Etiology: what triggers a fever?
The development of fever is always triggered by pyrogens. By origin, they are divided into two large groups:
- Primary pyrogens. These can be exogenous (infectious) and endogenous (aseptic).
- Infectious agents are collectively termed PAMPs (pathogen-associated molecular patterns). These include components of viruses, fungi, and bacteria. The highest pyrogenic activity is exhibited by lipopolysaccharide (LPS) of Gram-negative bacteria, specifically its component Lipid A.
- Endogenous pyrogens are DAMPs (damage-associated molecular patterns). These include DNA, ATP, or heat shock proteins released into the intercellular space upon the destruction of the body's own cells. They cause aseptic fever in myocardial infarction, 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 by themselves; their main task 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 transcription factor NF-κB and triggers the assembly of the inflammasome inside the cell. Within it, the enzyme caspase-1 cleaves the extra fragment from pro-interleukin-1, converting it into active IL-1 — a potent endogenous pyrogen.
Pathogenesis: how the “set point” shifts
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 in the preoptic and anterior areas of the hypothalamus.
This initiates a biochemical cascade:
- Phospholipase A2 is activated.
- Arachidonic acid metabolism is initiated.
- Under the action of the enzyme cyclooxygenase (COX), prostaglandin E2 (PGE2) is synthesized.
PGE2 increases cAMP levels in neurons, altering their excitability thresholds. Heat-sensitive neurons decrease their activity, while cold-sensitive neurons increase theirs. As a result, the thermoregulatory center begins to perceive normal blood temperature as too low and shifts the “set point” (set point) upward.
Stage I: Temperature rise
In the first stage (stadium incrementi), the body strives to heat up rapidly to the new “set point”. To achieve this, the heat balance changes radically: heat production begins to dominate over heat loss.
Activation of heat production:
- Shivering thermogenesis: the hypothalamus sends signals to the muscles, causing involuntary contractions at a frequency of 10–20 times per second. Muscle shivering occurs. No external work is performed, and all energy goes into rapidly warming the body.
- Non-shivering thermogenesis: metabolic reactions accelerate in the liver and other organs. In newborns, the cleavage of brown adipose tissue plays the main role here.
Reduction of heat loss: The sympathoadrenal system causes a generalized spasm of skin arterioles. Blood filling of peripheral vessels decreases, the skin becomes pale and cold.
Lowering of skin temperature stimulates cold receptors, which is subjectively perceived by the patient as chills. To reduce the surface area for heat loss, the person reflexively adopts a fetal position (curls up).
Stage II: Temperature plateau
When body temperature reaches the new “set point”, the second stage begins. Here, a new balance is established: intense heat production is balanced 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 intensity decreases slightly, and sweating increases to prevent overheating above the level set by the hypothalamus.
The dynamics of fever at this stage is strictly individual:
- Properties of the microorganism (infectious agent) determine the duration and pattern of the fever, as the rhythm of pyrogen release depends on them.
- Properties of the macroorganism (patient) determine how high the temperature will rise.
Briefly: answers to topical questions
What are the stages of fever and what is the third stage called?
There are three stages of fever. The third stage is called the stage of temperature defervescence.
- Stage I (st. incrementi) — temperature rise.
- Stage II — elevated temperature (temperature plateau).
- Stage III (st. decrementi) — temperature drop to the normal range.
What is the difference between critical and lytic temperature drop?
The difference lies in the speed of the process and the prognosis for the body.
| Criterion | Lytic drop (lysis) | Critical drop (crisis) |
|---|---|---|
| Speed | Gradual, over several days | Rapid, within a few hours |
| Features | Occurs more frequently, more favorable for the body | Sharp activation of heat loss. May lead to collapse due to a drop in blood pressure |
What types of temperature curves occur in fever?
There are three main types of temperature curves:
- Continuous fever (febris continua) — the daily fluctuation range does not exceed 1 °C.
- Remittent fever (febris remittens) — daily fluctuations exceed 1 °C, while the temperature does not return to the normal range.
- Intermittent fever (febris intermittens) — daily fluctuations are 1–2 °C, the temperature may normalize for several hours and then rise again.
What is the difference between fever and hyperthermia?
The main difference lies in the mechanism of development and biological significance.
| Criterion | Fever | Exogenous hyperthermia |
|---|---|---|
| Cause | Pyrogens | High ambient temperature |
| Key mechanism | Temporary dynamic restructuring of the thermoregulatory system (shift of the “set point”) | Failure of the body's adaptation mechanisms to the action of exogenous heat |
| Diurnal variations | Preserved | Absent |
| Biological significance | Protective, adaptive response | Pathological process, result of thermoregulation failure |
Pathogenetic chain of fever: PPCC 1. Primary pyrogens (PAMPs/DAMPs) 2. Cytokines (secondary pyrogens) 3. Prostaglandin E2 4. Centre of thermoregulation (set point shift)
Class and exam questions
Why does shivering occur during fever?
This is a mechanism of shivering thermogenesis. The hypothalamus sends signals to skeletal muscles, whose involuntary contractions generate energy exclusively as heat, helping the body warm up rapidly to the new set point.
How do antipyretic drugs (e.g., aspirin) work?
Non-steroidal anti-inflammatory drugs (NSAIDs) block the enzyme cyclooxygenase (COX). This halts the synthesis of prostaglandin E2 in the hypothalamus, and the set point returns to normal.
Can fever occur without infection?
Yes, this is called aseptic fever. It occurs in myocardial infarction, trauma, or hemolysis, when endogenous primary pyrogens (DAMPs) are released from destroyed cells, triggering the same pathogenetic cascade.
Does the room temperature affect the development of fever?
Practically none. It has been experimentally proven that the stage dynamics of fever are stereotyped and do not depend on the ambient temperature, since the thermoregulation system is not broken, but purposefully reprogrammed.
What else to study on this topic
- Molecular mechanisms of macrophage activation: CD14 receptor, TLR-4, and NF-κB factor.
- The role of the inflammasome and caspase-1 in the production of active interleukin-1.
- Features of non-shivering thermogenesis in newborns and the role of brown adipose tissue.
- Three variants of changes in the ratio of heat production and heat loss in stage I of fever.
- Stage III: mechanisms and clinical variants of body temperature reduction to normal.
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