Fever without a Focus

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Chapter 170 Fever without a Focus

Linda S. Nield, Deepak Kamat

Fever without a focus refers to a rectal temperature of 38°C or higher as the sole presenting feature. The terms “fever without localizing signs” and “fever of unknown origin” (FUO) are subcategories of fever without a focus.

Fever without Localizing Signs

Fever of acute onset, with duration of <1 wk and without localizing signs, is a common diagnostic dilemma in children <36 mo of age. The etiology and evaluation of fever without localizing signs depends on the age of the child. Traditionally, 3 age groups are considered: neonates or infants to 1 mo of age, infants >1 mo to 3 mo of age, and children >3 mo to 3 yr of age. In 1993, practice guidelines were published to aid the clinician in evaluating the otherwise healthy 0 to 36 mo old with fever without a source. However, with the advent and extensive use of the conjugate Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae vaccines, the rates of infections with these 2 pathogens have decreased substantially. As a consequence, modifications to the 1993 guidelines have been advocated as described later. Children in high-risk groups (Table 170-1) require a more-aggressive approach and consideration of a broader differential diagnosis.

Table 170-1 FEBRILE PATIENTS AT INCREASED RISK FOR SERIOUS BACTERIAL INFECTIONS

RISK GROUP DIAGNOSTIC CONSIDERATIONS
IMMUNOCOMPETENT PATIENTS
Neonates (<28 days) Sepsis and meningitis caused by group B streptococcus, Escherichia coli, Listeria monocytogenes; neonatal herpes simplex virus infection, enteroviruses
Infants 1-3 mo Serious bacterial disease in 10-15%, including bacteremia in 5%; urinary tract infection
Infants and children 3-36 mo Occult bacteremia in <0.5% of children immunized with both Haemophilus influenzae type b and pneumococcal conjugate vaccines; urinary tract infections
Hyperpyrexia (>40°C) Meningitis, bacteremia, pneumonia, heatstroke, hemorrhagic shock-encephalopathy syndrome
Fever with petechiae Bacteremia and meningitis caused by Neisseria meningitidis, H. influenzae type b, and Streptococcus pneumoniae
IMMUNOCOMPROMISED PATIENTS
Sickle cell disease Sepsis, pneumonia, and meningitis caused by S. pneumoniae, osteomyelitis caused by Salmonella and Staphylococcus aureus
Asplenia Bacteremia and meningitis caused by N. meningitidis, H. influenzae type b, and S. pneumoniae
Complement or properdin deficiency Sepsis caused by N. meningitidis
Agammaglobulinemia Bacteremia, sinopulmonary infections
AIDS S. pneumoniae, H. influenzae type b, and Salmonella infections
Congenital heart disease Infective endocarditis; brain abscess with right-to-left shunting
Central venous line Staphylococcus aureus, coagulase-negative staphylococci, Candida
Malignancy Bacteremia with gram-negative enteric bacteria, S. aureus, and coagulase-negative staphylococci; fungemia with Candida and Aspergillus

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.

Table 170-2 LOW RISK CRITERIA IN 1-3 MONTHS OLD WITH FEVER

BOSTON CRITERIA

Infants are at low risk if they appear well, have normal physical examination, have a caretaker reachable by telephone, and laboratory tests are as follows:

• CBC: <20,000 WBC/mm3
• Urine: negative leukocyte esterase
• CSF: leukocyte count less than 10 × 106/L,

PHILADELPHIA PROTOCOL

Infants are at low risk if they appear well, have a normal physical examination, and laboratory tests are as follows:

• CBC: <15,000 WBC/mm3; band: total neutrophil ratio <0.2
• Urine: <10 WBC/HPF; no bacteria on Gram stain
• CSF: <8 WBC/mm3; no bacteria on Gram stain
• Chest radiograph: no infiltrate
• Stool: no RBC; few to no WBC

PITTSBURGH GUIDELINES

Infants are at low risk if they appear well, have a normal physical examination, and laboratory tests are as follows:

• CBC: 5,000-15,000 WBC; peripheral absolute band count <1500/mm3
• Urine (enhanced urinalysis): 9 WBC/mm3 and no bacteria on Gram stain
• CSF: 5 WBC/mm3 and negative Gram stain; if bloody tap, then WBC : RBC ≤ 1 : 500
• Chest radiograph: no infiltrate
• Stool: 5 WBC/HPF with diarrhea

ROCHESTER CRITERIA

Infants are at low risk if they appear well, have a normal physical examination, and laboratory findings are as follows:

• CBC: 5,000-15,000 WBC/mm3; absolute band count ≤1500/mm3
• Urine: <10 WBC/HPF at 40×
• Stool: <5 WBC/HPF if diarrhea

CBC, complete blood count; CSF, cerebrospinal fluid; HPF, high-powered field; RBC, red blood cell; WBC: white blood cell.

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

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