Definition

Fever is defined as a rectal temperature ≥38°C, and a value >40°C is called hyperpyrexia. Body temperature fluctuates in a defined normal range (36.6°C-37.9°C rectally), so that the highest point is reached in early evening and the lowest point is reached in the morning. Any abnormal rise in body temperature should be considered a symptom of an underlying condition.

Pathogenesis

Body temperature is regulated by thermosensitive neurons located in the preoptic or anterior hypothalamus that respond to changes in blood temperature as well as cold and warm receptors located in skin and muscles. Thermoregulatory responses include redirecting blood to or from cutaneous vascular beds, increased or decreased sweating, regulation of extracellular fluid volume via arginine vasopressin, and behavioral responses, such as seeking a warmer or cooler environmental temperature.

Three different mechanisms can produce fever: pyrogens, heat production exceeding loss, and defective heat loss.

The first mechanism involves endogeneous and exogenous pyrogens that raise the hypothalamic temperature set point. Endogenous pyrogens include the cytokines interleukin 1 (IL)-1 and IL-6, tumor necrosis factor-α (TNF-α), and interferon (IFN)-β and IFN-γ. Stimulated leukocytes and other cells produce lipids that also serve as endogenous pyrogens. The best-studied lipid mediator is prostaglandin (PG)E_2, which attaches to the prostaglandin receptors in the hypothalamus to produce the new temperature set point. Exogenous pyrogens or substances that come from outside the body include mainly infectious pathogens and drugs. Microbes, microbial toxins, or other products of microbes are the most common exogenous pyrogens and stimulate macrophages and other cells to produce endogenous pyrogens.

Some substances produced within the body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigen-antibody complexes in the presence of complement, complement components, lymphocyte products, bile acids, and androgenic steroid metabolites. Endotoxin is one of the few substances that can directly affect thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release. Many drugs cause fever, and the mechanism for increasing body temperature varies with the class of drugs. Drugs that are known to cause fever include vancomycin, amphotericin B, and allopurinol. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens.

Heat production exceeding heat loss is the second mechanism that leads to fever, with examples including salicylate poisoning and malignant hyperthermia. Defective heat loss is the third mechanism of fever genesis, for example, in children with ectodermal dysplasia or victims of severe heat exposure.

Etiology

The causes of fever can be organized into 4 main categories: infectious, inflammatory, neoplastic, and miscellaneous. Self-limited viral infections (common cold, gastroenteritis) and uncomplicated bacterial infections (otitis media, pharyngitis, sinusitis) are the most common causes of acute fever and hyperpyrexia. The body temperature should not rise above potentially lethal levels (41.7°C) in the neurologically intact child unless extreme hyperthermic environmental conditions are present or other extenuating circumstances exist, such as underlying malignant hyperthermia or thyrotoxicosis.

The pattern of the fever can provide clues to the underlying etiology. Viral infections typically are associated with a slow decline of fever over a week, whereas bacterial infections are associated with a prompt resolution of fever after effective antimicrobial treatment is employed. Although administration of antimicrobial agents can result in a very rapid elimination of bacteria, if tissue injury has been extensive, the inflammatory response and fever can continue for days after all microbes have been eradicated.

Intermittent fever is an exaggerated circadian rhythm that includes a period of normal temperatures on most days; extremely wide fluctuations may be termed septic or hectic fever. Sustained fever is persistent and does not vary by more than 0.5°C/day. Remittent fever is persistent and varies by more than 0.5°C/day. Relapsing fever is characterized by febrile periods that are separated by intervals of normal temperature; tertian fever occurs on the first and third days (malaria caused by Plasmodium vivax), and quartan fever occurs on the first and fourth days (malaria caused by Plasmodium malariae). Diseases characterized by relapsing fevers (Table 169-1) should be distinguished from infectious diseases that have a tendency to relapse. Biphasic fever indicates a single illness with 2 distinct periods (camelback fever pattern); poliomyelitis is the classic example. A biphasic course is also characteristic of other enteroviral infections, leptospirosis, dengue fever, yellow fever, Colorado tick fever, spirillary rat-bite fever (Spirillum minus), and the African hemorrhagic fevers (Marburg, Ebola, and Lassa fevers). The term periodic fever is used narrowly to describe fever syndromes with a regular periodicity (cyclic neutropenia and PFAPA [periodic fever, aphthous stomatitis, pharyngitis, and adenopathy]) or more broadly to include disorders characterized by recurrent episodes of fever that do not follow a strictly periodic pattern (familial Mediterranean fever, Hibernian fever, TNF-receptor–associated periodic syndrome [TRAPS], hyper-IgD syndrome, the Muckle-Wells syndrome). Factitious fever, or self-induced fever, may be caused by intentional manipulation of the thermometer or injection of pyrogenic material.

The double quotidian fever (or fever that peaks twice in 24 hours) is classically associated with inflammatory arthritis. In general, a single isolated fever spike is not associated with an infectious disease. Such a spike can be attributed to the infusion of blood products and some drugs, as well as to some procedures, or to manipulation of a catheter on a colonized or infected body surface. Similarly, temperatures in excess of 41°C are most often associated with a noninfectious cause. Causes for very high temperatures (>41°C) include central fever (resulting from central nervous system (CNS) dysfunction involving the hypothalamus), malignant hyperthermia, malignant neuroleptic syndrome, drug fever, or heatstroke. Temperatures that are lower than normal (<36°C) can be associated with overwhelming sepsis but are more commonly related to cold exposure, hypothyroidism, or overuse of antipyretics.

Clinical Features

The clinical features of fever can range from no symptoms at all to extreme malaise. Children might complain of feeling hot or cold, display facial flushing, and experience shivering. Fatigue and irritability may be evident. Parents often report that the child looks ill or pale and has a decreased appetite. The underlying etiology also produces accompanying symptoms. Although the underlying etiologies can manifest in varied ways clinically, there are some predictable features. For instance, fever with petechiae in an ill-appearing patient indicates the high possibility of life-threatening conditions such as meningococcemia, Rocky Mountain spotted fever, or acute bacterial endocarditis.

Changes in heart rate, most commonly tachycardia, accompany fever. Relative tachycardia, when the pulse rate is elevated out of proportion to the temperature, is usually due to noninfectious diseases or infectious diseases in which a toxin is responsible for the clinical manifestations. Relative bradycardia (temperature-pulse dissociation), when the pulse rate remains low in the presence of fever, can accompany typhoid fever, brucellosis, leptospirosis, or drug fever. Bradycardia in the presence of fever also may be a result of a conduction defect resulting from cardiac involvement with acute rheumatic fever, Lyme disease, viral myocarditis, or infective endocarditis.

Evaluation

Most acute febrile episodes in a normal host can be diagnosed by a careful history and physical examination and require few, if any, laboratory tests. Because infection is the most likely etiology of the acute fever, the evaluation should initially be geared to discovering an underlying infectious cause (Table 169-2). The details of the history should include the onset and pattern of fever and any accompanying signs and symptoms. The patient often displays signs or symptoms that provide clues to the cause of the fever. Exposures to other ill persons at home, daycare, and school should be noted, along with any recent travel or medications. The past medical history should include information about underlying immune deficiencies or other major illnesses and receipt of childhood vaccines. In the acutely febrile child, the physical examination should focus on any localized complaints, but a complete head-to-toe screen is recommended, because clues to the underlying diagnosis may be found. For example, palm and sole lesions may be discovered during a thorough skin examination and provide a clue for infection with coxsackievirus. Vital signs should include pulse oximetry, because hypoxia indicates lower respiratory tract disease.

If a fever has an obvious cause, then the evaluation is complete, no further testing is advised, and care is tailored to the underlying diagnosis with as-needed re-evaluation. If the cause of the fever is not apparent, then further diagnostic testing should be considered on a case-by-case basis. The history of presentation and abnormal physical examination findings guide the evaluation. The child with respiratory symptoms and hypoxia can require a chest radiograph or rapid antigen testing for RSV or influenza. The child with pharyngitis can benefit from rapid antigen detection testing for group A Streptococcus and a throat culture. Dysuria, back pain, or history of vesicoureteral reflux should prompt a urinalysis and urine culture, and bloody diarrhea should prompt a stool culture. A complete blood count and blood culture should be considered in the ill-appearing child, along with cerebrospinal fluid studies if the child has neck stiffness. Well-defined high-risk groups require a more-extensive evaluation on the basis of age, associated disease, or immunodeficiency status and might warrant prompt antimicrobial therapy before a pathogen is identified. The evaluations of infants <3 mo old and children with recurrent fevers are discussed in Chapter 170.

Treatment

Although fear of fever is a common parental worry, evidence is lacking to support the belief that high fever can result in brain damage or other bodily harm, except in rare instances of febrile status epilepticus and heat stroke. Treating fever in self-limiting illnesses for the sole reason of bringing the body temperature back to normal is not necessary in the otherwise healthy child. Most evidence suggests that fever is an adaptive response and should be treated only in selected circumstances. In humans, increased temperatures are associated with decreased microbial replication and an increased inflammatory response. Although fever can have beneficial effects, it also increases oxygen consumption, carbon dioxide production, and cardiac output and can exacerbate cardiac insufficiency in patients with heart disease or chronic anemia (e.g., sickle cell disease), pulmonary insufficiency in patients with chronic lung disease, and metabolic instability in patients with diabetes mellitus or inborn errors of metabolism. Children between the ages of 6 mo and 5 yr are at increased risk for simple febrile seizures. Children with idiopathic epilepsy also often have an increased frequency of seizures associated with a fever.

Fever with temperatures <39°C in healthy children generally does not require treatment. However, as temperatures become higher, patients tend to become more uncomfortable, and treatment of fever is then reasonable. If a child is included in one of the high-risk groups or if the child’s caregiver is concerned that the fever is adversely affecting the child’s behavior and causing discomfort, treatment may be given to hasten the resolution of the fever. Other than providing symptomatic relief, antipyretic therapy does not change the course of infectious diseases. Encouraging good hydration is the first step to replace fluids that are lost related to the increased metabolic demands of fever. Antipyretic therapy is beneficial in high-risk patients who have chronic cardiopulmonary diseases, metabolic disorders, or neurologic diseases and in those who are at risk for febrile seizures. Hyperpyrexia (>41°C) indicates greater risk of hypothalamic disorders or CNS hemorrhage and should be treated with antipyretics. Some studies have shown that hyperpyrexia may be associated with a significantly increased risk of serious bacterial infection, but other studies have not substantiated this relationship. High fever during pregnancy may be teratogenic.

Acetaminophen at a dose of 10-15 mg/kg/dose every 4 hr and ibuprofen in children older than 6 months at a dose of 5-10 mg/kg/dose every 8 hours are the most commonly employed antipyretics. Antipyretics reduce fever by reducing production of prostaglandins. If used appropriately, antipyretics are safe; potential adverse effects include liver damage (acetaminophen) and gastrointestinal or kidney disturbances (ibuprofen). To reduce fever most safely, the caregiver should choose one type of medication and clearly record the dose and time of administration, so overdosage does not occur, especially if multiple caregivers are involved in the management. Physical measures such as tepid baths and cooling blankets are not considered effective to reduce fever. Evidence is also scarce for the use of complementary and alternative medicine interventions.

Fever due to specific underlying etiologies resolves when the condition is properly treated. Examples include administration of intravenous immunoglobulin to treat Kawasaki disease or the administration of antibiotics to treat bacterial infections.