Chapter 227. Acute Fever Without a Focus

Fever is defined as a regulated rise in core body temperature. That is, as distinct from hyperthermia, it is a measured response to internal regulatory processes. Most clinicians define fever as a rectal temperature of 38°C (101.4°F) or higher. Fever is the most common cause for sick child visits to the pediatrician and emergency room. Fever is part of the body’s response to many adverse stimuli, including inflammation, infection, and malignancy, among other causes. In the pediatric age group, infection due to a virus or bacteria is the most common cause of fever. The tendency to seek medical attention for fever is very much age dependent, with younger children seeking care most often. Although part of the tendency to seek medical attention for fever rests with parental anxiety, part rests appropriately with the increased risk of serious infection associated with fever in the youngest children, neonates, as well as in special risk groups.

The physiology of temperature regulation is detailed in Chapter 121 and further information on the management of the febrile child can be found in Chapter 105.

Fever is not a diagnosis per se. Often the pediatrician’s first goal is to separate serious causes of fever from minor self-limited intercurrent illnesses. The most useful tool in the diagnosis of the etiology of fever is the clinical examination. Many months of residency and years in clinical practice hone the pediatrician’s ability to identify the truly sick or “toxic” child. Perhaps no clinical skill is more important for a pediatrician, who is often dealing with young children who are not able to communicate directly, than the ability to identify the seriously ill child. Listlessness, poor feeding, poor perfusion of the extremities, weakness, rapid pulse, or lethargy are all clues, as are the more sinister presence of cyanosis or purpura. Often the signs are subtle and the child just does “not look right.” Once the child is identified as being toxic or seriously ill, then appropriate cultures, most often including urine, blood, and CSF, as well as other laboratory tests such as a peripheral white blood cell (WBC) count with differential, electrolytes, and urinalysis, should be obtained. Some clinicians also use C-reactive protein (CRP) or procalcitonin testing to evaluate febrile children because these are selectively elevated in children with bacterial infection.5 For the truly toxic child and especially for younger children, age-appropriate antibiotics that can treat sepsis and possible meningitis should be started. In most areas of the country, this must now include coverage against resistant gram-positive organisms through the inclusion of vancomycin. For the child that is less seriously ill, a more measured clinical evaluation is warranted. Such an evaluation should include history as well a physical examination to delineate the patient’s symptoms and clinical course. Knowledge of the most common infectious etiologies in a given age group is also important. Pharyngitis, upper respiratory infection, otitis media, gastroenteritis, and bronchiolitis are all common causes of fever and can often be diagnosed by review of the history and physical examination alone. Similarly, varicella, roseola, and scarlet fever, as well as Kawasaki disease, can also be diagnosed on the basis of physical examination. For other entities, it may not be possible to identify a specific focus of infection. For children without a readily identifiable focus, the most common etiology is a self-limited viral illness. Two common causes of fever in infants and children are urinary tract infection and occult bacteremia. Urinary tract infection is discussed further in Chapter 238. Prolonged fever of unknown origin is discussed in Chapter 228, and fever in the immunocompromised child is discussed in Chapter 229. Occult bacteremia is discussed below. An algorithm summarizing the evaluation and management of febrile infants and children is shown in Figure 227-1.

Fever patterns can occasionally be useful in the diagnosis of specific conditions such as malaria. In most situations, these patterns tend to be nonspecific. Similarly, dissociation between the pulse rate and the peak of temperature (high temperature, lower pulse than normally expected) can be seen in typhoid fever and brucellosis, but not in all cases. Neoplasia is also often associated with fever, especially in the case of leukemia and lymphoma. Other noninfectious causes of fever include drug fever, hyperthyroidism, adrenal insufficiency, and autoimmune disorders such as lupus and juvenile rheumatoid arthritis. Rarely, factitious fever can be seen in the young child. However, the most common cause of acute fever in children is infection, with most children having experienced at least one such febrile episode in the first year of life.

Occult bacteremia is usually defined as bacteremia occurring without the expected associated symptoms of toxicity, evidence of a focal infection, or cardiorespiratory changes. Prior to the introduction and routine use of pneumococcal conjugate vaccine in infancy, occult bacteremia due to the pneumococcus was a relatively common cause of fever in young children, accounting for 90% or more of positive blood cultures in children younger than 3 years. Prior to the use of conjugate vaccine, about 8% of children with a fever and an absolute neutrophil count (ANC) >10,000 had a positive blood culture for Streptococcus pneumoniae, and children with such an elevated ANC and a fever of >41°C had about a 20% risk of bacteremia. Of those children with pneumococcal bacteremia, the majority recovered spontaneously, but about 3% to 5% developed meningitis, and another 5% developed another focal infection, most commonly, pneumonia. Following introduction of conjugate vaccines against the pneumococcus and Haemophilus influenzae type b, the remaining pathogens causing occult bacteremia are the meningococcus and salmonella. Salmonella is more common in the developing world. The meningococcus is the most feared of the two, with as many as 50% such children developing meningitis and others developing meningococcemia with sepsis. However, occult meningococcal bacteremia is rare, occurring in less than 1% of febrile young children. Because of the severity of meningococcal infection, any association of petechiae or purpura with fever should instigate rapid clinical assessment and institution of appropriate antibiotic, such as high-dose intravenous penicillin or ceftriaxone. In a survey of practicing pediatricians and emergency physicians, it was found that 1-year-old febrile children with petechiae received intensive evaluations, whereas older children did not.6 This may reflect the higher incidence of meningococcal disease in infancy, but it should be realized that older children are also fully susceptible to meningococcal disease and that cautious evaluation is warranted in all age groups of children who present with fever and petechiae of unknown cause. It should also be noted that a high index of suspicion is warranted because although almost all children who present with meningococcal disease present with fever, only 62% present with a petechial or purpuric rash.7 Finally, in a systemic study of the causes of fever in young children following introduction of pneumococcal conjugate, Herz observed that urinary tract infections and Staphylococcus aureus now account for the majority of identifiable causes.8

Fever in the neonatal period (0–60 days of age) warrants special consideration. The neonate’s ability to respond to infection is not fully developed. Neutrophils exhibit decreased chemotaxis, adherence, and ability to kill bacteria. The germinal centers in lymph nodes are not fully developed until about 8 weeks of age. There is also decreased ability to kill viruses such as the herpes simplex virus (HSV) and varicella-zoster virus (VZV) in this age group. Immunoglobin G and complement levels are lower than those of older children. These developmental deficiencies make the infant more susceptible to serious infections and infections by organisms, which are much less common in older children or adults. Group B streptococcus, Listeria monocytogenes, enterococcus, staphylococcus, and HSV can cause sepsis in the first 2 months of life. Identification of sepsis in the neonate is more challenging than in older children. The febrile response is less developed such that a seriously ill infant may not develop a high fever. Behavioral changes are more difficult to identify because the range of behaviors in this age group is limited. Although changes in feeding habits, lethargy, and changes in sleep pattern or stool pattern can occur, their occurrence does not always indicate serious infection.

Because of the difficulty in identifying sepsis in the neonate and because such infections can progress so rapidly, special precautions should be taken in the evaluation and treatment of febrile neonates. In the first month of life, most experts believe that a “full septic workup” should be performed, including blood and urine cultures as well as a spinal tap with culture of cerebrospinal fluid (CSF). Admission to the hospital is warranted in this age group, with parenteral antibiotics being given pending culture results. If there is no obvious bacterial cause after initial evaluation, many experts also recommend the addition of parenteral acyclovir in this age group. For children 31 to 60 days of age, there is less consensus regarding management. Some pediatricians will evaluate and treat these children the same as children 0 to 30 days of age. Other pediatricians will perform a thorough assessment, including blood and urine cultures as well as a complete blood count (CBC) and urinalysis, with many also performing a spinal tap. If the CBC, urinalysis, and CSF are normal and the febrile child is feeding well and appears otherwise normal, children who have reliable parents are often cautiously observed at home with frequent visits on an outpatient basis to their pediatrician. This approach requires the willingness of the pediatrician to stay in contact with the parent as well as confidence in the parents’ ability to reassess the child. Several assessment scales have been developed to facilitate assessment of potentially ill young infants, but the specificity of these varies.9

Other conditions predispose children to develop bacterial infections. Children with asplenia or sickle cell disease are especially susceptible to overwhelming pneumococcal infections and infections due to salmonella, Escherichia coli, and other gram-negative organisms. Even if the child has received pneumococcal vaccine, the risk of pneumococcal infection due to serotypes not in the vaccine remains. Febrile young children with asplenia or sickle cell disease should receive prompt assessment and antibiotic treatment. Similarly, immunosuppressed or HIV-infected children often present with a severe infection. An aggressive approach to diagnosis and treatment of patients with HIV/AIDS can be found in Chapter 315. Fever in the immunocompromised child is discussed in Chapter 230. Children with foreign bodies such as central venous catheters, ventriculo-peritoneal shunts or implanted cardiac valves are all at increased risk of bacteremia and require early culture with antibiotic treatment when febrile.

The primary decision facing the physician in the evaluation of the febrile child is whether the child’s condition warrants presumptive antibiotic therapy and whether such therapy should be given on an outpatient basis or in the hospital. As discussed previously, for neonates, immunosuppressed or HIV-infected children, and children with asplenia, sickle cell disease, or other predisposing conditions, the decision is relatively straightforward, with aggressive diagnostic measures and antibiotic therapy often being required. For children without a history of underlying conditions or risk, consideration must be given to the child’s age (with children younger than 2 years with a fever and without an obvious focus warranting laboratory evaluation, especially including a urinalysis) and the reliability of the parents and home situation. For the pediatrician who knows the child and the family, it is often easier to rely on clinical judgment and careful follow-up. For the emergency room doctor, this approach may be more difficult. In all cases, one of the most important components of the evaluation and therapy of febrile infants and children is careful follow-up of the child.