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Fever Clinical Pathophysiology
September 7, 2005
Fred Arthur Zar, MD, FACPProfessor of Clinical Medicine
University of Illinois at [email protected]
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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.