04 fever

Dept. of PathologyDept. of Pathology
Medical CollegeMedical College
Hunan Normal UniversityHunan Normal University
(( 湖南范大学医学院病理学教研室师湖南范大学医学院病理学教研室师 )) 1
Chapter 4Chapter 4
FeverFever
（）发热（）发热

22
FeverFever
a.a. IntroductionIntroduction
b.b. Causes and MechanismCauses and Mechanism
c.c. Stages and ManifestationsStages and Manifestations
d.d. Alterations of Metabolism andAlterations of Metabolism and
FunctionFunction
e.e. Pathophysiological Basis ofPathophysiological Basis of
Prevention and TreatmentPrevention and Treatment

Life Stages
0-2 years old 3-10 years old 11-65 years old Over 65
Circadian variation
of body temperature
2am 2pm 2am
37.5
36.5
Q: Why stable temperature?
Normal Temperature range: 36℃ ~ 37.5℃
Oral temperature: 37℃

heat loss
peripheral
thermo-sensors
deep thermo-
sensors
set point
blood vessel
skeletal muscle
heat production
balance
POAH
sweat gland
Regulation of Normal Body Temperature
POAH: preoptic anterior hypothalamus (- body’s thermostat)

Homeostasis (36℃ ～
37℃ ）
Activates heat-loss center
in hypothalamus
Skin blood
vessels constrict
Skeletal muscles activated,
shivering begins
Skin blood
vessels dilate
Sweat glands
activated
Imbalance
Imbalance
Body
temperature
decreases
Activates heat-
promoting center in
hypothalamus
Hot stimulus
Blood warmer
than set point
Cold stimulus
Blood cooler
than set point
Body
temperature
increases

Definition of fever
Fever is a complicated pathological process characterized
by regulated elevation of body temperature following the
increased Set Point, which is caused by pyrogenic
substances.
Usually 0.5 higher℃ than normal body temperature.
There is no impairment in the thermoregulatory
mechanism during fever.
Q: Increase of body temperature = Fever?

Pathological elevation
Fever
Hyperthermia
Passive
Set Point: N
Physiological elevation
(Before menstruation, Strenuous exercise,
Stress)
Elevation
of body
temperature
Active
Set Point: ↑

1616
FeverFever
FunctionFunction

Pyrogenic
activator
Endogenous
pyrogen (EP)
EP
producing
cell
Producing
Releasing
Process of Fever Development

Causes of Fever
- Pyrogenic Activators

Pyrogenic activators ( 发热激活物 ) are
substances which can activate the EP-producing
cells to produce and release endogenous
pyrogen (EP).
Concept
Pyrogenic Activators

Classification of the
Pyrogenic Activators

Pyrogenic activators
Microbial pyrogens
Bacteria
Viruses
Other microorganisms
Non-microbial
Pyrogenic substances
Antigen-antibody
complexes
Component of
complement cascade
Steroids
Anticancer drugs

Gram-negative Bacteria:
(E. coli)
Pathogenic substance:
LPS (lipopolysaccharide, also named
endotoxin, ET)
Major pyrogenic component is
Lipid A
High m.w. (1,000 kDa)
Heat resistant: inactivated by
160℃ dry heat, 2 h
High pyrogenic activity
1 ng/kg to rabbit → fever
Tolerability (resistance to
repeated injection)

Gram-positive Bacteria:
Staphylococcus aureusStaphylococcus aureus,,
Streptococcus pneumoniaeStreptococcus pneumoniae
Pathogenic substances:Pathogenic substances:
Whole bacteria
ExotoxinExotoxin
PeptidoglycanPeptidoglycan

Viruses
Pathogenic substances:
 Protein coat - lipoprotein
 Haemagglutinin
Influenza virusInfluenza virus
Corona virusCorona virus

Substances that areSubstances that are produced by EP-producingproduced by EP-producing
cellscells under the action of pyrogenic activatorsunder the action of pyrogenic activators andand
cause the increase in the thermoregulatory setcause the increase in the thermoregulatory set
pointpoint in the hypothalamus.in the hypothalamus.
Fever-inducing cytokines (large, hydrophilicFever-inducing cytokines (large, hydrophilic
peptides).peptides).
Endogenous Pyrogens (EPs)

Monocytes/Macrophages
Endothelial cells
Lymphocytes
Tumor cells
Endogenous Pyrogen (EP)-
Producing Cells

Major Endogenous Pyrogens (EPs)
 Interleukin-1 (IL-1)Interleukin-1 (IL-1)
 Tumor necrosis factor (TNF)Tumor necrosis factor (TNF)
 Interferon (IFN)Interferon (IFN)
 Interleukin-6 (IL-6 )Interleukin-6 (IL-6 )

•Interleukin 1 (IL-1)Interleukin 1 (IL-1)
Produced by monocytes/macrophages, epithelialProduced by monocytes/macrophages, epithelial
cells,cells, etc.etc.
IL-1a and IL-1b have the same effect.IL-1a and IL-1b have the same effect.
Pyrogenic activity can be inhibited by cyclooxygenasePyrogenic activity can be inhibited by cyclooxygenase
inhibitorinhibitor (Aspirin).(Aspirin).
Heat sensitive: Inactivated by heating (70 30 min).℃Heat sensitive: Inactivated by heating (70 30 min).℃
No tolerance by repeated injections.No tolerance by repeated injections.

•Tumor necrosis factor (TNF)Tumor necrosis factor (TNF)
Produced byProduced by macrophagesmacrophages,, lymphoid cells, mast cells,lymphoid cells, mast cells,
endothelial cellsendothelial cells,, etc.etc.
inhibitor (Aspirin).inhibitor (Aspirin).
TNF-TNF-αα, TNF-, TNF-ββ are pyrogenic.are pyrogenic.
Heat sensitive: Inactivated by heating (70 30 min).℃Heat sensitive: Inactivated by heating (70 30 min).℃
No tolerance by repeated injections.No tolerance by repeated injections.

Interferon (IFN)Interferon (IFN)
Produced by lymphocytes, NK cells, fibroblasts,Produced by lymphocytes, NK cells, fibroblasts, etc.etc.
IFN-IFN-αα and IFN-and IFN-γγ can cause fever.can cause fever.
Can be tolerated after long period of use.Can be tolerated after long period of use.
Heat sensitive.Heat sensitive.

Interleukin 6 (IL-6)Interleukin 6 (IL-6)
Produced by mononuclear cells, fibroblasts, endothelialProduced by mononuclear cells, fibroblasts, endothelial
cells,cells, etc.etc.
Can be induced by ET, IL-1, TNF.Can be induced by ET, IL-1, TNF.
IL-6 is the downstream mediator of fever from otherIL-6 is the downstream mediator of fever from other
EPs (IL-1 and TNF).EPs (IL-1 and TNF).
inhibitor (Aspirin).inhibitor (Aspirin).

POAH
Thermoregulatory Center
Positive regulatory center:Positive regulatory center:
Located at preoptic anteriorLocated at preoptic anterior
hypothalamus (POAH)hypothalamus (POAH)
Warm-sensitive neuronsWarm-sensitive neurons
Cold-sensitive neuronsCold-sensitive neurons
Negative regulatory center:Negative regulatory center:
Medial amydaloid nucleus (MANMedial amydaloid nucleus (MAN [[ 中杏仁核中杏仁核 ])])
Ventral septal area (VSAVentral septal area (VSA [[ 腹中膈腹中膈 ])])
Arcuate nucleus (ARCArcuate nucleus (ARC [[ 弓状核弓状核 ])])

Routes for Endogenous Pyrogens toRoutes for Endogenous Pyrogens to
Enter Thermoregulatory CenterEnter Thermoregulatory Center
a.a. Passive transport via organum vasculosumPassive transport via organum vasculosum
laminate terminal (OVLTlaminate terminal (OVLT [[ 小丘脑终板血管器小丘脑终板血管器 ], also called], also called
supraoptic crestsupraoptic crest))
 Most importantMost important
a.a. Through stimulating vagus nerveThrough stimulating vagus nerve (( 迷走神经迷走神经 ))
b.b. Active transport across the blood brain barrierActive transport across the blood brain barrier
(BBB)(BBB)
 Important in pathological conditionsImportant in pathological conditions
EPs can not directly act on thermoregulatory center
because of BBB.

Central Mediators of FeverCentral Mediators of Fever
- The positive regulatory mediators- The positive regulatory mediators
Prostaglandin E2 (PGE2)Prostaglandin E2 (PGE2)
Corticotrophin-releasing hormone (CRH)Corticotrophin-releasing hormone (CRH)
Cyclic adenosine monophosphate (cAMP)Cyclic adenosine monophosphate (cAMP)
Nitric oxide (NO)Nitric oxide (NO)
NaNa++
/Ca/Ca2+2+
ratioratio

Prostaglandin E2 (PGE2)
PGE2 can induce fever when injected into cerebralPGE2 can induce fever when injected into cerebral
ventricles.ventricles.
Bacterial endotoxin and EP can stimulate theBacterial endotoxin and EP can stimulate the
hypothalamus to produce PGE2.hypothalamus to produce PGE2.
Cyclooxygenase inhibitor can inhibit the production ofCyclooxygenase inhibitor can inhibit the production of
PGE2.PGE2.
PGE2PGE2 ↑↑ in cerebrospinal fluid during fever.in cerebrospinal fluid during fever.

Arachidonic Acid Metabolism
Pain

Corticotrophin-releasing hormoneCorticotrophin-releasing hormone
(CRH)(CRH)
IL-1 and IL-6 can stimulate hypothalamus toIL-1 and IL-6 can stimulate hypothalamus to
secret CRH.secret CRH.
Intracerebroventricular injection of CRH causesIntracerebroventricular injection of CRH causes
body and rectum temperature ↑.body and rectum temperature ↑.
CRH receptor antagonist can inhibit theCRH receptor antagonist can inhibit the
fever caused by IL-1fever caused by IL-1ββ ，， IL-6.IL-6.

Cyclic AMP
(cAMP)cAMP levels in cerebrospinal fluid increase during fever induced
by endotoxin
cAMP initiates fever quickly if injected into cerebral ventricles
Adenylate cyclase (AC) inhibitor can decrease the effects
caused by cAMP.
PDE
Phosphodiesterase (PDE) inhibitor can increase the effects
caused by cAMP.
cAMPATP
Breakdown
AC PDE

NaNa++
/Ca/Ca2 +2 +
RatioRatio
NaNa++
/Ca/Ca2+2+
changes in the brain, the body temperaturechanges in the brain, the body temperature
also changes.also changes.
Intracerebroventricular perfusion of NaIntracerebroventricular perfusion of Na++
→ ↑→ ↑
body temperature.body temperature.
 NaNa++
/Ca/Ca2+2+
ratioratio ↑↑ cAMPcAMP ↑↑ Set pointSet point ↑↑
Intracerebroventricular perfusion of CaIntracerebroventricular perfusion of Ca2+2+
→→↓↓body temperature.body temperature.

Nitric Oxide (NO)Nitric Oxide (NO)
Action on OVLT & POAHAction on OVLT & POAH
Stimulating metabolism of brown adipose tissueStimulating metabolism of brown adipose tissue
(in infants)(in infants)
Inhibit the synthesis and secretion of negativeInhibit the synthesis and secretion of negative
regulatory mediators.regulatory mediators.

Febrile CeilingFebrile Ceiling
(Fever Limit)(Fever Limit)
Upper limit of the febrile response.Upper limit of the febrile response.
Human core body temperature almost neverHuman core body temperature almost never
rises above 41 -42 during fever.℃ ℃rises above 41 -42 during fever.℃ ℃
- This phenomenon is called- This phenomenon is called febrile ceilingfebrile ceiling..
Regulated by negative fever mediators.Regulated by negative fever mediators.

Negative Central Regulatory MediatorsNegative Central Regulatory Mediators
•Arginine vasopressin (AVP)Arginine vasopressin (AVP) - ADH- ADH
•Lipocortin-1 (LC-1)Lipocortin-1 (LC-1)
•αα-Melanocyte stimulating hormone-Melanocyte stimulating hormone
((αα-MSH)-MSH)

↑↑ feverfever
Arginine vasopressin (AVP)Arginine vasopressin (AVP) (ADH)(ADH)
Injection of AVPInjection of AVP
intracerebraventricularlyintracerebraventricularly
↓↓feverfever
AVP receptor antagonistAVP receptor antagonist

αα-melanocyte-stimulating hormone-melanocyte-stimulating hormone
((αα-MSH-MSH ））
Injection ofInjection of αα-MSH-MSH
intracerebraventricularlyintracerebraventricularly
↓↓feverfever
αα-MSH receptor antagonist-MSH receptor antagonist
↑↑ fever causedfever caused
by IL-1by IL-1
EndogenousEndogenous αα-MSH restricts the amplitude and-MSH restricts the amplitude and
duration of fever.duration of fever.

Lipocortin-1 (LC-1)Lipocortin-1 (LC-1)
Biological function of glucocorticoid (relievingBiological function of glucocorticoid (relieving
fever) depends on LC-1fever) depends on LC-1
Central injection of LC-1 inhibits the feverCentral injection of LC-1 inhibits the fever
caused by IL-1, IL-6 and CRHcaused by IL-1, IL-6 and CRH

Pyrogenic
activator
Endogenous
pyrogen (EP)
EP
producing
cell
Producing
Releasing
Pathogenesis of Fever

5757
FeverFever
FunctionFunction

Three stages of feverThree stages of fever
I: Fervescence stageI: Fervescence stage
II: Persistent febrile stageII: Persistent febrile stage
III: Defervescence stageIII: Defervescence stage
Stages and Manifestations of Fever
I II III

Clinical manifestations
Shivering
Pale skin
Feeling cold
Goose flesh ( 鸡皮 )
High metabolic rate
Feverescence stage:
Thermal metabolism characteristics
Heat loss↓
Heat production↑
T↑

Persistent Febrile Stage:Persistent Febrile Stage:
Thermal metabolism characteristicsThermal metabolism characteristics
T increases to the new level of set point
Balance of heat production and loss
- in a higher level
Clinical manifestationsClinical manifestations
Feeling hot
Dry skin
Flush (red)
High metabolic rate

Defervescence StageDefervescence Stage
Thermal metabolism characteristicsThermal metabolism characteristics
 Core temperature > set point → heat loss↑Core temperature > set point → heat loss↑
Clinical manifestationsClinical manifestations
SweatingSweating
Skin is warm and flushedSkin is warm and flushed

6262
FeverFever
FunctionFunction

Metabolic Changes During FeverMetabolic Changes During Fever
Basal metabolic rate increases by 13% with 1℃Basal metabolic rate increases by 13% with 1℃
elevation in body temperature.elevation in body temperature.
Glycolysis → Lactate ↑Glycolysis → Lactate ↑
Adipose tissue utilization → Ketone ↑, Weight lossAdipose tissue utilization → Ketone ↑, Weight loss
Glycogen degradation → Blood sugar ↑Glycogen degradation → Blood sugar ↑
Vitamin consumption ↑Vitamin consumption ↑

Systematic ChangesSystematic Changes
•Nervous systemNervous system
•Cardiovascular systemCardiovascular system
•Respiratory systemRespiratory system
•Digestive systemDigestive system
•Immune systemImmune system

Nervous systemNervous system
HeadacheHeadache
HallucinationHallucination
TwitchTwitch
Digestive systemDigestive system
Indigestion, anorexiaIndigestion, anorexia (no appetite)(no appetite)
Abdominal distensionAbdominal distension [[ 腹胀腹胀 ]]
ConstipationConstipation

Cardiovascular systemCardiovascular system
Increase of heart rate, 18 bpm/1℃Increase of heart rate, 18 bpm/1℃
Blood pressure changeBlood pressure change
Respiratory systemRespiratory system
Increase of respiratory rateIncrease of respiratory rate
HyperventilationHyperventilation
(may cause acid-base imbalance)(may cause acid-base imbalance)

Beneficial Effects of FeverBeneficial Effects of Fever
- Self defense- Self defense
Fever often increases the anti-infectionFever often increases the anti-infection
capacity of the body.capacity of the body.
The anti-tumor activity is also augmented duringThe anti-tumor activity is also augmented during
fever.fever.
EP can induce the acute phase response.EP can induce the acute phase response.

Biological Significance of FeverBiological Significance of Fever
Friend or Foe?Friend or Foe?
Answer:Answer: BothBoth

6969
FeverFever
FunctionFunction

Principles of Fever Treatment
Fever does not necessarily need to be treated.
Basic principles for common fever:
 Care
 Suitable medication when necessary

Need to be Treated Immediately
T > 39℃T > 39℃
Heart disease patientsHeart disease patients
Cachexia patientsCachexia patients
Pregnant womenPregnant women

MedicationMedication
1. Chemical medication1. Chemical medication
SalicylateSalicylate (Aspirin)(Aspirin)
- Inhibit the synthesis of PGE2- Inhibit the synthesis of PGE2
2. Steroid antipyretic drugs2. Steroid antipyretic drugs (Dexamethasone)(Dexamethasone)
Inhibit the synthesis and secretion of the EPsInhibit the synthesis and secretion of the EPs
Inhibit the immune and inflammatory reactionInhibit the immune and inflammatory reaction
Inhibit the synthesis of PGE2Inhibit the synthesis of PGE2

4. Other measures4. Other measures
physical coolingphysical cooling
3.Detoxificating Chinese herbs3.Detoxificating Chinese herbs
Four-Drug Juice [Four-Drug Juice [ 四磨汤四磨汤 ]]

04 fever

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