Dept. of PathologyDept. of Pathology

Medical CollegeMedical College

Hunan Normal UniversityHunan Normal University

(( 湖南师范大学医学院病理学教研室湖南师范大学医学院病理学教研室 )) 1

Chapter 4Chapter 4

FeverFever（发热）（发热）

22

FeverFever

①① IntroductionIntroduction

②② Causes and MechanismCauses and Mechanism

③③ Stages and ManifestationsStages and Manifestations

④④ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction

⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

Prevention and TreatmentPrevention and Treatment

Life Stages

0-2 years old 3-10 years old 11-65 years oldOver 65Circadian 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 feverFever 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

HyperthermiaPassive

Set Point: N

Physiological elevation

(Before menstruation, Strenuous exercise, Stress)

Elevation

of body temperature

Active

Set Point: ↑

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FeverFever

①① IntroductionIntroduction

②② Causes and MechanismCauses and Mechanism

③③ Stages and ManifestationsStages and Manifestations

④④ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction

⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

Prevention and TreatmentPrevention and Treatment

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 pyrogensBacteriaVirusesOther microorganisms

Non-microbial

Pyrogenic substances

Antigen-antibody complexesComponent of complement cascadeSteroids Anticancer drugs

Gram-negative Bacteria:

(E. coli)Pathogenic substance:

LPS (lipopolysaccharide, also named endotoxin, ET)

Major pyrogenic component is Lipid AHigh m.w. (1,000 kDa)Heat resistant: inactivated by 160℃ dry heat, 2 hHigh pyrogenic activity

1 ng/kg to rabbit → feverTolerability (resistance to repeated injection)

Gram-positive Bacteria:

Staphylococcus aureusStaphylococcus aureus, , Streptococcus pneumoniae Streptococcus pneumoniae

Pathogenic substances:Pathogenic substances:

Whole bacteria

ExotoxinExotoxin

PeptidoglycanPeptidoglycan

Viruses

Pathogenic substances:

Protein coat - lipoprotein

Haemagglutinin

Influenza virusInfluenza virusCorona virusCorona virus

Substances that are Substances that are produced by EP-producing produced by EP-producing cellscells under the action of pyrogenic activators under the action of pyrogenic activators and and cause the increase in the thermoregulatory set cause the increase in the thermoregulatory set pointpoint in the hypothalamus. in the hypothalamus.

Fever-inducing cytokines (large, hydrophilic Fever-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, epithelial Produced 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 cyclooxygenase Pyrogenic activity can be inhibited by cyclooxygenase inhibitor inhibitor (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 by Produced by macrophagesmacrophages, , lymphoid cells, mast cells, lymphoid cells, mast cells, endothelial cellsendothelial cells,, etc.etc.

Pyrogenic activity can be inhibited by cyclooxygenase Pyrogenic activity can be inhibited by cyclooxygenase 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, endothelial Produced 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 other IL-6 is the downstream mediator of fever from other EPs (IL-1 and TNF).EPs (IL-1 and TNF).

Pyrogenic activity can be inhibited by cyclooxygenase Pyrogenic activity can be inhibited by cyclooxygenase inhibitor (Aspirin).inhibitor (Aspirin).

Mechanisms of Fever

POAH

Thermoregulatory Center

Positive regulatory center:Positive regulatory center: Located at preoptic anterior Located at preoptic anterior hypothalamus (POAH)hypothalamus (POAH)

Warm-sensitive neuronsWarm-sensitive neuronsCold-sensitive neurons Cold-sensitive neurons

Negative regulatory center:Negative regulatory center:Medial amydaloid nucleus (MAN Medial amydaloid nucleus (MAN [[ 中杏仁核中杏仁核 ])])

Ventral septal area (VSA Ventral septal area (VSA [[ 腹中膈腹中膈 ])])

Arcuate nucleus (ARC Arcuate nucleus (ARC [[ 弓状核弓状核 ])])

Routes for Endogenous Pyrogens to Routes for Endogenous Pyrogens to Enter Thermoregulatory CenterEnter Thermoregulatory Center

①① Passive transport via organum vasculosum Passive transport via organum vasculosum laminate terminal (OVLT laminate terminal (OVLT [[ 小丘脑终板血管器小丘脑终板血管器 ], also called ], also called

supraoptic crest supraoptic crest) ) Most importantMost important

②② Through stimulating vagus nerve Through stimulating vagus nerve (( 迷走神经迷走神经 ) )

③③ Active transport across the blood brain barrier Active transport across the blood brain barrier (BBB)(BBB) Important in pathological conditionsImportant in pathological conditions

④④ Through generation of PGE2 – BBB-permeableThrough generation of PGE2 – BBB-permeable

EPs can not directly act on thermoregulatory center because of BBB.

Positive Regulation of Fever

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 cerebral PGE2 can induce fever when injected into cerebral ventricles.ventricles.

Bacterial endotoxin and EP can stimulate the Bacterial endotoxin and EP can stimulate the hypothalamus to produce PGE2.hypothalamus to produce PGE2.

Cyclooxygenase inhibitor can inhibit the production of Cyclooxygenase inhibitor can inhibit the production of PGE2.PGE2.

PGE2 PGE2 ↑ ↑ 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 to IL-1 and IL-6 can stimulate hypothalamus to secret CRH.secret CRH.

Intracerebroventricular injection of CRH causes Intracerebroventricular injection of CRH causes body and rectum temperature ↑.body and rectum temperature ↑.

CRH receptor antagonist can inhibit the CRH receptor antagonist can inhibit the fever caused by IL-1fever caused by IL-1 ，， 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.

cAMPATPBreakdown

AC PDE

NaNa++/Ca/Ca2 + 2 + RatioRatio

NaNa++/Ca/Ca2+ 2+ changes in the brain, the body temperature changes 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+ ratio ratio cAMP cAMP Set point Set 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 tissue Stimulating metabolism of brown adipose tissue (in infants)(in infants)

Inhibit the synthesis and secretion of negative Inhibit the synthesis and secretion of negative regulatory mediators.regulatory mediators.

Negative Regulation of Fever

Febrile CeilingFebrile Ceiling(Fever Limit)(Fever Limit)

Upper limit of the febrile response. Upper limit of the febrile response.

Human core body temperature almost never Human 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 Negative Central Regulatory MediatorsMediators

•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 AVP Injection of AVP intracerebraventricularlyintracerebraventricularly ↓↓feverfever

AVP receptor antagonistAVP receptor antagonist

-melanocyte-stimulating hormone -melanocyte-stimulating hormone ((-MSH-MSH ））

Injection of Injection of -MSH -MSH intracerebraventricularlyintracerebraventricularly ↓↓feverfever

-MSH receptor antagonist-MSH receptor antagonist ↑ ↑ fever caused fever caused by IL-1by IL-1

Endogenous Endogenous -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 (relieving Biological function of glucocorticoid (relieving fever) depends on LC-1fever) depends on LC-1

Central injection of LC-1 inhibits the fever Central 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

①① IntroductionIntroduction

②② Causes and MechanismCauses and Mechanism

③③ Stages and ManifestationsStages and Manifestations

④④ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction

⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

Prevention and TreatmentPrevention and Treatment

Three stages of feverThree stages of feverI: Fervescence stage I: Fervescence stage

II: Persistent febrile stage II: Persistent febrile stage

III: Defervescence stage III: Defervescence stage

Stages and Manifestations of Fever

I II III

Clinical manifestationsShiveringPale skinFeeling coldGoose flesh (鸡皮 )High metabolic rate

Feverescence stage:

Thermal metabolism characteristics Heat loss↓Heat production↑T↑

Persistent Febrile Stage:Persistent Febrile Stage:

Thermal metabolism characteristics Thermal metabolism characteristics T increases to the new level of set pointBalance of heat production and loss

- in a higher level

Clinical manifestationsClinical manifestationsFeeling hotDry 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 manifestationsSweatingSweatingSkin is warm and flushedSkin is warm and flushed

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FeverFever

①① IntroductionIntroduction

②② Causes and MechanismCauses and Mechanism

③③ Stages and ManifestationsStages and Manifestations

④④ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction

⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

Prevention and TreatmentPrevention and Treatment

Metabolic Changes During Metabolic Changes During FeverFeverBasal 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 systemHeadache Headache

HallucinationHallucination

TwitchTwitch

Digestive systemDigestive system

Indigestion, anorexia Indigestion, anorexia (no appetite)(no appetite)

Abdominal distension Abdominal 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

Hyperventilation Hyperventilation

(may cause acid-base imbalance)(may cause acid-base imbalance)

Beneficial Effects of Fever Beneficial Effects of Fever

- Self defense- Self defense

Fever often increases the anti-infection Fever often increases the anti-infection capacity of the body.capacity of the body.

The anti-tumor activity is also augmented during The 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 Biological Significance of FeverFever

Friend or Foe? Friend or Foe?

Answer:Answer: BothBoth

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FeverFever

①① IntroductionIntroduction

②② Causes and MechanismCauses and Mechanism

③③ Stages and ManifestationsStages and Manifestations

④④ Alterations of Metabolism and Alterations of Metabolism and

FunctionFunction

⑤⑤ Pathophysiological Basis of Pathophysiological Basis of

Prevention and TreatmentPrevention and Treatment

Principles of Fever TreatmentFever 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 medicationSalicylate Salicylate (Aspirin) (Aspirin)

- Inhibit the synthesis of PGE2- Inhibit the synthesis of PGE2

2. Steroid antipyretic drugs 2. 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 measures 4. Other measures physical coolingphysical cooling

3.Detoxificating Chinese herbs3.Detoxificating Chinese herbsFour-Drug Juice [Four-Drug Juice [ 四磨汤四磨汤 ]]