Etiology: What Triggers Fever?
The development of fever is always caused by pyrogens. According to their origin, they are divided into two major groups:
- Primary pyrogens. These can be exogenous (infectious) or endogenous (aseptic).
- Infectious agents are collectively referred to as PAMPs (pathogen-associated molecular patterns). These include components of viruses, fungi, and bacteria. Lipopolysaccharide (LPS) of gram-negative bacteria possesses the highest pyrogenicity, specifically its Lipid A component.
- Endogenous pyrogens are DAMPs (damage-associated molecular patterns). These include DNA, ATP, or heat shock proteins released into the extracellular space when host cells are destroyed. They cause aseptic fever during myocardial infarctions, trauma, tumor lysis, or hemolysis.
- Secondary pyrogens. These are pro-inflammatory cytokines (IL-1, IL-6, TNF, interferon-gamma). Primary pyrogens do not alter temperature directly; their primary role is to induce immune cells (macrophages, monocytes) to synthesize secondary pyrogens.
How does this work at the cellular level? Bacterial LPS binds to the TLR-4 receptor on the macrophage membrane. This signal activates the NF-κB transcription factor and triggers the assembly of the inflammasome within the cell. Inside it, the enzyme caspase-1 cleaves a fragment from pro-interleukin-1, converting it into active IL-1 — a potent endogenous pyrogen.
Pathogenesis: Shifting the 'Set Point'
Secondary pyrogens reach the brain via the bloodstream. In the region of the vascular organ of the lamina terminalis, they cross the blood-brain barrier and act on neurons of the preoptic and anterior areas of the hypothalamus.
A biochemical cascade is initiated here:
- Phospholipase A2 is activated.
- Arachidonic acid metabolism is triggered.
- Under the action of the enzyme cyclooxygenase (COX), prostaglandin E2 (PGE2) is synthesized.
PGE2 increases cAMP levels in neurons, altering their excitability thresholds. Warm-sensitive neurons decrease their activity, while cold-sensitive neurons increase theirs. As a result, the thermoregulatory center perceives normal blood temperature as too low and shifts the set point upward.
Stage I: Temperature Elevation
In the first stage (stadium incrementi), the body strives to warm up rapidly to the new set point. To achieve this, the thermal balance changes radically: heat production begins to dominate over heat loss.
Activation of Heat Production:
- Shivering thermogenesis: the hypothalamus sends signals to muscles, causing involuntary contractions at a frequency of 10–20 Hz. Muscle shivering occurs. No external mechanical work is performed, and all energy is dissipated as rapid body warming.
- Non-shivering thermogenesis: metabolic reactions in the liver and other organs accelerate. In newborns, the breakdown of brown adipose tissue plays a major role here.
Reduction of Heat Loss: getCNS sympathetic-adrenal activation causes generalized constriction of skin arterioles. Blood filling of peripheral vessels drops, and the skin becomes pale and cold.
Cooling of the skin stimulates cold receptors, which the patient subjectively experiences as chills. To minimize the surface area available for heat loss, the person reflexively adopts the fetal position (curls up).
Stage II: Temperature Plateau
When body temperature reaches the new set point, the second stage begins. A new balance is established: intense heat production is counterbalanced by equivalent heat loss, but at a higher level.
Adrenergic influences are replaced by cholinergic ones. Vascular spasm subsides, skin arterioles dilate, and arterial hyperemia develops — the patient's skin becomes hot and red. Metabolic rate decreases slightly, and sweating increases to prevent overheating above the hypothalamic set point.
Fever dynamics at this stage are strictly individual:
- Microorganism properties (infectious agent) determine the duration and pattern of the fever because they dictate the rhythm of pyrogen release.
- Host properties (patient) determine how high the temperature will rise.