Fever

Body Temperature
• 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).
• 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.

• 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

A. age (lower by 0.02°C for every 10-year increase in age),

B. demographics (African-American women have

temperatures 0.052°C higher than white men)

C. comorbid conditions (cancer is associated with 0.02°C

higher temperatures eg.hypothyroidism is linked to
temperatures lower by 0.01°C).
 Variation in temperature in Men &
women
• 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

• stays at that level until menses occur.

• During the luteal phase, the amplitude of the circadian

rhythm remains the same
 Definition of Fever

• 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).

• Temperature of >37.7°C (>99.9°F) defines a fever.

Grading of fever
 Response of body
• 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 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 vasodilation continues until the blood

temperature at the hypothalamic level matches the lower setting.

• Behavioral changes (e.g., removal of clothing) facilitate heat loss.

 Hyperpyrexia
• 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 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.
 Hyperthermia
• 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.

• hyperthermia can be rapidly fatal and characteristically does

not respond to antipyretics.
•

• 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.
 Pathogenesis
• PYROGENS: Exogenous pyrogens are derived from out- side
the patient; most are microbial products, microbial toxins, or
whole microorganisms (including viruses).

• 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. hese cytokines trigger
the hypothalamus to raise the set point to febrile levels.
 ELEVATION OF THE
HYPOTHALAMIC SET POINT BY
CYTOKINES
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

 APPROACH TO THE PATIENT
• HISTORY AND PHYSICAL EXAMINATION : The chronology of
events preceding fever, including exposure to other
symptomatic individuals or to vectors of disease, should be
ascertained.

• 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 : CBC, ESR, CRP , Other acute phase

reactants etc.
Patterns of fever
 Treatment
• THE DECISION TO TREAT FEVER : 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
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
• The objectives in treating fever are first to reduce the elevated
hypohalamic 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.
• 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.
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.

• Although fever can be a manifestation of auto-immune 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.

• 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.

• 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 note- worthy anti-inflammatory activity; in the brain,
however, acetaminophen is oxidized by the P450 cytochrome system, and the
oxidized form inhibits cyclooxygenase activity.

• 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.
• 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 pro- duction and
may contribute to the antipyretic activity of NSAIDs.
 Fever of Unknown Origin
• Fever ≥38.3°C (≥101°F) on at least two occasions

• Illness duration of ≥3 weeks

• No known immunocompromised state

• Diagnosis that remains uncertain after a thorough history-taking,

physical examination, and the following obligatory investigations:
determination of erythrocyte sedimentation rate (ESR) and C-reactive protein
(CRP) level; platelet count; leukocyte count and differential; measurement of
levels of hemoglobin, electrolytes, creatinine, total protein, alkaline
phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate
dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and
rheumatoid factor; protein electropho- resis; urinalysis; blood cultures (n =
3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin
test (TST) or inter- feron γ release assay (IGRA).
Thank you