Fever Fever
Dec 26, 2015
FeverFeverFeverFever
Regulation mode of normal body temperature Regulation mode of normal body temperature
Preoptic anteriorPreoptic anterior hypothalamus, hypothalamus, POAHPOAH
Set-pointSet-point ,, 37℃37℃
Thermal receptorThermal receptor
Heat production
Heat dissipation
Elevation of body temperatureElevation of body temperature
•physiological elevationphysiological elevation
•Pathophysiological elevationPathophysiological elevation feverfever hyperthermiahyperthermia
An elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point----fever
Fever and Fever and hyperthermiahyperthermia
Fever due to a disturbance of thermal regulatory control----hyperthermiaFor example:
●● excessive heat production (vigorous exercise, reaction to some anesthetics)
● ● decreased dissipation (dehydration)● loss of regulation (hypothalmic injury)
●● excessive heat production (vigorous exercise, reaction to some anesthetics)
● ● decreased dissipation (dehydration)● loss of regulation (hypothalmic injury)
Etiology and Mechanism of FeverEtiology and Mechanism of FeverEtiology and Mechanism of FeverEtiology and Mechanism of Fever
Development of Development of feverfever
Macrophage, monocyte, lymphocyte, Macrophage, monocyte, lymphocyte, etc.etc.
Endogenous pyrogenEndogenous pyrogen
Thermoregulatory CentreThermoregulatory Centre
feverfever
Mediators in regulation Mediators in regulation of body temperatureof body temperature
Rise in set pointRise in set point
Pyrogenic activatorPyrogenic activator
Pyrogenic activatorPyrogenic activator
11 .. Exogenous pyrogenExogenous pyrogen
bacteriabacteria virusvirus
other microorganismother microorganism
2. internal metabolic product 2. internal metabolic product
antigen-antibody complex antigen-antibody complex
steroid steroid
inflammatory substanceinflammatory substance
A substance that can manufacture and release endogeneous pyrogen which produces a fever.
Exogenous pyrogenExogenous pyrogen
1. 1. Gram-negative bacteriumGram-negative bacterium
Lipoplysaccharide,LPSLipoplysaccharide,LPS
Endotoxin,ETEndotoxin,ET
structure of ETstructure of ET pyrogenic and toxic substance----lipid Apyrogenic and toxic substance----lipid A
。 。 LPS---strong heat resistance which allows bacteria to endure LPS---strong heat resistance which allows bacteria to endure 160 ℃ dry 160 ℃ dry
heat for about 2 hoursheat for about 2 hours
。。
2. g2. gram-positive bacteriumram-positive bacterium
engulfed by macrophagesengulfed by macrophages ;;
exogenous toxin exogenous toxin (( enterotoxin enterotoxin 、、 erythogenic toxin, diphthera toxinerythogenic toxin, diphthera toxin ))
peptide polysaccharidepeptide polysaccharide
Exogenous pyrogenExogenous pyrogen
3. Virus and other microorganism3. Virus and other microorganism
1. pyrogen of virus related with lipoprotein, hemagglutinin 1. pyrogen of virus related with lipoprotein, hemagglutinin
within the envelopewithin the envelope ;; 2. pyrogens of 2. pyrogens of
fungusfungus 、、 Spirochaeta Spirochaeta 、、 Chlamydia Chlamydia 、、 plasmodium may plasmodium may
be considered to be LPS be considered to be LPS
Pyrogenic activator—Pyrogenic activator—internal metabolic productinternal metabolic product
1. Ag-Ab1. Ag-Ab complexcomplex
activation of pyrogenic cellsactivation of pyrogenic cells 。。
2. Steroid and inflammatory 2. Steroid and inflammatory
Testosterone’s metabolic intermediateTestosterone’s metabolic intermediate (( etiocholanoloneetiocholanolone
)) Uric Acid CrystalsUric Acid Crystals
Development of Development of feverfever
endogenous pyrogenic endogenous pyrogenic cellscells
Endogenous pyrogenEndogenous pyrogen
Nerve centerNerve center
feverfever
Mediators in Mediators in regulation of body regulation of body
temperaturetemperatureRise in set pointRise in set point
Pyrogenic activatorPyrogenic activator
Endogenous PyrogenEndogenous Pyrogen
Source of EPSource of EP
monocytes and macrophages monocytes and macrophages :: blood blood
mononuclear cell mononuclear cell 、、 hepatic stellate hepatic stellate
cells cells 、、 pulmonary alveolar pulmonary alveolar
macrophage macrophage 、、 peritoneal macrophageperitoneal macrophage
Cancer cellCancer cell :: hodgkin cancer hodgkin cancer
cellcell 、、 leukemia cell leukemia cell 、、 renal carcinoma cellrenal carcinoma cell
other cellsother cells ::lymphocytes lymphocytes 、、 fibroblast fibroblast 、、 endothelial endothelial
cellscells
Endogenous pyrogenic cellsEndogenous pyrogenic cells
A fever-inducing substance (protein) produced by cells of the A fever-inducing substance (protein) produced by cells of the
host body, such as leukocytes and macrophageshost body, such as leukocytes and macrophages
Types of EPTypes of EP
(( 11 )) IL-1 (Interleukin-1)IL-1 (Interleukin-1)
mainly from monocytes and macrophagesmainly from monocytes and macrophages
(( 22 )) IL-6 (Interleukin-6)IL-6 (Interleukin-6)
mainly from monocytes fibroblasts and TB mainly from monocytes fibroblasts and TB lymphocytes lymphocytes
(( 33 )) TNF (Tumor necrosis factor)TNF (Tumor necrosis factor) TNF-TNF- 、、 TNF-TNF-
rTNFrTNF used for treatment during the stage I of tumor, used for treatment during the stage I of tumor,
however with side effect “ fever ”however with side effect “ fever ” to the patientsto the patients
(( 44 )) IFN (Interferon)IFN (Interferon) IFN-IFN- with strong pathogenicitywith strong pathogenicity
(( 55 )) Macrophage inflammatory proteinMacrophage inflammatory protein -1-1 (( MIP-MIP-11 ))
Site affected by EPSite affected by EP ::
Advanced thermoregulator Advanced thermoregulator centre-centre-
Preoptic anterior Preoptic anterior hypothalamushypothalamus (( POAHPOAH ))
Lower thermoregulator Lower thermoregulator centre-centre-
Medulla oblongataMedulla oblongata 、、 ponspons 、、mesencephalonmesencephalon 、、 spinal spinal cordcord
Pyrogenic activatorPyrogenic activator
Macrophage, monocyte, Macrophage, monocyte, lymphocyte, etc.lymphocyte, etc.
Endogenous pyrogenEndogenous pyrogen
Thermoregulatory CentreThermoregulatory Centre
feverfever
Mediators in regulation of body Mediators in regulation of body temperaturetemperature
Rise in set pointRise in set point
EP’s ways of affecting EP’s ways of affecting nervous system nervous system
(( 11 )) blood-brain barrierblood-brain barrier
IL-1, IL-6, TNF through saturable transport system IL-1, IL-6, TNF through saturable transport system
infilterating to the brain from choroid plexus infilterating to the brain from choroid plexus
(( 22 )) organum vasculosum laminae terminalis organum vasculosum laminae terminalis (OVLT)(OVLT)
OVLT: the blood-brain barrier’s weakest site comprising OVLT: the blood-brain barrier’s weakest site comprising
fenestrated capillary with high permeabilityfenestrated capillary with high permeability
(( 33 )) indirect regulation through vagus nerveindirect regulation through vagus nerve
EP conduct impulse to the brain by stimulating vagus EP conduct impulse to the brain by stimulating vagus nerve.nerve.
Mediators of positive regulationMediators of positive regulation
3. CRH3. CRH (( Corticotrophin releasing hormoneCorticotrophin releasing hormone ))
2. cAMP2. cAMP (( Cyclin adenosine monophosphateCyclin adenosine monophosphate )) cAMP, second messager cellscAMP, second messager cells ,, regultion of cellular regultion of cellular function and synaptic transmission in POAH function and synaptic transmission in POAH
neuronsneurons ,, positive regulation of body temperaturepositive regulation of body temperature 。。
1. PGE1. PGE
4. Na4. Na++/Ca/Ca2+2+ ratioratio
* * NaNa++/Ca/Ca2+2+ratio↑ elevated thermoregulationratio↑ elevated thermoregulation
** ventricle[Caventricle[Ca2+2+] ↑ limit EP and cAMP in cerebrospinal ] ↑ limit EP and cAMP in cerebrospinal fluid ↑ fluid ↑
EP PGEEP PGE22↑↑ NaNa++/Ca/Ca2+2+ratio↑ cAMP↑ elevated ratio↑ cAMP↑ elevated
thermoregulationthermoregulation ↑↑ 5. NO5. NO
* * new type of neurotransmitternew type of neurotransmitter
** mechanism ①act on POAHmechanism ①act on POAH 、、 OVLTOVLT
② ②stimulate metabolism of brown fat to produce heatstimulate metabolism of brown fat to produce heat
③ ③inhibit negative regulationinhibit negative regulation
Mediators of positive regulationMediators of positive regulation
3. A1(annexin A1)3. A1(annexin A1)
the working together of positive and negative the working together of positive and negative regulation to produce heat rise in the course of feverregulation to produce heat rise in the course of fever
2. α-melanocyte stimulating hormone,α-MSH2. α-melanocyte stimulating hormone,α-MSH
decomposition product of adrenocorticotropic hormonedecomposition product of adrenocorticotropic hormone ,, highly highly effective in reducing temperatureeffective in reducing temperature
Mediators of negative regulationMediators of negative regulation
1. Arginine vasopressin, AVP1. Arginine vasopressin, AVP
AVP ↑ VSAAVP ↑ VSA 、、 MAN MAN
EPEP↓ ↓ PO/AH temperature↓ PO/AH temperature↓
OVLT capOVLT cap permeability ↓permeability ↓
Action mode of EPAction mode of EP
EPEP
Positive regulation Positive regulation center center POAHPOAH
Negative regulation Negative regulation center center VSA,MANVSA,MAN
Elevated set Elevated set pointpoint
CRH↑CRH↑
cAMP↑cAMP↑
PGEPGE22↑↑
CaCa2+2+↓↓
↑↑AVPAVP
↑ ↑α-MSHα-MSH
↑↑CaCa2+2+
VVentral entral SSeptaleptal A Arearea
Medical Amygdaloid Medical Amygdaloid NeuleusNeuleus
The phase of feverThe phase of fever
Ⅰ .feverscence period
Ⅱ .fastigium
Ⅲ.defeverscene
period
ⅠⅠ ⅡⅡ ⅢⅢ
phasephase characteristicscharacteristics Clinical Clinical manifestationsmanifestations
Onset of fever Set point core temperature Set point core temperature lower than the set point lower than the set point
Dissipation < productionDissipation < production
Pale Pale skinskin ,, chillychilly ,, shivshiverer
Persistent of fever
Core temeprature meets set Core temeprature meets set pointpoint
Dissipation = productionDissipation = production
rubefactionrubefaction ,, dry dry skinskin ,, hot hot
Subsidence of fever
Set pointSet point normal set pointnormal set pointDissipation > productionDissipation > production
Heavy perspirationHeavy perspiration
1.Metabolic features and clinical 1.Metabolic features and clinical manifestationsmanifestations
■■ cardiovascularcardiovascular :: heartbeat, blood heartbeat, blood
pressurepressure
■■ respiratory: respiratory: fever, blood temperature, fever, blood temperature,
metabolism, acid metabolism, acid
production, production,
respiration frequencyrespiration frequency
■■ digestivedigestive :: appetiteappetite ,, digestiondigestion
■■CNS: CNS: headache, illusion, febrile headache, illusion, febrile
convulsion convulsion
2.Changes in physiological 2.Changes in physiological functionsfunctions
Anti-infectionAnti-infection inactivation of some heat-sensitive pathogenic
microorganism like streptococcus , enhancement of the ability of some immune cells like human lymphocytes, while reduced function of some immune cells like NK cells
Cancer cellsCancer cells
to some extent, EP could inhibit cancer cells growth..
Acute phase responseAcute phase response
definition : a series of reactions against injury caused
by bacteria infection and tissue damages, including
increased acute phase proteins and changes in microelements
of blood plasma and white cells
3.Changes in immune systems3.Changes in immune systems
Prevention and treatment Prevention and treatment
1. Primary affection1. Primary affection
2. Basic treatment of fever2. Basic treatment of fever
3. Cases in need of treatment in time3. Cases in need of treatment in time
11. high fever (> 40℃). high fever (> 40℃)
22. patients with heart disease . patients with heart disease
33. pregnant women. pregnant women
4. headache, disturbance of 4. headache, disturbance of consciousness, infantile convulsionconsciousness, infantile convulsion
Cases Cases need need emergencemergency y treatmenttreatment
drugs
Chemicals like
salicylic acid
TreamentTreament
Physical measures
Herbal drugsSteroids like
glucocorticoids