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Fever Clinical Pathophysiology

September 7, 2005

Fred Arthur Zar, MD, FACPProfessor of Clinical Medicine

University of Illinois at Chicagofazar@uic.edu

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Body Temperature

Core Temperature Aortic blood temperature Esophageal temperature Tympanic membrane temperature

Clinical Approximates Sublingual (oral) temperature = 0.7 o F < core Axillary temperature = 1.8 o F < core

Rectal temperature = 0.9o

F > core

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Normal Thermoregulation

Afferent Sensing Cold receptors > A delta fibers Warm receptors > C fibers Integrated in spinal cord and CNS > hypothalamus

Central Integration 20% each contribution from: skin, deep chest and abdomen, spinal

cord, CNS, hypothalamus Skin input predominates behavioral responses Cold and warm response thresholds only 0.4 apart

Efferent Responses Behavioral (clothing, adjusting environment) Response to heat: sweat, cutaneous dilation Response to cold: digital vasoconstriction ( agonism)

Nonshivering thermogenesis ( agonism)Shivering

Sessler DI: NEJM 336:1730 7, 1997.

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Endogenous Pyrogens

Interleukin 1 (alpha*, beta) Interleukin 6 Interleukin 11 Tumor necrosis factor (alpha) Interferon (alpha, beta, gamma) Prostaglandin E 2 Platelet activating factor Ciliary neurotropic factor (CNTF) Oncostatin M Cardiotropin 1 Leukemic inhibitory factor (LIF)

*first cloned by Auron PE: Proc Natl Acad Sci USA 81:7907 11, 1984.

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Pyrogenic Cytokine Producing Cells

Monocytes, tissue macrophages Keratinocytes Gingival epithelium Corneal epithelium

Renal mesangial cells Brain astrocytes Vascular endothelium Vascular smooth muscle NK cells Fibroblasts

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Fever and Host Defense Enhancement

Neutrophil function Enhanced migration Enhanced superoxide production

Mononuclear function Enhanced interferon production Enhanced interferon tumor and viral activity

T cell proliferation

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The Structure of the Febrile State Endocrine/Metabolic

CRH > ACTH > GCGHAldosterone

Insulin (if available)GlucagonAcute phase reactants

TSHADH

AutonomicCutaneous vasoconstriction

PRBPSweating

BehavioralSeek warmth (chill)Shivering (rigor)AnorexiaSomnolenceMalaise

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Cytokines Inducing Acute Phase Reactants

Interleukin 1 Interleukin 6 Interleukin 11 Tumor Necrosis Factor Oncostatin M Ciliary Neurotrophic Factor Cardiotropin 1 Leukemic Inhibitory Factor

Dinarello CA: Sem Onc 24:288 98, 1997.

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Acute Phase Proteins(The concentration changes +/ 25%)

Increased in Sepsis Ceruloplasmin, ferritin, hemopexin, haptoglobin 1 protease inhibitor, 1 antichymotrypsin, pancreatic secretory

trypsin inhibitor, inter trypsin inhibitors C3, C4, C9, C1 inhibitor, C4b binding protein, C4b binding lectin,

factor B

Fibrinogen, plasminogen, TPA, urokinase, protein S, vitronectin,plasminogen activator inhibitor 1 CRP, serum amyloid A, 1-acid glycoprotein, 2 macroglobulin,

phospholipase A2, fibronectin, manose binding protein,lipopolysaccharide binding protein, IL 1 receptor antagonist, GCSF

Decreased in Sepsis

Albumin, transthyretin, transferrin, 2-HS glycopreotein, FP, TBGinsulin like growth factor, Factor XII

Mackowiak PA: Arch IM 158:1870 81, 1998. Gabay C: NEJM 340:448-54, 1999

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Afebrile Infections in the Elderly Incidence

Bacteremia 5 31% Endocarditis 7 21% Pneumonia 20 56% Meningitis 41%

Mechanisms

Technical pseudo -euthermia Poorly taken oral/axillary temps Chronic antipyretic drug ingestion Behavioral changes Physiologic changes

Decreased BMR

Late, less efficient shivering Autonomic neuropathy Decreased temperature perception Decreased production of endogenous pyrogens

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Intrinsic Antipyretics Somatostatin Melanocyte stimulating factor Vasopressin

CRH >ACTH >GC Thyroliberin GIP Neuropeptide Y

Bombesin IL 1ra, soluble TNF receptor

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Antipyretic Drugs Cyclo oxygenase (COX) Inhibitors

Acetaminophen Poor peripheral activity

0.02% as active as indomethacin In CNS oxidized by p450 to potent inhibitor of PG E2 synthesis

10% as active as indomethacin Acetylsalacyclic acid (ASA) Other NSAIDs

Corticosteroids Inhibit phospholipase A 2 > PG E2 synthesis

Block mRNA transcription of pyrogenic cytokines Phenothiazines

Block peripheral vasoconstriction

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Two critical assumptions are made when prescribing antipyretic therapy. One is that fever is, at least in part, noxious, and the otheris that suppression of fever will reduce, if not eliminate, thenoxious effects of fever. At present, neither assumption has beenvalidated experimentally.

Mackowiak, P: CID 31(Supple 5): S185 9, 2000.

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The Downside of Antipyresis The febrile state is beneficial to the host Fever is rarely harmful Fever is a useful parameter to follow response to Rx Intermittent defervescence is uncomfortable Animal studies

decreased survival if febrile response to infection isablated 1 5

Human studies slower healing of varicella 6 and longer duration of

malaria 7 infection if antipyretics are given1ARRD 130:857-62, 1984. 2JID 155:991-7, 1987. 3J Vet Pharm Ther 1:69-76, 1978. 4Fed Proc 36:511, 1977.5Brain Res Bull 5:69-73,1980. 6Doran TF: J Ped 114:1045-8, 1989. 7Brandts CH: Lancet 350:705 9, 1997.

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Adverse Effects of Fever Central Nervous System

oC oF Consequences41 105.8 Delerium, seizures42 107.6 Coma, CNS damage41.6 42.0 106.9 7.6 Death (critical thermal max)*

Ox phos uncouples Other Consequences BMR 15% per 1 oC PR 15 bpm per 1 oC Muscle proteolysis for acute phase reactant synthesis Bone resorption > hypercalcuria

*Bynum GD: Am J Phys 235:R228 36, 1978.

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Fever vs. Hyperthermia Fever

Hypothalamic set point increased by cytokines Peripheral mechanisms generate and conserve heat

Response to antipyretics Hyperthermia

Hypothalamic set point is normal Peripheral mechanisms fail to match set point No response to antipyretics

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Marathon Hyperthermia

Finish Line, Chicago Marathon October 22, 2000

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Non Infectious Etiologies of Fever

CNS lesions Stroke, trauma, encephalitis High cord transection Autonomic neuropathy

Endocrine diseases Pheochromocytoma Thyrotoxicosis Addisons disease

Skin Diseases Ichthyosis Absent sweat glands

Miscellaneous Severe CHF Malignant hyperthermia Neuroleptic malignant

syndrome Vasculitides Malignancies Inflammatory bowel disease

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Causes of True Hyperthermia Increased Heat Production

Exertional hyperthermia Exertional heat stroke Malignant hyperthermia Neuroleptic malignant

syndrome Lethal catatonia Thyrotoxicosis Pheochromocytoma Delerium tremens Status epilepticus Tetanus

Drugs blockers Sympathomimetics Anti-cholinergics Salicylate toxicity

Decreased Heat Loss Classic heat stroke Occlusive dressings Dehydration Autonomic dysfunction

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Clinically Benign Fevers Diurnal variation Meals Ovulation Smoking Chewing gum/tobacco Exercise

Weinstein L: RID 7:692, 1985.

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Low Grade and High Grade FeversTemperature < 102 o Temperature > 102 o Acute cholecystitis CholangitisAcute MI PericarditisSimple phlebitis PyophlebitisPulmonary emboli Septic pulmonary emboli

Acute pancreatitis Abscess/infected pseudocystViral hepatitis (A E) Leptospirosis/drug feverWound infection SubQ abscess/Strep., V. vulnificusGastrointestinal bleed Bowel infarction

Cystitis PyelonephritisAtelectasis PneumoniaHematoma Infected hematoma

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The Isolated Fever Spike Manipulation of colonized surface

Wound debridement/irrigation Flushing of drainage devices Endoscopies Foley in or out Lines in or out

Blood/blood product transfusions

Contaminated infusates Human error

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Temperatures > 106 o

Central fever Drug fever Heat stroke Malignant hyperthermia Neuroleptic malignant syndrome Malaria

Smallpox

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Central Fever Reason Plateau fever curve Poor response to antipyretics Relative bradycardia No sweating

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Tumors Commonly Causing Fever Lymphomas

Hodgkins disease (IL 1, IL 6, TNF) Non- Hodgkins lymphoma (IL 1) Leukemias

AML, ALL, CML, HCL (IL 1) CLL (IL 1, IL 6) Adult T cell leukemia (IL 1)

Multiple myeloma (IL 1, IL 6)

Renal cell carcinoma (IL 6) Hepatoma, hepatoblastoma (IL 1) Atrial myxoma (IL 6) Melanoma (IL 1) Ovarian CA (IL 1) Transitional cell CA (IL 1) Osteogenic SA (IL 1) Malignant histiocytosis Metastatic tumors to liver

Dinarello CA: Sem Onc 24:288 98, 1997.