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Chapter 9 Fever

Chapter 9 Fever. Current Epidemics in Brazil. Introduction. Fever (Pyrexia): Typical manifestations. ?. Feeling cold Skin is pale, covered with goose flesh Shivering. The Fervescence Stage. The Persistent Febrile Stage. Feeling warm Skin is dry and flushed. The Defervescence Stage.

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Chapter 9 Fever

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  1. Chapter 9 Fever

  2. Current Epidemics in Brazil

  3. Introduction Fever (Pyrexia):Typical manifestations ? Feeling cold Skin is pale, covered with goose flesh Shivering The Fervescence Stage The Persistent Febrile Stage Feeling warm Skin is dry and flushed The Defervescence Stage Sweating Skin is warm and flushed

  4. Life Stages

  5. Normal Body Temperature • rectal 36.9~37.9 C (Core Temperature) • oral36.6~37.6 C • axillary36.2~37.2 C 37.5 36.5 Circadian variation （周期波动）<1C 2am 2pm 2am

  6. Body Temperature Regulation

  7. Conditions of body temperature elevation Physiological elevation of body temperature （Before menstruation, Strenuous exercise, Stress） Elevation of body temperature（体温升高）

  8. 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）

  9. 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.

  10. 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）

  11. Difference between Fever and Hyperthermia Heat Production ↑ Heat Loss ↓ Thermoregulatory Center Disfunction Pyrogen Thermoregulatory Set Point ↑ Passive elevation of T(>0.5 C) T ﹥ SP regulatory elevation of T(>0.5 C) Hyperthermia Fever

  12. 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

  13. T I. Etiology and Pathogenesis Pyrogenic activators （发热激活物） Endogenous pyrogen producing cells （产内生致热原细胞） Central mediators releasing Thermoregulatory center（体温调节中枢） EP production and releasing Heat production Shivering 寒颤 Skin vasoconstriction SP elevated （调定点上移） Heat loss

  14. 1. Pyrogenic activator • Substance that stimulate the body to produce cytokines. Exogenous pyrogens 外致热原 Lipopolysaccharide (LPS) / Endotoxin G- bacteria Pyrogenic activators 发热激活物 PepG（肽聚糖）, LTA（磷壁酸）, SE（肠毒素）, TSST（中毒性休克综合征毒素）-1 G＋bacteria Viruses Whole virus, Hemagglutinin others Leptospira, Plasmodium, Epiphyte Endogenous substances 体内物质 Antigen-antibody complexes Steroids: etiocholanolone（本胆烷醇酮）, lithocholic acid（石胆酸） Inflammatory substances

  15. 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

  16. 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）

  17. 1980, Hanson: monocyte J. Exp.Med. Volume 151, June 1980, 1360~1371.

  18. Classifications of EP • Interleukin-1, IL-1（白细胞介素-1） • Tumor necrosis factor, TNF（肿瘤坏死因子） • Interferon, IFN（干扰素） • Macrophage inflammatory protein-1, MIP-1（巨噬细胞炎症蛋白-1） • Interleukin-6, IL-6（白细胞介素-6）

  19. 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

  20. TNF • Macrophages: 17kD • Subtypes: TNFα, TNFβ • TNF iv rabbit: • low dose single-phase fever • high dose double-phase fever • Intracerebroventricular injection: • PGE↑

  21. IFN • Subtypes: IFNα, IFNβ, IFNγ • Antiviral and anti-tumor effect, 15~17kD • 1984, Dinarello: • IFNα iv single-phase fever • Repeated injection: tolerance • IFN→PGE↑

  22. MIP-1 • Wolpe: monokine • 8kD • Neutrophils: H2O2 • Davatelis: • rabbit, iv: single-phase fever

  23. 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

  24. 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）

  25. LPS Activate NF-κB EP gene transcription and expression Activation of EP producing cells LPS binding protein Toll like receptor EP producing cell

  26. 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↑

  27. M M POAH neuron POAH neuron (2) Pyretic signal to the central nervous system ① Organum Vasculosum Laminae Terminalis (下丘脑终板血管器) OVLT capillary EP 3rd ventricle supra-optic recess Optic chiasma

  28. （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

  29. (3) Positive and negative regulatory mediators Central mediators Positive regulatory mediators Negative regulatory mediators CRH PGE2 Na+/ Ca2+ cAMP NO AVP α-MSH lipocortin-1 (Annexin A1)

  30. PGE2（前列腺素E2） The most important among central mediators PLA2（磷脂酶A2） Cyclooxygenase，COX （环加氧酶）

  31. 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

  32. 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

  33. Na+/Ca2+ ratio Intracerebroventricular perfusion: 0.9%NaCl T↑ sucrose T unchanged Ca2+ T↓ EGTA T↑ cAMP↑ EP →hypothalamic Na+/Ca2+ ↑→cAMP↑→set point↑

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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

  39. 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

  40. 4. Pathogenesis of fever

  41. 42 C 37C Persistent Febrile Defervescence Normal T Fervescence II. Stages and manifestations of fever Three stages SP recovered SP upregulated

  42. 1. Fervescence Period • Pale, cold, shivering, goose flesh • Characteristics: • heat loss↓heat production↑，T↑ • heat production↑ • Shivering • Brown adipose tissue • Metabolic rate↑

  43. 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

  44. 3. Defervescence Period • sweating • Disappearing of EP and thermoregulatory mediators → SP decrease to normal • Core temperature>set point → heat loss↑ • vasodilation

  45. Stages of fever

  46. III. Alterations of metabolism and function • Physiological functions • Metabolisms • Self defence

  47. 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↓

  48. 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

  49. 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

  50. 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）

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