1. Fever Jianzhong Sheng MD, PhD
Department of Pathology & Pathophysiology
School of Medicine, Zhejiang University

2. Body temperature Normal body temperature: 37oC (set point，体温调定点)
Circadian variation <1o C ： oC
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）

3. Pyrogens (exogenous or endogenous) T  = Elevated set-point
Fever
Pyrogens (exogenous or endogenous)
Elevated set-point
Maintaining an abnormally elevated Temperature
BMR (basal metabolic rate) increases
BMR 10% = T  0.6oC
T  = Elevated set-point

4. 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 in the hypothalamic regulatory center)

5. Excessive heat production Decreased dissipation
Hyperthermia
Excessive heat production
T  > unchanged set-point
Decreased dissipation
Loss of regulation

6. 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 may be transferred to the surrounding medium

7. 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)

8. Heat loss By varying the volume of blood flowing
to skin’s surface (>100 fold)
By vaporization (exocrine sweating)

9. 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

10. sympathetic (交感神经）outflow
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

11. Heat Production 390C Heat Loss 370C
Set -point
Heat Production
390C
Heat Loss
Sweating
Vasodilation
elevating
cooling
Shivering
Metabolic activity
vasoconstriction
Heat Loss
Heat Production
370C

12. Pathophysiology Hypothalamic thermostat
Inherent Set Point: 37oC
lowest: 4 a.m; peak: 2~5 p.m
Factors affecting body temperature
exercise
menstrual cycle
environmental temperature

13. Pathogenesis of fever Pyrogens (致热原） Either exogenous or endogenous
Substances that can cause fever
Either exogenous or endogenous
外源性致热原 内源性致热原

14. 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 produce and release endogenous pyrogen

15. exotoxins (外毒素) and enterotoxins (肠毒素）
Exogenous Pyrogens
Majority are products or toxins of microorganism,
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）

16. Exogenous Pyrogens Others complement products
steroid hormone metabolites
antigen-antibody complex with complement

17. Endogenous Pyrogen cytokines （细胞因子） 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）

18. Endogenous Pyrogen Cytokines IL-1 IL-1 TNF TNF IFN IL-6
Phagocytes and lymphocytes: major source of pyrogenic cytokines
It may also be released through autonomous production and secretion

19. Pathogenesis of fever Bacteria provoke release of IL-1
Viral proteins stimulate IFN
Combined production of several cytokines cause fever

20. 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E) and cAMP

21. Production of endogenous pyrogens
促肾上腺皮质激素
促皮质激素释放因子

22. ExP EnP Set point hypothalamus Heat loss Fever Heat production
Macrophage
lymphocyte
hypothalamus
EnP
Heat loss
Fever
Set point
Heat production

23. Etiology and classification
Infective fever
Non-infective fever

24. common cause of infective fever (43%)
Metabolites from organism cause fever
Most common causes of fever (50%~60%)
Bacteria pyrogens:
common cause of infective fever (43%)
Viral pyrogens: (6%)

25. injury ischemic necrosis cell necrosis
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

26. 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

27. Clinical manifestation
The grade of fever
Low grade fever: ~38oC
Moderate fever: ~39oC
High fever: ~41oC
Hyperthermia fever: >41oC

28. 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: varied patterns
Subsidence: due to crisis or lysis

29. septicaemia (败血症) , septic inflammation (脓毒血症)
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)

30. 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
days; sudden decrease to the normal repeatedly
Hodgkin disease (何杰金病)

31. Character of fever Undulant （波浪热）
T: rising gradually to the peak (>39oC)
decreasing gradually to the normal
repeatedly for several times
Brucellosis（布鲁氏杆菌病）
Irregular（不规则热）
tuberculosis, rheumatic fever, brochopneumonia

33. Fever pattern as diagnostic clues
Fever Pattern Cause
Alternate-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

34. 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)

35. 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

36. (diabetes 糖尿病 chronic renal failure)
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

37. 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

38. 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

39. Summary Etiology: infective or noninfective Fever types
Associated symptoms
Diagnostic points