FeverShanghai Institute of Digestive Disease

Department of Gastroenterology , Renji Hospital

Shanghai Jiaotong University, School of Medicine

郑青

Fever•Normal body temperature:

37oC (set point ，体温调定点 )

Circadian variation <1o C ： 36.3 - 37.2oC

•Definition of fever:

An elevation of core body temperature above the normal range

rectal T 0.5oC > oral T 0. 5oC > axillary T （腋温）

FeverPyrogens 致热原

Elevated set-point

Maintaining an abnormally elevated Temperature

BMR(basal metabolic rate) increases

T = Elevated set-point

BMR 10% = T 0.6oC

Hyperthermia ( 过热）•fever due to a disturbance of thermal regulatory control excessive heat production (e.g. vigorous exercise, a reaction to some anesthetics)

decreased dissipation (e.g. dehydration)

loss of regulation (injury to the hypothalamic( 下丘脑的 ) regulatory center)

Hyperthermia

Excessive heat production

T > unchanged set-point

Decreased dissipation

Loss of regulation

Pathophysiology•Body temperature is determined by two opposing processes

heat production heat loss

• They are regulated by the central nervous system

• Energy in the form of heat is generated by living tissues (thermogenesis 生热作用 )

• Energy may be passively absorbed from the environment and transfer the energy to the surrounding medium

Heat production

•Increased BMR, by varying the level of circulating thyroxine （甲状腺素 )

( controlled by hypothalamus 下丘脑 )

•Increased muscle sensitivity (shivering)

Heat loss

•By varying the volume of blood flowing

to skin’s surface (>100 fold)

•By vaporization (exocrine sweating)

Pathophysiology

•The body temperature is under control of the

preoptic area of the anterior hypothalamus（视前区下丘脑前部）Thermostat （恒温器）

•It receives input from both central receptors and peripheral receptors

Pathophysiology

•Elevation of body Temperature

shivering thermogenesis and dermal vasoconstriction

sympathetic ( 交感神经） outflow

•Cooling mechanism

sweating and dermal vasodilation

mixture of sympathetic and parasympathetic pathways

370C370C

390C390C

Heat ProductionHeat Production

Heat LossHeat LossHeat Production

Heat Production

Heat Loss

Heat Loss

Shivering

Metabolic activity

vasoconstriction

SweatingVasodilation

Set -point

coolingelevating

Pathophysiology

•Hypothalamic thermostat Inherent Set Point: 37oC

lowest: 4 a.m; peak: 6~10 p.m

•Fever follow this pattern

•Factors affect body Temperature exercise

menstrual cycle

environmental temperature

Pathogenesis of fever

Pyrogens ( 致热原）• Substances that can cause fever

• Either exogenous or endogenous 外源性致热原 内源性致热原

Exogenous Pyrogens•From outside the host

(some may be the endogenous products)

•Most of them are with high molecule weight

•Could not penetrate blood-brain barrier

Stimulating monocytes and macrophages to induce the formation of endogenous pyrogen

Exogenous Pyrogens

Majority are microorganism, their products or toxins

Gram-: endotoxin 内毒素

(lipopolysaccaride 脂多糖 , LPS)

Gram+: lipoteichoic acid （脂磷壁酸） peptidoglycan （肽聚糖） exotoxins( 外毒素 )and enterotoxins( 肠毒素）

Exogenous Pyrogens

Others complement products

steroid hormone metabolites

antigen-antibody complex with complement

Endogenous Pyrogen

•In response to invasive stimuli:

exogenous pyrogen

chemical agents (amphotericin and other drug) 两性霉素 B

•Produced by cells of immune system of the host

(macrophages, lymphocytes)

•Proteins designated ‘monokines’ and ‘lymphokines’

cytokines （细胞因子）

Endogenous Pyrogen

•Cytokines

IL-1 IL-1 TNFTNF IFN IL-6

•Phagocytes and lymphocytes: major source of pyrogenic cytokines

•It may also released through autonomous production and secretion

Pathogenesis of fever

•Bacteria provoke release of IL-1

Viral proteins stimulate IFN

•Combined production of several cytokines cause fever

Pathogenesis of fever

•Pyrogenic cytokines bind receptors present on vascular endothelial cells that lie within the hypothalamus

•Resetting the hypothalamic thermoregulatory center by increased prostaglandin (PGE, 前列腺素 ) and cAMP

Production of endogenous pyrogens

促肾上腺皮质激素

促皮质激素释放因子

Set point

hypothalamus

Heat loss

Heat production

FeverFever

ExP Macrophagelymphocyte EnP

Etiology and classification

•Infective fever

•Non-infective fever

Infective fever

•Metabolites from organism cause fever

•Most common causes of fever (50%~60%)

Bacteria pyrogens:

common cause of infective fever (43%)

Viral pyrogens: (6%)

Non-infective fever

•Absorption of necrotic substances:

injury ischemic necrosis cell necrosis 缺血性坏死•Allergy

antibiotics (penicillin-based)

•Endocrine and metabolic disturbances:

hyperthyroidism （甲亢） dehydration （脱水）•Decreased elimination of heat from skin:

heat failure

Non-infective fever

•Dysfunction of central heat regulation

physical: heat stroke 中暑

chemical: barbiturate poisoning 巴比妥酸盐中毒

mechanical: cerebral hemorrhage 脑出血

•Dysfunction of vegetative nervous system

sympathetic overactivity 交感功能亢进

Clinical manifestation

•The grade of fever Low grade fever: 37.3~38oC

Moderate fever: 38~39oC

High fever: 39.1~41oC

Hyperthermia fever: >41oC

Clinical manifestation

•Clinical course of fever

Onset: Sudden onset within few hours

pneumonia 肺炎

Gradual onset gradually for few days

typhoid 伤寒

Persistence: varies pattern

Subsidence: by crisis or lysis

Character of fever

•Continued （稽留热）T: kept at 39oC~40oC constantly

Circadian variation: < 1oC

pneumonia 肺炎 typhoid fever 伤寒

•Remittent （弛张热）T: >39oC circadian variation >2oC

rheumatic fever 风湿热 tuberculosis 结核 septicaemia 败血症 septic inflammation 脓毒血症

Character of fever

•Intermittent （间歇热）T: sudden rising (few hours) and sudden decreasing

malaria 疟疾 acute pyelonephritis 急性肾盂肾炎

•Recurrent （回归热）T: abruptly rising to the peak, lasting for several

day, sudden decrease to the normal repeatedly

Hodgkin disease 何杰金病

Character of fever

•Undulant （波浪热）T: rising gradually to the peak (>39oC)

decreasing gradually to the normal

repeatedly for several timesBrucellosis （布鲁氏杆菌病）

•Irregular （不规则热）tuberculosis rheumatic fever brochopneumonia

Fever pattern as diagnostic clues

Fever Pattern CauseAlternate-day fever Plasmodium vivax, P. Ovale

fever every third day P. Malariae ( 间日疟原虫）

Relapsing fever

daily for 3~6 days Borrelia sp ( 包柔螺旋体菌 ),

fever-free interval rat bite fever

for about 1 week

Continuous “undulating” Brucellosis, typhoid

Periodic pyrexia Hodgkin’s disease

(Pel-Ebstein Phenomenon)

with variable cycles

Associated symptoms

•Chills or rigor: septicemia acute infections 畏寒或寒战•Congestion of conjunctiva: hemorrhage fever 结膜充血•Herpes simplex: herpes virus (lobar pneumonia) 单纯疱疹•Bleeding tendency: in severe infection (hepatitis)

出血倾向 blood dyscrasia (leukemia)

Associated symptoms•Lymphadenopathy: lymphoma cancer metastasis 淋巴结病•Enlargement of liver and spleen: hepatitis 肝脾肿大•Rash: drug rash measles ( 麻疹） 皮疹•Arthralgia: gout rheumatic disease 关节痛•Coma: barbiturate posioning cerebral hemorrhage 昏迷

Diagnostic points•Other symptoms besides fever

•Duration and magnitude of fever

•Close contacts with similar illness

•Occupational, travel, recreational exposure

•History of diseases associated with other organ(diabetes 糖尿病 chronic renal failure)

•Current medication (antibiotics and antipyretics 退热剂 )

•Allergy

Fever of unknown origin (FUO)

•FUO defined by Petersdorf and Beeson (1961)

Fevers higher than 38.3oC on several occasions

A duration of more than 3 weeks

Failure to reach a diagnosis after 1 week of inpatient

investigation

70%~90% of the cases can be diagnosed

•Modification

Three outpatient visits or three days in the hospital

2 weeks of fever

Summary• Fever: elevation of set point （ hypothalamus ） Heat production shivering dermal vasoconstriction

Heat loss sweating dermal vasodilation

• Pyrogen: exogenous or endogenous endotoxin (LPS) pyrogenic cytokines

PGEs cAMP Set-point

Summary• Etiology: infective or noninfective

• Fever types

•Associated symptoms

•Diagnostic points