Fever – Fact Sheet

Fever (also known as pyrexia, or a febrile response from the Latin word febris, meaning fever, and archaically known as ague) is a frequent medical symptom that describes an increase in internal body temperature to levels that are above normal (the common oral measurement of normal human body temperature is 36.8±0.7 °C or 98.2±1.3 °F). Fever is most accurately characterized as a temporary elevation in the body’s thermoregulatory set-point, usually by about 1-2°C. Fever differs from hyperthermia, which is an increase in body temperature over the body’s thermoregulatory set-point (due to excessive heat production or insufficient thermoregulation, or both). Carl Wunderlich discovered that fever is not a disease but a symptom of disease.

The elevation in thermoregulatory set-point means that the previous "normal body temperature" is considered hypothermic, and effector mechanisms kick in. The person who is developing the fever has a cold sensation, and an increase in heart rate, muscle tone and shivering attempt to counteract the perceived hypothermia, thereby reaching the new thermoregulatory set-point.

When a patient has or is suspected of having a fever, that person's body temperature is measured using thermometer. At a first glance, fever is present if:

Ø temperature in the anus (rectum/rectal) or in the ear (otic) is at, or higher than 38 degrees Celsius (100.4 degrees Fahrenheit)

Ø oral temperature (in the mouth) is at, or higher than 37.5 degrees Celsius (99.5 degrees Fahrenheit)

Ø axillary temperature (underarm) is at, or higher than 37.2 degrees Celsius (99 degrees Fahrenheit)

However, there are many variations in normal body temperature, and this needs to be considered when measuring fever. The values given are for an otherwise healthy, non-fasting adult, dressed comfortably, indoors, in a room that is kept at a normal room temperature, during the morning, but not shortly after arising from sleep. Furthermore, for oral temperatures, the subject must not have eaten, drunk, or smoked anything in at least the previous fifteen minutes.

Body temperature normally fluctuates over the day, with the lowest levels at 4A.M. and the highest at 6P.M. Therefore, an oral temperature of 37.5C would strictly be a fever in the morning, but not in the afternoon. Normal body temperature may differ as much as 0.4C (0.7F) between individuals or from day to day. In women, temperature differs at various points in the menstrual cycle, and this can be used for family planning (although it is only one of the variables of temperature). Temperature is increased after meals, and psychological factors (like the first day in the hospital) also influence body temperature.

There are different locations where temperature can be measured, and these differ in temperature variability. Tympanic membrane thermometers measure radiant heat energy from the tympanic membrane (infrared). These may be very convenient, but may also show more variability.

Children develop higher temperatures with activities like playing, but this is not fever because their set-point is normal. Elderly patients may have a decreased ability to generate body heat during a fever, so even a low-grade fever can have serious underlying causes in geriatrics.

Mechanism

Temperature is regulated in the hypothalamus, in response to PGE2. PGE2 release, in turn, comes from a trigger, a pyrogen. The hypothalamus generates a response back to the rest of the body, making it increase the temperature set-point.

Pyrogens

Substances that induce fever are called pyrogens. These are both internal or endogenous, and external or exogenous, such as the bacterial substance LPS.

Endogenous

The cytokines (such as interleukin 1) are a part of the innate immune system, produced by phagocytic cells, and cause the increase in the thermoregulatory set-point in the hypothalamus. Other examples of endogenous pyrogens are interleukin 6 (IL-6), and the tumor necrosis factor-alpha.

These cytokine factors are released into general circulation where they migrate to the circumventricular organs of the brain, where the blood-brain barrier is reduced. The cytokine factors bind with endothelial receptors on vessel walls, or interact with local microglial cells. When these cytokine factors bind, they activate the arachidonic acid pathway.

Exogenous

One model for the mechanism of fever caused by exogenous pyrogens includes lipopolysaccharide (LPS), which is a cell wall component of gram-negative bacteria. An immunological protein called Lipopolysaccharide-Binding Protein (LBP) binds to LPS. The LBP-LPS complex then binds to the CD14 receptor of a nearby macrophage. This binding results in the synthesis and release of various endogenous cytokine factors, such as interleukin 1 (IL-1), interleukin 6 (IL-6), and the tumor necrosis factor-alpha. In other words, exogenous factors cause release of endogenous factors, which, in turn, activate the arachidonic acid pathway.

PGE2 release

PGE2 release comes from the arachidonic acid pathway. This pathway (as it relates to fever), is mediated by the enzymes phospholipase A2 (PLA2), cyclooxygenase-2 (COX-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 set-point temperature of the body will remain elevated until PGE2 is no longer present. PGE2 acts on neurons in the preoptic area (POA) through the EP3 subtype of PGE receptors and the EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe pallidus nucleus in the medulla oblongata (rRPa) and the paraventricular nucleus of the hypothalamus (PVN). Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic output system, which evokes non-shivering thermogenesis to produce body heat and skin vasoconstriction to decrease heat loss from the body surface. 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.

Hypothalamus response

The brain ultimately orchestrates heat effector mechanisms. These may be

Ø increased heat production by increased muscle tone, shivering and hormones like epinephrine.

Ø prevention of heat loss, such as vasoconstriction.

The autonomic nervous system may also activate brown adipose tissue to produce heat (=non-exercise associated thermogenesis, also known as non-shivering thermogenesis), but this seems mostly important for babies. Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.

Types

Pyrexia (fever) can be classed as

Ø low grade: 38 - 39 °C (100.4 - 102.2 °F)

Ø moderate: 39 - 40 °C (102.2 - 104 °F)

Ø high-grade: > 40 °C (> 104 °F)

Ø Hyperpyrexia: > 42 °C (> 107.6 °F)

The last is clearly a medical emergency because it approaches the upper limit compatible with human life.

Most of the time, fever types can not be used to find the underlying cause. However, there are specific fever patterns that may occasionally hint the diagnosis:

Ø Pel-Ebstein fever is a specific kind of fever associated with Hodgkin's lymphoma, being high for one week and low for the next week and so on. However, there is some debate whether this pattern truly exists.

Ø Continuous fever: temperature remains above normal throughout the day and does not fluctuate more than 1 degree C in 24 hours. Eg: lobar pneumonia, typhoid, urinary tract infection, brucellosis, typhus, etc. Typhoid fever may show a specific fever pattern, with a slow stepwise increase and a high plateau.

Ø Intermittent fever: temperature is present only for some hours of the day and becomes normal for remaining hours.Eg: malaria, kala-azar, pyaemia, septicemia etc In malaria, there may be a fever with a periodicity of 24 hours (quotidian) 48 hours (tertian fever) or 72 hours (quartan fever, indicating Plasmodium vivax). These patterns may be less clear in travelers.

Ø Remittent fever: temperature remains above normal throughout the day and fluctuates more than 1 degree C in 24 hours.Eg: infective endocarditis etc

Febricula is a mild fever of short duration, of indefinite origin, and without any distinctive pathology.

Causes

Fever is a common symptom of many medical conditions:

Ø infectious disease, e.g. influenza, common cold, HIV, malaria, infectious mononucleosis, gastroenteritis, etc..

Ø Various skin inflammations such as boils, pimples, acne, abscess, etc.

Ø Immunological diseases like lupus erythematosus, sarcoidosis, inflammatory bowel diseases, etc..

Ø Tissue destruction, which can occur in hemolysis, surgery, infarction, crush syndrome, rhabdomyolysis, cerebral hemorrhage, etc..

Ø Drug fever

1. directly caused by the drug (e.g. lamictal, progesterone, chemotherapeutics causing tumor necrosis)

2. as an adverse reaction to drugs (e.g. antibiotics, sulfa drugs, etc.)

3. after drug discontinuation, like with heroin withdrawal

Ø Cancers such as Hodgkin disease (with Pel-Ebstein fever)

Ø Metabolic disorders like gout, porphyria, etc..

Ø Thrombo-embolic processes (i.e. pulmonary embolism, deep venous thrombosis)

Persistent fever which cannot be explained after repeated routine clinical inquiries, is called fever of unknown origin.

Usefulness of fever

There are arguments for and against the usefulness of fever, and the issue is controversial. There are studies using warm-blooded vertebrates and humans in vivo, with some suggesting that they recover more rapidly from infections or critical illness due to fever.

Theoretically, fever has been conserved during evolution because of its advantage for host defense. There are certainly some important immunological reactions that are sped up by temperature, and some pathogens with strict temperature preferences could be hindered. The overall conclusion seems to be that both aggressive treatment of fever and too little fever control can be detrimental. This depends on the clinical situation, so careful assessment is needed.

Fevers may be useful to some extent since they allow the body to reach high temperatures. This causes an unbearable environment for some pathogens. White blood cells also rapidly proliferate due to the suitable environment and can also help fight off the harmful pathogens and microbes that invaded the body.

Treatment

Fever should not necessarily be treated. Fever is an important signal that there's something wrong in the body, and it can be used for follow-up. Moreover, not all fevers are of infectious origin.

Even when treatment is not indicated, however, febrile patients are generally advised to keep themselves adequately hydrated, as the dehydration produced by a mild fever can be more dangerous than the fever itself. Water is generally used for this purpose, but there is always a small risk of hyponatremia if the patient drinks too much water. For this reason, some patients drink sports drinks or products designed specifically for this purpose.

Most people take medication against fever because the symptoms cause discomfort. Fever increases heart rate and metabolism, thus potentially putting an additional strain on elderly patients, patients with heart disease, etc. This may even cause delirium. Therefore, potential benefits must be weighed against risks in these patients. In any case, fever must be brought under control in instances when fever escalates to hyperpyrexia and tissue damage is imminent.

Treatment of fever should be based primarily on lowering the setpoint, but facilitating heat loss may also contribute. The former is accomplished with antipyretics. Wet cloth or pads are also used for treatment, and applied to the forehead. Heat loss may be an effect of (possibly a combination of) heat conduction, convection, radiation or evaporation (sweating, perspiration). This may be particularly important in babies, where drugs should be avoided. However, if water that is too cold is used, it induces vasoconstriction and prevents adequate heat loss.