Fever Clinical Pathophysiology September 7, 2005

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Fever Clinical PathophysiologySeptember 7, 2005

• Fred Arthur Zar, MD, FACP
• Professor of Clinical Medicine
• University of Illinois at Chicago
• fazar_at_uic.edu

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Body Temperature

• Core Temperature
• Aortic blood temperature
• Esophageal temperature
• Tympanic membrane temperature
• Clinical Approximates
• Sublingual (oral) temperature 0.7o F lt core
• Axillary temperature 1.8o F lt core
• Rectal temperature 0.9o F gt core

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Normal Thermoregulation

• Afferent Sensing
• Cold receptors gt A delta fibers
• Warm receptors gt C fibers
• Integrated in spinal cord and CNS gt 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 33617307, 1997.
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Endogenous Pyrogens

• Interleukin1 (alpha, beta)
• Interleukin6
• Interleukin11
• Tumor necrosis factor (alpha)
• Interferon (alpha, beta, gamma)
• ProstaglandinE2
• Platelet activating factor
• Ciliary neurotropic factor (CNTF)
• Oncostatin M
• Cardiotropin1
• Leukemic inhibitory factor (LIF)

first cloned by Auron PE Proc Natl Acad Sci USA
81790711, 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
• Tcell proliferation

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The Structure of the Febrile State

• Endocrine/Metabolic
• ??CRH gt ACTH gt 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

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Cytokines Inducing Acute Phase Reactants

• Interleukin1
• Interleukin6
• Interleukin11
• Tumor Necrosis Factor
• OncostatinM
• Ciliary Neurotrophic Factor
• Cardiotropin1
• Leukemic Inhibitory Factor

Dinarello CA Sem Onc 2428898, 1997.
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Acute Phase Proteins(The concentration changes
/ 25)

• Increased in Sepsis
• Ceruloplasmin, ferritin, hemopexin, haptoglobin
• ?1protease inhibitor, ?1antichymotrypsin,
  pancreatic secretory trypsin inhibitor,
  inter?trypsin inhibitors
• C3, C4, C9, C1 inhibitor, C4bbinding protein,
  C4bbinding lectin, factor B
• Fibrinogen, plasminogen, TPA, urokinase, protein
  S, vitronectin, plasminogen activator inhibitor1
• CRP, serum amyloid A, ?1-acid glycoprotein, ?2
  macroglobulin, phospholipase A2, fibronectin,
  manose binding protein, lipopolysaccharidebindi
  ng protein, IL1 receptor antagonist, GCSF
• Decreased in Sepsis
• Albumin, transthyretin, transferrin, ?2-HS
  glycopreotein, ?FP, TBG, insulinlike growth
  factor, Factor XII

Mackowiak PA Arch IM 158187081, 1998. Gabay C
NEJM 340448-54, 1999
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Afebrile Infections in the Elderly

• Incidence
• Bacteremia 531
• Endocarditis 721
• Pneumonia 2056
• 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
• Melanocytestimulating factor
• Vasopressin
• CRHgtACTHgtGC
• Thyroliberin
• GIP
• Neuropeptide Y
• Bombesin
• IL1ra, soluble TNF receptor

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Antipyretic Drugs

• Cyclooxygenase (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 gt ?PGE2 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
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) S1859, 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 is ablated15
• Human studies
• slower healing of varicella6 and longer duration
  of malaria7 infection if antipyretics are given

1ARRD 130857-62, 1984. 2JID 155991-7, 1987. 3J
Vet Pharm Ther 169-76, 1978. 4Fed Proc 36511,
1977. 5Brain Res Bull 569-73,1980. 6Doran TF J
Ped 1141045-8, 1989. 7Brandts CH Lancet
3507059, 1997.
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Adverse Effects of Fever

• Central Nervous System
• oC oF Consequences
• 41 105.8 Delerium, seizures
• 42 107.6 Coma, CNS damage
• 41.642.0 106.97.6 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 gt hypercalcuria

Bynum GD Am J Phys 235R22836, 1978.
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Fever vs. Hyperthermia

• Fever
• Hypothalamic setpoint increased by cytokines
• Peripheral mechanisms generate and conserve heat
• Response to antipyretics
• Hyperthermia
• Hypothalamic setpoint is normal
• Peripheral mechanisms fail to match setpoint
• No response to antipyretics

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Marathon Hyperthermia
Finish Line, Chicago Marathon October 22, 2000
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NonInfectious 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
• ßblockers
• 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 7692, 1985.
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Low Grade and High Grade Fevers

• Temperature lt 102o Temperature gt 102o
• Acute cholecystitis Cholangitis
• Acute MI Pericarditis
• Simple phlebitis Pyophlebitis
• Pulmonary emboli Septic pulmonary emboli
• Acute pancreatitis Abscess/infected pseudocyst
• Viral hepatitis (AE) Leptospirosis/drug fever
• Wound infection SubQ abscess/Strep., V.
  vulnificus
• Gastrointestinal bleed Bowel infarction
• Cystitis Pyelonephritis
• Atelectasis Pneumonia
• Hematoma 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 gt 106o

• 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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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
• JarischHerxheimer reaction
• Cancer chemotherapy
• G6PD induced hemolysis
• Administration Related Fever
• Endotoxin in drug/vaccine
• Amphotericin B, bleomycin
• Phlebitis, IM induced abscess

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Tumors Commonly Causing Fever

• Lymphomas
• Hodgkins disease (IL1, IL6, TNF)
• Non-Hodgkins lymphoma (IL1)
• Leukemias
• AML, ALL, CML, HCL (IL1)
• CLL (IL1, IL6)
• Adult Tcell leukemia (IL1)
• Multiple myeloma (IL1, IL6)
• Renal cell carcinoma (IL6)
• Hepatoma, hepatoblastoma (IL1)
• Atrial myxoma (IL6)
• Melanoma (IL1)
• Ovarian CA (IL1)
• Transitional cell CA (IL1)
• Osteogenic SA (IL1)
• Malignant histiocytosis
• Metastatic tumors to liver

Dinarello CA Sem Onc 2428898, 1997.