Chapter 9 Fever
Current Epidemics in Brazil
Introduction
Fever (Pyrexia): Typical manifestations
The Fervescence
Stage
Feeling cold
Skin is pale, covered with goose flesh
Shivering
The Persistent
Febrile Stage
Feeling warm
Skin is dry and flushed
The Defervescence Sweating
Skin is warm and flushed
Stage
Life Stages
Normal Body Temperature
 rectal
36.9~37.9 C
(Core Temperature)
 oral
36.6~37.6 C
 axillary 36.2~37.2 C
37.5
36.5
Circadian variation
（周期波动）<1C
2am
2pm
2am
Body Temperature Regulation
Conditions of body temperature elevation
Physiological elevation of body temperature
（Before menstruation, Strenuous exercise, Stress）
Elevation of
body
temperature
（体温升高）
Conditions of body temperature elevation
Physiological elevation of body temperature
（Before menstruation, Strenuous exercise, Stress）
Elevation of
body
temperature
Fever （发热）
(Regulatory/Active elevation of T)
Pathological
elevation of body
temperature
(Non-regulatory/Passive elevation of T）
Hyperthermia （过热）
Definitions
• Fever（发热）:
Regulated elevation of core body temperature
0.5℃ higher than normal, accommodated to the
increased hypothalamic Set Point (下丘脑体温调定点)
in response to pyretic substances.
• Hyperthermia（过热）:
Pathological elevation of body temperature,
characterized by overwhelmed thermoregulatory
mechanisms (dysfunction of thermoregulatory center,
impairment of heat-production or heat-loss), without
changes of set point.
Examples for Hyperthermia
• Loss of regulation:
– central nervous system
injury
• Impairment of heat-loss:
– heliosis（中暑）
– ichthyosis（鱼鳞病）
• Excessive heat
production:
– hyperthyroidism（甲亢）
Difference between Fever and Hyperthermia
Pyrogen
Thermoregulat
ory Set Point ↑
regulatory
elevation of
T(>0.5 C)
Fever
Heat
Production ↑
Heat Loss ↓
Thermoregulatory
Center
Disfunction
Passive elevation
of T(>0.5 C)
T ﹥ SP
Hyperthermia
Typical fever types（热型）
伤寒、大叶性肺炎
布鲁菌病
风湿热、败血症、脓毒血症、肝脓肿
何杰金氏病
疟疾、肾盂肾炎
结核、风湿热、瘤性发热
I. Etiology and Pathogenesis
Pyrogenic
activators
Endogenous pyrogen
producing cells
（发热激活物）
（产内生致热原细胞）
Central
mediators
releasing
Thermoregulatory
center（体温调节
中枢）
Shivering 寒颤
SP elevated
（调定点上移）
Skin
vasoconstriction
EP production and
releasing
Heat
production
T
Heat
loss
1. Pyrogenic activator
• Substance that stimulate the body to produce cytokines.
Endogenous substances
体
内
物
质
Exogenous pyrogens
Pyrogenic activators
发
热
激
活
物
外
致
热
原
G- bacteria
Lipopolysaccharide (LPS) / Endotoxin
G＋ bacteria
PepG（肽聚糖）, LTA（磷壁酸）, SE（肠毒
素）, TSST（中毒性休克综合征毒素）-1
Viruses
Whole virus, Hemagglutinin
others
Leptospira, Plasmodium, Epiphyte
Antigen-antibody complexes
Steroids: etiocholanolone（本胆烷醇酮）,
lithocholic acid （石胆酸）
Inflammatory substances
Endotoxin (ET) 内毒素
• Heat stable substance: 160 C,
2h
• Derived from gram-negative
bacteria cell walls
• Molecular weight: 1000~2000
kD
• Can not penetrate BBB
• Composed by O-specific side
chain（O-特异侧链）, core
polysaccharide（核心多糖）
and lipoA（脂质A）
• Activate complement cascade
（补体级联活化）
• Stimulate EP production and
releasing
2. Endogenous Pyrogen (内生致热原)
– Cytokines produced from cells activated by pyrogenic activators
– Induce fever by resetting thermoregulatory Set Point
• 1948, Beeson (J Clin Invest, Volume 27(4) July 1948: 524):
– leucocytic pyrogen（LP）
1980, Hanson: monocyte
J. Exp.Med. Volume 151, June 1980, 1360~1371.
Classifications of EP
① Interleukin-1, IL-1（白细胞介素-1）
② Tumor necrosis factor, TNF（肿瘤坏死因子）
③ Interferon, IFN（干扰素）
④ Macrophage inflammatory protein-1, MIP-1
（巨噬细胞炎症蛋白-1）
⑤ Interleukin-6, IL-6（白细胞介素-6）
IL-1
• Mononuclear cells, macrophages, epithelial cells, et al.
• Polypeptide, 17kD, two subtypes: IL-1α, IL-1β
• The receptor of IL-1 were found throughout the brain
tissue, with the greatest density in the outer
hypothalamus near the thermoregulatory center.
• IL-1 iv to mouse or rabbit→fever
–
–
low dose
high dose
single-phase fever
double-phase fever
• IL-1β-/- mice stimulated with LPS:
–
–
low dose
high dose
slightly fever, IL-6↑
almost no fever
TNF
• Macrophages: 17kD
• Subtypes: TNFα, TNFβ
 TNF iv rabbit:


low dose
high dose
single-phase fever
double-phase fever
 Intracerebroventricular injection:

PGE↑
IFN
• Subtypes: IFNα, IFNβ, IFNγ
• Antiviral and anti-tumor effect, 15~17kD
• 1984, Dinarello:
–
IFNα iv
single-phase fever
• Repeated injection: tolerance
• IFN→PGE↑
MIP-1
• Wolpe: monokine
• 8kD
• Neutrophils: H2O2
• Davatelis:
–
rabbit, iv: single-phase fever
IL-6
• 21kD
• Induced by ET、IL-1、TNF、PGF
• Rabbit, mouse iv or intracerebroventricular
injection
• Serum and Cerebrospinal fluid IL-6↑
• TNFα、 IL-1β
IL-6
Other EPs
• IL-2
– Late phase fever
– Induce TNF, IFNγ
– Indirect activator
• Ciliary neurotrophic factor, CNTF（睫状
神经营养因子）
• IL-8
• Endothelin, ET（内皮素）
Activation of EP producing cells
LPS
LPS
binding
protein
Activate NF-κB
EP gene transcription and expression
EP producing cell
3. Mechanisms of thermoregulation
（1）Thermoregulatory center
• Positive：POAH
（视前区下丘脑前部）
• Negative：
– MAN（中杏仁核 ）
– VSA（腹中膈 ）
•
EP→thermoregulatory center→central mediators →change
of the set point
•
Blood T↑ →Heat-sensitive neuron→ Heat loss↑
Blood T ↓ →Cold-sensitive neuron→ Heat production↑
(2) Pyretic signal to the central nervous system
① Organum
Vasculosum Laminae Terminalis
(下丘脑终板血管器)
M
OVLT M
capillary
EP
POAH
neuron
3rd
ventricle
supra-optic recess
Optic chiasma
POAH
neuron
（2）Pyretic signal to the central nervous system
② Penetrate the Blood Brain Barrier directly
• Inflammation
• injury
③ Transmit pyretic signal through vagus（迷走
神经）
• Kupffer cells in liver: produce IL-1
• Receptor for IL-1 on the nerve of vagus ganglia
(3) Positive and negative regulatory mediators
Central mediators
Positive regulatory
mediators
PGE2
Na+/
Ca2+
cAMP
CRH
Negative regulatory
mediators
NO
AVP
α-MSH
lipocortin-1
(Annexin A1)
PGE2（前列腺素E2）
The most important
among central mediators
PLA2（磷脂酶A2）
Cyclooxygenase，COX
（环加氧酶）
PGE2
• Supportive data：
– EP induced fever: CSF PGE2↑
– PGE injected into ventricles→dose dependant fever
– EP cocultured with hypothalamic tissue→PGE2↑
– PGE inhibitors (Arachidonic acid, Ibuprofen )
decrease T induced by IL-1, IFN, TNF
cAMP（环磷酸腺苷）
Cyclic adenosine monophosphate
• Caffeine, theophylline(茶碱)→cAMP↑ →T↑
• Endotoxin induced fever: cAMP in CSF↑
• cAMP intraventricular injection→fever immediately
– Shorter latent period
• Hyperthermia: cAMP doesn’t change
• cAMP is a mediator of late stage during fever
Na+/Ca2+ ratio
Intracerebroventricular perfusion:
0.9%NaCl
T↑
sucrose
T unchanged
Ca2+
T↓
EGTA
T↑ cAMP↑
EP →hypothalamic Na+/Ca2+ ↑→cAMP↑→set point↑
CRH（促肾上腺皮质激素释放素）
Corticotropin releasing hormone
– IL-1β、IL-6→hypothalamus releasing CRH→T↑
– CRH monoclonal antibody
inhibit CRH
or CRH-R antagonist
inhibit fever induced by EP
NO（一氧化氮）
Nitric Oxide
• Nitric oxide synthase, NOS
• Probable mechanisms:
– ① act on POAH、OVLT and induce fever
– ② increases heat production by brown adipose tissue
– ③ inhibits synthesis and secretion of the negative
regulation mediators related to fever
Negative Regulatory Mediators
• febrile ceiling (热限)
– Human core body temperature is almost never
permitted to rise above 41~42℃ during fever.
• Self protection mechanism
– Thermoregulatory neurons
– Endogenous antipyretics
– Soluble receptors for the pyrogenic cytokine
mediators of the febrile response
AVP（精氨酸加压素）
Arginine Vasopressin
• 1970s, Cooper:
– Antipyretic substance in pregnant women’s blood
• Supportive data:
– Febrile animals: Intracerebroventricular or intrahypothalamic
administration of AVP→T↓
• 4℃ inhibition of heat production
• 25℃ increasing heat loss
α-MSH（黑素细胞刺激素）
α-Melanocyte-Stimulating Hormone
• Intracerebroventricular or iv α—MSH:
– Antipyretic, in doses with no effect on normal body T
• EP induced fever:
– Ventral septal area (VSA) α-MSH↑
• Endogenous α-MSH limit time and extent of fever
lipocortin-1 (脂皮质蛋白-1)
also called Annexin A1（膜联蛋白A1 ）
• Phospholipid-binding protein
• Inhibit PLA2
• Inhibit fever induced by IL-1β、IL-6、IL-8、CRH
4. Pathogenesis of fever
II. Stages and manifestations of fever
Three stages
42 C
SP recovered
SP upregulated
37C
Normal T
Fervescence
Persistent
Febrile Defervescence
1. Fervescence Period
• Pale, cold, shivering, goose flesh
• Characteristics:
– heat loss↓heat production↑，T↑
• heat production↑
– Shivering
– Brown adipose tissue
– Metabolic rate↑
2. Persistent Febrile Period
Fastigium（高热稽留期）
• Feeling hot, skin dry and flush
• T increased to the new level of set point
• Balance of heat production and loss in a higher level
• Stop shivering, vasodilation
3. Defervescence Period
• sweating
• Disappearing of EP and thermoregulatory
mediators → SP decrease to normal
• Core temperature>set point → heat loss↑
• vasodilation
Stages of fever
III. Alterations of metabolism and function
1. Physiological functions
2. Metabolisms
3. Self defence
1. Physiological functions
⑴ Cardiovascular system
• Heart Rate↑：
–
–
–
–
T↑ 1℃→HR↑18 bpm
T↑→sinoatrial node（窦房结）
sympathetic-adrenal-medulla axis（+）
Oxygen consumption↑, CO2↑
• Blood pressure：
– Fervescence:
• HR↑ & vasoconstriction→ Bp↑
– Fastigium & Defervescence:
• water loss & vasodilation→Bp↓
1. Physiological functions
（2）Central Nervous System
• Excitability↑
– Irritability, delirium（谵妄）, hallucinations（幻觉）
– vasodilation→headache
• Children: febrile seizures (高热惊厥)
– Chidren (6 months~ 6 years)
– Immaturity of children’s central nervous system
1. Physiological functions
(3) Respiratory system ：
– T↑→ stimulate respiratory center→ hyperventilation
– heat loss↑
(4) Digestive system：
– Sympathetic exciting, water loss→ digestive fluid↓→
digestive disfunction
– EP→ PGs→ anorexia, nausea
2. metabolisms
• T↑1℃→ basic metabolic rate ↑13%
(1) proteins:
• T↑, PGE↑→ catabolism of proteins of skeletal
muscle
• Used for synthesis of acute phase proteins and
tissue repair
• Negative nitrogen balance（负氮平衡）
2. metabolisms
（2）Glucose and lipid
• Heat production↑→ catabolism↑→ glycogen
（糖原）↓→ lactic acid↑
• Shrivering → glycolysis（糖酵解）↑ → lactic
acid↑
• glycogen↓→ lipid mobilization（脂肪动员）
• sympathetic-adrenal-medulla axis⊕ → lipolytic
hormones（脂解激素）↑
2. metabolism
（3）Water and Salt
– Fervescence：
• renal flow↓→urine↓→Na+Cl- excretion↓
– Fatigium & Defervescence：
• water loss from skin and lung→ dehydration
• urine↑, sweating→ Na+Cl- excretion↑
（4）Vitamin
– Long term fever: vitamin
3. Self Defence
（1）Anti-infection：
– EP→ serum Fe↓→ anti-microorganisms
– Immunocytes (higher activity at 39℃):
• lymphocytes, neutrophils, macrophages↑
• NK↓
（2）Anti-tumor：
– IL-1，TNF，IFN: killing or inhibiting tumor cells
– Tumor cells are less tolerant (more sensitive) to heat
– Fever therapy, pyretotherapy（发热疗法）
3. Self Defence
（3） Acute phase response（急性期反应）
• A series of reaction at acute phase of bacteria
infection or tissue injury
–
–
–
Acute phase protein↑
WBC↑
Serum Fe↓Zn↓Cu↑
IV. Pathophysiological basis
of prevention and treatment
1. Two-edge sword of fever
(1) Benefits of fever
– The hypothalamus will not allow the temp to rise above 41.5ºC.
– WBCs work best and kill the most bacteria at 38-40ºC.
– Neutrophils make more superoxide anion, and there is more and
increased activity of IFN.
– Coxsackie and polio virus replication is directly inhibited.
(2) Harmful aspects
–
–
–
–
Catabolism
Cell death
Abnormality
Microenvironment imbalance
2. Pathophysiological basis of prevention and treatment
(1) Therapy for the primary disease
(2) Common management:
– T<39℃, no need to use antifebrile
– Observation and diagnosis
– Nutrition, vitamin, water
(3) Urgent conditions
• High fever >40℃
– Heart failure, coma, delirium
– Febrile convulsion of children
• Patients with cardiopathy（心脏病）
– Heart disease, heart failure
• Women in gestation (妊娠)
– ⑴Early stage: abnormality
– ⑵Late stage: heart failure
Principles of therapy
• Anti-pyretic drugs（药物解热）
– Salicylates
– Glucocorticoid
– Chinese Herbs
• Physical methods（物理降温）
– Freezing by ice bag or hat
– Wiping with ethanol
– Sometimes harmful
Case Study 1
• A girl of 2 years old was sent to hospital for fever
and angina 3 days, and convulsion half an hour.
– In the morning of 3 days ago, the girl was feeling cold and
shivering, the skin was pale and covered with goose flesh.
– She had fever at night and could not sleep, with dysphoria
and headache.
– She was sleepy the next day, and sometimes with nausea
and vomitting.
– Half hours before admission, she had convulsion suddenly.
Case Study 1
• PE：T41.4℃，P116 bpm，R24/min，
BP13.3/8kPa.
• Fatigue, sleepiness, flush face, dry lips, pharynx
congestion, swelling of tonsil（++）.
• Lab：WBC17.4×109/L, L 16%，N 80%.
CO2CP 17.94mmol/L
• Therapy: physical control of T, transfusion,
correct acidosis, antibiotics.
• 1h later, sweating, T 38.4 ℃
• 3 days later, dismissed
Discussion 1
1. What stages of fever did the patient display?
What’s the manifestations in each stage?
2. Would the body temperature continue to increase
if the girl hadn’t been to hospital? Why?
3. Was the therapy correct？
Case Study 2
A 36-year-old man, One day prior to
admission he was made worse by
headach ,dizzy, aching pain and fever.
Check:
T 39℃,Ｐ100/min, R 20/min, Bp 100/70 mmHg,
congestion of throat, swelling of tonsil,
respiratory rudeness, no bubbling sound
Lab findings:
WBC：13.3×109/L,
lymphocyte 16%, neutrophil 83%
Case Study 2
He was given antibiotic.
During transfusion, the patient suffer from
chilly, shake, dysphoria and tempreture rose
to Ｔ41.3℃, Ｐ120/min, R 24/min,
Dexamethasone intravenous injection
Discussion 2
1.What pathogenic mechanism account for this
patient’s fever?
2.Why the patient shown chilly, shake, dysphoria
and temperature rose more?
3.How to treat and give medical order of nursing?