Neonates

Neonates who experience fever without focus are a challenge to evaluate because they display limited signs of infection, making it difficult to clinically distinguish between a serious bacterial infection and self-limited viral illness. Immature immune responses in the first few months of life also increase the significance of fever in the young infant. In general, neonates who have a fever and do not appear ill have a 7% risk of having a serious bacterial infection. Serious bacterial infections include occult bacteremia, meningitis, pneumonia, osteomyelitis, septic arthritis, enteritis, and urinary tract infections. Although neonates with serious infection can acquire community pathogens, they are mainly at risk for late-onset neonatal bacterial diseases (group B streptococci, Escherichia coli, and Listeria monocytogenes) and perinatally acquired herpes simplex virus (HSV) infection.

Practice guidelines recommend that if a neonate has had a fever recorded at home by a reliable parent, the patient should be treated as a febrile neonate. If excessive clothing and blankets encasing the infant are suspected of falsely elevating the body temperature, then the excessive coverings should be removed and the temperature retaken in 15 to 30 minutes. If body temperature is normal after the covers are removed, then the infant is considered afebrile.

Owing to the unreliability of physical findings and the presence of an immature immune system, all febrile neonates should be hospitalized; blood, urine, and cerebrospinal fluid (CSF) should be cultured, and the child should receive empirical intravenous antibiotics. CSF studies should include cell counts, glucose and protein levels, Gram stain, and culture; HSV and enterovirus polymerase chain reaction should be considered. Stool culture and chest radiograph may also be part of the evaluation. Combination antibiotics such as ampicillin and cefotaxime are recommended. Acyclovir should be included if HSV infection is suspected owing to the presence of CSF pleocytosis or known maternal history of genital HSV, especially at the time of delivery.

1 Month to 3 Months

The large majority of children with fever without localizing signs in the 1-3 mo age group likely have a viral syndrome. In contrast to bacterial infections, most viral diseases have a distinct seasonal pattern: respiratory syncytial virus and influenza A virus infections are more common during the winter, whereas enterovirus infections usually occur in the summer and fall. Although a viral infection is the most likely etiology, fever in this age group should always suggest the possibility of serious bacterial disease. Organisms to consider include group B streptococcus, L. monocytogenes, Salmonella enteritis, E. coli, Neisseria meningitidis, S. pneumoniae, Hib, and Staphylococcus aureus. Pyelonephritis is more common in uncircumcised infant boys and infants with urinary tract anomalies. Other potential bacterial diseases in this age group include otitis media, pneumonia, omphalitis, mastitis, and other skin and soft tissue infections.

Ill-appearing (toxic) febrile infants ≤3 mo of age require prompt hospitalization and immediate parenteral antimicrobial therapy after cultures of blood, urine, and CSF are obtained. Ampicillin (to cover L. monocytogenes and enterococcus) plus either ceftriaxone or cefotaxime is an effective initial antimicrobial regimen for ill-appearing infants without focal findings. This regimen is effective against the usual bacterial pathogens causing sepsis, urinary tract infection, and enteritis in young infants. However, if meningitis is suspected because of CSF abnormalities, vancomycin should be included to treat possible penicillin-resistant S. pneumoniae until the results of culture and susceptibility tests are known.

Many academic institutions have investigated the optimal management of low-risk patients in this age group with fever without a focus (Table 170-2). The use of viral diagnostic studies (enteroviruses, respiratory viruses, rotavirus, and herpesvirus) in combination with the Rochester Criteria or similar criteria can enhance the ability to determine which infants are at high risk for serious bacterial infections (see Table 170-2). Febrile infants in whom a virus has been detected are at low or no risk of a serious bacterial infection. Well-appearing infants 1-3 mo of age can be managed safely using low-risk laboratory and clinical criteria as indicated in Table 170-2 if reliable parents are involved and close follow-up is assured.

Infants 1-3 mo of age with fever who appear generally well; who have been previously healthy; who have no evidence of skin, soft tissue, bone, joint, or ear infection; and who have a peripheral white blood cell (WBC) count of 5,000-15,000 cells/µL, an absolute band count of <1,500 cells/µL, and normal urinalysis and negative culture (blood and urine) results are unlikely to have a serious bacterial infection. The negative predictive value with 95% confidence of these criteria for any serious bacterial infection is >98% and for bacteremia is >99%. Among serious bacterial infections, pyelonephritis is the most common and may be seen in well-appearing infants who have fever without a focus or in those who appear ill. Urinalysis may be negative in infants <2 mo of age with pyelonephritis. Bacteremia is present in <30% of infants with pyelonephritis.

The decision to obtain CSF studies in the well-appearing 1-3 mo old infant depends on the decision to administer empirical antibiotics. If close observation without antibiotics is planned, a lumbar puncture may be deferred. If the child deteriorates clinically, a full sepsis evaluation should be performed, and intravenous antibiotics should be administered. If empirical antibiotics are initiated, CSF studies should be obtained, preferably before administering antibiotics.

3 Months to 36 Months of Age

Approximately 30% of febrile children in the 3-36 mo age group have no localizing signs of infection. Viral infections are the cause of the vast majority of fevers in this population, but serious bacterial infections do occur and are caused by the same pathogens listed for patients 1-3 mo of age, except for the perinatally acquired infections. S. pneumoniae, N. meningitidis, and Salmonella account for most cases of occult bacteremia. Hib was an important cause of occult bacteremia in young children before universal immunization with conjugate Hib vaccines and remains common in underdeveloped countries that have not implemented these vaccines.

Risk factors indicating increased probability of occult bacteremia include temperature ≥39°C, WBC count ≥15,000/µL, and elevated absolute neutrophil count, band count, erythrocyte sedimentation rate, or C-reactive protein. The incidence of bacteremia and/or pneumonia or pyelonephritis, among infants 3-36 mo of age increases as the temperature (especially >40°C) and WBC count (especially >25,000) increase. However, no combination of laboratory tests or clinical assessment is completely accurate in predicting the presence of occult bacteremia. Socioeconomic status, race, sex, and age (within the range of 3-36 mo) do not appear to affect the risk for occult bacteremia.

Without therapy, occult bacteremia due to pneumococcus can resolve spontaneously without sequelae, can persist, or can lead to localized infections such as meningitis, pneumonia, cellulitis, pericarditis, osteomyelitis, or suppurative arthritis. The pattern of sequelae may be related to host factors and the offending organism. In some children, the occult bacteremic illness can represent the early signs of serious localized infection rather than a transient disease state. Hib bacteremia is characteristically associated with a higher risk for localized serious infection than is bacteremia due to S. pneumoniae. Hospitalized children with Hib bacteremia often develop focal infections, such as meningitis, epiglottitis, cellulitis, pericarditis, or osteoarticular infection, and spontaneous resolution of bacteremia is rare. Among patients with pneumococcal bacteremia (occult or focal), spontaneous resolution occurs in 30-40%, with a higher rate of spontaneous resolution among well-appearing children.

Important bacterial infections among children 3-36 mo of age with localizing signs include otitis media, sinusitis, pneumonia (not always evident without a chest x-ray), enteritis, urinary tract infection, osteomyelitis, and meningitis.

Treatment of toxic-appearing febrile children 3-36 mo of age who do not have focal signs of infection includes hospitalization and prompt institution of antimicrobial therapy after specimens of blood, urine, and CSF are obtained for culture. Consensus practice guidelines published in 1993 recommended that children 3-36 mo of age who have a temperature of <39°C and do not appear toxic be observed as outpatients without performing diagnostic tests or administering antimicrobial agents. For nontoxic-appearing infants with a rectal temperature of ≥39°C, options include obtaining a blood culture and administering empirical antibiotic therapy (ceftriaxone, a single dose of 50 mg/kg, not to exceed 1 g); if the WBC count is >15,000/µL, obtaining a blood culture and beginning empirical antibiotic therapy; or obtaining a blood culture and observing as outpatients without empirical antibiotic therapy, with return for re-evaluation within 24 hr. Guidelines for managing febrile children 3-36 mo of age who have received both Hib and S. pneumoniae conjugate vaccines have not been established, but careful observation without empirical administration of antibiotic therapy is generally prudent. Because fully vaccinated young children are at a much lower risk of occult bacteremia and meningitis as the cause of acute fever without localizing signs, some advocate that the only laboratory tests needed in this age group when temperature is >39°C are a urinalysis and urine culture for circumcised boys <6 mo of age and uncircumcised boys and all girls <24 mo of age. Regardless of the management option (Table 170-3), the family should be instructed to return immediately if the child’s condition deteriorates or new symptoms develop.

Table 170-3 MANAGEMENT OF FEVER WITHOUT LOCALIZING SIGNS

GROUP	MANAGEMENT
Any toxic-appearing child 0-36 mo and temperature ≥38°C	Hospitalize, broad cultures plus other tests,* parenteral antibiotics
Child <1 mo and temperature ≥38°C	Hospitalize, broad cultures plus other tests,* parenteral antibiotics
Child 1-3 mo and temperature ≥38°C	Two-step process 1 Determine risk based on history, physical examination, and laboratory studies. Low risk: • Uncomplicated medical history • Normal physical examination • Normal laboratory studies • Urine: negative leukocyte esterase, nitrite and <10 WBC/HPF • Peripheral blood: 5,000-15,000 WBC/mm3; <1,500 bands or band : total neutrophil ratio <0.2 • Stool studies if diarrhea (no RBC and <5 WBC/HPF) • CSF cell count (<8 WBC/mm3) and negative Gram stain • Chest radiograph without infiltrate 2 If child fulfills all low-risk criteria, administer no antibiotics, ensure follow-up in 24 hr and access to emergency care if child deteriorates. Daily follow-up should occur until blood, urine, and CSF cultures are final. If any cultures are positive, child returns for further evaluation and treatment. If child does not fulfill all low-risk criteria, hospitalize and administer parenteral antibiotics until all cultures are final and definitive diagnosis determined and treated.

Child 3-36 mo and temperature 38-39°C Reassurance that diagnosis is likely self-limiting viral infection, but advise return with persistence of fever, temperatures >39°C, and new signs and symptoms Child 3-36 mo and temperature >39°C

If did not receive conjugate pneumococcal and H. influenzae type b vaccines, manage according to the 1993 Guidelines (see Baraff et al. Pediatrics 1993;92:1-12)

Etiology

The many causes of FUO in children are infections and rheumatologic (connective tissue or autoimmune) diseases (Table 170-5). Neoplastic disorders should also be seriously considered, although most children with malignancies do not have fever alone. The possibility of drug fever should be considered if the patient is receiving any drug. Drug fever is usually sustained and not associated with other symptoms. Discontinuation of the drug is associated with resolution of the fever, generally within 72 hr, although certain drugs, such as iodides, are excreted for a prolonged period with fever that can persist for as long as 1 mo after drug withdrawal.

Most fevers of unknown or unrecognized origin result from atypical presentations of common diseases. In some cases, the presentation as an FUO is characteristic of the disease, such as juvenile idiopathic arthritis, but the definitive diagnosis can be established only after prolonged observation because initially there are no associated or specific findings on physical examination and all laboratory results are negative or normal.

In the USA, the systemic infectious diseases most commonly implicated in children with FUO are salmonellosis, tuberculosis, rickettsial diseases, syphilis, Lyme disease, cat-scratch disease, atypical prolonged presentations of common viral diseases, infectious mononucleosis, cytomegalovirus (CMV) infection, viral hepatitis, coccidioidomycosis, histoplasmosis, malaria, and toxoplasmosis. Less common infectious causes of FUO include tularemia, brucellosis, leptospirosis, and rat-bite fever. AIDS alone is not usually responsible for FUO, although febrile illnesses often occur in patients with AIDS as a result of opportunistic infections (see Table 170-4).

Juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are the connective tissue diseases associated most commonly with FUO. Inflammatory bowel disease, rheumatic fever, and Kawasaki disease are also commonly reported as causes of FUO. If factitious fever (inoculation of pyogenic material or manipulation of the thermometer by the patient or parent) is suspected, the presence and pattern of fever should be documented in the hospital. Prolonged and continuous observation, which can include electronic or video surveillance, of patients is imperative. FUO lasting >6 mo is uncommon in children and suggests granulomatous or autoimmune disease. Repeat interval evaluation, including history, physical examination, laboratory evaluation, and roentgenographic studies is required.

Diagnosis

The evaluation of FUO requires a thorough history and physical examination supplemented by a few screening laboratory tests and additional laboratory and radiographic tests as indicated by the history or abnormalities on examination or initial screening (see Table 170-5).

Treatment

The ultimate treatment of FUO is tailored to the underlying diagnosis. Fever and infection in children are not synonymous; antimicrobial agents should not be used as antipyretics, and empirical trials of medication should generally be avoided. An exception may be the use of antituberculous treatment in critically ill children with suspected disseminated tuberculosis. Empirical trials of other antimicrobial agents may be dangerous and can obscure the diagnosis of infective endocarditis, meningitis, parameningeal infection, or osteomyelitis. After a complete evaluation, antipyretics may be indicated to control fever and relieve symptoms.

Prognosis

Children with FUO have a better prognosis than do adults. The outcome in a child depends on the primary disease process, which is usually an atypical presentation of a common childhood illness. In many cases, no diagnosis can be established and fever abates spontaneously. In as many as 25% of cases in whom fever persists, the cause of the fever remains unclear, even after thorough evaluation.