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Fever Clinical Pathophysiology September 7, 2005

Fever Clinical Pathophysiology September 7, 2005. Fred Arthur Zar, MD, FACP Professor of Clinical Medicine University of Illinois at Chicago fazar@uic.edu. Body Temperature. “ Core Temperature ” Aortic blood temperature Esophageal temperature Tympanic membrane temperature

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Fever Clinical Pathophysiology September 7, 2005

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  1. FeverClinical PathophysiologySeptember 7, 2005 Fred Arthur Zar, MD, FACP Professor of Clinical Medicine University of Illinois at Chicago fazar@uic.edu

  2. Body Temperature • “Core Temperature” • Aortic blood temperature • Esophageal temperature • Tympanic membrane temperature • Clinical Approximates • Sublingual (oral) temperature = 0.7o F < core • Axillary temperature = 1.8o F < core • Rectal temperature = 0.9o F > core

  3. 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 0.4º 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.

  4. Endogenous Pyrogens • Interleukin–1 (alpha*, beta) • Interleukin–6 • Interleukin–11 • Tumor necrosis factor (alpha) • Interferon (alpha, beta, gamma) • Prostaglandin–E2 • 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.

  5. 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

  6. 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

  7. Endocrine/Metabolic CRH –> ACTH –> GC GH Aldosterone Insulin (if available) Glucagon Acute phase reactants TSH ADH Autonomic Cutaneous vasoconstriction PR BP Sweating Behavioral Seek warmth (chill) Shivering (rigor) Anorexia Somnolence Malaise The Structure of the Febrile State

  8. 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.

  9. 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, TBG, insulin–like growth factor, Factor XII Mackowiak PA: Arch IM 158:1870–81, 1998. Gabay C: NEJM 340:448-54, 1999

  10. 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

  11. Intrinsic Antipyretics • Somatostatin • Melanocyte–stimulating factor • Vasopressin • CRH–>ACTH–>GC • Thyroliberin • GIP • Neuropeptide Y • Bombesin • IL–1ra, soluble TNF receptor

  12. 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 PGE2 synthesis • 10% as active as indomethacin • Acetylsalacyclic acid (ASA) • Other NSAIDs • Corticosteroids • Inhibit phospholipase A2 –> PGE2 synthesis • Block mRNA transcription of pyrogenic cytokines • Phenothiazines • Block peripheral vasoconstriction

  13. “Two critical assumptions are made when prescribing antipyretic therapy. One is that fever is, at least in part, noxious, and the other is that suppression of fever will reduce, if not eliminate, the noxious effects of fever. At present, neither assumption has been validated experimentally”. Mackowiak, P: CID 31(Supple 5): S185–9, 2000.

  14. 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 is ablated1–5 • Human studies • slower healing of varicella6 and longer duration of malaria7 infection if antipyretics are given 1ARRD 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.

  15. Adverse Effects of Fever • Central Nervous System oC oF Consequences 41 105.8 Delerium, seizures 42 107.6 Coma, CNS damage 41.6–42.0 106.9–7.6 Death (critical thermal max)* Ox phos uncouples • Other Consequences • BMR 15% per 1oC • PR 15 bpm per 1oC • Muscle proteolysis for acute phase reactant synthesis • Bone resorption –> hypercalcuria *Bynum GD: Am J Phys 235:R228–36, 1978.

  16. 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

  17. Marathon Hyperthermia Finish Line, Chicago Marathon October 22, 2000

  18. CNS lesions Stroke, trauma, encephalitis High cord transection Autonomic neuropathy Endocrine diseases Pheochromocytoma Thyrotoxicosis Addison’s disease Skin Diseases Ichthyosis Absent sweat glands Miscellaneous Severe CHF Malignant hyperthermia Neuroleptic malignant syndrome Vasculitides Malignancies Inflammatory bowel disease Non–Infectious Etiologies of “Fever”

  19. Increased Heat Production Exertional hyperthermia Exertional heat stroke Malignant hyperthermia Neuroleptic malignant syndrome Lethal catatonia Thyrotoxicosis Pheochromocytoma Delerium tremens Status epilepticus Tetanus Drugs ß–blockers Sympathomimetics Anti-cholinergics Salicylate toxicity Decreased Heat Loss Classic heat stroke Occlusive dressings Dehydration Autonomic dysfunction Causes of True Hyperthermia

  20. Clinically Benign Fevers • Diurnal variation • Meals • Ovulation • Smoking • Chewing gum/tobacco • Exercise Weinstein L: RID 7:692, 1985.

  21. Low Grade and High Grade Fevers Temperature < 102oTemperature > 102o Acute cholecystitis Cholangitis Acute MI Pericarditis Simple phlebitis Pyophlebitis Pulmonary emboli Septic pulmonary emboli Acute pancreatitis Abscess/infected pseudocyst Viral hepatitis (A–E) Leptospirosis/drug fever Wound infection SubQ abscess/Strep., V. vulnificus Gastrointestinal bleed Bowel infarction Cystitis Pyelonephritis Atelectasis Pneumonia Hematoma Infected hematoma

  22. 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

  23. Temperatures > 106o • Central fever • Drug fever • Heat stroke • Malignant hyperthermia • Neuroleptic malignant syndrome • Malaria • Smallpox

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

  25. Mechanisms of Drug Fever • Hypersensitivity Reactions • Drug as hapten, tissue binding, cell mediated • Idiosyncratic Mechanisms • Malignant hyperthermia, neuroleptic malignant syndrome • Altered Thermoregulatory Mechanisms • Thyroxine, sympathomimetics, anticholinergics, MAOI • Cytolysis • Jarisch–Herxheimer reaction • Cancer chemotherapy • G6PD induced hemolysis • Administration Related Fever • Endotoxin in drug/vaccine • Amphotericin B, bleomycin • Phlebitis, IM induced abscess

  26. Tumors Commonly Causing Fever • Lymphomas • Hodgkin’s disease (IL–1, IL–6, TNF) • Non-Hodgkin’s 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.

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