CHAPTER 67

Fever and Bacteremia

Eric R. Schmitt, MD, MPH, FACEP, FAAP

Fever is among the most common chief complaints among pediatric patients seeking medical attention in physician offices, urgent care centers, and emergency departments and accounts for up to 30% of these visits. Most such patients have a benign, self-limited viral illness. Some patients, however, have a serious bacterial infection (SBI), such as meningitis, urinary tract infection (UTI) and/or pyelonephritis, pneumonia, bacteremia, septic arthritis, osteomyelitis, cellulitis, or deep tissue infection. Bacteremia is a bacterial infection within the bloodstream; it is considered occult in the absence of an apparent source of infection after a thorough physical examination in an otherwise healthy-appearing child.

Epidemiology

Historically, management decisions about febrile children have been largely dictated by age. Patients are typically divided into the following age-defined categories: newborns and infants younger than 90 days, infants and young children 3 to 36 months of age, and children age 3 years and older. Febrile newborns and young infants (ie, younger than 90 days) have higher rates of SBI than older children and often represent a diagnostic challenge. They have relatively immature immune systems, which renders them particularly susceptible to bacterial infections and have not yet received most of their immunizations. They often have limited responses to bacterial infections and exhibit relatively nonspecific signs and symptoms. In addition, newborns and young infants have different bacterial pathogens that can cause these serious infections, including Escherichia coli; Streptococcus agalactiae (group B streptococci); less commonly, Streptococcus pneumoniae; and, rarely, Listeria monocytogenes and other gram-negative organisms (Box 67.1). The overall prevalence of SBI among febrile newborns and infants younger than 90 days with a temperature of 38.0°C (100.4°F) or higher is approximately 10%; the rate approaches 20% in newborns younger than 28 days. Urinary tract infections are by far the most common source of SBI, with a smaller percentage having pneumonia, bacteremia, or meningitis. Contemporary studies have demonstrated that febrile newborns and young infants with diagnosed viral infections have lower rates of SBI than those without viral infections (4% and 12%, respectively). In these studies, none of the febrile newborns and young infants with viral infections confirmed on diagnostic testing had meningitis, but some did have UTIs and, rarely, bacteremia.

Febrile infants and children age 3 to 36 months are at a higher risk for bacteremia than older children but less so than newborns and young infants. Although the physical examination is more reliable in this age group than in newborns and younger infants, in many patients the examination is normal without any localizing source of infection. These individuals may, in turn, have occult bacteremia. Vaccine development and widespread immunization programs have dramatically changed the epidemiology and clinical course of bacteremia in this age group within the United States over the past several decades. Before the introduction of the Haemophilus influenzae type b (Hib) and pneumococcal vaccines, the prevalence rates of bacteremia were approximately 3%. During this time, Haemophilus was considered the most significant organism causing bacteremia because of its invasiveness and ability to cause localized infection, particularly meningitis. In the mid-1980s, the Hib vaccine was introduced, which has nearly eliminated this particularly invasive organism. In the post-Hib but prepneumococcal conjugate vaccine era, the rates of occult bacteremia ranged from 1.6% to 1.9% in children with a temperature of 39.0°C (102.2°F) or higher and no obvious source of infection. More than 90% of cases of occult bacteremia in this age group were caused by S pneumoniae, with the remainder being caused by Salmonella, Neisseria meningitides, Staphylococcus aureus, and a few other rare organisms. Pneumococcus is not as virulent a microorganism as some other bacteria, and many cases of occult pneumococcal bacteremia resolved spontaneously without any intervention. Left untreated, a small percentage (3%–5%) went on to develop pneumococcal meningitis, which has the most serious complication and fatality rate. In 2000, the heptavalent pneumococcal conjugate vaccine was licensed by the US Food and Drug Administration for use within the United States. This vaccine provided coverage against the 7 main serotypes of S pneumoniae, which were responsible for approximately 80% of the cases of invasive pneumococcal disease in the United States and Canada at the time. Following the introduction of this vaccine, the rate of invasive pneumococcal disease (including bacteremia) and carriage for the serotypes covered by the vaccine dropped considerably. Additionally, there was evidence suggestive of herd immunity, in that a decline in invasive pneumococcal disease was noted among older individuals who had not received the vaccine. Consequently, a selective pressure has increased the prevalence of invasive pneumococcal disease caused by strains not covered by the heptavalent vaccine, although the overall magnitude of this effect appears to be relatively small. Additionally, other bacteria, such as E coli, Salmonella, and S aureus, appear to have increased in relative frequency as a source of bacteremia. In 2010, a new 13-valent pneumococcal conjugate vaccine (PCV13) was licensed and expanded coverage to include 6 different serotypes that have emerged with increasing frequency as a cause of invasive pneumococcal disease following the introduction of the heptavalent vaccine. The American Academy of Pediatrics and the Advisory Committee on Immunization Practices currently recommends the pneumococcal conjugate vaccine (ie, PCV13) for all infants in a 4-dose regimen to be given at 2, 4, 6, and 12 to 15 months of age. A pneumococcal polysaccharide vaccine (PPSV23) was approved in late 2014 that provides even broader protection. The addition of PPSV23 is recommended for children older than 2 years with certain high-risk chronic medical conditions after they have received PCV13. Continued surveillance of invasive disease is necessary to ascertain what effect the changes in epidemiology of these newer vaccines may have on the diagnosis and management of bacteremia in young febrile children. Preliminary data have shown a 42% decrease overall in the incidence of invasive pneumococcal infection in 2011 after the implementation of routine PCV13 immunization and a 53% decrease in the incidence in children younger than 24 months compared with years 2007 through 2009.

^a Hib disease has been nearly eliminated with the routine use of Hib conjugate vaccines.

Clinical Presentation

In many children, fever is the only symptom or manifestation of disease and no other signs or symptoms may be apparent. These children may look well and behave normally. Young children, especially newborns and infants younger than 3 months, are likely to have fewer and more subtle behavioral signs with bacterial infections. Physicians must, therefore, maintain a high index of suspicion for the presence of an SBI, even in the absence of localizing signs (Box 67.2). Occult bacteremia, by definition, has no abnormal physical manifestations aside from fever.

Pathophysiology

Fever is an elevation in the thermoregulatory set point of the body. The thermoregulatory center is located in the preoptic region of the anterior hypothalamus, and an elevation in the hypothalamic set point above the normal body temperature initiates the physiologic changes that result in fever. Exogenous pyrogens (eg, bacteria, viruses, antigen-antibody complexes) stimulate host inflammatory cells (eg, macrophages, polymorphonuclear cells) to produce endogenous pyrogens. Interleukin-1 is currently regarded as the prototypical endogenous pyrogen. Endogenous pyrogens cause the hypothalamic endothelium to increase intermediary substances, such as prostaglandins and neurotransmitters, which then act on the preoptic neurons of the anterior hypothalamus to produce an elevated set point. The body uses physiologic mechanisms (eg, peripheral vasoconstriction, shivering) and behavioral actions (eg, bundling up, drinking hot tea) to increase body temperature to reach and maintain this higher set point, thus producing fever (Figure 67.1).

This contrasts with hyperthermia, in which the thermoregulatory set point of the body is normal. Because of abnormal physiologic processes, heat gain exceeds heat loss, and the body temperature rises despite efforts to return to the control set point.

Differential Diagnosis

In most cases, the duration of fever in children is short, and signs and symptoms are localized. Fever without a source involves an acute episode of fever that lasts 1 week or less in children in whom history, physical examination, and laboratory tests do not reveal a source. Most affected children are eventually diagnosed with an acute, generally benign, infectious illness. Occult bacteremia remains a major concern in young children, primarily in infants younger than 3 months. High-risk factors for occult bacteremia are presented in Box 67.3. Fever of unknown origin is fever of at least 8 days’ duration in infants or children in whom routine history, physical examination, and laboratory assessment do not reveal a source.

Figure 67.1. Pathophysiology of fever production. Antipyretic agents work by blocking the synthesis of prostaglandin E₂ (PGE₂).

The differential diagnosis of children with an acute febrile illness is primarily infectious (Box 67.4), including benign and generally self-limited illnesses (eg, upper respiratory infections) and less common but more serious illnesses (eg, meningitis, osteomyelitis). Occasionally, a child with a fever without a source has a noninfectious illness, such as collagen vascular disease or neoplasia. By comparison, the differential diagnosis of children with fever of unknown origin is quite broad and includes infectious and non-infectious disorders (Box 67.5).

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