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Fever Definition

Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypothalamic set point (e.g., from 37°C to 39°C).

Fever is one of several innate immune responses mediated by cytokines, whose release is triggered by infection



Exogenous pyrogens (foreign substances from outside a patient that induce pyrogenic cytokine production)
Microbial macromolecules from infections or as contaminants in intravenous fluids or drugs

Pyrogenic cytokines (endogenous pyrogens) released from immune cells in response to infection or other exogenous pyrogens, inflammatory disease, tissue trauma, immune-complex disease



Small (10-30kDa) proteins secreted from immune and non-immune cells that regulate inflammation, immune responses, and hematopoiesis.

Normally produced at low levels, locally, transiently

Higher, systemic, and persistent levels are associated with disease states

Biological activities:
Pro-inflammatory cytokines (includes pyrogenic cytokines)
Anti-inflammatory cytokines
Growth and differentiation factors for many cell types


Endogenous Pyrogens

IL-1: most potent endogenous pyrogen in humans

TNF alpha: soluble and membrane bound forms

IL-6: acts distally of TNF and IL-1 in cytokine cascade

Ciliary Neurotropic Factor (CNTF): low activity
IFN alpha: low activity


Recognition of Exogenous Microbial Pyrogens by Immune Cells

Microbes express “conserved molecular patterns” not found in self tissues

Phagocytes (macrophages) recognize pathogen-associated molecular patterns (PAMPs) via “pattern recognition receptors” such as Toll-like receptors (TLR); TLR binding to PAMPs signals pyrogenic cytokine gene expression

TLR ligation stimulates macrophage production and secretion of proinflammatory and pyrogenic cytokines


Exogenous Pyrogens from Microbes

Gram-negative bacteria:
Lipopolysaccharide (LPS), lipoproteins, peptidoglycan, flagellin, bacterial DNA (unmethylated CpG motifs)

Gram-positive bacteria:
Peptidoglycan, lipoteichoic acid, lipoproteins, bacterial DNA (unmethylated CpG-containing oligonucleotides), superantigens

Viruses: double stranded RNA, superantigens

Fungi/parasites: glucan/mannan cell walls



LPS is a conserved cell wall structure in gram-negative bacteria = bacterial “endotoxin”
Very potent exogenous pyrogen
LPS from growing or dead bacteria is a ubiquitous environmental contaminant in water and must be removed from any intravenously administered fluids to render them “nonpyrogenic”.


Endotoxin vs. Exotoxin

Endotoxin: structural component of the microbe and released only when microbe dies; not secreted toxin

Exotoxin: released into the ECM by the bacterial cell



Microbial patterns trigger inflammasome formation and caspase-1 activation

Caspase-1 converts pro-IL1b into active IL1b

Inflammasome: chronic fevers because of chronic activation

Auto-inflammatory disorders: inflammosomes are always active from some reaction and have chronic fever response

A result of some of these cytoplasmic TLRs, some of them assemble into inflammosome and go from pro-IL1 to IL-1 beta; other things can signal this response other than an infection



Exogenous microbial pyrogens that activate lymphocytes to release pyrogenic cytokines

Proteins that nonspecifically bind and activate T lymphocytes via TcR resulting in large amounts of cytokine production

Both viral and bacterial superantigens exist

Many staphylococcal and streptococcal toxins (enterotoxins, pyrogenic exotoxins) associated with “toxic shock” syndromes are superantigens


Alternative Models for Fever via Local Production and Action of Cytokines

Cytokines released locally by infected tissues:
Stimulate release of phospholipase A2 into circulation causing PG release in brain
Stimulate primary vagal nerve terminals in liver which trigger norepinephrine and then PG in the brain

Cytokines produced locally by brain endothelium following binding by activated monocytes or exogenous pyrogens


Anti-Pyretic Actions

Inhibition of cyclooxygenases (synthesize PGE2)
aspirin, acetaminophen, NSAIDS

Inhibition of phospholipases (release arachidonic acid needed for PGE2 synthesis): glucocorticoids

Inhibition of cytokine gene expression: glucocorticoids

Neutralization of cytokines: anti-cytokine antibodies, cytokine receptor antagonists