Chapter 9 Fever

Current Epidemics in Brazil

IntroductionFever (Pyrexia): Typical manifestationsThe Fervescence StageFeeling coldSkin is pale, covered with goose fleshShiveringThe Persistent Febrile StageFeeling warmSkin is dry and flushedThe Defervescence StageSweatingSkin 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 CNormal Body TemperatureCircadian variation

Body Temperature Regulation

Elevation of body temperature Physiological elevation of body temperatureBefore menstruation, Strenuous exercise, Stress Conditions of body temperature elevation

Pathological elevation of body temperature Fever Hyperthermia (Regulatory/Active elevation of T) (Non-regulatory/Passive elevation of T Conditions of body temperature elevationElevation of body temperature Physiological elevation of body temperatureBefore menstruation, Strenuous exercise, Stress

DefinitionsFever: Regulated elevation of core body temperature 0.5 higher than normal, accommodated to the increased hypothalamic Set Point () in response to pyretic substances.

Hyperthermia: 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 HyperthermiaLoss of regulation: central nervous system injury

Impairment of heat-loss: heliosisichthyosis

Excessive heat production: hyperthyroidism

Difference between Fever and HyperthermiaHeat Production Heat Loss Thermoregulatory Center DisfunctionPassive elevation of T(>0.5 C)T SPPyrogenregulatory elevation of T(>0.5 C)Thermoregulatory Set Point FeverHyperthermia

Typical fever types

I. Etiology and PathogenesisPyrogenic activators Endogenous pyrogen producing cellsEP production and releasingThermoregulatory centerCentral mediators releasingSP elevatedShivering Skin vasoconstrictionHeat production Heat loss

1. Pyrogenic activatorSubstance that stimulate the body to produce cytokines.Endogenous substancesG- bacteriaG bacteriaVirusesAntigen-antibody complexes Steroids: etiocholanolone, lithocholic acid Inflammatory substancesLipopolysaccharide (LPS) / EndotoxinPepG, LTA, SE, TSST-1Whole virus, HemagglutininExogenous pyrogensPyrogenic activators othersLeptospira, Plasmodium, Epiphyte

Endotoxin (ET) Heat stable substance: 160 C, 2hDerived from gram-negative bacteria cell wallsMolecular weight: 1000~2000 kDCan not penetrate BBBComposed by O-specific side chainO-, core polysaccharide and lipoAA Activate complement cascadeStimulate EP production and releasing

2. Endogenous Pyrogen ()Cytokines produced from cells activated by pyrogenic activatorsInduce fever by resetting thermoregulatory Set Point1948, Beeson (J Clin Invest, Volume 27(4) July 1948: 524): leucocytic pyrogenLP

1980, Hanson: monocyteJ. Exp.Med. Volume 151, June 1980, 1360~1371.

Classifications of EPInterleukin-1, IL-1-1

Tumor necrosis factor, TNF

Interferon, IFN

Macrophage inflammatory protein-1, MIP-1-1

Interleukin-6, IL-6-6

IL-1Mononuclear cells, macrophages, epithelial cells, et al.Polypeptide, 17kD, two subtypes: IL-1, IL-1The 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 rabbitfever low dose single-phase fever high dose double-phase feverIL-1-/- mice stimulated with LPS: low dose slightly fever, IL-6 high dose almost no fever

TNFMacrophages: 17kDSubtypes: TNF, TNF

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

Intracerebroventricular injection: PGE

IFNSubtypes: IFN, IFN, IFNAntiviral and anti-tumor effect, 15~17kD

1984, Dinarello: IFN iv single-phase fever

Repeated injection: tolerance

IFNPGE

MIP-1Wolpe: monokine8kDNeutrophils: H2O2

Davatelis: rabbit, iv: single-phase fever

IL-621kDInduced by ETIL-1TNFPGF

Rabbit, mouse iv or intracerebroventricular injection

Serum and Cerebrospinal fluid IL-6

TNF IL-1 IL-6

Other EPsIL-2Late phase feverInduce TNF, IFNIndirect activator

Ciliary neurotrophic factor, CNTFIL-8Endothelin, ET

Activation of EP producing cellsLPS binding proteinEP producing cellToll like receptor

1Thermoregulatory centerPositivePOAH NegativeMAN VSA

EPthermoregulatory centercentral mediators change of the set point

Blood T Heat-sensitive neuron Heat loss Blood T Cold-sensitive neuron Heat production3. Mechanisms of thermoregulation

(2) Pyretic signal to the central nervous system EPOptic chiasma3rd ventriclesupra-optic recess Organum Vasculosum Laminae Terminalis () OVLTcapillary

2Pyretic signal to the central nervous system Penetrate the Blood Brain Barrier directlyInflammationinjury

Transmit pyretic signal through vagusKupffer cells in liver: produce IL-1Receptor for IL-1 on the nerve of vagus ganglia

(3) Positive and negative regulatory mediatorsCentral mediators Positive regulatory mediators Negative regulatory mediatorsPGE2 Na+/Ca2+cAMP CRH AVP -MSH lipocortin-1(Annexin A1) NO

PGE2E2The most important among central mediators

PLA2A2

CyclooxygenaseCOX

PGE2Supportive data

EP induced fever: CSF PGE2

PGE injected into ventriclesdose dependant fever

EP cocultured with hypothalamic tissuePGE2

PGE inhibitors (Arachidonic acid, Ibuprofen ) decrease T induced by IL-1, IFN, TNF

cAMPCyclic adenosine monophosphate

Caffeine, theophylline()cAMP TEndotoxin induced fever: cAMP in CSFcAMP intraventricular injectionfever immediatelyShorter latent periodHyperthermia: cAMP doesnt change

cAMP is a mediator of late stage during fever

Na+/Ca2+ ratioIntracerebroventricular perfusion: 0.9%NaCl T sucrose T unchanged Ca2+ T EGTA T cAMP

EP hypothalamic Na+/Ca2+ cAMPset point

CRHCorticotropin releasing hormone

IL-1IL-6hypothalamus releasing CRHT

CRH monoclonal antibody inhibit CRH or CRH-R antagonist

inhibit fever induced by EP

NONitric Oxide

Nitric oxide synthase, NOS

Probable mechanisms: act on POAHOVLT and induce fever increases heat production by brown adipose tissue inhibits synthesis and secretion of the negative regulation mediators related to fever

Negative Regulatory Mediatorsfebrile ceiling ()Human core body temperature is almost never permitted to rise above 41~42 during fever.

Self protection mechanismThermoregulatory neuronsEndogenous antipyreticsSoluble receptors for the pyrogenic cytokine mediators of the febrile response

AVPArginine Vasopressin

1970s, Cooper: Antipyretic substance in pregnant womens blood

Supportive data:Febrile animals: Intracerebroventricular or intrahypothalamic administration of AVPT4 inhibition of heat production25 increasing heat loss

-MSH-Melanocyte-Stimulating Hormone

Intracerebroventricular or iv MSH:Antipyretic, in doses with no effect on normal body T

EP induced fever: Ventral septal area (VSA) -MSH

Endogenous -MSH limit time and extent of fever

lipocortin-1 (-1)also called Annexin A1A1

Phospholipid-binding protein

Inhibit PLA2

Inhibit fever induced by IL-1IL-6IL-8CRH

4. Pathogenesis of fever

II. Stages and manifestations of feverThree stagesSP upregulatedSP recovered

1. Fervescence PeriodPale, cold, shivering, goose flesh

Characteristics: heat lossheat productionT

heat productionShiveringBrown adipose tissueMetabolic rate

2. Persistent Febrile PeriodFastigium

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 Periodsweating

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 functionPhysiological functions

Metabolisms

Self defence

Cardiovascular system

Heart RateT 1HR18 bpmTsinoatrial nodesympathetic-adrenal-medulla axis+Oxygen consumption, CO2

Blood pressureFervescence: HR & vasoconstriction Bp Fastigium & Defervescence:water loss & vasodilationBp

1. Physiological functions

1. Physiological functions2Central Nervous System

ExcitabilityIrritability, delirium, hallucinationsvasodilationheadache

Children: febrile seizures ()Chidren (6 months~ 6 years)Immaturity of childrens central nervous system

1. Physiological functions(3) Respiratory system T stimulate respiratory center hyperventilationheat loss

(4) Digestive systemSympathetic exciting, water loss digestive fluid digestive disfunctionEP PGs anorexia, nausea

2. metabolisms

T1 basic metabolic rate 13%

(1) proteins:T, PGE catabolism of proteins of skeletal muscle Used for synthesis of acute phase proteins and tissue repairNegative nitrogen balance

2. metabolisms2Glucose and lipid

Heat production catabolism glycogen lactic acidShrivering glycolysis lactic acid

glycogen lipid mobilization sympathetic-adrenal-medulla axis lipolytic hormones

2. metabolism3Water and Salt

Fervescencerenal flowurineNa+Cl- excretionFatigium & Defervescencewater loss from skin and lung dehydrationurine, sweating Na+Cl- excretion4Vitamin Long term fever: vitamin

1Anti-infectionEP serum Fe anti-microorganismsImmunocytes (higher activity at 39):lymphocytes, neutrophils, macrophagesNK

2Anti-tumorIL-1TNFIFN: killing or inhibiting tumor cellsTumor cells are less tolerant (more sensitive) to heatFever therapy, pyretotherapy3. Self Defence

3. Self Defence3 Acute phase response

A series of reaction at acute phase of bacteria infection or tissue injury Acute phase protein WBC Serum FeZnCu

IV. Pathophysiological basis of prevention and treatment1. Two-edge sword of fever

(1) Benefits of feverThe hypothalamus will not allow the temp to rise above 41.5C.WBCs work best and kill the most bacteria at 38-40C.Neutrophils make more superoxide anion, and there is more and increased activity of IFN.Coxsackie and polio virus replication is directly inhibited.

(2) Harmful aspectsCatabolismCell deathAbnormalityMicroenvironment imbalance

2. Pathophysiological basis of prevention and treatment(1) Therapy for the primary disease

(2) Common management:T

(3) Urgent conditionsHigh fever >40Heart failure, coma, deliriumFebrile convulsion of children

Patients with cardiopathyHeart disease, heart failure

Women in gestation ()Early stage: abnormalityLate stage: heart failure

Principles of therapyAnti-pyretic drugsSalicylatesGlucocorticoid Chinese Herbs

Physical methodsFreezing by ice bag or hatWiping with ethanolSometimes harmful

Case Study 1A 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 1PET41.4P116 bpmR24/minBP13.3/8kPa.Fatigue, sleepiness, flush face, dry lips, pharynx congestion, swelling of tonsil++. LabWBC17.4109/L, L 16%N 80%. CO2CP 17.94mmol/L

Therapy: physical control of T, transfusion, correct acidosis, antibiotics.1h later, sweating, T 38.4 3 days later, dismissed

Discussion 11. What stages of fever did the patient display? Whats the manifestations in each stage?

2. Would the body temperature continue to increase if the girl hadnt 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 39,100/min, R 20/min, Bp 100/70 mmHg, congestion of throat, swelling of tonsil, respiratory rudeness, no bubbling soundLab findings: WBC13.3109/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 41.3, 120/min, R 24/min,

Dexamethasone intravenous injection

Discussion 21.What pathogenic mechanism account for this patients fever?

2.Why the patient shown chilly, shake, dysphoria and temperature rose more?

3.How to treat and give medical order of nursing?