Chapter 174 

– Fever
Keith R. Powell

Fever is a controlled increase in body temperature over the normal values for an individual.
Body temperature is regulated by thermosensitive neurons located in the preoptic or anterior
hypothalamus that respond to changes in blood temperature as well as to direct neural
connections with cold and warm receptors located in skin and muscle. Thermoregulatory
responses include redirecting blood to or from cutaneous vascular beds, increased or
decreased sweating, extracellular fluid volume regulation (via arginine vasopressin), and
behavioral responses, such as seeking a warmer or cooler environmental temperature.
Normal body temperature also varies in a regular pattern each day. This circadian temperature
rhythm, or diurnal variation, results in lower body temperatures in the early morning and
temperatures approximately 1?C higher in the late afternoon or early evening.

PATHOGENESIS.

Fever is regulated in the same manner as normal temperature is maintained in a cool

environment, the difference being that the body's thermostat has been reset at a higher
temperature (Fig. 174-1). Regardless of whether fever is associated with infection, rheumatic
disease, or malignancy, the thermostat is reset in response to endogenous pyrogens,
including the cytokines interleukin 1 (IL-1) and IL-6, tumor necrosis factor-α (TNF-α), and
interferon-β (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 E 2 (PGE2).
Most endogenous pyrogen molecules are too large to cross the blood-brain barrier in an
efficient manner. However, circumventricular organs in close proximity to the hypothalamus
lack a blood-brain barrier and allow for neuronal contact with circulating factors through
fenestrated capillaries.

Figure 174-1  The pathogenesis of fever. Various infectious toxins and other mediators
induce the production of endogenous pyrogens by host inflammatory cells. Endogenous
pyrogens include the cytokines interleukin 1 (IL-1) and IL-6, tumor necrosis factor-α
(TNF-α), and interferon-β (IFN-β) and IFN-γ. Endogenous pyrogenic cytokines directly
stimulate the hypothalamus to produce prostaglandin E2 (PGE2), which then resets the
temperature regulatory set point. Neuronal transmission from the hypothalamus leads to
conservation and generation of heat, thus raising core body temperature.(From
Dinarello CA, Cannon JG, Wolff SM: New concepts on the pathogenesis of fever. Rev
Infect Dis 1988;10:168–189.)

Microbes, microbial toxins, or other products of microbes are the most common “exogenous
pyrogens,” which are substances that come from outside of the body, stimulate macrophages
and other cells to produce endogenous pyrogens, and result in fever. 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 1 of the few substances that can directly affect
thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release.
Fever may be caused by infection, vaccines, biologic agents (granulocyte-macrophage colony-
stimulating factor, interferons, interleukins), tissue injury (infarction, pulmonary emboli, trauma,
intramuscular injections, burns), malignancy (leukemia, lymphoma, hepatoma, metastatic
disease), drugs (cocaine, amphotericin B, drug fever), immunologic-rheumatologic disorders
(systemic lupus erythematosus, rheumatoid arthritis), inflammatory diseases (e.g.,
inflammatory bowel disease), granulomatous diseases (sarcoidosis), endocrine disorders
 (e.g., thyrotoxicosis, pheochromocytoma), metabolic disorders (gout, uremia, Fabry disease,
type 1 hyperlipidemia), genetic disorders (familial Mediterranean fever), and unknown or
poorly understood entities. Factitious fever, or self-induced fever, may be due to intentional
manipulation of the thermometer or injection of pyrogenic material.

Increasing body temperature in response to microbial pathogens is a response observed in

reptiles, fish, birds, and mammals. When fish are given an exogenous pyrogen, they swim to
warmer water to raise their body temperature. In a similar fashion, lizards given exotoxin lie in
the sun until they have raised their body temperature to the febrile range. In humans,
increased temperatures are associated with decreased microbial reproduction and an
increased inflammatory response. Most evidence suggests that fever is an adaptive response
and should be treated only in selected circumstances. However, fever increases oxygen
consumption, carbon dioxide production, and cardiac output, and may exacerbate cardiac
insufficiency in patients with heart disease or chronic anemia (e.g., sickle cell disease),
pulmonary insufficiency in those with chronic lung disease, and metabolic instability in children
with diabetes mellitus or inborn errors of metabolism. Furthermore, children between the ages
of 6 mo and 5 yr are at increased risk for benign febrile seizures, whereas those with
idiopathic epilepsy may have an increased frequency of seizures associated with a febrile
illness (see Chapter 593.1).

CLINICAL MANIFESTATIONS.

Although fever patterns per se are not often helpful in determining a specific diagnosis,
observing the clinical characteristics of fever can provide useful information. 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, some drugs, some procedures, or 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 of very high temperatures
(>41?C) include central fever (resulting from central nervous system 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.

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 1st and 3rd days (malaria caused by Plasmodium vivax), and quartan fever occurs on the
1st and 4th days (malaria caused by Plasmodium malariae). Diseases characterized by
relapsing fevers (Table 174-1) should be distinguished from those 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 leptospirosis, dengue fever, yellow fever, Colorado tick fever, spirillary rat-bite
fever (Spirillum minus), and the African hemorrhagic fevers (Marburg, Ebola, and Lassa fever).
Periodic fever is used narrowly to describe fever syndromes with a regular periodicity (cyclic
neutropenia, and periodic fever, aphthous stomatitis, pharyngitis, and adenopathy [PFAPA]) 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).

TABLE 174-1   -- Fevers Prone to Relapse

INFECTIOUS CAUSES
   Relapsing fever (Borrelia recurrentis)
   Trench fever (Rochalimaea quintana)
   Q Fever (Coxiella burnetii)
   Typhoid fever (Salmonella typhi)
   Syphilis (Treponema pallidum)
   Tuberculosis
   Histoplasmosis
   Coccidioidomycosis
   Blastomycosis
   Melioidosis (Pseudomonas pseudomallei)
   Lymphocytic choriomeningitis (LCM) virus
   Dengue fever
   Yellow fever
   Chronic meningococcemia
   Colorado tick fever
   Leptospirosis
   Brucellosis
   Oroya fever (Bartonella bacilliformis)
   Acute rheumatic fever
   Rat-bite fever (Spirillum minus)
   Visceral leishmaniasis
   Lyme disease (Leptospira burgdorferi)
   Malaria
   Babesiosis
   Noninfluenza respiratory viruses
   Epstein-Barr virus

NONINFECTIOUS CAUSES

   Beh?et disease
   Crohn disease
   Weber-Christian disease (panniculitis)
   Leukoclastic angiitis
   Sweet syndrome
   Systemic lupus erythematosus

PERIODIC FEVER SYNDROMES

   Familial Mediterranean fever

   Cyclic neutropenia
   Periodic fever, aphthous stomatitis, pharyngitis, adenopathy (PFAPA)
   Hyper IgD syndrome
   Hibernian fever (tumor necrosis factor super-family IgA-associated syndrome [TRAPS])
   Muckle-Wells syndrome
Modified from Cunha BA: The clinical significance of fever patterns. Infect Dis Clin North Am
1996;10:33–44.

The relationship between a patient's pulse rate and temperature can be informative. 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, suggests 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.

Most infections result in some type of injury that induces an inflammatory response and
subsequently results in the release of endogenous pyrogens. Administration of antimicrobial
agents can result in a very rapid elimination of bacteria, but if tissue injury has been extensive,
the inflammatory response and fever can continue for days after all microbes have been
eradicated.

TREATMENT.

Fever with temperatures less than 39?C in healthy children generally does not require
treatment. As temperatures become higher, patients tend to become more uncomfortable and
administration of antipyretics often makes patients feel better. Other than providing
symptomatic relief, antipyretic therapy does not change the course of infectious diseases.
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 for severe infection, hypothalamic
disorders, or central nervous system hemorrhage, and should always be treated with
antipyretics. High fever during pregnancy may be teratogenic.

Acetaminophen, aspirin, and ibuprofen are inhibitors of hypothalamic cyclo-oxygenase, thus

inhibiting PGE2 synthesis. These drugs all are equally effective antipyretic agents. Because
aspirin has been associated with Reye syndrome in children and adolescents, it is not
recommended for the treatment of fever. Acetaminophen, 10–15 mg/kg orally every 4 hr, is not
associated with significant adverse effects; however, prolonged use may produce renal injury,
and massive overdose may produce hepatic failure. Ibuprofen, 5–10 mg/kg orally every 6–8
hr, is also effective and may cause dyspepsia, gastrointestinal bleeding, reduced renal blood
flow, and rarely, aseptic meningitis, hepatic toxicity, or aplastic anemia. Serious injury from
ibuprofen overdose is unusual. Alternating acetaminophen and ibuprofen Q 4–6 hr or giving
both drugs at the same time are also effective. Tepid sponge bathing in warm water (not
alcohol) is another recommended method of reducing hyperpyrexia due to infection or
hyperthermia resulting from external causes (heatstroke). The decline of body temperature
after antipyretic therapy does not distinguish serious bacterial from less serious viral diseases.