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Physiology, Fever

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Last Update: August 28, 2021.


Fever is the elevation of an individual's core body temperature above a 'set-point' that is normally regulated by the body's thermoregulatory center in the hypothalamus. This increase in the body's 'set point' temperature is often secondary to a pathological process that involves the release of immunological mediators to trigger the thermoregulatory center of the hypothalamus to elevate the body's core temperature.

The normal temperature of the human body is considered to be 37 degrees C and varies by about 0.5 degrees C through the course of the day. This minor variation of the core temperature is the result of many normal physiological processes of the human body, including sleep/wake cycles, metabolic changes, hormone variability, and activity levels. In fever, however, the increase in the core body temperature is often greater than 0.5 degrees C and attributed to a fever-inducing substance (pyrogen).

It is important to distinguish that the definition of fever is not synonymous with the definition of hyperthermia. In fever, there is an increase in the 'set-point' temperature brought about by the hypothalamus, which enables the body to maintain a controlled 'increase' of the core temperature and general functionality of all organ systems. In hyperthermia, however, the increase of the body's core temperature is beyond the confines of the set-point temperature and regulation of the hypothalamus.

Issues of Concern

Most patients with raised body temperature have a fever; there are a few instances where an increased temperature refers to hyperthermia. These include heat stroke, specific metabolic ailments, and the impacts of certain medications that affect thermoregulation.[1] In contradiction to fever, the thermoregulatory set-point stays unaltered at normothermic levels during hyperthermia while body temperature elevates in an uncontrolled manner and beyond the capacity to lose heat.[2] Exogenous heat exposure and endogenous heat production are methods by which hyperthermia can bring about hazardously high body temperatures.

It is clinically essential to make the differentiation between fever and hyperthermia. Hyperthermia can be quickly lethal, and its treatment contrasts with that of fever.


In tissues or the blood, when there are bacteria or their breakdown products are present, they become engulfed by the leukocytes, tissue macrophages, and huge granular lymphocytes. Cytokines are released when these bacterial products are digested as part of the immune responses. Interleukin-1 is the most significant cytokine in causing fever, likewise called endogenous or leukocyte pyrogen.[3][4]


Numerous proteins and their breakdown products, and certain substances, particularly lipopolysaccharide toxins liberated from bacterial cell layers, can raise the set-point of the hypothalamic thermostat. Substances that cause this impact are called pyrogens. Pyrogens discharged from toxic microscopic organisms or those discharged from disintegrating body tissues cause fever during infectious conditions.[5] 

At the point when the set-point of the hypothalamic thermostat gets higher than typical, all the processes for raising the internal heat level come into play, including heat preservation and heat production increases. Within a couple of hours, after the set-point has elevated, the body temperature as well moves toward this level.

In older adults, the ability to develop fever becomes impaired, and most of the time, have low baseline body temperatures compared to younger adults. Due to this impaired ability, only modest fever is observed in older adults even when they are severely infected.

Organ Systems Involved

Metabolic effects:

  • Increased need for oxygen
    • Increases heart rate
    • Increases respiration
  • Increased use of body proteins as an energy source
  • During fever body switches from using glucose (an excellent medium for bacterial growth) to metabolism based on protein and fat breakdown
  • Enhances immune function
    • Increases motility and activity of WBC
    • Stimulates interferon production and activation of T cells
  • Inhibits growth of certain microbial agents
    • Many microbial agents that cause infection to grow at normal body temperatures

Adverse effects of high temperature: The pathological effects observed in a person who died of hyperpyrexia are local hemorrhages and parenchymatous degeneration of cells all through the whole body, however, particularly in the brain. Damaged neuronal cells can never be replaced. Likewise, harm to the liver, kidneys, and different organs can regularly be serious enough that damage of at least one of these organs, in the long run, causes demise, which usually occurs after several days of the occurrence of heatstroke.


The idea of a "set-Point" for temperature control is that at a basic core body temperature of about 37.1 degrees C (98.8 degrees F), intense changes happen in the paces of both heat loss and heat production. At temperatures over this level, the pace of heat loss is more prominent than that of heat production, so the internal heat level falls and approaches the 37.1 degrees C level.

At temperatures beneath this level, the pace of heat production is more prominent than that of heat loss, so the internal heat level ascents and again moves toward the 37.1 degrees C level. This significant temperature level is known as the "set-point" of the temperature control component. In this way, all the temperature control processes constantly endeavor to take the internal heat level back to this set-point level.


The quick change in the set point in the hypothalamic thermostat causes an elevation in core body temperature by triggering several physiological reactions. Temperature-increasing mechanisms incorporate the following:

  1. Posterior hypothalamic sympathetic center stimulation causes skin vasoconstriction all through the body.
  2. Piloerection, which is hairs "raising on end." The excitement of the sympathetic system causes the contraction of the arrector pili muscles, which results in a standing position of the hairs. This process is significant in lower creatures, which permits them to capture a layer of non-conducting air close to the skin, which significantly depresses the heat transfer to the surroundings.
  3. Heat production or thermogenesis increases through shivering, sympathetic stimulation, and thyroxine discharge.

Related Testing

A diagnostic approach to fever or hyperthermia includes the following:

A thorough history and a detailed physical examination of all the systems of the body can help narrow down the list of differential diagnoses.

Diagnostic Testing

  • ESR and CRP
  • Procalcitonin-elevated in certain bacterial infections
  • Tuberculin skin test
  • HIV
  • Serum LDH
  • Routine blood cultures
  • RF, ANA, heterophile antibody in children and young adults
  • CPK
  • Serum protein electrophoresis
  • Imaging studies like CT chest, abdomen based on history
  • CNS signs should prompt for Lumbar puncture
  • A person with a travel history to malaria-endemic areas should be tested with thick and thin peripheral smears.
  • Rule out thrombophlebitis and infective endocarditis in IV drug abuse

Several other specific tests can be performed based on the history and physical exam findings in different patients of varying age groups.


The most crucial component initiating fever in the human body is the presence of a pyrogen. A pyrogen is a substance that physiologically induces fever in the body.[6] Pyrogens can be classified as endogenous or exogenous depending on whether they originate from inside the body or a fever triggering component from outside the body (e.g., toxins).[7] 

Many infectious pathogens normally trigger exogenous pyrogens as a part of their virulence. For example, the cause of a febrile response in a Neisseria Meningitidis infection is commonly triggered by the lipopolysaccharide (LPS) component of this bacteria's cell wall, which subsequently induces the production of the cytokine prostaglandin-E2.[8] Cytokines, natural mediators of the body's immunological response, operate as endogenous pyrogens to trigger the activation of the fever response. Common cytokines known to induce the febrile response include but are not exclusive to IL-1, IL-6, and TNF.[9]

After the release of cytokine or exogenous pyrogens into the circulatory system, they bind to specific receptors on the epithelial, vascular system. This process subsequently causes the production and release of prostaglandin-E2 (PGE2), which is the ultimate inflammatory mediator associated with many of the effects and symptoms related to the febrile response.[10] In the brain, the presence of the PGE2 stimulates the increase in the set-point temperature of the hypothalamus and enables the increase in the core body temperature.[11]

Clinical Significance

The normal internal heat level is low in the early morning and high at night, shifting 0.5 degrees C (0.9 degrees F) through the span of the day, controlled in the thermoregulatory focus situated in the anterior hypothalamus.

  • Fever occurs when there is an elevation in the body's thermoregulatory set-point either by endogenous or by exogenous pyrogen. In hyperthermia, the set-point is unaltered, and the body temperature becomes elevated in an uncontrolled fashion due to exogenous heat exposure or endogenous heat production.
  • Hyperpyrexia is the term for an exceptionally high fever (more than 41.5 degrees C), which can occur in patients with serious infections; however, most ordinarily happen in patients with CNS hemorrhages.
  • Inhibitors of cyclooxygenases, for example, aspirin and acetaminophen help reduce fever.[12]
  • Observation of a pattern of fever can be helpful in certain conditions; for example, a fever that occurs every 48 to 72 hrs in certain types of malaria, evening rise of temperature occurs in tuberculosis.
  • For instance, the everyday highs and lows of typical temperatures are emphasized in many fevers. However, these variations might be turned around in typhoid fever and disseminated tuberculosis. Temperature-pulse dissociation occurs in typhoid fever, brucellosis, leptospirosis, some medication prompted fevers, and factitious fever. In healthy people, the temperature-pulse relationship is directly proportional with an expansion in the pulse of 4.4 beats/minute for each 1 degree C (2.44 beats/minute for each 1 degree F) an increase in core temperature.
  • During infections, fever may not be observed in babies, older adults, patients with CKD, and in patients taking corticosteroids; on the contrary, hypothermia may be present.

Review Questions


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