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 ± 0.5oC
 – Aortic blood temperature
 –
Esophageal temperature
• Clinical Approximates
 – Sublinguall (oral) temperature
Sublingua = 0.7o  F (0.3 oC ) < core
 –
Axillary temperature = 1.8o F (1 oC ) < core
 – Rectal temperature = 0.9o F (0.5 oC ) > core
 

Normal Thermoregulation
•

Afferent
 –
Sensing
Cold receptors –> A delta fibers
 – Warm receptors –> C fibers
 – Integrated
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
predominates behavioral responses
• Efferent
Efferent Responses
Respon ses
 –
Behavioral (clothing, adjusting environment)
Behavioral environment)
 – Response to heat: sweat, cutaneous dilation
 – Response to cold: digital vasoconstriction ( –agonism)
Nonshivering thermogenesis ( –agonism)
Shivering

Sessler DI: NEJM 336:1730 – 7,

7, 1997.
 

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,
11, 1984.
 

Pyrogenic
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
migration
 –
Enhanced superoxide production
• Mononuclear function
 – Enhanced interferon production
•
Enhanced interferon
interferon tumor and viral activity
 – T –cell proliferation
 

The Structure of the Febrile State 

• Endocrine/Metabolic • Autonomic
Cutaneous vasoconstriction
vasoconstriction
 CRH –> ACTH –> GC
 PR
 GH
 Aldosterone  BP
 Sweating
 Insulin (if available) • Behavioral
 Glucagon Seek warmth

 Acute phase reactants Shivering

Anorexia
Somnolence
/N TSH Malaise
 

Cytokines Inducing Acute Phase Reactants

Reactants
• Interleukin –1
• Interleukin –6
•

Interleukin –11
• Tumor Necrosis Factor
• Oncostatin –M
•

Ciliary Neurotr
Neurotrophic
ophic Factor
• Cardiotropin –1
• Leukemic Inhibitory Factor

Dinarello CA: Sem Onc 24:288 – 98,

98, 1997.
 

Acute Phase Proteins

(The concentration changes +/ – 25%) 
• Increased in Sepsis
 –  Ceruloplasmin, ferritin, hemopexin, haptoglobin
 –  1 –protease inhibitor, 1 –antichymo
antichymotrypsin,
trypsin, pancreatic secretory
trypsin inhibitor, inter – –trypsin inhibitors
 –
 C3, C4, C9, C1 inhibitor, C4b –binding protein, C4b –binding lectin, factor B
 –  Fibrinogen, plasminogen, TPA,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, Factor XII
X II

Mackowiak PA: Arch IM 158:1870 – 81,

81, 1998. Gabay C: NEJM 340:448-54, 1999
 

Afebrile Infections
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
 – Physiologic changes
• Decreased BMR
• Late, less efficient shivering
•
Autonomic neuropathy
• Decreased temperature perception
• Decreased production of endogenous pyrogens
pyrogens
 

Intrinsic Antipyretics
• Somatostatin
• Melanocyte –stimulating factor
•

Vasopressin
• CRH –>ACTH –>GC
• Thyroliberin (TRH,TRF)
•

GIP
• Neuropeptide
Neuropeptide Y
• Bombesin
•

IL –1ra, 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 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, 1984. JID 155:991-7, 1987. J Vet Pharm Ther 1:69-76, 1978. Fed Proc 36:511, 1977.
5
Brain Res Bull 5:69-73,1980. 6Doran TF: J Ped 114:1045-8, 1989. 7Brandts CH: Lancet 350:705 – 9,
9, 1997. 
1997. 
 

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
 –
o

 –
   BMR 13-15%
PR 7-10 per 1
bpm per 1oC
C **
 –  Muscle proteolysis for acute phase reactant synthesis
 –   Bone resorption –> hypercalcuria

*Bynum GD: Am J Phys 235:R228 – 36,

36, 1978.
** Davies P:Emerg Med J 2009;26:9 641-643  
 

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
 

Non –Inf
 –Infectious
ectious Etiologies of “Fever” 
“Fever”

• CNS lesions • Miscellaneous

 – Stroke, trauma, encephalitis
Stroke,  – Severe CHF
 – High cord transection
 – Malignant hyperthermia
 –
Autonomic neuropathy  – Neuroleptic malignant syndr
• Endocrine diseases
 – Pheochromocytoma  – Vasculitides
 – Thyrotoxicosis  – Malignancies
 –  –
Addison’s disease  Inflammatory
Inflammatory bowel disease
diseas e
• Skin Diseases
 – Ichthyosis
 – Absent sweat glands

Causes of True Hyperthermia 
• Increased Heat Production
 – Exertional hyperthermia
 – Exertional heat stroke
 – Malignant hyperthermia
 – Neuroleptic malignant syndrome
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
 

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 < 39o Temperature > 39o 
Acute cholecystitis Cholangitis
Acute MI Pericarditis
Simple phlebitis Pyophlebitis
Pulmonary emboli Septic pulmonary emboli
Acute pancreatitis Abscess/inf
Abscess/infected
ected pseudocyst
Viral hepatitis (A –E) Leptospirosis/drug fev
fever
er
Wound infection SubQ abscess/Strep., V. vulnif
vulnificus
icus
Gastrointestinal bleed Bowel infarction
Cystitis Pyelonephritis
Atelectasis Pneumonia
Hematoma Infected hematoma
 

The Isolated Fever Spik

Spike
e 
• Manipulation of colonized surface
surface
 – Wound debridement/irrigation
 –
Flushing of drainage devices
 – Endoscopies
 – Foley in or out
•
Blood/blood product transfus
transfusions
ions
• Contaminated infusates
 

Temperatures > 41o 

• Central fever
• Drug fever
• Heat stroke
• Malignant hyperth
hyperthermia
ermia
•

Neuroleptic malignant syndrome

• Malaria
• Smallpox
 

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

Mechanisms of Drug Fever 

•

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

Tumors Common
Commonly
ly Cau
Causing
sing Fever
•
Lymphomas
 – Hodgkin’s disease (IL–1, IL –6, TNF)
 – Non-Hodgkin’
Hodgkin’ss lymphoma (IL–1)
• Leukemias
 – AML, ALL, CML, HCL (IL –1)
 –

 –
CLL
Adult(IL –
T –1,cell
IL –leukemia
6) (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