38. Pathogenesis of fever

General

A fever is an active core temperature elevation that occurs because the hypothalamus increases the set point temperature value. It doesn’t occur due to deficiency of warm-defence.

At the beginning of a fever the set point temperature is elevated, let’s say from 37 to 39°C. After this is the core temperature still 37°C, so the body understands that the body is colder than the hypothalamus wants it to be. The body then starts to increase the core temperature by causing the person to wrap themselves in clothing or blankets, and they start to shiver. Eventually will the core temperature reach the new set point of 39°C. At this point is this temperature maintained until the hypothalamus decreases the set point to the normal value.

The febrile reaction can be divided into stages:

  • Stadium incrementi – the stage where the body temperature is rising
  • Stadium fastigii – the stage where the body temperature is stable and the fever is maintained
  • Stadium decrementi – the stage where the body temperature is decreasing

During the stadium incrementi the body produces more heat than it loses. The person feels cold as the core temperature is lower than the set point. This is both due to behavioural changes, like influencing the person to wrap themselves up, and due to autonomic changes. These changes involve shivering, piloerection, peripheral vasoconstriction and sympathetic activation. Vasoconstriction reduces the amount of blood in the periphery, causing less blood to be exposed to the colder surroundings. The metabolic rate increases.

During the stadium fastigii heat loss and heat production is approximately the same. The core temperature is now the same as the elevated set point temperature.

During the stadium decrementi the body loses more heat than it produces. It begins when the hypothalamus lowers the set point temperature to the normal value of 37°C. The person feels warm. Increased heat loss is mostly attributed to increased sweating and vasodilation. The core temperature eventually reaches the normal set point value, at which point heat loss and heat production are balanced once again.

There exist several types of fever, each of which are characteristic for certain diseases. The diseases themselves are not important to know but are included anyway.

Type of fever Course Associated diseases
Continuous fever Temperature permanently over 38°C, daily fluctuation < 1°C Viral and bacterial infections
Remittent fever Temperature permanently over 38°C, daily fluctuation > 1°C Viral infections, acute bacterial endocarditis
Intermittent fever Febrile and non-febrile periods alternating within one day Pyogenic infection, tuberculosis
Recurrent fever Febrile and non-febrile days alternating Malaria

The temperature is considered subfebrile until 37.5°C, febrile until 41.5°C and hyperpyrexia above 41.5°C (40°C according to the book). Hyperpyrexia is a medical emergency as it usually indicates a serious underlying condition such as brain damage.

Pathomechanism

Fever is usually a response to an infection. The causative agent, whether it’s a bacterium or virus, contain exogenous pyrogens like LPS. Bacteria or viruses, together with the exogenous pyrogens, are phagocytosed by macrophages, which then react by producing endogenous pyrogens. The endogenous pyrogens and not the exogenous ones act directly on the CNS. Some evidence suggests that macrophages in the liver (Kupffer cells) transmit a pyrogenic signal to the CNS through vagal afferents too.

The most important endogenous pyrogens are IL-1, IL-6, IL-8, TNF-α and interferons. These cytokines are not only produced in response to infection, so fever can occur in other inflammations as well. Some of these pyrogens activate the acute phase reaction, and all of them act on the circumventricular organs of the CNS. Here they trigger the arachidonic acid pathway, producing prostaglandin E2 (PGE2) which causes the hypothalamus to increase the set point temperature to a higher level.

Pyrogens may not always cause fever. In a cold environment may they rather cause hypothermia. Development of hypothermia instead of fever is also characteristic in neonates or very old people. Starvation may inhibit the fever reaction. In sepsis either fever or hypothermia may develop.


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37. Heat stroke and malignant hyperthermia

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39. Fever and sickness-behavior. The biological value of fever

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