Pathophysiology

Fever

Fever
Fever is defined as an elevation in body temperature
resulting from disease
"Fever is merely a symptom and we are not sure that
it is an enemy. It may be a friend Dubois (1946)
"Fever, the Heat that Heals Benjamin (1959)
Body Temperature
Core Temperature = 37

0.5
o
C
Aortic blood temperature
Esophageal temperature
Clinical Approximates
Sublingual (oral) temperature = 0.7
o
F (0.3
o
C ) < core
Axillary temperature = 1.8
o
F (1
o
C ) < core
Rectal temperature = 0.9
o
F (0.5
o
C ) > core
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
Efferent Responses
Behavioral (clothing, adjusting environment)
Response to heat: sweat, cutaneous dilation
Response to cold: digital vasoconstriction (o
1,2
agonism)
Nonshivering thermogenesis (|
3
agonism)
Shivering
Sessler DI: NEJM 336:17307, 1997.
Endogenous Pyrogens
Interleukin1 (alpha*, beta)
Interleukin6
Interleukin11
Tumor necrosis factor (alpha)
Interferon (alpha, beta, gamma)
ProstaglandinE
2

Platelet activating factor
Ciliary neurotropic factor (CNTF)
Oncostatin M
Cardiotropin1
Leukemic inhibitory factor (LIF)
*first cloned by Auron PE: Proc Natl Acad Sci USA 81:790711, 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
Tcell proliferation
The Structure of the Febrile State
Endocrine/Metabolic
| CRH > ACTH > GC
| GH
| Aldosterone
| Insulin (if available)
| Glucagon
| Acute phase reactants

+/N TSH
Autonomic
Cutaneous vasoconstriction
| PR
| BP
+ Sweating
Behavioral
Seek warmth
Shivering
Anorexia
Somnolence
Malaise
Cytokines Inducing Acute Phase Reactants
Interleukin1
Interleukin6
Interleukin11
Tumor Necrosis Factor
OncostatinM
Ciliary Neurotrophic Factor
Cardiotropin1
Leukemic Inhibitory Factor
Dinarello CA: Sem Onc 24:28898, 1997.
Acute Phase Proteins
(The concentration changes +/ 25%)
Increased in Sepsis
Ceruloplasmin, ferritin, hemopexin, haptoglobin
o1protease inhibitor, o1antichymotrypsin, pancreatic secretory
trypsin inhibitor, interotrypsin 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, o1-acid glycoprotein, o2 macroglobulin,
phospholipase A2, fibronectin, manose binding protein,
lipopolysaccharidebinding protein, IL1 receptor antagonist, GCSF
Decreased in Sepsis
Albumin, transthyretin, transferrin, o2-HS glycopreotein, oFP, TBG,
insulinlike growth factor, Factor XII
Mackowiak PA: Arch IM 158:187081, 1998. Gabay C: NEJM 340:448-54, 1999
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
Physiologic changes
Decreased BMR
Late, less efficient shivering
Autonomic neuropathy
Decreased temperature perception
Decreased production of endogenous pyrogens
Intrinsic Antipyretics
Somatostatin
Melanocytestimulating factor
Vasopressin
CRH>ACTH>GC
Thyroliberin (TRH,TRF)
GIP
Neuropeptide Y
Bombesin
IL1ra, soluble TNF receptor
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 ablated
1
5

Human studies
slower healing of varicella
6
and longer duration of malaria
7

infection if antipyretics are given
1
ARRD 130:857-62, 1984.
2
JID 155:991-7, 1987.
3
J Vet Pharm Ther 1:69-76, 1978.
4
Fed Proc 36:511, 1977.
5
Brain Res Bull 5:69-73,1980.
6
Doran TF: J Ped 114:1045-8, 1989.
7
Brandts CH: Lancet 350:7059, 1997.
Adverse Effects of Fever
Central Nervous System
o
C
o
F 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 13-15% per 1
o
C
| PR 7-10 bpm per 1
o
C **
Muscle proteolysis for acute phase reactant synthesis
| Bone resorption > hypercalcuria
*Bynum GD: Am J Phys 235:R22836, 1978.
** Davies P:Emerg Med J 2009;26:9 641-643
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
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
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
Clinically Benign Fevers
Diurnal variation
Meals
Ovulation
Smoking
Chewing gum/tobacco
Exercise
Weinstein L: RID 7:692, 1985.
Low Grade and High Grade Fevers
Temperature < 39
o
Temperature > 39
o

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
The Isolated Fever Spike
Manipulation of colonized surface
Wound debridement/irrigation
Flushing of drainage devices
Endoscopies
Foley in or out
Blood/blood product transfusions
Contaminated infusates
Temperatures > 41
o
Central fever
Drug fever
Heat stroke
Malignant hyperthermia
Neuroleptic malignant syndrome
Malaria
Smallpox
Central Fever
Plateau fever curve
Poor response to antipyretics
Relative bradycardia
No sweating
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
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 24:28898, 1997.