Chapter 9 Fever

Current Epidemics in Brazil

Introduction

Fever (Pyrexia): Typical manifestations

The Fervescence Stage

Feeling coldSkin is pale, covered with goose fleshShivering

The Persistent Febrile Stage

Feeling warmSkin is dry and flushed

The Defervescence Stage

SweatingSkin is warm and flushed

Life Stages

rectal 36.9~37.9 C

(Core Temperature)

oral 36.6~37.6 C

axillary 36.2~37.2 C

Normal Body Temperature

Circadian variation （周期波动） <1C

2am 2pm 2am

37.5

36.5

Body Temperature Regulation

Elevation of body temperature （体温升高）

Physiological elevation of body temperature

（ Before menstruation, Strenuous exercise, Stress ）

Conditions of body temperature elevation

Pathological elevation of body temperature

Fever （发热）

Hyperthermia （过热）

(Regulatory/Active elevation of T)

(Non-regulatory/Passive elevation of T ）

Conditions of body temperature elevation

Elevation of body temperature

Physiological elevation of body temperature

（ Before menstruation, Strenuous exercise, Stress ）

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 inj

ury

• Impairment of heat-loss: – heliosis （中暑）– ichthyosis （鱼鳞病）

• Excessive heat production: – hyperthyroidism （甲

亢）

Difference between Fever and Hyperthermia

Heat Production ↑

Heat Loss ↓

Thermoregulatory Center Disfunctio

n

Passive elevation of T(>0.5 C)

T SP﹥

Pyrogen

regulatory elevation of T(>0.5 C)

Thermoregulatory Set Point ↑

Fever Hyperthermia

Typical fever types （热型）

伤寒、大叶性肺炎 风湿热、败血症、脓毒血症、肝脓肿 疟疾、肾盂肾炎

布鲁菌病 何杰金氏病 结核、风湿热、瘤性发热

I. Etiology and Pathogenesis

Pyrogenic activators

（发热激活物）

Endogenous pyrogen producing cells

（产内生致热原细胞）

EP production and releasing

Thermoregulatory center （体温调节

中枢）

Central mediators releasing

SP elevated

（调定点上移）

Shivering 寒颤

Skin vasoconstriction

T

Heat production 　

Heat loss

1. Pyrogenic activator• Substance that stimulate the body to produce cytokines.

End

ogenous substances

体内物质

G- bacteria

G ＋ bacteria

Viruses

Antigen-antibody complexes

Steroids: etiocholanolone （本胆烷醇酮） , lithocholic acid （石胆酸）

Inflammatory substances

Lipopolysaccharide (LPS) / Endotoxin

PepG （肽聚糖） , LTA （磷壁酸） , SE （肠毒素） , TSST （中毒性休克综合征毒素） -1

Whole virus, Hemagglutinin

Exog

eno

us p

yrog

ens

外致热原

Pyrog

enic a

ctivators

发热激活物

others Leptospira, Plasmodium, Epiphyte

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 ch

ain （ 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: monocyteJ. 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 single-phase fever

– high dose double-phase fever

• IL-1β-/- mice stimulated with LPS:– low dose slightly fever, IL-6↑

– high dose almost no fever

TNF

• Macrophages: 17kD• Subtypes: TNFα, TNFβ

TNF iv rabbit: low dose single-phase fever high dose 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）

LPSLPS

binding protein

EP producing cell

Toll like receptor

Activate NF-κB

EP gene transcription and expression

Activation of EP producing cells

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↑

EP

M M

POAHneuronPOAH

neuron

Optic chiasma

3rd ventriclesupra-optic recess

① Organum Vasculosum Laminae Terminalis ( 下丘脑终板血管器 )

OVLTcapillary

(2) Pyretic signal to the central nervous system

（ 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

Negative regulatory mediators

PGE2 Na+/

Ca2+

cAMP CRH AVP α-MSH lipocortin-1

(Annexin A1)

NO

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 permi

tted 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

Three stages

37C

42 C

Normal TFervescence

Persistent Febrile Defervescence

SP

upregulated

SP

recovered

II. Stages and manifestations of fever

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↓→ d

igestive 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 ti

ssue 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 h

ormones （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 cell

s

– 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 increas

ed 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%. CO

2CP 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 ,℃ Ｐ 100/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 Ｔ 41.3 , ℃ Ｐ 120/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?