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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

• Clinical Approximates
– Sublingual (oral) temperature = 0.7o F < core
– Axillary temperature
= 1.8o F < core
– Rectal temperature
= 0.9o F > core

Normal Thermoregulation

Afferent Sensing

Central Integration

Efferent Responses

– Cold receptors –> A delta fibers
– Warm receptors –> C fibers
– Integrated in spinal cord and CNS –> hypothalamus
– 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
– 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.

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. beta) Interleukin–6 Interleukin–11 Tumor necrosis factor (alpha) Interferon (alpha.Endogenous Pyrogens • • • • • • • • • • • Interleukin–1 (alpha*. . beta. 1984.

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 .

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 .

The Structure of the Febrile State • 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 .

. 1997.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.

transthyretin. phospholipase A2. ferritin. factor B – Fibrinogen.Acute Phase Proteins (The concentration changes +/– 25%) • Increased in Sepsis • Decreased in Sepsis – Ceruloplasmin. Gabay C: NEJM 340:448-54. IL–1 receptor antagonist. lipopolysaccharide–binding protein. 2 macroglobulin. 2-HS glycopreotein. 1998. pancreatic secretory trypsin inhibitor. manose binding protein. vitronectin. C4b–binding lectin. C4. plasminogen. plasminogen activator inhibitor–1 – CRP. C1 inhibitor. 1–antichymotrypsin. haptoglobin – 1–protease inhibitor. 1-acid glycoprotein. hemopexin. C9. insulin–like growth factor. 1999 . protein S. TBG. transferrin. inter––trypsin inhibitors – C3. urokinase. TPA. serum amyloid A. FP. GCSF – Albumin. fibronectin. C4b–binding protein. Factor XII Mackowiak PA: Arch IM 158:1870–81.

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 .

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

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 .Antipyretic Drugs • Cyclo–oxygenase (COX) Inhibitors – Acetaminophen • Poor peripheral activity – 0.

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

1978. J Vet Pharm Ther 1:69-76. 1997.1980. .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 1 2 3 4 ARRD 130:857-62. 1989. 7Brandts CH: Lancet 350:705–9. JID 155:991-7. 6Doran TF: J Ped 114:1045-8. 1984. 1987. 5 Brain Res Bull 5:69-73. Fed Proc 36:511. 1977.

6 106.0 oF 105.6 • Other Consequences – – – – Consequences Delerium. CNS damage Death (critical thermal max)* Ox phos uncouples 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.Adverse Effects of Fever • Central Nervous System oC 41 42 41.6–42. 1978.8 107. .9–7. seizures Coma.

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 .Fever vs.

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

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

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

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

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

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

HCL (IL–1) – CLL (IL–1. TNF) – Non-Hodgkin’s lymphoma (IL–1) Leukemias – AML. 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. IL–6) – Adult T–cell leukemia (IL–1) Multiple myeloma (IL–1. ALL. IL–6) Renal cell carcinoma (IL–6) Hepatoma. CML. 1997.Tumors Commonly Causing Fever • • • • • • • • • • • • Lymphomas – Hodgkin’s disease (IL–1. . IL–6.