128 PART 2 Cardinal Manifestations and Presentation of Diseases

Herniated cervical disks are responsible for ~25% of cervical radiculopathies. Extension and lateral rotation of the neck narrow the ipsilateral intervertebral foramen and may reproduce radicular symptoms

(Spurling’s sign). In young adults, acute nerve root compression from

a ruptured cervical disk is often due to trauma. Cervical disk herniations are usually posterolateral near the lateral recess. Typical patterns

of reflex, sensory, and motor changes that accompany cervical nerve

root lesions are summarized in Table 17-4. Although the classic patterns are clinically helpful, there are numerous exceptions because (1)

there is overlap in sensory function between adjacent nerve roots, (2)

symptoms and signs may be evident in only part of the injured nerve

root territory, and (3) the location of pain is the most variable of the

clinical features.

■ CERVICAL SPONDYLOSIS

Osteoarthritis of the cervical spine may produce neck pain that radiates

into the back of the head, shoulders, or arms, or may be the source of

headaches in the posterior occipital region (supplied by the C2-C4

nerve roots). Osteophytes, disk protrusions, or hypertrophic facet or

uncovertebral joints may alone or in combination compress one or

several nerve roots at the intervertebral foramina; these causes together

account for 75% of cervical radiculopathies. The roots most commonly

affected are C7 and C6. Narrowing of the spinal canal by osteophytes,

ossification of the posterior longitudinal ligament (OPLL), or a large

central disk may compress the cervical spinal cord and produce signs

of myelopathy alone or radiculopathy with myelopathy (myeloradiculopathy). When little or no neck pain accompanies cervical cord

involvement, other diagnoses to be considered include amyotrophic

lateral sclerosis (Chap. 437), multiple sclerosis (Chap. 444), spinal

cord tumors, or syringomyelia (Chap. 442). Cervical spondylotic

myelopathy should be considered even when the patient presents

with symptoms or spinal cord signs in the legs only. MRI is the study

of choice to define soft tissues in the cervical region including the

spinal cord, whereas plain CT is optimal to identify bone pathology

including foraminal, lateral recess, OPLL, or spinal canal stenosis. In

spondylotic myelopathy, focal enhancement by MRI, sometimes in a

characteristic “pancake pattern,” may be present at the site of maximal

cord compression.

There is no evidence to support prophylactic surgery for asymptomatic cervical spinal stenosis unaccompanied by myelopathic signs

or abnormal spinal cord findings on MRI, except in the setting of

dynamic instability (see spondylolisthesis above). If the patient has

postural neck pain, a prior history of whiplash or other spine/head

injury, a Lhermitte sign, or preexisting listhesis at the stenotic segment

on cervical MRI or CT, then cervical spine flexion-extension x-rays or

MRI are indicated to look for dynamic instability. Surgical intervention

is not recommended for patients with listhesis alone, unaccompanied

by dynamic instability.

■ OTHER CAUSES OF NECK PAIN

Rheumatoid arthritis (RA) (Chap. 358) of the cervical facet joints

produces neck pain, stiffness, and limitation of motion. Synovitis of

the atlantoaxial joint (C1-C2; Fig. 17-2) may damage the transverse

ligament of the atlas, producing forward displacement of the atlas on

the axis (atlantoaxial subluxation). Radiologic evidence of atlantoaxial

subluxation occurs in up to 30% of patients with RA and plain x-ray

films of the neck should be routinely performed preoperatively to

assess the risk of neck hyperextension in patients requiring intubation. The degree of subluxation correlates with the severity of erosive

disease. When subluxation is present, careful assessment is important

to identify early signs of myelopathy that could be a harbinger of

life-threatening spinal cord compression. Surgery should be considered

when myelopathy or spinal instability is present. Ankylosing spondylitis is another cause of neck pain and less commonly atlantoaxial

subluxation.

Acute herpes zoster can present as acute posterior occipital or neck

pain prior to the outbreak of vesicles. Neoplasms metastatic to the

cervical spine, infections (osteomyelitis and epidural abscess), and

metabolic bone diseases may be the cause of neck pain, as discussed

above. Neck pain may also be referred from the heart with coronary

artery ischemia (cervical angina syndrome). Rheumatologic disease

should be considered if the neck pain is accompanied by shoulder or

hip girdle pain.

■ 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 transverse 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 compressing the subclavian artery.

Venous TOS is due to subclavian vein thrombosis resulting in swelling 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. Major depression,

chronic symptoms, work-related injury, and diffuse arm symptoms

predict poor surgical outcomes. Multidisciplinary pain management

is a conservative approach, although treatment is often unsuccessful.

■ 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, including 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

weakness 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. 78) is another cause 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 surgical 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 3 years, and full functional recovery can be expected in

the majority of patients.

129Back and Neck Pain CHAPTER 17

Occasional cases of carpal tunnel syndrome produce pain and

paresthesias extending into the forearm, arm, and shoulder resembling 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. 446.

■ SHOULDER

Pain arising from the shoulder can 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, adhesive capsulitis, or rotator cuff impingement under the acromion) and

referred pain (subdiaphragmatic irritation, angina, 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 the usual 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.

■ GLOBAL CONSIDERATIONS

Many of the considerations described above for LBP also apply to neck

pain. The Global Burden of Diseases Study 2019 reported that neck

pain ranked second only to back pain as a cause of total years lived

with disability (YLD). In general, neck pain rankings were also higher

in developed regions of the world.

TREATMENT

Neck Pain Without Radiculopathy

The evidence regarding treatment for neck pain is less comprehensive than that for LBP, but the approach is remarkably similar in

many respects. As with LBP, spontaneous improvement is the norm

for acute neck pain. The usual goals of therapy are to promote a

rapid return to normal function and provide pain relief while healing proceeds.

Acute neck pain is often treated with NSAIDs, acetaminophen,

cold packs, or heat, alone or in combination while awaiting recovery. Patients should be specifically educated regarding the favorable

natural history of acute neck pain to avoid unrealistic fear and

inappropriate requests for imaging and other tests. For patients kept

awake by symptoms, cyclobenzaprine (5–10 mg) at night can help

relieve muscle spasm and promote drowsiness. For patients with

neck pain unassociated with trauma, supervised exercise with or

without mobilization appears to be effective. Exercises often include

shoulder rolls and neck stretches. The evidence in support of nonsurgical treatments for whiplash-associated disorders is generally

of limited quality and neither supports nor refutes the common

treatments used for symptom relief. Gentle mobilization of the

cervical spine combined with exercise programs may be beneficial.

Evidence is insufficient to recommend the use of cervical traction,

TENS, ultrasound, trigger point injections, botulinum toxin injections, tricyclic antidepressants, and SSRIs for acute or chronic neck

pain. Some patients obtain modest pain relief using a soft neck

collar; there is little risk or cost. Massage can produce temporary

pain relief.

For patients with chronic neck pain, supervised exercise programs can provide symptom relief and improve function. Acupuncture provided short-term benefit for some patients when compared

to a sham procedure and is an option. Spinal manipulation alone

has not been shown to be effective and carries a risk for injury.

Surgical treatment for chronic neck pain without radiculopathy or

spine instability is not recommended.

Neck Pain With Radiculopathy

The natural history of acute neck pain with radiculopathy due to

disk disease is favorable, and many patients will improve without specific therapy. Although there are no randomized trials of

NSAIDs for neck pain, a course of NSAIDs, acetaminophen, or

both, with or without muscle relaxants, and avoidance of activities

that trigger symptoms are reasonable as initial therapy. Gentle

supervised exercise and avoidance of inactivity are reasonable as

well. A short course of high-dose oral glucocorticoids with a rapid

taper, or epidural steroids administered under imaging guidance

can be effective for acute or subacute disk-related cervical radicular

pain, but have not been subjected to rigorous trials. The risk of

injection-related complications is higher in the neck than the low

back; vertebral artery dissection, dural puncture, spinal cord injury,

and embolism in the vertebral arteries have all been reported. Opioid analgesics can be used in the emergency department and for

short courses as an outpatient. Soft cervical collars can be modestly

helpful by limiting spontaneous and reflex neck movements that

exacerbate pain; hard collars are in general poorly tolerated.

If cervical radiculopathy is due to bony compression from cervical spondylosis with foraminal narrowing, periodic follow-up to

assess for progression is indicated and consideration of surgical

decompression is reasonable. Surgical treatment can produce rapid

pain relief, although it is unclear if long-term functional outcomes

are improved over nonsurgical therapy. Indications for cervical

disk surgery include a progressive motor deficit due to nerve root

compression, functionally limiting pain that fails to respond to

conservative management, or spinal cord compression. In other

circumstances, clinical improvement over time regardless of therapeutic intervention is common.

Surgical treatments include anterior cervical diskectomy alone,

laminectomy with diskectomy, or diskectomy with fusion. The risk of

subsequent radiculopathy or myelopathy at cervical segments adjacent to a fusion is ~3% per year and 26% per decade. Although this

risk is sometimes portrayed as a late complication of surgery, it may

also reflect the natural history of degenerative cervical disk disease.

■ FURTHER READING

Agency for Healthcare Research and Quality (AHRQ): Noninvasive treatments for low back pain. AHRQ Publication No.

16-EHC004-EF. February 2016, https://effectivehealthcare.ahrq.gov/

ehc/products/553/2178/back-pain-treatment-report-160229.pdf

Austevoll IM et al: Decompression with or without fusion in degenerative lumbar spondylolisthesis. N Engl J Med 385:526, 2021.

Bailey CS et al: Surgery versus conservative care for persistent sciatica

lasting 4 to 12 months. N Engl J Med 19;382:1093, 2020.

Cieza A et al: Global estimates of the need for rehabilitation based

on the Global Burden of Disease study 2019: A systematic analysis

for the Global Burden of Disease Study 2019. Lancet 396:2006,

2021.

Engstrom JW: Physical and Neurologic Examination. In Steinmetz

et al (eds). Benzel’s Spine Surgery, 5th ed. Philadelphia, Elsevier, 2021.

Goldberg H et al: Oral steroids for acute radiculopathy due to a herniated lumbar disk. JAMA 313:1915, 2015.

Hawk K et al: Past-year prescription drug monitoring program opioid

prescriptions and self-reported opioid use in an emergency department

population with opioid use disorder. Acad Emerg Med 25:508, 2018.

Jarvik JG et al: Association of early imaging for back pain with clinical

outcomes in older adults. JAMA 313:1143, 2015.

Katz JN, Harris MB: Clinical practice. Lumbar spinal stenosis. N

Engl J Med 358:818, 2008.

Theodore N: Degenerative cervical spondylosis. N Engl J Med

383:159, 2020.

Zygourakis CC et al: Geographic and hospital variation in cost of

lumbar laminectomy and lumbar fusion for degenerative conditions.

Neurosurgery 81:331, 2017.

130 PART 2 Cardinal Manifestations and Presentation of Diseases

Section 2 Alterations in Body

Temperature

18 Fever

Neeraj K. Surana, Charles A. Dinarello,

Reuven Porat

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 hypothalamus 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).

A normal body temperature is ordinarily maintained despite environmental 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 temperatures; 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.

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 thermometers 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 hypothalamic 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. Nonshivering 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 afebrile 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 vasodilation

continues until the blood temperature at the hypothalamic level

matches the lower setting. Behavioral changes (e.g., removal of clothing) facilitate heat loss.

A fever of >41.5°C (>106.7°F) is called hyperpyrexia. This extraordinarily 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

infectious diseases rarely exceeded 106°F, and there has been speculation that this natural “thermal ceiling” is mediated by neuropeptides

functioning as central antipyretics.

In rare cases, the hypothalamic set point is elevated as a result of

local trauma, hemorrhage, tumor, or intrinsic hypothalamic malfunction. 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 hyperthermia 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. 465.

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 thermoregulation. 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.

131 Fever CHAPTER 18

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 microorganisms (including viruses). The classic example of an

exogenous pyrogen is the lipopolysaccharide (endotoxin) produced

by all gram-negative bacteria. Pyrogenic products of gram-positive

organisms include the enterotoxins of Staphylococcus aureus and the

groups A and B streptococcal toxins, also called superantigens. One

staphylococcal toxin of clinical importance is that associated with

isolates of S. aureus from patients with toxic shock syndrome. These

products of staphylococci and streptococci cause fever in experimental

animals when injected intravenously at concentrations of 1–10 μg/kg.

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.

■ 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 hypothalamic 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 endothelium 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. 18-1.

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 myalgias 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 different 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

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. 18-1, 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.

■ 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 injection 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 18-1). The chronology of

events preceding fever, including exposure to other symptomatic

individuals or to vectors of disease, should be ascertained. Electronic devices for measuring oral, tympanic membrane, or rectal

temperatures are reliable, but the same site should be used consistently 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.

Infection, microbial toxins,

 mediators of inflammation,

 immune reactions

Microbial toxins

Fever

Monocytes/macrophages,

 endothelial cells, others

Heat conservation,

 heat production

Hypothalamic Pyrogenic cytokines endothelium

 IL-1, IL-6, TNF, IFN

Elevated

 thermoregulatory

 set point

Circulation

PGE2

Cyclic

AMP

FIGURE 18-1 Chronology of events required for the induction of fever. AMP,

adenosine 5′-monophosphate; IFN, interferon; IL, interleukin; PGE2

, prostaglandin

E2

; TNF, tumor necrosis factor.

132 PART 2 Cardinal Manifestations and Presentation of Diseases

TABLE 18-1 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

LABORATORY TESTS

The workup should include a complete blood count; a differential

count should be performed manually or with an instrument sensitive to the identification of 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 sedimentation 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

levels may vary during a febrile disease, CRP levels remain elevated.

Acute-phase reactants are discussed in Chap. 304.

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, IL-17, or TNF in patients with Crohn’s disease, rheumatoid

arthritis, or psoriasis, the possibility that these therapies blunt the

febrile response should be kept in mind.

The blocking of cytokine activity has the distinct clinical drawback 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 anticytokine 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 perturbation 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 resolution 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 infecting organism, and the routine use of antipyretics can mask an inadequately 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. Hypothermia can develop in patients with septic shock.

Some infections have characteristic patterns in which febrile

episodes 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 followed by afebrile periods of 3–10 days; this pattern

can be classic for Hodgkin’s 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. 369). 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. 349). Although fever can be a manifestation of autoimmune diseases, recurrent fevers are characteristic of autoinflammatory diseases, including uncommon diseases such as adult and

juvenile Still’s 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. Anticytokines therefore reduce fever in autoimmune and autoinflammatory

diseases. Although fevers in autoinflammatory diseases are mediated 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 membrane, and this release is the rate-limiting step in the synthesis of

PGE2

. Therefore, inhibitors of cyclooxygenase are potent antipyretics. 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 noteworthy anti-inflammatory activity; in the brain, however, acetaminophen 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 inhibitors of COX-2 also are excellent antipyretics. Chronic, high-dose

133 Fever and Rash CHAPTER 19

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.

Second, 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 production 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 hypothalamic 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, acetaminophen or oral ibuprofen must be used because aspirin increases the

risk of Reye’s syndrome. 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

can aggravate the condition of patients with preexisting impairment

of cardiac, pulmonary, or CNS function. Children with a history of

febrile or nonfebrile seizure should be aggressively treated to reduce

fever. However, it is unclear what triggers the febrile seizure, and

there is no correlation between absolute temperature elevation and

onset of a febrile seizure in susceptible children.

In hyperpyrexia, the use of cooling blankets facilitates the reduction of temperature; however, cooling blankets should not be used

without oral antipyretics. In hyperpyretic patients with CNS disease

or trauma (CNS bleeding), reducing core temperature mitigates the

detrimental effects of high temperature on the brain.

For a discussion of treatment for hyperthermia, see Chap. 465.

■ FURTHER READING

Dinarello CA et al: Treating inflammation by blocking interleukin-1

in a broad spectrum of diseases. Nature Rev 11:633, 2012.

Gattorno M et al: Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78:1025, 2019.

Kullenberg T et al: Long-term safety profile of anakinra in patients

with severe cryopyrin-associated periodic syndromes. Rheumatology

55:1499, 2016.

Sakkat A et al: Temperature control in critically ill patients with fever:

A meta-analysis of randomized controlled trials. J Crit Care 61:89,

2021.

The acutely ill patient with fever and rash often presents a diagnostic

challenge for physicians, yet the distinctive appearance of an eruption

in concert with a clinical syndrome can facilitate a prompt diagnosis

and the institution of life-saving therapy or critical infection-control

interventions. Representative images of many of the rashes discussed

in this chapter are included in Chap. A1.

19 Fever and Rash

Elaine T. Kaye, Kenneth M. Kaye

APPROACH TO THE PATIENT

Fever and Rash

A thorough history of patients with fever and rash includes the

following relevant information: immune status, medications taken

within the previous month, specific travel history, immunization

status, exposure to domestic pets and other animals, history of

animal (including arthropod) bites, recent dietary exposures, existence of cardiac abnormalities, presence of prosthetic material,

recent exposure to ill individuals, and sexual exposures. The history

should also include the site of onset of the rash and its direction and

rate of spread.

PHYSICAL EXAMINATION

A thorough physical examination entails close attention to the rash,

with an assessment and precise definition of its salient features.

First, it is critical to determine what type of lesions make up the

eruption. Macules are flat lesions defined by an area of changed

color (i.e., a blanchable erythema). Papules are raised, solid lesions

<5 mm in diameter; plaques are lesions >5 mm in diameter with a

flat, plateau-like surface; and nodules are lesions >5 mm in diameter with a more rounded configuration. Wheals (urticaria, hives)

are papules or plaques that are pale pink and may appear annular

(ringlike) as they enlarge; classic (nonvasculitic) wheals are transient, lasting only 24 h in any defined area. Vesicles (<5 mm) and

bullae (>5 mm) are circumscribed, elevated lesions containing fluid.

Pustules are raised lesions containing purulent exudate; vesicular

processes such as varicella or herpes simplex may evolve to pustules. Nonpalpable purpura is a flat lesion that is due to bleeding

into the skin. If <3 mm in diameter, the purpuric lesions are termed

petechiae; if >3 mm, they are termed ecchymoses. Palpable purpura

is a raised lesion that is due to inflammation of the vessel wall (vasculitis) with subsequent hemorrhage. An ulcer is a defect in the skin

extending at least into the upper layer of the dermis, and an eschar

(tâche noire) is a necrotic lesion covered with a black crust.

Other pertinent features of rashes include their configuration

(i.e., annular or target), the arrangement of their lesions, and their

distribution (i.e., central or peripheral).

For further discussion, see Chaps. 56, 58, 122, and 129.

■ CLASSIFICATION OF RASH

This chapter reviews rashes that reflect systemic disease, but it does

not include localized skin eruptions (i.e., cellulitis, impetigo) that may

also be associated with fever (Chap. 129). The chapter is not intended

to be all-inclusive, but it covers the most important and most common

diseases associated with fever and rash. Rashes are classified herein

on the basis of lesion morphology and distribution. For practical purposes, this classification system is based on the most typical disease

presentations. However, morphology may vary as rashes evolve, and

the presentation of diseases with rashes is subject to many variations

(Chap. 58). For instance, the classic petechial rash of Rocky Mountain

spotted fever (Chap. 187) may initially consist of blanchable erythematous macules distributed peripherally; at times, however, the rash

associated with this disease may not be predominantly acral, or no rash

may develop at all.

Diseases with fever and rash may be classified by type of eruption:

centrally distributed maculopapular, peripheral, confluent desquamative erythematous, vesiculobullous, urticaria-like, nodular, purpuric,

ulcerated, or with eschars. Diseases are listed by these categories in

Table 19-1, and many are highlighted in the text. However, for a more

detailed discussion of each disease associated with a rash, the reader is

referred to the chapter dealing with that specific disease. (Reference

chapters are cited in the text and listed in Table 19-1.)

■ CENTRALLY DISTRIBUTED MACULOPAPULAR

ERUPTIONS

Centrally distributed rashes, in which lesions are primarily truncal, are

the most common type of eruption. The rash of rubeola (measles) starts