# 09 - 20 Fever

### 20 Fever

PAIN ARISING IN THE SHOULDER REGION
■
■THORACIC OUTLET SYNDROMES
The thoracic outlet contains the first rib, the subclavian artery and 
vein, the brachial plexus, the clavicle, and the lung apex. Injury to these 
structures may result in postural or movement-induced pain around 
the shoulder and supraclavicular region, classified as follows.
True neurogenic thoracic outlet syndrome (TOS) is an uncommon 
disorder resulting from compression of the lower trunk of the brachial 
plexus or ventral rami of the C8 or T1 nerve roots, caused most often 
by an anomalous band of cartilaginous tissue connecting an elongate 
transverse process at C7 with the first rib. Pain is mild or may be 
absent. Signs include weakness and wasting of intrinsic muscles of the 
hand and diminished sensation on the palmar aspect of the fifth digit. 
An anteroposterior cervical spine x-ray will show an elongate C7 trans­
verse process (an anatomic marker for the anomalous cartilaginous 
band), and EMG and NCSs confirm the diagnosis. Treatment consists 
of surgical resection of the anomalous band. The weakness and wasting 
of intrinsic hand muscles typically do not improve, but surgery halts 
the insidious progression of weakness.
Arterial TOS results from compression of the subclavian artery by 
a cervical rib, resulting in poststenotic dilatation of the artery and in 
some cases secondary thrombus formation. Blood pressure is reduced 
in the affected limb, and signs of emboli may be present in the hand. 
Neurologic signs are absent. Ultrasound can confirm the diagnosis 
noninvasively. Treatment is with thrombolysis or anticoagulation (with 
or without embolectomy) and surgical excision of the cervical rib com­
pressing the subclavian artery.
Venous TOS is due to subclavian vein thrombosis resulting in swell­
ing of the arm and pain. The vein may be compressed by a cervical 
rib or anomalous scalene muscle. Venography is the diagnostic test of 
choice.
Disputed TOS accounts for 95% of patients diagnosed with TOS; 
chronic arm and shoulder pain are prominent and of unclear cause. 
The lack of sensitive and specific findings on physical examination or 
specific markers for this condition results in diagnostic uncertainty. 
The role of surgery in disputed TOS is controversial. Multidisciplinary 
pain management is a conservative approach, although treatment is 
often unsuccessful.
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■BRACHIAL PLEXUS AND NERVES
Pain from injury to the brachial plexus or peripheral nerves of the arm 
can occasionally mimic referred pain of cervical spine origin, includ­
ing cervical radiculopathy, but the pain typically begins distal to the 
posterior neck region in the shoulder girdle or upper arm. Neoplastic 
infiltration of the lower trunk of the brachial plexus may produce 
shoulder or supraclavicular pain radiating down the arm, numbness 
of the fourth and fifth fingers or medial forearm, and weakness of 
intrinsic hand muscles innervated by the lower trunk and medial cord 
of the brachial plexus. Delayed radiation injury may produce weak­
ness in the upper arm or numbness of the lateral forearm or arm due 
to involvement of the upper trunk and lateral cord of the plexus. Pain 
is less common and less severe than with neoplastic infiltration. A 
Pancoast tumor of the lung (Chap. 83) is another cause of injury to the 
brachial plexus and should be considered especially when a concurrent 
Horner’s syndrome is present. Acute brachial neuritis is often confused 
with radiculopathy; the acute onset of severe shoulder or scapular pain 
is followed typically over days by weakness of the proximal arm and 
shoulder girdle muscles innervated by the upper brachial plexus. The 
onset may be preceded by an infection, vaccination, or minor surgi­
cal procedure. The long thoracic nerve may be affected, resulting in 
a winged scapula. Brachial neuritis may also present as an isolated 
paralysis of the diaphragm with or without involvement of other nerves 
of the upper limb. Recovery may take up to several years, and full func­
tional recovery can be expected in the majority of patients.
Occasional cases of carpal tunnel syndrome produce pain and 
paresthesias extending into the forearm, arm, and shoulder resem­
bling a C5 or C6 root lesion. Lesions of the radial or ulnar nerve can 
also mimic radiculopathy at C7 or C8, respectively. EMG and NCSs 

can accurately localize lesions to the nerve roots, brachial plexus, or 
peripheral nerves.

For further discussion of peripheral nerve disorders, see Chap. 457.
SHOULDER
Pain arising from the shoulder can also on occasion mimic pain from 
the spine. If symptoms and signs of radiculopathy are absent, then 
the differential diagnosis includes mechanical shoulder pain (bicipital 
tendonitis, frozen shoulder, bursitis, rotator cuff tear, dislocation, adhe­
sive capsulitis, or rotator cuff impingement under the acromion) and 
referred pain (subdiaphragmatic irritation, angina, or Pancoast tumor). 
Mechanical pain is often worse at night, associated with local shoulder 
tenderness, and aggravated by passive abduction, internal rotation, 
or extension of the arm. Demonstrating normal passive full range of 
motion of the arm at the shoulder without worsening of the pain can 
help exclude mechanical shoulder pathology as a cause of neck region 
pain. Pain from shoulder disease may radiate into the arm or hand, but 
focal neurologic signs (sensory, motor, or reflex changes) are absent.
Fever
CHAPTER 20
Acknowledgment
The authors acknowledge the contributions of John W. Engstrom to ear­
lier editions of this chapter.
■
■FURTHER READING
Cohen SP, Hooten WM: Advances in the diagnosis and management 
of neck pain. BMJ 358:j3221, 2017.
Popescu A, Lee H: Neck pain and lower back pain. Med Clin North 
Am 104:279, 2020.
Rupp R et al: International standards for neurological classification of 
spinal cord injury: Revised 2019. Top Spinal Cord Inj Rehabil 27:1, 
2021.
Shin DW et al: Global, regional, and national neck pain burden in the 
general population, 1990-2019: An analysis of the global burden of 
disease study 2019. Front Neurol 13:955367, 2022.
Vazirizadeh-Mahabadi M, Yarahmadi M: Canadian C-spine Rule 
versus NEXUS in screening of clinically important traumatic cervi­
cal spine injuries: A systematic review and meta-analysis. Arch Acad 
Emerg Med 11:e5, 2023.
Section 2	 Alterations in Body 
Temperature
Charles A. Dinarello, Neeraj K. Surana

Fever
Body temperature is controlled by the hypothalamus. Neurons in both 
the preoptic anterior hypothalamus and the posterior hypothalamus 
receive two kinds of signals: one from peripheral nerves that transmit 
information from warmth/cold receptors in the skin and the other 
from the temperature of the blood bathing the region. These two types 
of signals are integrated by the thermoregulatory center of the hypo­
thalamus to maintain normal temperature. In a neutral temperature 
environment, the human metabolic rate produces more heat than 
is necessary to maintain the core body temperature in the range of 
36.5–37.5°C (97.7–99.5°F).
NORMAL BODY TEMPERATURES
A normal body temperature is ordinarily maintained despite environ­
mental variations because the hypothalamic thermoregulatory center 
balances the excess heat production derived from metabolic activity

in muscle and the liver with heat dissipation from the skin and lungs. 
According to a study of >35,000 individuals ≥18 years of age seen 
in routine medical visits, the mean oral temperature is 36.6°C (95% 
confidence interval, 35.7–37.3°C). In light of this study, a temperature 
of >37.7°C (>99.9°F), which represents the 99th percentile for healthy 
individuals, defines a fever. Importantly, higher ambient temperatures 
are linked to higher baseline body temperatures. Additionally, body 
temperatures have diurnal and seasonal variation, with low levels 
at 8 a.m. and during summer and higher levels at 4 p.m. and during 
winter. Baseline temperatures are also affected by age (lower by 0.02°C 
for every 10-year increase in age), demographics (African-American 
women have temperatures 0.052°C higher than white men), and 
comorbid conditions (cancer is associated with 0.02°C higher tempera­
tures; hypothyroidism is linked to temperatures lower by 0.01°C). After 
controlling for age, sex, race, vital signs, and comorbidities, an increase 
in baseline temperature of 0.15°C (or 1 standard deviation) intriguingly 
translates into a 0.52% absolute increase in 1-year mortality.

PART 2
Cardinal Manifestations and Presentation of Diseases
Rectal temperatures are generally 0.4°C (0.7°F) higher than oral 
readings. The lower oral readings are probably attributable to mouth 
breathing, which is a factor in patients with respiratory infections and 
rapid breathing. Lower-esophageal temperatures closely reflect core 
temperature. Tympanic membrane thermometers measure radiant heat 
from the tympanic membrane and nearby ear canal and display that 
absolute value (unadjusted mode) or a value automatically calculated 
from the absolute reading on the basis of nomograms relating the 
radiant temperature measured to actual core temperatures obtained 
in clinical studies (adjusted mode). These measurements, although 
convenient, may be more variable than directly determined oral or 
rectal values. Studies in adults show that readings are lower with 
unadjusted-mode than with adjusted-mode tympanic membrane ther­
mometers and that unadjusted-mode tympanic membrane values are 
0.8°C (1.6°F) lower than rectal temperatures.
In women who menstruate, the a.m. temperature is generally lower 
during the 2 weeks before ovulation; it then rises by ~0.6°C (1°F) with 
ovulation and stays at that level until menses occur. During the luteal 
phase, the amplitude of the circadian rhythm remains the same.
FEVER VERSUS HYPERTHERMIA
Fever is an elevation of body temperature that exceeds the normal daily 
variation and occurs in conjunction with an increase in the hypotha­
lamic set point (e.g., from 37°C to 39°C). This shift of the set point from 
“normothermic” to febrile levels very much resembles the resetting of 
the home thermostat to a higher level in order to raise the ambient 
temperature in a room. Once the hypothalamic set point is raised, 
neurons in the vasomotor center are activated and vasoconstriction 
commences. The individual first notices vasoconstriction in the hands 
and feet. Shunting of blood away from the periphery to the internal 
organs essentially decreases heat loss from the skin, and the person 
feels cold. For most fevers, body temperature increases by 1–2°C. 
Shivering, which increases heat production from the muscles, may 
begin at this time; however, shivering is not required if mechanisms 
of heat conservation raise blood temperature sufficiently. Nonshiver­
ing heat production from the liver also contributes to increasing core 
temperature. Behavioral adjustments (e.g., putting on more clothing or 
bedding) help raise body temperature by decreasing heat loss.
The processes of heat conservation (vasoconstriction) and heat 
production (shivering and increased nonshivering thermogenesis) 
continue until the temperature of the blood bathing the hypothalamic 
neurons matches the new “thermostat setting.” Once that point is 
reached, the hypothalamus maintains the temperature at the febrile 
level by the same mechanisms of heat balance that function in the afe­
brile state. When the hypothalamic set point is again reset downward 
(in response to either a reduction in the concentration of pyrogens or 
the use of antipyretics), the processes of heat loss through vasodilation 
and sweating are initiated. Loss of heat by sweating and vasodila­
tion continues until the blood temperature at the hypothalamic level 
matches the lower setting. Behavioral changes (e.g., removal of cloth­
ing) facilitate heat loss.

A fever of >41.5°C (>106.7°F) is called hyperpyrexia. This extraor­
dinarily high fever can develop in patients with severe infections but 
most commonly occurs in patients with central nervous system (CNS) 
hemorrhages. In the preantibiotic era, fever due to a variety of infec­
tious diseases rarely exceeded 106°F, and there has been speculation 
that this natural “thermal ceiling” is mediated by neuropeptides func­
tioning as central antipyretics.
In rare cases, the hypothalamic set point is elevated as a result of 
local trauma, hemorrhage, tumor, or intrinsic hypothalamic mal­
function. The term hypothalamic fever is sometimes used to describe 
elevated temperature caused by abnormal hypothalamic function. 
However, most patients with hypothalamic damage have subnormal, 
not supranormal, body temperatures.
Although most patients with elevated body temperature have fever, 
there are circumstances in which elevated temperature represents not 
fever but hyperthermia (heat stroke). Hyperthermia is characterized by 
an uncontrolled increase in body temperature that exceeds the body’s 
ability to lose heat. The setting of the hypothalamic thermoregulatory 
center is unchanged. In contrast to fever in infections, hyperthermia 
does not involve pyrogenic molecules. Exogenous heat exposure and 
endogenous heat production are two mechanisms by which hyperther­
mia can result in dangerously high internal temperatures. Excessive 
heat production can easily cause hyperthermia despite physiologic 
and behavioral control of body temperature. For example, work or 
exercise in hot environments can produce heat faster than peripheral 
mechanisms can lose it. For a detailed discussion of hyperthermia, 
see Chap. 478.
It is important to distinguish between fever and hyperthermia 
since hyperthermia can be rapidly fatal and characteristically does not 
respond to antipyretics. In an emergency situation, however, making 
this distinction can be difficult. For example, in systemic sepsis, fever 
(hyperpyrexia) can be rapid in onset, and temperatures can exceed 
40.5°C (104.9°F). Hyperthermia is often diagnosed on the basis of the 
events immediately preceding the elevation of core temperature—e.g., 
heat exposure or treatment with drugs that interfere with thermo­
regulation. In patients with heat stroke syndromes and in those taking 
drugs that block sweating, the skin is hot but dry, whereas in fever, the 
skin can be cold as a consequence of vasoconstriction. Antipyretics 
do not reduce the elevated temperature in hyperthermia, whereas in 
fever—and even in hyperpyrexia—adequate doses of either aspirin or 
acetaminophen usually result in some decrease in body temperature.
PATHOGENESIS OF FEVER
■
■PYROGENS
The term pyrogen (Greek pyro, “fire”) is used to describe any substance 
that causes fever. Exogenous pyrogens are derived from outside the 
patient; most are microbial products, microbial toxins, or whole micro­
organisms (including viruses). The classic example of an exogenous 
pyrogen is the lipopolysaccharide (endotoxin) produced by all gramnegative bacteria. Endotoxin is a highly pyrogenic molecule in humans: 
when injected intravenously into volunteers, a dose of 2–3 ng/kg produces 
fever, leukocytosis, acute-phase proteins, and generalized symptoms of 
malaise. While cell wall components of gram-positive organisms are less 
pyrogenic than endotoxin, these organisms often produce toxins that 
act as superantigens and induce fever (e.g., Staphylococcus aureus toxic 
shock syndrome toxin-1, staphylococcal enterotoxins, streptococcal 
pyrogenic exotoxins). These products of staphylococci and strepto­
cocci cause fever in experimental animals when injected intravenously 
at concentrations of 1–10 μg/kg.
■
■PYROGENIC CYTOKINES
Cytokines are small proteins (molecular mass, 10,000–20,000 Da) that 
regulate immune, inflammatory, and hematopoietic processes. For 
example, the elevated leukocytosis seen in several infections with an 
absolute neutrophilia is attributable to the cytokines interleukin (IL) 
1 and IL-6. Some cytokines also cause fever; formerly referred to as 
endogenous pyrogens, they are now called pyrogenic cytokines. The 
pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF),

and ciliary neurotropic factor, a member of the IL-6 family. Fever is a 
prominent side effect of interferon α therapy. Each pyrogenic cytokine 
is encoded by a separate gene, and each has been shown to cause fever 
in laboratory animals and in humans. When injected into humans at 
low doses (10–100 ng/kg), IL-1 and TNF produce fever; in contrast, for 
IL-6, a dose of 1–10 μg/kg is required for fever production.
A wide spectrum of bacterial and fungal products induce the 
synthesis and release of pyrogenic cytokines. However, fever can be 
a manifestation of disease in the absence of microbial infection. For 
example, inflammatory processes such as pericarditis, trauma, stroke, 
and routine immunizations induce the production of IL-1, TNF, and/
or IL-6; individually or in combination, these cytokines trigger the 
hypothalamus to raise the set point to febrile levels.
■
■ELEVATION OF THE HYPOTHALAMIC SET POINT 
BY CYTOKINES
During fever, levels of prostaglandin E2 (PGE2) are elevated in hypo­
thalamic tissue and the third cerebral ventricle. The concentrations of 
PGE2 are highest near the circumventricular vascular organs (organum 
vasculosum of lamina terminalis)—networks of enlarged capillaries 
surrounding the hypothalamic regulatory centers. Destruction of these 
organs reduces the ability of pyrogens to produce fever. Most studies 
in animals have failed to show, however, that pyrogenic cytokines pass 
from the circulation into the brain itself. Thus, it appears that both 
exogenous pyrogens and pyrogenic cytokines interact with the endo­
thelium of these capillaries and that this interaction is the first step in 
initiating fever—i.e., in raising the set point to febrile levels.
The key events in the production of fever are illustrated in Fig. 20-1. 
Myeloid and endothelial cells are the primary cell types that produce 
pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6, and 
TNF are released from these cells and enter the systemic circulation. 
Although these circulating cytokines lead to fever by inducing the 
synthesis of PGE2, they also induce PGE2 in peripheral tissues. The 
increase in PGE2 in the periphery accounts for the nonspecific myal­
gias and arthralgias that often accompany fever. It is thought that some 
systemic PGE2 escapes destruction by the lung and gains access to the 
hypothalamus via the internal carotid. However, it is the elevation of 
PGE2 in the brain that starts the process of raising the hypothalamic 
set point for core temperature.
There are four receptors for PGE2, and each signals the cell in differ­
ent ways. Of the four receptors, the third (EP-3) is essential for fever: 
when the gene for this receptor is deleted in mice, no fever follows the 
injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor 
genes leaves the fever mechanism intact. Although PGE2 is essential for 
fever, it is not a neurotransmitter. Rather, the release of PGE2 from the 
brain side of the hypothalamic endothelium triggers the PGE2 receptor 
Infection, microbial toxins,
  mediators of inflammation,
  immune reactions
Microbial toxins
Fever
Heat conservation,
  heat production
Cyclic
AMP
Monocytes/macrophages,
  endothelial cells, others
Elevated
  thermoregulatory
  set point
PGE2
Hypothalamic
  endothelium
Pyrogenic cytokines
  IL-1, IL-6, TNF, IFN
Circulation
FIGURE 20-1  Chronology of events required for the induction of fever. AMP, 
adenosine 5′-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin 
E2; TNF, tumor necrosis factor.

on glial cells, and this stimulation results in the rapid release of cyclic 
adenosine 5′-monophosphate (cAMP), which is a neurotransmitter. 
As shown in Fig. 20-1, the release of cAMP from glial cells activates 
neuronal endings from the thermoregulatory center that extend into 
the area. The elevation of cAMP is thought to account for changes in 
the hypothalamic set point either directly or indirectly (by inducing the 
release of neurotransmitters). Distinct receptors for microbial products 
are located on the hypothalamic endothelium. These receptors are 
called Toll-like receptors and are similar in many ways to IL-1 receptors. 
IL-1 receptors and Toll-like receptors share the same signal-transducing 
mechanism. Thus, the direct activation of Toll-like receptors or IL-1 
receptors results in PGE2 production and fever.

Fever
CHAPTER 20
■
■PRODUCTION OF CYTOKINES IN THE CNS
Cytokines produced in the brain may account for the hyperpyrexia of 
CNS hemorrhage, trauma, or infection. Viral infections of the CNS 
induce microglial and possibly neuronal production of IL-1, TNF, and 
IL-6. In experimental animals, the concentration of a cytokine required 
to cause fever is several orders of magnitude lower with direct injec­
tion into the brain substance or brain ventricles than with systemic 
injection. Therefore, cytokines produced in the CNS can raise the 
hypothalamic set point, bypassing the circumventricular organs. CNS 
cytokines likely account for the hyperpyrexia of CNS hemorrhage, 
trauma, or infection.
APPROACH TO THE PATIENT
Fever
HISTORY AND PHYSICAL EXAMINATION
There are a range of disease processes that present with fever as a 
cardinal manifestation, and a thorough history can help distinguish 
between these broad categories (Table 20-1). The chronology of 
events preceding fever, including exposure to other symptomatic 
individuals or to vectors of disease, should be ascertained. Elec­
tronic devices for measuring oral, tympanic membrane, or rectal 
temperatures are reliable, but the same site should be used consis­
tently to monitor a febrile disease. Moreover, physicians should be 
aware that newborns, elderly patients, patients with chronic hepatic 
or renal failure, and patients taking glucocorticoids or being treated 
with an anticytokine may have active disease in the absence of fever 
because of a blunted febrile response. 
LABORATORY TESTS
The workup should include a complete blood count; a differential 
count should be performed manually or with an instrument sensi­
tive to the identification of neutrophil juvenile or band forms, toxic 
granulations, and Döhle bodies, which are suggestive of bacterial 
infection. Neutropenia may be present with some viral infections.
Measurement of circulating cytokines in patients with fever is 
not helpful since levels of cytokines such as IL-1 and TNF in the 
circulation often are below the detection limit of the assay or do not 
coincide with fever. However, in patients with low-grade fevers or 
with suspected occult disease, the most valuable measurements are 
the C-reactive protein (CRP) level and the erythrocyte sedimenta­
tion rate. These markers of inflammatory processes are particularly 
helpful in detecting occult disease. Measurement of circulating 
IL-6, which induces CRP, can be useful. However, whereas IL-6 
TABLE 20-1  Disease Categories That Present with Fever as a Cardinal Sign 
Infectious diseases
Autoimmune and noninfectious inflammatory disorders
Cancer
Medication related (e.g., vaccines, drug fever)
Endocrine disorders (e.g., hyperthyroidism)
Intrinsic hypothalamic malfunction

levels may vary during a febrile disease, CRP levels remain elevated. 
Acute-phase reactants are discussed in Chap. 315. 
FEVER IN PATIENTS RECEIVING ANTICYTOKINE THERAPY
Patients receiving long-term treatment with anticytokine-based 
regimens are at increased risk of infection because of lowered host 
defenses. For example, latent Mycobacterium tuberculosis infection 
can disseminate in patients receiving anti-TNF therapy. With the 
increasing use of anticytokines to reduce the activity of IL-1, IL-6, 
IL-12/23, IL-17, or TNF in patients with Crohn disease, rheumatoid 
arthritis, or psoriasis, the possibility that these therapies blunt the 
febrile response should be kept in mind.
PART 2
Cardinal Manifestations and Presentation of Diseases
The blocking of cytokine activity has the distinct clinical draw­
back of lowering the level of host defenses against both routine 
bacterial and opportunistic infections such as M. tuberculosis and 
fungal infections. The use of monoclonal antibodies to reduce IL-17 
in psoriasis increases the risk of systemic candidiasis.
In nearly all reported cases of infection associated with anticy­
tokine therapy, fever is among the presenting signs. However, the 
extent to which the febrile response is blunted in these patients 
remains unknown. Therefore, low-grade fever in patients receiving 
anticytokine therapies is of considerable concern. The physician 
should conduct an early and rigorous diagnostic evaluation in these 
cases. The febrile response is also blunted in patients receiving 
chronic glucocorticoid therapy or anti-inflammatory agents such as 
nonsteroidal anti-inflammatory drugs (NSAIDs).
TREATMENT
Fever
THE DECISION TO TREAT FEVER
In deciding whether to treat fever, it is important to remember that 
fever itself is not an illness: it is an ordinary response to a pertur­
bation of normal host physiology. Most fevers are associated with 
self-limited infections, such as common viral diseases. The use of 
antipyretics is not contraindicated in these infections: no significant 
clinical evidence indicates either that antipyretics delay the resolu­
tion of viral or bacterial infections or that fever facilitates recovery 
from infection or acts as an adjuvant to the immune system. In 
short, treatment of fever and its symptoms with routine antipyretics 
does no harm and does not slow the resolution of common viral 
and bacterial infections.
However, in bacterial infections, the withholding of antipyretic 
therapy can be helpful in evaluating the effectiveness of a particular 
antibiotic, especially in the absence of positive cultures of the infect­
ing organism, and the routine use of antipyretics can mask an inad­
equately treated bacterial infection. Withholding antipyretics in 
some cases may facilitate the diagnosis of an unusual febrile disease. 
Temperature–pulse dissociation (relative bradycardia) occurs in 
typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, 
and factitious fever. As stated earlier, in newborns, elderly patients, 
patients with chronic liver or kidney failure, and patients taking 
glucocorticoids, fever may not be present despite infection. Hypo­
thermia can develop in patients with septic shock.
Some infections have characteristic patterns in which febrile epi­
sodes are separated by intervals of normal temperature. For example, 
Plasmodium vivax causes fever every third day, whereas fever occurs 
every fourth day with Plasmodium malariae. Another relapsing 
fever is related to Borrelia infection, with days of fever followed by 
a several-day afebrile period and then a relapse into additional days 
of fever. In the Pel-Ebstein pattern, fever lasting 3–10 days is fol­
lowed by afebrile periods of 3–10 days; this pattern can be classic for 
Hodgkin disease and other lymphomas. In cyclic neutropenia, fevers 
occur every 21 days and accompany the neutropenia. There are also 
a number of periodic fever syndromes (e.g., familial Mediterranean 
fever, TNF receptor–associated periodic syndrome [TRAPS]) that 
differ in their periodicity, duration of attack, constellation of clinical 

features, genetic causes, and therapies (Chap. 381). Understanding 
these clinical differences can help tailor diagnostic testing to confirm 
the diagnosis and guide therapy. 
ANTICYTOKINE THERAPY TO REDUCE FEVER IN 
AUTOIMMUNE AND AUTOINFLAMMATORY DISEASES
Recurrent fever is documented at some point in most autoimmune 
diseases and many autoinflammatory diseases, which include the 
periodic fever syndromes as well as disorders of inflammasomes 
(e.g., NLRP3, pyrin) and other components of the innate immune 
system (Chap. 360). Although fever can be a manifestation of auto­
immune diseases, recurrent fevers are characteristic of autoinflam­
matory diseases, including uncommon diseases such as adult and 
juvenile Still disease, familial Mediterranean fever, and hyper-IgD 
syndrome but also common diseases such as idiopathic pericarditis 
and gout. In addition to recurrent fevers, neutrophilia and serosal 
inflammation characterize autoinflammatory diseases. The fevers 
associated with many of these illnesses are dramatically reduced by 
blocking of IL-1 activity with anakinra or canakinumab. Anticyto­
kines therefore reduce fever in autoimmune and autoinflammatory 
diseases. Although fevers in autoinflammatory diseases are medi­
ated by IL-1β, patients also respond to antipyretics. 
MECHANISMS OF ANTIPYRETIC AGENTS
The reduction of fever by lowering of the elevated hypothalamic 
set point is a direct function of reduction of the PGE2 level in the 
thermoregulatory center. The synthesis of PGE2 depends on the 
constitutively expressed enzyme cyclooxygenase. The substrate for 
cyclooxygenase is arachidonic acid released from the cell mem­
brane, and this release is the rate-limiting step in the synthesis of 
PGE2. Therefore, inhibitors of cyclooxygenase are potent antipyret­
ics. The antipyretic potency of various drugs is directly correlated 
with the inhibition of brain cyclooxygenase. Acetaminophen is a 
poor cyclooxygenase inhibitor in peripheral tissue and lacks note­
worthy anti-inflammatory activity; in the brain, however, acetamin­
ophen is oxidized by the P450 cytochrome system, and the oxidized 
form inhibits cyclooxygenase activity. Moreover, in the brain, the 
inhibition of another enzyme, COX-3, by acetaminophen may 
account for the antipyretic effect of this agent. However, COX-3 is 
not found outside the CNS.
Oral aspirin and acetaminophen are equally effective in reducing 
fever in humans. NSAIDs such as ibuprofen and specific inhibi­
tors of COX-2 also are excellent antipyretics. Chronic, high-dose 
therapy with antipyretics such as aspirin or any NSAID does not 
reduce normal core body temperature. Thus, PGE2 appears to play 
no role in normal thermoregulation.
As effective antipyretics, glucocorticoids act at two levels. First, 
similar to the cyclooxygenase inhibitors, glucocorticoids reduce 
PGE2 synthesis by inhibiting the activity of phospholipase A2, which 
is needed to release arachidonic acid from the cell membrane. Sec­
ond, glucocorticoids block the transcription of the mRNA for the 
pyrogenic cytokines. Limited experimental evidence indicates that 
ibuprofen and COX-2 inhibitors reduce IL-1-induced IL-6 produc­
tion and may contribute to the antipyretic activity of NSAIDs. 
REGIMENS FOR THE TREATMENT OF FEVER
The objectives in treating fever are first to reduce the elevated hypo­
thalamic set point and second to facilitate heat loss. Reducing fever 
with antipyretics also reduces systemic symptoms of headache, 
myalgias, and arthralgias.
Oral aspirin and NSAIDs effectively reduce fever but can 
adversely affect platelets and the gastrointestinal tract. Therefore, 
acetaminophen is preferred as an antipyretic. In children, acetamin­
ophen or oral ibuprofen must be used because aspirin increases the 
risk of Reye syndrome with certain viral infections. If the patient 
cannot take oral antipyretics, parenteral preparations of NSAIDs 
and rectal suppositories of various antipyretics can be used.
Treatment of fever in some patients is highly recommended. 
Fever increases the demand for oxygen (i.e., for every increase of 
1°C over 37°C, there is a 13% increase in oxygen consumption) and