Fever
Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with body temperature exceeding the normal range caused by an increase in the body's temperature set point in the hypothalamus. There is no single agreed-upon upper limit for normal temperature: sources use values ranging between in humans.
The increase in set point triggers increased muscle contractions and causes a feeling of cold or chills. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. Rarely a fever may trigger a febrile seizure, with this being more common in young children. Fevers do not typically go higher than.
A fever can be caused by many medical conditions ranging from non-serious to life-threatening. This includes viral, bacterial, and parasitic infections—such as influenza, the common cold, meningitis, urinary tract infections, appendicitis, Lassa fever, COVID-19, and malaria. Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication or vaccination, and cancer. It differs from hyperthermia, in that hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss.
Treatment to reduce fever is generally not required. Treatment of associated pain and inflammation, however, may be useful and help a person rest. Medications such as ibuprofen or paracetamol may help with this as well as lower temperature. Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms. Hyperthermia requires treatment.
Fever is one of the most common medical signs. It is part of about 30% of healthcare visits by children and occurs in up to 75% of adults who are seriously sick. While fever evolved as a defense mechanism, treating a fever does not appear to improve or worsen outcomes. Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as "fever phobia".
Associated symptoms
A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, loss of appetite, sleepiness, hyperalgesia, dehydration, and the inability to concentrate. Sleeping with a fever can often cause intense or confusing nightmares, commonly called "fever dreams". Mild to severe delirium may also present itself during high fevers.Differential diagnosis
Hyperthermia
is an elevation of body temperature over the temperature set point, due to either too much heat production or not enough heat loss. Hyperthermia is thus not considered fever. Hyperthermia should not be confused with hyperpyrexia.Clinically, it is important to distinguish between fever and hyperthermia as hyperthermia may quickly lead to death and does not respond to antipyretic medications. The distinction may however be difficult to make in an emergency setting, and is often established by identifying possible causes.
Mechanism
Hypothalamus
Temperature is regulated in the hypothalamus. The trigger of a fever, called a pyrogen, results in the release of prostaglandin E2. PGE2 in turn acts on the hypothalamus, which creates a systemic response in the body, causing heat-generating effects to match a new higher temperature set point. There are four receptors in which PGE2 can bind, with a previous study showing the EP3 subtype is what mediates the fever response. Hence, the hypothalamus can be seen as working like a thermostat. When the set point is raised, the body increases its temperature through both active generation of heat and retention of heat. Peripheral vasoconstriction both reduces heat loss through the skin and causes the person to feel cold. Norepinephrine increases thermogenesis in brown adipose tissue, and muscle contraction through shivering raises the metabolic rate.If these measures are insufficient to make the blood temperature in the brain match the new set point in the hypothalamus, the brain orchestrates heat effector mechanisms via the autonomic nervous system or primary motor center for shivering. These may be:
- Increased heat production by increased muscle tone, shivering and release of hormones like epinephrine; and
- Prevention of heat loss, e.g., through vasoconstriction.
This contrasts with hyperthermia, in which the normal setting remains, and the body overheats through undesirable retention of excess heat or over-production of heat. Hyperthermia is usually the result of an excessively hot environment or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications.
In infants, the autonomic nervous system may also activate brown adipose tissue to produce heat.
Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.
Pyrogens
A pyrogen is a substance that induces fever. In the presence of an infectious agent, such as bacteria, viruses, viroids, etc., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are lipopolysaccharides produced by Gram-negative bacteria such as E. coli. But pyrogens include non-endotoxic substances as well. The types of pyrogens include internal and external to the body.The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers.
Endogenous
Endogenous pyrogens are cytokines released from monocytes. In general, they stimulate chemical responses, often in the presence of an antigen, leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated molecular patterns such as cases like rheumatoid arthritis or lupus.Major endogenous pyrogens are interleukin 1 and interleukin 6. Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-β, macrophage inflammatory protein-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ. Tumor necrosis factor-α also acts as a pyrogen, mediated by interleukin 1 release. These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier. The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells, resulting in activation of the arachidonic acid pathway.
Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenase which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature.
Exogenous
Exogenous pyrogens are external to the body and are of microbial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint.An example of a class of exogenous pyrogens are bacterial lipopolysaccharides present in the cell wall of gram-negative bacteria. According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein, binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage. The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines, e.g., interleukin 1, interleukin 6, and tumor necrosis factor-alpha. A further downstream event is activation of the arachidonic acid pathway.
Neural circuit mechanism with PGE2 action
PGE2 release comes from the arachidonic acid pathway. This pathway, is mediated by the enzymes phospholipase A2, cyclooxygenase-2, and prostaglandin E2 synthase. These enzymes ultimately mediate the synthesis and release of PGE2.PGE2 is the ultimate mediator of the febrile response. The setpoint temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area through the prostaglandin E receptor 3. EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus, the rostral raphe pallidus nucleus in the medulla oblongata, and the paraventricular nucleus of the hypothalamus. Under normal conditions, EP3-expressing neurons in the POA are important thermoregulatory neurons, which provide continuous inhibitory signals with the transmitter GABA to control sympathetic output neurons in the DMH and rRPa, thereby performing bidirectional regulation of basal body temperature. During infection, PGE2 produced in the brain inhibits the activity of EP3-expressing neurons in the POA to attenuate the inhibition of sympathetic output, and thereby activates the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface, leading to fever. It is presumed that the innervation from the POA to the PVN mediates the neuroendocrine effects of fever through the pathway involving pituitary gland and various endocrine organs.
Diagnosis
A range for normal temperatures has been found. Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures.Fever is generally agreed to be present if the elevated temperature is caused by a raised set point and:
- Temperature in the anus is at or over. An ear or forehead temperature may also be used.
- Temperature in the mouth is at or over in the morning or over in the afternoon
- Temperature under the arm is usually about below core body temperature.
Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more. Normal daily temperature variation has been described as 0.5 °C. A raised temperature is not always a fever. For example, the temperature rises in healthy people when they exercise, but this is not considered a fever, as the set point is normal. On the other hand, a "normal" temperature may be a fever, if it is unusually high for that person; for example, medically frail elderly people have a decreased ability to generate body heat, so a "normal" temperature of may represent a clinically significant fever.