Fever

1. Fever Jianzhong Sheng MD, PhD Department of Pathology & Pathophysiology School of Medicince, Zhejiang University Email: shengjz@zju.edu.cn

2. Body temperature 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）

3. Elevated set-point Pyrogens (exogenous or endogenous) Fever 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 Loss of regulation T  > unchanged set-point Hyperthermia

6. Pathophysiology Body temperature is determined by two opposing processes heat productionheat loss They are regulated by the central nervous system Energy in the form of heat is generated by living tissues (thermogenesis) 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. Pathophysiology Elevation of body temperature shivering thermogenesis and dermal vasoconstriction sympathetic outflow Cooling mechanism sweating and dermal vasodilation mixture of sympathetic and parasympathetic pathways

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

23. Etiology and classification Infective fever Non-infective fever

24. 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%)

25. 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: 37.3~38oC Moderate fever: 38~39oC High fever: 39.1~41oC 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. 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 (痛风), rheumatic disease 关节痛 Coma: barbiturate poisoning, cerebral hemorrhage 昏迷

36. 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, 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 losssweating dermal vasodilation Pyrogen: exogenous or endogenous endotoxin (LPS) pyrogenic cytokines PGEscAMP Set-point

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