streptococcus), is critically important. Immunization status, sick contacts, use of antipyretics before evaluation, and prior use of antibiotics are also important historical items. Defervescence after acetaminophen administration has not been shown to reliably exclude bacteremia in children of any age. 15 Prior antibiotic use may mask the classic findings in diseases such as meningitis. Cough and congestion may suggest pneumonia or viral upper respiratory infection, whereas a harsh, barking, or seal-like cough is often a predominant complaint in viral laryngotracheitis (croup). Parents may report vomiting and diarrhea as a component of gastroenteritis or the presence of sore throat and lymphadenopathy with viral or streptococcal pharyngitis. Decreased oral intake or decreased urine output is frequently a complaint in gastroenteritis, but it may also be seen in patients with stomatitis as the painful aphthous ulcerations in the mouth make fluid intake difficult. Any history of lethargy, irritability, or altered mental status can be elicited with severe dehydration but raises the specter of meningitis or encephalitis. A rash occurs in many viral illnesses, such as roseola, but it also may be seen in life-threatening conditions, such as meningococcemia, Rocky Mountain spotted fever, and toxic shock syndrome. Complaints of headache and neck pain (meningitis or encephalitis) or ear pain (otitis media) are also important historical points. Physical Examination The physical examination of the febrile child should begin with a complete set of vital signs, including pulse oximetry. Hypoxia or significant respiratory distress manifested by tachypnea, grunting respirations, nasal flaring, or retractions may accompany sepsis or pulmonary infection. Stridor can be seen with croup but also with retropharyngeal abscess, epiglottitis, or bacterial tracheitis. Signs of shock, such as hypotension and poor peripheral perfusion, should be noted. Children typically mount a tachycardic response to fever, and hypotension is often a late and dire finding. Tachycardia is often due to the fever itself, but tachycardia out of proportion to the degree of fever is often seen in other conditions, such as early shock, myopericarditis, and dehydration. Greenes and colleagues found that in infants younger than 12 months, heart rate increases linearly by 9.6 beats/minute with each 1 C increase in body temperature; however, caution must be exercised in attributing tachycardia to fever alone. 16 Once oxygenation, ventilation, and perfusion have been assessed and deemed adequate, the physical examination should focus on a thorough search for focal infection. In young infants, particularly those younger than 3 months, and in children who lack immunocompetence, fever may be the only presenting sign of serious illness, including meningitis. The physical examination in this age group is sufficiently insensitive to exclude SBI, and clinicians should not be falsely reassured by a normal physical examination in small children. Ancillary Testing Numerous laboratory and radiographic studies can be used to evaluate the febrile child. In general, testing should be directed at identification of the source of infection or evaluation for complications. Several guidelines exist for the evaluation of febrile children, although there is marked variation in adherence to these guidelines. Pantell and associates found that office-based practitioners followed published guidelines only 42% of the time in the evaluation of febrile children. 17 Clinicians with less experience and those based in the hospital tend to order more tests compared with more experienced clinicians and those practicing in an office setting. White Blood Cell Count An elevated white blood cell (WBC) count (>15,000/mm 3 ) can be an indicator of bacteremia but is also present in many viral illnesses. Leukopenia (<5000/mm 3 ) can also be a sign of SBI or early sepsis. Pneumococcal infection is classically associated with leukocytosis, whereas infection with N. meningitidis and H. influenzae may be present even with normal WBC counts. Lee and colleagues found that the rate of pneumococcal bacteremia increased from 0.5% in highly febrile children (>39.0 C) with a WBC count between 10,000 and 15,000/mm 3 to 3.5% if the WBC count was 15,000 to 20,000/mm 3 and up to 18% with a WBC count above 30,000/mm The WBC differential has also been used to risk stratify febrile children in various models; an increase in polymorphonuclear leukocytes and immature band forms increases the risk of bacterial disease. A rise in polymorphonuclear leukocytes is also seen early in some viral infections. An absolute neutrophil count (ANC) above 10,000/mm 3 suggests increased risk of pneumococcal bacteremia in febrile children (0.8% for children with an ANC below 10,000/mm 3 vs. 8% for children with an ANC above 10,000/mm 3 ). 19 Blood Culture A blood culture is a useful diagnostic test when bacteremia is suspected. In infants and children, blood should be obtained after sterile preparation of the skin, which includes an alcohol preparation and swabbing of the skin with povidone-iodine solution, which is then allowed to dry. Many centers obtain blood for culture during intravenous catheter placement after sterile preparation of the skin has been performed. This technique has the advantage of eliminating a second venipuncture solely to obtain blood for culture, although the rates of contamination with this technique have been shown to be higher in children (9.1 vs. 2.8%). 20 The risks of contamination should be weighed against the ability to obtain blood through a separate venipuncture. The yield of a single blood culture in infants and small children is actually good. The routine sending of more than one sample is generally not needed, and bacteremia is often accurately detected even if only 0.5 to 1 ml of blood is obtained. The advent of automated blood culture systems led to the identification of true pathogens more quickly than by traditional methods, often within 24 hours. Pathogens isolated in the first 24 hours are more likely to be true pathogens than are bacteria isolated after 24 hours. 21 Urinalysis and Urine Culture UTIs are common causes of bacterial illness in febrile children. Accurate documentation of UTI is imperative both to diagnose the cause of a fever and to identify those infants who need follow-up radiographic imaging (typically voiding cystourethrography, renal ultrasonography, or both) to exclude anatomic

4 abnormalities that will predispose them to further infection. The only reliable method to obtain urine in a non toilet-trained child is bladder catheterization or suprapubic aspiration. Bag collection of urine is notoriously unreliable; up to 85% of cultures from bag specimens will be falsely positive (defined as a culture growing a single organism with >10 5 colony-forming units [CFU]/mL or a mix of two or more organisms), which then places these children at risk for unneeded, potentially painful, and expensive follow-up diagnostic testing and antibiotics. A clean catch urine specimen is appropriate for older toilet-trained children. UTI is defined as the combination of bacteriuria and pyuria. Bacteriuria in the absence of WBCs on microscopic examination represents asymptomatic bacteriuria. Urine is typically analyzed with a dipstick, followed by microscopic analysis of a centrifuged specimen of urine. Hoberman and colleagues described the test characteristics of an enhanced urinalysis, which is examination with a hemocytometer of an unspun specimen of urine for pyuria (defined as >10 WBCs per high-power field) or the presence of any bacteria per high-power field in Gram s stain of unspun urine. They reported a negative predictive value of 99.8%, perhaps making urine culture unneeded if pyuria and bacteriuria are absent by use of the enhanced urinalysis method. 22 Many centers are not using this enhanced method. Because dipstick and microscopic analysis have lower sensitivities, most experts recommend sending urine for culture in high-risk groups (febrile girls <24 months of age, uncircumcised boys <12 months of age, and circumcised boys <6 months of age). A positive urine culture is defined as the growth of more than 10,000 CFU/mL of a uropathogen from urine obtained from a catheterized or suprapubic sample. In older children, in whom urine is typically obtained from a clean catch specimen, a higher threshold of more than 100,000 CFU/mL is typically used. Lumbar Puncture A sample of cerebrospinal fluid (CSF) should be obtained from any child with signs and symptoms of meningitis. Fluid should be obtained with the smallest pencil-point or noncutting spinal needle possible (typically a 22-gauge spinal needle) and sent for cell counts, manual differential, Gram s staining, culture, and measurement of CSF protein and glucose concentrations. Meningoencephalitis due to HSV is a potential cause of fever, particularly in children, and if it is suspected, sending of CSF for HSV polymerase chain reaction testing is indicated. The CSF in bacterial meningitis typically contains more than 1000 WBCs/mL, although there is considerable overlap in the CSF profile of bacterial and viral meningitis, making a determination of viral or aseptic meningitis difficult on the basis of CSF parameters such as cell count, protein, and glucose; thus CSF culture of a pathogenic bacterium is the gold standard. A prediction rule has been developed and validated to differentiate bacterial from aseptic meningitis. 23 Children who lack all of the following criteria have a low risk (0.1%) of bacterial meningitis: positive CSF Gram s stain, CSF ANC of at least 1000 cells/ml, CSF protein concentration of at least 80 mg/dl, peripheral blood ANC of at least 10,000 cells/ml, and history of seizure before or at the time of presentation. This may obviate the need for empirical antibiotic therapy and hospital admission in some children who are at low risk for bacterial meningitis. Contraindications to lumbar puncture include cellulitis over the proposed site of puncture, cardiopulmonary instability, bleeding diathesis or platelet count below 50,000/µL, focal neurologic deficits, and signs of increased intracranial pressure, including papilledema. In these patients, lumbar puncture should be deferred until the child is stable, and blood should be obtained for culture while the child is treated empirically, recognizing that up to 50% of children with meningitis will not have bacteremia. 24 Chapter 167 / Pediatric Fever 2099 CSF contaminated by blood, or a traumatic lumbar puncture, can make interpretation of cell counts and differentials difficult. In these cases, fluid should be obtained for Gram s stain and culture and the child treated presumptively for meningitis until culture data are available. Nigrovic and co-workers have shown that risk factors for a traumatic lumbar puncture include operator experience, excessive patient movement during the procedure, advancement of the needle with the stylet in place, and lack of local anesthesia. 25 Stool Studies Stool studies are indicated in patients in whom bacterial gastroenteritis may be a cause of fever. A stool guaiac test for blood as well as Gram s stain for WBCs should be performed. Presence of more than 5 WBCs per high-power field in the stool of a febrile child should trigger a culture of stool for Salmonella, Shigella, Campylobacter, enterotoxigenic Escherichia coli, and Yersinia species. Patients with sickle cell disease are at particular risk for focal complications such as osteomyelitis from Salmonella infection. Chest Radiography Chest radiographs may be useful in the workup of the febrile child and are indicated when hypoxemia, respiratory distress, tachypnea, or focal findings on lung examination are present. Children younger than 6 months may present with tachypnea as the sole finding of bacterial pneumonia. Truly occult pneumonia can also occur, particularly in the highly febrile child (>39.0 C) without apparent source of fever. Bachur and associates found that 26% of children with temperature above 39.0 C and WBC counts higher than 20,000 had radiographic evidence of pneumonia. 26 Of note, this study was done in the era before the conjugate pneumococcal vaccine. Rapid Viral Antigen Testing Many clinical laboratories have the ability to perform rapid viral antigen testing for such common pediatric viral illnesses as influenza A and B and RSV. The presence of a viral source for the fever in an ill child may obviate the need for expensive, painful, and lengthy diagnostic workups for bacterial processes. Bonner and colleagues evaluated the impact of physician knowledge of the presence of a positive rapid influenza assay result. 27 The investigators studied 391 patients aged 2 months to 21 years who presented with classic signs and symptoms of influenza. Of these patients, more than half had positive rapid assays for influenza, and the investigators noted that significantly fewer laboratory and radiographic studies were ordered if the treating clinician was aware of these results. There were also fewer antibiotics prescribed. A large multicenter trial of febrile infants 60 days of age or younger revealed a decreased risk (2.5 vs. 11.7%) if the infant was influenza positive. 28 RSV is also a frequent cause of fever in children. As previously noted, RSV decreases but does not completely eliminate the risk of SBI in children. This is especially true of UTI in infants younger than 28 days. SPECIFIC DISORDERS General Approach to the Febrile Infant and Child The initial approach to any child with a febrile illness is a rapid assessment for evidence of cardiopulmonary compromise or shock. Significant respiratory distress, hypoxemia unresponsive to

5 2100 PART V Special Populations / Section One The Pediatric Patient supplemental oxygen, or altered mental status may necessitate intubation by rapid sequence induction and mechanical ventilation. Evidence of shock (poor perfusion, hypotension, altered mentation) should be aggressively treated with fluid resuscitation. An intravenous or intraosseous line should be placed, and the initial resuscitative fluid should be 20 ml/kg of isotonic crystalloid. This should be repeated to a total of 60 ml/kg if signs of hypovolemia persist, after which vasopressor therapy (dopamine 1-20 µg/kg/min or norepinephrine µg/kg/min titrated to blood pressure) should be considered. Every effort should be made to obtain appropriate specimens for culture (blood and urine), even in the critically ill child, before antibiotic administration. Lumbar puncture may be deferred in the critically ill child until stabilization occurs. Empirical antibiotic therapy should be directed at the most likely causative organisms based on age. Sterilization of the CSF occurs quickly once antibiotic administration has been initiated: within 15 minutes to 2 hours in patients with meningococcal meningitis and within 4 to 10 hours in patients with pneumococcal meningitis % 60% 50% 40% 30% 20% 10% 0% 1st week 2nd week 3rd week Figure Age at presentation for neonatal herpes simplex virus infection. Serious Bacterial Illness Infants 0 to 28 Days of Age Children presenting with temperature above 38.0 C who are younger than 28 days are at particularly high risk for bacterial illness, with rates as high as 12% quoted in the literature. 30,31 Often, fever is the only manifestation of potentially life-threatening disease, and other signs and symptoms may be exceedingly subtle. This has led to an aggressive approach to diagnostic testing, empirical antibiotic therapy, and hospitalization in this age group, even if the child appears well. Children in this age group often present with nonspecific complaints, such as irritability, lethargy, poor feeding, and grunting. Besides fever, other signs of serious illness include a bulging fontanel, mottled extremities, petechiae, and tachypnea. Bacterial pathogens in this age group include group B streptococcus, L. monocytogenes, N. meningitidis, S. pneumoniae, and E. coli. Viral pathogens, including RSV and HSV, are also important considerations. Neonatal HSV infection in particular carries a high degree of morbidity and mortality and should be considered in any febrile neonate with a maternal history of genital herpes, who appears ill, who presents with fever and seizure, who has cutaneous vesicles on physical examination, or who has evidence of transaminitis or coagulopathy. HSV meningoencephalitis should also be considered in patients with fever and CSF pleocytosis but a negative CSF Gram s stain. The risk period for HSV disease tends to be between 2 and 12 days of age (Fig ). Other noninfectious causes of a septic-appearing neonate include the acute saltwasting crisis associated with congenital adrenal hyperplasia and undiagnosed duct-dependent congenital heart disease. Because of the high risk of bacterial pathogens and the difficulty in clinical assessment of children younger than 28 days, these patients require an aggressive diagnostic evaluation, including a complete septic workup. This consists of a complete blood count (CBC) with differential, blood culture, urinalysis and urine culture, and lumbar puncture. Lumbar puncture is indicated even in the presence of a UTI because of the risk of concomitant meningitis. 32 All children in this age group should be admitted to the hospital with empirical antibiotics until culture data become available. Appropriate parenteral antibiotic regimens include ampicillin (100 mg/kg/24 hr divided every 6 hours) plus either gentamicin (5 mg/kg/24 hr divided every 8 to 12 hours) or cefotaxime (150 mg/kg/24 hr divided every 8 hours). Ceftriaxone should be avoided in infants younger than 28 days because of a theoretic risk of inducing acute bilirubin encephalopathy as ceftriaxone causes bilirubin to be displaced from its protein binding sites. Empirical acyclovir should be added if risk factors for HSV disease exist (60 mg/kg/24 hr, divided every 8 hours). Infants 29 to 90 Days of Age Although there is a relative consensus as to the evaluation and management of febrile infants younger than 28 days, there is debate about the appropriate workup for the slightly older febrile infants. Ill-appearing children of any age should have a complete sepsis evaluation performed and be admitted to the hospital with empirical antibiotic therapy. Appropriate antibiotic therapy for high-risk children includes coverage of neonatal pathogens such as L. monocytogenes and group B streptococci as well as coverage against H. influenzae, N. meningitidis, and S. pneumoniae. Ampicillin, 50 to 100 mg/kg every 6 hours, plus cefotaxime, 50 mg/kg every 8 hours parenterally, is one alternative. Vancomycin, 40 to 60 mg/kg intravenously (IV) every 6 to 8 hours, should be considered if S. pneumoniae resistant to penicillins and cephalosporins is suspected. Various strategies (herein referred to as the Rochester, Philadelphia, and Boston criteria) for the evaluation of well-appearing children have been reported, compared, and retested in the literature Each strategy has unique features, including the definition of fever (38.0 C vs C), the study population (0-3 months of age, 1-2 months of age, and 1-3 months of age), the clinical and laboratory variables studied, and the disposition (hospitalization with or without antibiotics or outpatient treatment with or without antibiotics). Each strategy seeks to identify a set of low-risk criteria that, if met, will allow less aggressive treatment or the withholding of empirical antibiotic therapy. The three main strategies are highlighted in Table Baraff synthesized the recommendations of the Rochester, Philadelphia, and Boston criteria into an algorithm for the management of the previously healthy febrile infant 29 to 90 days of age (Fig ). 36 To be low risk, the child had to have been previously healthy with an uncomplicated nursery stay, to be nontoxic clinically, and to have no focal source of bacterial infection. Low-risk laboratory criteria in this schema included a normal WBC count (between 5000 and 15,000 WBCs/mm 3 ), fewer than 1500 bands/mm 3, normal urinalysis (negative Gram s stain and <5 WBCs per high-power field), and negative CSF Gram s stain and cell counts (<8 WBCs/mm 3 ), if obtained. When diarrhea was present, fewer than 5 WBCs per high-power field was the threshold for low risk. Once the child is deemed to be at low risk by these criteria, two options are available to the clinician on the basis of the Philadelphia and Boston criteria. The first management strategy calls for a CBC, blood culture, urinalysis, and urine culture. Once these

6 Chapter 167 / Pediatric Fever 2101 Table PHILADELPHIA ROCHESTER BOSTON Age days <60 days days Temperature >38.2 C >38.0 C >38.0 C Examination Well, no focus Well, no focus Well, no focus Laboratory values (define low risk) Summary of Major Strategies for the Management of Febrile Infants Younger than 3 Months WBCs > 15,000/mm 3 Band/neutrophil ratio < 0.2 UA < 10 WBCs/hpf (negative Gram s stain) CSF < 8 WBCs/hpf (negative Gram s stain) Chest radiograph normal, stool negative (if obtained) WBCs ,000/mm 3 Absolute band count < 1500 UA < 10 WBCs/hpf Stool < 5 WBCs/hpf (if obtained) WBCs < 20,000/mm 3 UA < 10 WBCs/hpf CSF < 10 WBCs/hpf Chest radiograph normal (if obtained) High risk Admission + IV antibiotics Admission + IV antibiotics Admission + IV antibiotics Low risk Home, no antibiotics Home, no antibiotics Home, empirical antibiotics Performance Sensitivity 98% (92-100%) Specificity 42% (38-46%) PPV 14% (11-17%) NPV 99.7% (98-100%) Sensitivity 92% (83-97%) Specificity 50% (47-53%) PPV 12% (10-16%) NPV 98.9% (97-100%) Sensitivity not available Specificity not available PPV not available NPV 94.6% CSF, cerebrospinal fluid; IV, intravenous; NPV, negative predictive value; PPV, positive predictive value; UA, urinalysis; WBCs/hpf, white blood cells per high-power field. NOT eligible for outpatient treatment Admit to hospital Parenteral abx No Infant appears toxic or <28 days Yes days of age Admit to hospital Sepsis workup Parenteral abx Sepsis workup Eligible for outpatient treatment Option 1 (if lumbar puncture performed) Ceftriaxone 50 mg/kg Reevaluation in 24 hours Option 2 (only blood and urine culture obtained) Discharge home off antibiotics Reevaluation in 24 hours Figure Algorithm for the management of febrile infants younger than 3 months. abx, antibiotics. studies have been obtained and the results are normal, the child may be discharged with close outpatient follow-up. The second option, based on the Boston criteria, calls for a complete sepsis evaluation, including lumbar puncture, followed by empirical treatment with ceftriaxone (50 mg/kg IV or intramuscularly [IM]) and reevaluation within 24 hours. The important difference between these two strategies is that empirical antibiotics should not be administered unless a complete sepsis evaluation is performed, including a lumbar puncture. Otherwise, if a lumbar puncture is not initially performed and the child returns for reevaluation and a lumbar puncture is subsequently performed with the finding of CSF pleocytosis, pretreatment with antibiotics makes interpretation of culture results difficult. Thus a child with a possible viral process may be subjected to inpatient admission and 14 days of parenteral antibiotic therapy. Infants 3 to 36 Months of Age Fever in children 3 to 36 months of age is incredibly common; most cases represent self-limited viral illnesses. Common causes of fever in this age group include viral upper respiratory infections, croup, bronchiolitis, stomatitis (typically caused by HSV or Coxsackievirus), gastroenteritis, roseola, and fifth disease (parvovirus B19 infection). Focal infections, such as pyelonephritis, periorbital cellulitis, bacterial pharyngitis (group A streptococcus), septic arthritis, retropharyngeal abscess, meningitis, and bacterial pneumonia, also become common in this age group. Typically, these focal infections are apparent on the basis of history and physical examination findings, and diagnostic testing and treatment should be directed accordingly. The history in this age group should focus on the duration of illness, associated symptoms that may focus the evaluation, immunization history (particularly vaccination for H. influenzae type B and pneumococcus), and sick contacts. A thorough physical examination is essential to rule out serious focal infection, such as meningitis. Young children may demonstrate inconsolable irritability or lethargy as the sole manifestation of meningitis; furthermore, classic meningeal signs, such as nuchal rigidity, are seen in less than 27% of infants (0-6 months) with bacterial meningitis. 37 Prior research has focused on assessment of children in this age group for the presence of occult bacteremia. It was found that a small percentage of highly febrile children (>39.0 C) 3 to 36 months of age were bacteremic. 36,38-41 These children were noted to be highly febrile but lacked any localizing signs of infection. No historical or physical examination findings were sufficiently sensitive or specific to identify cases of occult bacteremia, making universal diagnostic testing necessary A typical workup included a CBC and blood culture, and empirical antibiotic therapy was prescribed for children with WBC counts above 15,000/mm 3. Empirical antibiotics were justified on the basis of studies that revealed treatment with antibiotics prevented focal sequelae of bacteremia such as meningitis and shortened the duration of fever Before the advent of almost universal immunization against S. pneumoniae, the rate of occult bacteremia was approximately 3%, and although pneumococcal bacteremia resolves

7 2102 PART V Special Populations / Section One The Pediatric Patient without therapy up to 75% of the time, a small proportion of children have sepsis or focal infections such as meningitis. Pneumococcal meningitis has a high degree of morbidity and mortality, including permanent neurologic disability, hearing loss, and death. 48,49 Since the advent of Prevnar (conjugate pneumococcal vaccine), the number of invasive pneumococcal infections caused by vaccine-serogroup isolates among eight U.S. children s hospitals has decreased more than 75% among children younger than 24 months. Because of the decline in invasive pneumococcal disease brought on by vaccination, the cost-effectiveness of mandatory blood testing has been called into question. 50,51 Lee and colleagues evaluated the cost-effectiveness of various management strategies: no workup, relying on clinical judgment, blood culture, blood culture plus empirical antibiotics, WBC count plus blood culture and empirical antibiotics, and WBC count plus selective blood culture for WBC counts above 15,000 and empirical antibiotics. They found that at rates of pneumococcal bacteremia greater than 1.5%, obtaining a WBC count plus selective blood culture and empirical antibiotics were the most cost-effective approach. At rates of pneumococcal bacteremia less than 0.5%, strategies that used empirical testing and treatment were no longer cost-effective. They concluded that at lower rates of bacteremia, clinical judgment is more useful in selecting out high-risk populations who might benefit from selective testing and treatment. 52 Although the incidence of pneumococcal bacteremia has declined in infants 3 to 36 months of age because of the aggressive campaign to vaccinate, infants 3 to 6 months of age have not yet completed the primary series of immunizations against S. pneumoniae and to a lesser extent H. influenzae. Thus, highly febrile infants (>39.0 C) without an apparent source on examination should be considered at risk for occult bacteremia and consideration given to obtaining a WBC count and blood culture as a screen. Empirical antibiotic therapy should be reserved for infants with WBC counts above 15,000/mm 3 or those with an ANC 10,000/mm 3. Although the conjugate pneumococcal vaccine contains antigens from the seven most common serotypes that cause invasive disease, there are approximately 90 serotypes that are capable of infecting humans. Continued bacterial surveillance is necessary to ensure that other serotypes do not rise in incidence to fill the void left by vaccination. No clinical prediction algorithm correctly identifies all patients with meningococcal disease. 53 Additional signs and symptoms that may suggest meningococcemia are purpuric rash, bandemia, limb pain, and exposure to a person with the disease. An appropriate flow diagram for the workup of febrile infants 3 to 36 months of age is presented in Figure Children Aged 3 Years to Adulthood The incidence of occult bacteremia decreases after 3 years of age. Focal infections such as streptococcal pharyngitis, septic arthritis, pneumonia, peritonsillar abscess (most often in adolescents), and cellulitis become more common. Viral pathogens are also common, such as infectious mononucleosis. Infection with atypical pathogens, such as Mycoplasma pneumoniae, should also be considered in children presenting with pneumonia. Skin infections secondary to community-acquired methicillin-resistant Staphylococcus aureus (CMRSA) are also becoming more common. CMRSA occurs in all age groups but has clustered among such children as wrestlers (associated with contaminated wrestling mats) and football players (infected equipment). 54,55 This diagnosis should be considered in all children who present with pyogenic skin infection and skin abscesses. Appropriate therapy includes incision and drainage of the abscess cavity. Antibiotic therapy in addition to incision and drainage for simple abscesses has not been shown to hasten resolution of the infection but should be considered for patients with large abscesses (>5 cm), with cellulitis, or with Figure Algorithm for the management of febrile infants 3 to 36 months of age. CBC, complete blood count; WBC, white blood cell count. fever. 56 The antibiotics used are dependent on local resistance patterns but could include trimethoprim-sulfamethoxazole or clindamycin. There is also a second peak in incidence of meningococcal disease in adolescent children with an attack rate of 1.2 infections per 100,000 population. As opposed to infants, adolescents with meningococcal infection are more likely to present with meningococcemia (40 vs. 20%) and shock (69 vs. 27%) and to have a fatal outcome (22.5 vs. 4.6%). Meningococcal disease typically is manifested with one of three clinical syndromes: meningitis, bacteremia, or a combination of the two. College students residing in dormitories are at particular risk for infection, with attack rates of 3.2/100,000 population. 57 The history in cases of meningococcal infection is often one of rapidly progressive fever, headache, and stiff neck. Shock, altered mental status or frank coma, petechiae or purpura, seizures, and myalgias are also seen. Some of the first signs of meningococcal infection include leg pain, cold hands and feet, and abnormal skin mottling. 58 Children exposed to a patient with meningococcemia, particularly those with close contact with nasopharyngeal secretions, and who have any of the presenting signs should receive a full septic workup, admission to the hospital, and empirical treatment with antibiotics until results of blood and CSF cultures are known. Appropriate initial therapy for children suspected of having meningococcal infection is ceftriaxone 100 mg/kg IV. In January 2005, the Food and Drug Administration approved the quadrivalent meningococcal conjugate vaccine (Menactra) for use in adolescents. This vaccine is a polysaccharide-protein conjugate directed against the four serotypes that cause most cases of invasive meningococcal disease in humans. The Advisory Committee on Immunization Practices recommends vaccination of adolescents at their 11- or 12-year-old well-child checkup, and the American Academy of Pediatrics (AAP) has also advised that all college freshmen living in dormitories be vaccinated. Use of the vaccine is associated with a 67% decrease in invasive disease and a 66% decrease in carriage rates. 59 Febrile Seizures Temperature 39 C Fully vaccinated (2-, 4-, 6-month vaccines) Yes No Urinalysis and culture +/ chest x-ray* Yes Females <24 months Male circumcised <6 months, uncircumcised <12 months Febrile seizures are a common cause of convulsions in children younger than 5 years. They are defined as a seizure accompanied by fever without the presence of CNS infection. They typically occur in infants and children aged 6 months to 5 years. It is No Antipyresis Further labs per clinical judgment CBC and blood culture Urinalysis and culture ± +/ chest x-ray* Antibiotics for WBC >15,000 *Chest x-ray for symptoms or WBC >20,000

8 thought that the at-risk period is the rapid rise or defervescence of a fever, rather than the absolute height of the fever. Many parents worry about the subsequent risk of epilepsy after a febrile seizure, although studies have borne out that the risk is only slightly increased. The risk of epilepsy in the general population is thought to be 0.5 to 1%, whereas the risk in a patient who has had a febrile seizure is 1 to 2%. Although they are generally benign in course, febrile seizures can sometimes be the presenting complaint of infants and children with CNS infection such as meningitis. Febrile seizures are classified as either simple or complex. Simple febrile seizures are brief (<15 minutes), single, and nonfocal or generalized tonic-clonic. Complex febrile seizures are prolonged, recurrent (more than one within 24 hours), or typically focal. Differentiation of a benign febrile seizure from one that heralds CNS infection can be difficult. The AAP has published consensus guidelines for the evaluation and management of febrile seizures. 60 Laboratory and radiographic evaluation should be directed at finding the source of the fever, not driven by the seizure itself. The AAP suggests that a lumbar puncture be performed in any child with signs of meningeal irritation after the first febrile seizure and be considered in children who are incompletely immunized or have received prior antibiotic therapy. Routine referral for neuroimaging or electroencephalography is not indicated. 61 There is also no role for antiepileptic therapy after a single febrile seizure. Two retrospective studies have shown that the incidence of meningitis after the simple or complex febrile seizures is exceedingly low and that infants with meningitis will demonstrate signs of sepsis or meningitis after the seizure, making empirical lumbar puncture based solely on a febrile seizure unnecessary. 62,63 Parents should be warned that 33% of children who have a febrile seizure will have another one and that 75% of these will occur within a year. The younger a child is at the age of the first seizure, the more likely it is that a second one will occur. Children who seize at lower temperatures are also at higher risk for recurrence (35% at 38.5 C vs. 13% at 40 C). Fever and Petechiae The presence of a petechial rash in the setting of a febrile illness is classically associated with meningococcal infection. In fact, Baker and colleagues found that the incidence of meningococcal infection was 7 to 11% in patients hospitalized with fever and petechiae. 64 The rate of bacteremia of any cause was found to be much lower (1.9%) in an ED population. The differential diagnosis of fever and petechiae also includes disseminated intravascular coagulation, Rocky Mountain spotted fever, pneumococcal bacteremia, Streptococcus pyogenes infection, various viral infections, idiopathic thrombocytopenic purpura, Henoch-Schönlein purpura, and leukemia. Petechiae can also be caused mechanically from a tourniquet, retching, or violent coughing. Petechiae due to vomiting or coughing are typically confined to the skin above the nipple line, but petechiae caused by SBI can have any distribution. Because of the risk of serious illness in children with fever and petechiae, blood should be obtained for CBC and culture. In cases associated with pharyngitis, testing for group A streptococcus infection is indicated. Mandl and colleagues performed a prospective cohort study of 411 patients presenting to a pediatric ED with temperature higher than 38.0 C and petechiae in the hope of identifying clinical and laboratory criteria that would provide a means to screen for bacteremia. 65 They found that an abnormal WBC count (<5000 WBCs/mm 3 and >15,000 WBCs/ mm 3 ) or abnormal coagulation studies were predictive but not diagnostic of invasive bacteremia. Also, well-appearing children with normal WBC and coagulation studies were exceedingly Chapter 167 / Pediatric Fever 2103 unlikely to have invasive bacteremia. In their study, only two wellappearing children had bacteremia (S. pneumoniae), and this study was done in the pre-prevnar era. Empirical antibiotic therapy (ceftriaxone 50 mg/kg IV or IM) should be considered in all children presenting with fever and petechiae, even if an outpatient disposition is anticipated. Kawasaki Disease (Mucocutaneous Lymph Node Syndrome) Kawasaki disease (KD) is one of the most common vasculitides in childhood and should be considered in any infant or child with prolonged fever. 66 A more complete discussion of KD can be found in Chapter 171. Accurate diagnosis is important because the main complication of KD is the development of coronary artery aneurysms. Some patients will present with incomplete KD, which occurs when not all diagnostic criteria are met. Despite the lack of classic findings, these children are still at risk for coronary complications. Laboratory abnormalities found in cases of KD include leukocytosis, thrombocytosis (platelet counts as high as 1,000,000/mm 3 ), and evidence of systemic inflammation with elevation in the erythrocyte sedimentation rate and C-reactive protein level. Children with suspected KD should be hospitalized and receive therapy with intravenous immune globulin (2 g/kg infused during hours) and aspirin (initial dose mg/kg daily divided every 6 hours). 67 Pediatric cardiology consultation for echocardiography is also indicated. Toxic Shock Syndrome Toxic shock syndrome (TSS) refers to the toxin-mediated clinical syndrome that occurs with infection with Staphylococcus aureus, although a similar illness is caused by infection with group A streptococcus. The toxin implicated in TSS is an exotoxin termed TSS toxin 1. The syndrome is classically associated with tampon use by menstruating women, although cases also occur in males and prepubertal girls and also result from other sources of infection with S. aureus Clinical manifestations of TSS include fever (>38.9 C), hypotension, diffuse erythroderma, and multisystem involvement. Patients may present with vomiting or diarrhea, severe myalgias, oropharyngeal hyperemia, or altered mental status. Laboratory abnormalities are common and include elevated creatine kinase, elevated blood urea nitrogen or creatinine, transaminitis, and thrombocytopenia. The Centers for Disease Control and Prevention (CDC) has developed a set of findings for case definition (Box 167-1). Treatment of TSS involves aggressive fluid resuscitation as these patients typically have immense requirements and antistaphylococcal antibiotic therapy with clindamycin (25-40 mg/kg per day in three divided doses) and vancomycin (40 mg/kg per day IV in four divided doses). Fever and Underlying Chronic Medical Illness Oncology Patients Children with cancer, particularly those undergoing treatment with cytotoxic chemotherapy, are at particular risk for sepsis and bacterial infection. 71 These life-threatening infections are most common during periods of profound neutropenia. Neutropenia is defined as an ANC of less than 500/mL or an ANC of less than 1000/mL that is falling. Children with cancer also frequently have indwelling catheters, predisposing them to surgical line infections.