Fever
Regulation mode of normal body temperature
Thermal receptor
Heat dissipation
Preoptic anterior
hypothalamus, POAH
Set-point，37℃
Heat production
Elevation of body temperature
•physiological elevation
•Pathophysiological elevation
fever
hyperthermia
Fever and hyperthermia
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 due to a disturbance of thermal regulatory
control----hyperthermia
For example:
● excessive heat production (vigorous exercise,
to some anesthetics)
● decreased dissipation (dehydration)
● loss of regulation (hypothalmic injury)
reaction
Etiology and Mechanism of Fever
Development of fever
Pyrogenic activator
Macrophage, monocyte, lymphocyte, etc.
Endogenous pyrogen
Thermoregulatory Centre
Mediators in regulation of
body temperature
Rise in set point
fever
Pyrogenic activator
A substance that can manufacture and release
endogeneous pyrogen which produces a fever.
1．Exogenous pyrogen
bacteria
virus
other microorganism
2. internal metabolic product
antigen-antibody complex
steroid
inflammatory substance
Exogenous pyrogen
1. Gram-negative bacterium
Lipoplysaccharide,LPS
Endotoxin,ET
structure of ET
pyrogenic and toxic substance----lipid A
。
LPS---strong heat resistance which allows bacteria to endure 160 ℃ dry
heat for about 2 hours
。
Exogenous pyrogen
2. gram-positive bacterium
engulfed by macrophages；
exogenous toxin （enterotoxin 、erythogenic toxin, diphthera toxin）
peptide polysaccharide
3. Virus and other microorganism
1. pyrogen of virus related with lipoprotein, hemagglutinin
within the envelope；
2. pyrogens of fungus、Spirochaeta 、Chlamydia 、plasmodium
may be considered to be LPS
Pyrogenic activator—internal
metabolic product
1. Ag-Ab complex
activation of pyrogenic cells。
2. Steroid and inflammatory
Testosterone’s metabolic intermediate （etiocholanolone ）
Uric Acid Crystals
Development of fever
Pyrogenic activator
endogenous pyrogenic
cells
Endogenous pyrogen
Nerve center
Mediators in regulation
of body temperature
Rise in set point
fever
Endogenous Pyrogen
A fever-inducing substance (protein) produced by cells of the host
body, such as leukocytes and macrophages
Source of EP
 monocytes and macrophages ： blood
mononuclear cell 、 hepatic stellate cells 、
pulmonary alveolar macrophage 、 peritoneal
macrophage
 Cancer cell ： hodgkin cancer cell 、 leukemia
cell 、renal carcinoma cell
 other cells ： lymphocytes 、 fibroblast 、
Endogenous pyrogenic cells endothelial cells
Types of EP
（1）IL-1 (Interleukin-1)
mainly from monocytes and macrophages
（2）IL-6 (Interleukin-6)
mainly from monocytes fibroblasts and TB lymphocytes
（3）TNF (Tumor necrosis factor)
TNF- 、TNF-
rTNF used for treatment during the stage I of tumor,
however with side effect “ fever ” to the patients
（4）IFN (Interferon)
IFN- with strong pathogenicity
（5）Macrophage inflammatory protein -1（MIP-1）
Site affected by EP：
Pyrogenic activator
Macrophage, monocyte, lymphocyt
Advanced thermoregulator
etc.
centrePreoptic anterior hypothalamus
Endogenous pyrogen
（POAH）
Lower thermoregulator centreMedulla oblongata、pons、
mesencephalon、spinal cord
Thermoregulatory Centre
Mediators in regulation of body
temperature
Rise in set point
fever
EP’s ways of affecting
nervous system
（1）blood-brain barrier
IL-1, IL-6, TNF through saturable transport system
infilterating to the brain from choroid plexus
（2）organum vasculosum laminae terminalis (OVLT)
OVLT: the blood-brain barrier’s weakest site comprising
fenestrated capillary with high permeability
（3）indirect regulation through vagus nerve
EP conduct impulse to the brain by stimulating vagus nerve.
Mediators of positive regulation
1. PGE
2. cAMP（Cyclin adenosine monophosphate）
cAMP, second messager cells ， regultion of cellular
function and synaptic transmission in POAH neurons，positive
regulation of body temperature。
3. CRH（Corticotrophin releasing hormone）
Mediators of positive regulation
4. Na+/Ca2+ ratio
＊ Na+/Ca2+ratio↑
elevated thermoregulation
＊ ventricle[Ca2+] ↑
limit EP and cAMP in cerebrospinal fluid ↑
EP PGE2↑ Na+/Ca2+ratio↑
cAMP↑ elevated thermoregulation ↑
5. NO
＊ new type of neurotransmitter
＊ mechanism ①act on POAH、OVLT
②stimulate metabolism of brown fat to produce heat
③inhibit negative regulation
Mediators of negative regulation
1. Arginine vasopressin, AVP
AVP ↑
VSA、MAN
EP↓
PO/AH
temperature↓
OVLT cap permeability ↓
2. α-melanocyte stimulating hormone,α-MSH
decomposition product of adrenocorticotropic hormone ， highly
effective in reducing temperature
3. A1(annexin A1)
the working together of positive and negative regulation
to produce heat rise in the course of fever
Ventral Septal Area
Action mode of EP
Medical Amygdaloid Neuleus
EP
Positive regulation
center
POAH
CRH↑
cAMP↑
PGE2↑
Ca2+↓
Negative regulation
center
VSA,MAN
↑AVP
↑α-MSH
Elevated set
point
↑Ca2+
The phase of fever
Ⅰ.feverscence period
Ⅱ.fastigium
Ⅲ.defeverscene period
Ⅰ
Ⅱ
Ⅲ
1.Metabolic features and clinical
manifestations
Clinical
manifestations
phase
characteristics
Onset of fever
Set point
core temperature
lower than the set point
Dissipation < production
Pale skin，chilly，
shiver
Persistent of
fever
Core temeprature meets set
point
Dissipation = production
rubefaction ，dry
skin，hot
normal set point
Subsidence of Set point
Dissipation > production
fever
Heavy perspiration
2.Changes in physiological functions
■ cardiovascular：heartbeat, blood pressure
■ respiratory: fever, blood temperature,
metabolism, acid production,
respiration frequency
■ digestive：appetite，digestion
■CNS: headache, illusion, febrile convulsion
3.Changes in immune systems
 Anti-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 cells
to some extent, EP could inhibit cancer cells growth.
 Acute 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
Prevention and treatment
1. Primary affection
2. Basic treatment of fever
Cases need
emergency
treatment
3. Cases in need of treatment in time
1. high fever (> 40℃)
2. patients with heart disease
3. pregnant women
4. headache, disturbance of consciousness,
infantile convulsion
Treament
drugs
Physical measures
Chemicals like
Steroids like
salicylic acid
glucocorticoids
Herbal drugs