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
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Afferent Sensing
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Central Integration
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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.
Endogenous Pyrogens
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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.
Pyrogenic Cytokine Producing Cells
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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
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Endocrine/Metabolic
CRH –> ACTH –> GC
GH
Aldosterone
Insulin (if available)
Glucagon
Acute phase reactants
TSH
ADH
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Autonomic
Cutaneous vasoconstriction
PR
BP
Sweating
Behavioral
Seek warmth (chill)
Shivering (rigor)
Anorexia
Somnolence
Malaise
Cytokines Inducing Acute Phase Reactants
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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.
Acute Phase Proteins
(The concentration changes +/– 25%)
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Increased in Sepsis
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Decreased 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
– 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
Afebrile Infections in the Elderly
• Incidence
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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
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Decreased BMR
Late, less efficient shivering
Autonomic neuropathy
Decreased temperature perception
Decreased production of endogenous pyrogens
Intrinsic Antipyretics
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Somatostatin
Melanocyte–stimulating factor
Vasopressin
CRH–>ACTH–>GC
Thyroliberin
GIP
Neuropeptide Y
Bombesin
IL–1ra, soluble TNF receptor
Antipyretic Drugs
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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
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– Acetylsalacyclic acid (ASA)
– Other NSAIDs
Corticosteroids
– Inhibit phospholipase A2 –> PGE2 synthesis
– Block mRNA transcription of pyrogenic cytokines
Phenothiazines
– Block peripheral vasoconstriction
“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.
The Downside of Antipyresis
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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
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ARRD 130:857-62, 1984. JID 155:991-7, 1987. J Vet Pharm Ther 1:69-76, 1978. Fed Proc 36:511, 1977.
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Brain Res Bull 5:69-73,1980. 6Doran TF: J Ped 114:1045-8, 1989. 7Brandts CH: Lancet 350:705–9, 1997.
Adverse Effects of Fever
• Central Nervous System
oC
41
42
41.6–42.0
oF
105.8
107.6
106.9–7.6
• Other Consequences
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Consequences
Delerium, seizures
Coma, 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, 1978.
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
Marathon Hyperthermia
Finish Line, Chicago Marathon October 22, 2000
Non–Infectious Etiologies of “Fever”
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CNS lesions
– Stroke, trauma, encephalitis
– High cord transection
– Autonomic neuropathy
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Endocrine diseases
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Skin Diseases
– Pheochromocytoma
– Thyrotoxicosis
– Addison’s disease
– Ichthyosis
– Absent sweat glands
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Miscellaneous
– Severe CHF
– Malignant hyperthermia
– Neuroleptic malignant
syndrome
– Vasculitides
– Malignancies
– Inflammatory bowel disease
Causes of True Hyperthermia
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Increased Heat Production
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Exertional hyperthermia
Exertional heat stroke
Malignant hyperthermia
Neuroleptic malignant
syndrome
Lethal catatonia
Thyrotoxicosis
Pheochromocytoma
Delerium tremens
Status epilepticus
Tetanus
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Drugs
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ß–blockers
Sympathomimetics
Anti-cholinergics
Salicylate toxicity
Decreased Heat Loss
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Classic heat stroke
Occlusive dressings
Dehydration
Autonomic dysfunction
Clinically Benign Fevers
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Diurnal variation
Meals
Ovulation
Smoking
Chewing gum/tobacco
Exercise
Weinstein L: RID 7:692, 1985.
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., V. vulnificus
Bowel infarction
Pyelonephritis
Pneumonia
Infected hematoma
The Isolated Fever Spike
• Manipulation of colonized surface
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Wound debridement/irrigation
Flushing of drainage devices
Endoscopies
Foley in or out
Lines in or out
• Blood/blood product transfusions
• Contaminated infusates
• Human error
Temperatures >
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o
106
Central fever
Drug fever
Heat stroke
Malignant hyperthermia
Neuroleptic malignant syndrome
Malaria
Smallpox
Central Fever
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Reason
Plateau fever curve
Poor response to antipyretics
Relative bradycardia
No sweating
Mechanisms of Drug Fever
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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
Tumors Commonly Causing Fever
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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.