Fever, and temperature regulation at large, are controlled by intricate processes of the human brain. The brain, or more specifically, the region of the brain known as the hypothalamus, plays a central role in the cause and resolution of fevers.
Before we get into the nitty gritty of how fevers are caused and how they are subsequently normalised, let’s find out more about the key players involved in this response.
1. The Hypothalamus
The hypothalamus is a tiny, almond-shaped structure located at the base of the brain. The hypothalamus is instrumental in regulating many vital processes that govern our life, such as hunger, sleep, thirst, circadian rhythms and relevantly to us, body temperature. The hypothalamus is also crucial as a bridge between the nervous and endocrine systems, playing a key role in the activation of several “master” hormones of the pituitary gland.
The hypothalamus, with regard to temperature, can quite accurately be compared to a thermostat. It is responsible for maintaining the body temperature within a tight range, usually around 37°C [98.6 °F]. This is the temperature that is most optimal for the body to conduct its metabolic processes efficiently.
The term “pyrogen” (Greek, meaning “fever producer”) refers to a class of cellular messenger proteins which play a key role in the signalling response associated with fever.
Pyrogens can be exogenous or endogenous. Exogenous pyrogens (eg. Lipopolysaccharide) are substances produced by infectious agents like bacteria, which our bodies have evolved to respond to with a temperature increase. Usually, they work indirectly by stimulating the production of endogenous pyrogens (eg. Interleukin-1, Interleukin-2, TNF-alpha), which are “cytokines” which form a part of the body’s immune system. They play the role of alerting the hypothalamus to signs of infection, which prompts an increase in the “set-point” of the hypothalamus.
Prostaglandins are a class of physiologically active compounds that have a variety of effects on the body. In our case, the most relevant is prostaglandin E2, which plays a key role in alerting the hypothalamus to increase its “set-point” to a higher temperature setting.
When the body’s immune cells detect a sign of infection by bacteria or other pathogens, through the presence of exogenous pyrogens, the immune system produces one of many endogenous pyrogens, such as Interleukin-1, or Tumour Necrosis Factor-alpha. These chemical messengers float around in the blood until they are carried to the brain, where they interact with the brain and produce prostaglandin E2 (PGE2)
through a process called the “arachidonic acid pathway”. PGE2 interacts with the “pre optic area” of the hypothalamus and causes an increase in the temperature set-point.
Once the hypothalamic set point has been increased to the “new normal”, the hypothalamus triggers a cascade of physiological changes, aimed at increasing heat production and retaining heat. This is done both through hormones and through the sympathetic nervous system. The sympathetic nervous system, when activated, constricts the blood vessels of the body (peripheral vasoconstriction) which reduces heat loss through the skin. This is why we feel cold during a fever and start shivering, which further generates more heat. Additionally, the hypothalamus also signals for norepinephrine to be released by the adrenal glands, which causes a spike in the burning of brown adipose tissue, which produces more heat (thermogenesis). It also cranks up the body’s metabolic rate and causes an increase in muscle tone and shivering, which are also aimed at increasing the body’s temperature to match the new thermostat setting.
The temperature setting of the hypothalamus continues to be high until PGE2 is present. When the cause of the fever is dealt with and PGE2 is no longer produced, the hypothalamus reverses its set-point back to normal, which again causes a host of physiological changes, aimed at bringing the body’s temperature back to normal. This is done primarily through the activation of the parasympathetic nervous system, which dilates the blood vessels (peripheral vasodilation), causing more heat loss. Also, at this point, the body starts sweating, in a bid to further cool down, until it reaches a normal temperature again.
Although fevers are ubiquitous and rather simple to treat, the processes that underlie their production and management are awe-inspiringly intricate. With all our advancement in the study of these processes, we are humbled by the fact that not all the reasons and benefits of the fever response are clearly understood, even today.