Chapter 176

Fever

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1278 Part XVII

Infectious Diseases

body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigenantibody complexes in the presence of complement, complement components, lymphocyte products,
bile acids, and androgenic steroid metabolites.
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. 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 drug. Drugs that are known to
cause fever include vancomycin, amphotericin B, and allopurinol.
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

Chapter

176

Fever
Linda S. Nield and Deepak Kamat
DEFINITION

Fever is defined as a rectal temperature 38C (100.4F), and a value

>40C (104F) is called hyperpyrexia. Body temperature fluctuates in
a defined normal range (36.6-37.9C [97.9-100.2F] 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 by 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 endogenous and exogenous pyrogens
that raise the hypothalamic temperature set point. Endogenous
pyrogens include the cytokines interleukins 1 and 6, tumor necrosis
factor , and interferons and . Stimulated leukocytes and other
cells produce lipids that also serve as endogenous pyrogens. The
best-studied lipid mediator is prostaglandin E2, which attaches to the
prostaglandin receptors in the hypothalamus to produce the new
temperature set point. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens. Some substances produced within the

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. The body temperature rarely rises above potentially lethal levels (42C [107.6F]) 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 wk, whereas bacterial infections are often 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 0.5C (0.9F)/day. Remittent fever is
persistent and varies by more than 0.5C (0.9F)/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 176-1) 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 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, tumor necrosis factor receptorassociated periodic syndrome [Hibernian fever], hyperimmunoglobulin D syndrome,
the Muckle-Wells syndrome) (see Chapter 163). 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 hr) 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

Table 176-1

Fevers Prone to Relapse

INFECTIOUS CAUSES
Relapsing fever (Borrelia recurrentis)
Trench fever (Bartonella quintana)
Q fever (Coxiella burnetii)
Typhoid fever (Salmonella typhi)
Syphilis (Treponema pallidum)
Tuberculosis
Histoplasmosis
Coccidioidomycosis
Blastomycosis
Melioidosis (Pseudomonas pseudomallei)
Lymphocytic choriomeningitis (LCM) infection
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 (Borrelia burgdorferi)
Malaria
Babesiosis
Noninfluenza respiratory viral infection
Epstein-Barr virus infection
NONINFECTIOUS CAUSES
Behet disease
Crohn disease
Weber-Christian disease (panniculitis)
Leukoclastic angiitis syndromes
Sweet syndrome
Systemic lupus erythematosus and other autoimmune disorders
PERIODIC FEVER SYNDROMES (see Chapter 163)
Familial Mediterranean fever
Cyclic neutropenia
Periodic fever, aphthous stomatitis, pharyngitis, adenopathy
(PFAPA)
Hyperimmunoglobulin D syndrome
Hibernian fever (tumor necrosis factor superfamily immunoglobulin
Aassociated syndrome [TRAPS])
Muckle-Wells syndrome
Others

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 41C (105.8F) are most often associated with a noninfectious
cause. Causes for very high temperatures (>41C [105.8F]) 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 (<36C [96.8F]) 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.

Chapter 176
Table 176-2

Evaluation of Acute Fever

Thorough history: onset, other symptoms, exposures (daycare,

school, family, pets, playmates), travel, medications, other
underlying disorders, immunizations
Physical examination: complete, with focus on localizing symptoms
Laboratory studies on a case-by-case basis:
Rapid antigen testing
Nasopharyngeal: respiratory viruses by polymerase chain reaction
Throat: group A Streptococcus
Stool: rotavirus
Blood: complete blood count, blood culture, C-reactive protein,
sedimentation rate, procalcitonin
Urine: urinalysis, culture
Stool: Hemoccult, culture
Cerebrospinal fluid: cell count, glucose, protein, Gram stain,
culture
Chest radiograph or other imaging studies on a case-by-case
basis

Changes in heart rate, most commonly tachycardia, accompany

fever. Normally heart rate rises by 10 beats/min per 1C (1.8F) rise in
temperature for children >2 mo of age. Relative tachycardia, when the
pulse rate is elevated disproportionately to the temperature, is usually
caused by noninfectious diseases or infectious diseases in which a toxin
is responsible for the clinical manifestations. Relative bradycardia
(temperaturepulse 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 176-2). 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.
Physical examination should begin with a complete evaluation of
vital signs, which should include pulse oximetry because hypoxia may
indicate lower respiratory infection. 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.
If a fever has an obvious cause, then laboratory evaluation may not
be required, and management is tailored to the underlying cause with
as-needed reevaluation. If the cause of the fever is not apparent, then
further diagnostic evaluation 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 may require a chest radiograph or rapid antigen testing
for respiratory syncytial virus 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 a history of vesicoureteral reflux should prompt a urinalysis and urine culture, and bloody
diarrhea should prompt a stool culture. A complete blood count and

Fever

1279

blood culture should be considered in the ill-appearing child, along

with cerebrospinal fluid studies if the child has neck stiffness or if the
possibility of meningitis is considered. 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 of age and children with recurrent fevers are discussed
in Chapter 177.

MANAGEMENT

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 heatstroke. 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. The focus of the evaluation and treatment of febrile
seizures is aimed at determining the underlying cause of the fever. Children with idiopathic epilepsy also often have an increased frequency
of seizures associated with a fever. High fever during pregnancy may
be teratogenic.
Fever with temperatures <39C (102.2F) 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 1 of the high-risk
groups or if the childs caregiver is concerned that the fever is adversely
affecting the childs 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 (>41C [105.8F]) indicates high probability of hypothalamic disorders or central nervous system hemorrhage and should
be treated with antipyretics. Some studies show that hyperpyrexia may
be associated with a significantly increased risk of serious bacterial
infection, but other studies have not substantiated this relationship.
Acetaminophen at a dose of 10-15 mg/kg/dose every 4 hr and ibuprofen in children >6 mo at a dose of 5-10 mg/kg/dose every 8 hr 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 1 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 caused by 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.
Bibliography is available at Expert Consult.