fever

fever, elevation of body temperature above the normal level, which in humans is about 98°F; (37°C;) when measured orally. Fever is considered to be a symptom of a disorder rather than a disease in itself. Under normal conditions the heat that is generated by the burning of food by the body is dissipated through such processes as perspiration and breathing. It is believed that infectious diseases, injury to the body tissues, and other conditions that cause inflammation lead to the release of prostaglandins, a type of hormone, which bind to sites in the hypothalamus, the center of temperature control in the body. The rise in temperature that is triggered as a result acts as part of the body's defenses against infection; white blood cells become more active, and most bacteria do not thrive as well. The effects of fever on the body are weakness, exhaustion, and sometimes a depletion of body fluids through excessive perspiration. Extremely high fevers may cause convulsive reactions and eventual death. In addition to infectious diseases (such as pneumonia and tonsillitis), disorders of the brain, certain types of cancer, and severe heatstroke may cause fever. There are also cases of fever where the cause cannot be detected. Treatment includes increasing the intake of fluids and administering aspirin and other fever-reducing medications. Aspirin may be dangerous in fevers of children because of Reye's syndrome. However, primary treatment is directed at the underlying cause unless the fever is very high (above 104°F;/40°C;). Persons with such dangerously high fevers are sometimes sponged with cool water or immersed in cool baths.

Acute infectious tropical disease, sometimes occurring in temperate zones. Abrupt onset of headache, backache, fever, nausea, and vomiting is followed by either recovery with immunity or by higher fever, slow pulse, and vomiting of blood. Patients may die in a week. Jaundice is common (hence the name). One of the world's great plagues for 300 years, it is caused by a virus transmitted by several species of mosquitoes. Carlos Finlay suggested and Walter Reed proved this means of spread, leading to near elimination of the disease through mosquito control (see William Gorgas). Treatment consists of supportive care, particularly fever reduction. Control of mosquitoes near cities and live-virus vaccines—developed by Max Theiler (1899–1972), who won a 1951 Nobel Prize for his work—have made yellow fever completely preventable.

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or Malta fever or Mediterranean fever or undulant fever

Infectious disease of humans and domestic animals. It is characterized by gradual onset of fever, chills, sweats, weakness, and aches, and it usually ends within six months. It is named after the British physician David Bruce (b. 1855—d. 1931), who first identified (1887) the causative bacteria. Three main species in the genus Brucella commonly cause the disease in humans, who contract it from infected animals (goats, sheep, pigs, cattle). Brucellosis is rarely transmitted between humans but spreads rapidly in animals, causing severe economic losses. Drug therapy is not practical for animal brucellosis, but vaccination of young animals is useful. Infected animals must be removed from herds. Antibiotics are effective against acute disease in humans, in whom it can cause liver and heart problems if untreated.

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or typhoid fever

Acute infectious disease resembling typhus (and distinguished from it only in the 19th century). Salmonella typhi, usually ingested in food or water, multiplies in the intestinal wall and then enters the bloodstream, causing septicemia. Symptoms begin with headache, aching, and restlessness. High fever gradually develops, with delirium. A rash appears on the trunk. The sites where the bacilli multiplied become inflamed and may ulcerate, leading to intestinal bleeding or peritonitis. Patients become exhausted and emaciated; up to 25percnt die if not treated. Antibiotic treatment is effective. Patients can carry typhoid for weeks to months or years. Carriers can contaminate the food they handle. Prevention depends mainly on water and sewage treatment and excluding carriers from food-handling jobs.

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or swine fever

Often fatal viral disease of swine in Europe, North America, and Africa, transmitted by vehicles used to carry pigs, people dealing with them, and uncooked garbage in feed. Fever progresses to symptoms that include appetite loss; affected eyes and digestive tract; respiratory difficulty; rash; and inflamed mouth and throat. The pig moves reluctantly and staggers; later it cannot rise; coma follows. Antiserum is rarely effective. Survivors become chronically ill and can spread the virus. Illness must be reported, infected animals slaughtered, and quarantine instituted. A vaccine can control it. The African strain causes death sooner and has no effective prevention or treatment.

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Infectious disease of warm-blooded animals, caused by Bacillus anthracis, a bacterium that, in spore form, can retain its virulence in contaminated soil or other material for many years. A disease chiefly of herbivores, the infection may be acquired by persons handling the wool, hair, hides, bones, or carcasses of affected animals. Infection may lead to death from respiratory or cardiac complications (within 1–2 days if acute), or the animal may recover. In humans, anthrax occurs as a cutaneous, pulmonary, or intestinal infection. The most common type, which occurs as an infection of the skin, may lead to fatal septicemia (blood poisoning). The pulmonary form of the disease is usually fatal. Sanitary working environments for susceptible workers are critical to preventing anthrax; early diagnosis and treatment are also of great importance. In recent decades, various countries have attempted to develop anthrax as a weapon of biological warfare; many factors, including its extreme potency (vastly greater than any chemical-warfare agent), make it the preferred biological-warfare agent. Concerns about anthrax mounted in 2001 after it was found in letters mailed to members of the U.S. government and news agencies.

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or scarlatina

Acute infectious disease caused by some types of streptococcus bacteria. Fever, sore throat, headache, and, in children, vomiting are followed in two to three days by a rash. The skin peels in about one-third of cases. After a coating disappears, the tongue is swollen, red, and bumpy (strawberry tongue). Glands are usually swollen. Complications frequently involve the sinuses, ears (sometimes with mastoiditis), and neck. Abscesses are common. Nephritis, arthritis, or rheumatic fever may occur later. Treatment involves penicillin, bed rest, and adequate fluid intake. Scarlet fever has become uncommon and much milder since the mid-20th century, independent of the use of antibiotics.

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Generalized disease caused by certain types of streptococcus bacteria. It occurs mostly in children and young adults. Symptoms may be mild or severe. Sudden fever, joint pain, and inflammation may begin days to weeks after a streptococcal infection, usually of the throat (see pharyngitis). Other symptoms may include skin nodules and rashes, chorea, abdominal pain, nosebleeds, and weight loss. Heart inflammation, with accompanying rapid heartbeat, murmurs, and enlargement, can lead to valve scarring, markedly shortening life. After recovery, survivors are prone to future attacks. Penicillin given when the initial infection is diagnosed can prevent it. Otherwise, salicylic acid derivatives or corticosteroids help the symptoms.

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Infectious disease with recurring fever, caused by several spirochetes of the genus Borrelia, transmitted by lice, ticks, and bedbugs. Onset is sudden, with high fever, which breaks within a week with profuse sweating. Symptoms return about a week later. There may be 2 to 10 relapses, usually decreasing in severity. Mortality usually ranges from 0 to 6percnt, up to 30percnt in rare epidemics. Central nervous system involvement causes various (usually mild) neurological symptoms. The first microscopic organisms clearly associated with serious human disease (1867–68), the spirochetes mutate repeatedly, changing their antigens so that the host's immunity no longer is effective, which produces the relapses. Antibiotics can be effective, but inadequate therapy may leave spirochetes alive in the brain, and they may reinvade the bloodstream.

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or childbed fever

Infection of the female reproductive system after childbirth or abortion, with fever over 100 °F (38 °C) in the first 10 days. The inner surface of the uterus is most often infected, but lacerations of any part of the genital tract can give bacteria (often Streptococcus pyogenes) access to the bloodstream and lymphatic system to cause septicemia, cellulitis (cellular inflammation), and pelvic or generalized peritonitis. Severity varies. Puerperal fever has become very rare in developed countries but is still seen after abortions performed in unhygienic surroundings.

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Seasonal sneezing, nasal congestion, and tearing and itching of the eyes caused by allergy to the pollen of certain plants. These plants are chiefly those pollinated by the wind (e.g., ragweed in North America, timothy grass in Britain). Antihistamines and corticosteroids may provide temporary relief, but the most effective long-range treatment is desensitization. Unless properly treated, about one-third of patients with hay fever develop asthma.

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or glandular fever

Common infection, caused by Epstein-Barr virus. It occurs most often at ages 10–35. Infected young children usually have little or no illness but become immune. Popularly called “the kissing disease,” it is spread mostly by oral contact with exchange of saliva. It usually lasts 7–14 days. The most common symptoms are malaise, sore throat, fever, and lymph-node enlargement. Liver involvement is usual but rarely severe. The spleen often enlarges and in rare cases ruptures fatally. Less frequent features include rash, pneumonia, encephalitis (sometimes fatal), meningitis, and peripheral neuritis. Relapse and second attacks are rare. Diagnosis may require blood analysis. There is no specific therapy.

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or pyrexia

Abnormally high body temperature or a disease characterized by it. It most often occurs with infection. Normal core body temperature, measured orally, does not exceed 99°F (37.2°C). Up to 105°F (40.6°C), fever causes weakness and is best treated with aspirin, acetaminophen, or other antipyretic drugs. At 108°F (42.2°C) or more, it can lead to convulsions and death. In treatment, it is important to know the underlying cause. Fever appears to be a defense against infectious disease, stimulating leukocytes and increasing antibody production and perhaps killing or inhibiting bacteria and viruses that live within a narrow temperature range.

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or breakbone fever or dandy fever

Infectious, disabling mosquito-borne fever. Other symptoms include extreme joint pain and stiffness, intense pain behind the eyes, a return of fever after brief pause, and a characteristic rash. Dengue is caused by a virus carried by mosquitoes of the genus Aedes, usually A. aegypti, which also carries yellow fever. There are four strains of virus; infection with one type does not confer immunity to the remaining three. Treatment focuses on relieving symptoms. Patients should be isolated during the first three days, when mosquitoes can pick up the disease from them. Prevention relies on mosquito control.

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Typhus-like disease first seen in the Rocky Mountain region, caused by the bacterium Rickettsia rickettsii (see rickettsia) and transmitted by various ticks. In severe cases the rash bleeds more and is especially prominent on the wrists and ankles. Central nervous system involvement causes restlessness, insomnia, and delirium. Prostration may progress to coma, with death possible in a week or more. Mortality increases with age. Recovery is slow but usually complete as visual disturbances, deafness, and mental confusion pass. Prompt antibiotic treatment hastens it and reduces mortality. Prevention depends on avoiding tick bites, by wearing long, light-coloured clothing and insect repellent and inspecting for ticks. A vaccine reduces the risk of infection somewhat and of death greatly.

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Fever (also known as pyrexia, from the Greek pyretos meaning fire, or a febrile response, from the Latin word febris, meaning fever, and archaically known as ague) is a frequent medical sign that describes an increase in internal body temperature to levels above normal. 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. Hyperthermia 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. A fever is one of the body's mechanisms to try to neutralize the perceived threat inside the body, be it bacterial or viral.

Measurement and normal variation

When a patient has or is suspected of having a fever, that person's body temperature is measured using a thermometer.

At a first glance, fever is present if:

• Temperature in the anus (rectum/rectal) or in the ear (otic) is at or over 38.0°C (100.4°F)
• Temperature in the mouth (oral) is at or over 37.5 °C (99.5 °F)
• Temperature under the arm (axillary) is at or over 37.2 °C (99.0 °F)

The common oral measurement of normal human body temperature is 36.8±0.7 °C (98.2±1.3 °F). This means that any oral temperature between 36.1 and 37.5 °C (96.9 and 99.5 °F) is likely to be normal.

However, there are many variations in normal body temperature, and this needs to be considered when measuring for 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 (22.7 to 24.4°C or 73 to 76 °F ) , 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 to twenty minutes.

Body temperature normally fluctuates over the day, with the lowest levels around 4 a.m. and the highest around 6 p.m. (assuming the subject follow the prevalent pattern, i.e, sleeping at nighttime and staying awake during daytime). Therefore, an oral temperature of 37.2 °C (99.0 °F) would strictly be a fever in the morning, but not in the afternoon. An oral body temperature reading up to 37.5 °C (99.5 °F) in the early/late afternoon or early/late evening also wouldn't be a fever. Normal body temperature may differ as much as 1.0 °F 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 temperature is only one of the variables). Temperature is increased after eating, and psychological factors 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 prostaglandin E2 (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

A pyrogen is a substance that induces fever. These can be either internal (endogenous) or external (exogenous). The bacterial substance lipopolysaccharide (LPS) is an example of an exogenous pyrogen. Because exposure to exogenous pyrogens can cause a dangerous reaction, the FDA has set limits on the amount of permissible endotoxin in drugs. Depyrogenation may be achieved through filtration, distillation, chromatography, or inactivation.

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 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 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 prostaglandin E receptor 3 (EP3). 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 via the autonomic nervous system. These may be:

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

According to one common rule of thumb, fever is generally classified for convenience as:

Fever classification

Grade	°C	°F
low grade	38–39	100.4–102.2
moderate	39–40	102.2–104.0
high-grade	40–42	104.0–107.6
hyperpyrexia	>42	>107.6

The last is 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:

• Pel-Ebstein fever: 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 as to whether this pattern truly exists.
• Continuous fever: Temperature remains above normal throughout the day and does not fluctuate more than 1°C in 24 hours, e.g. lobar pneumonia, typhoid, urinary tract infection, brucellosis, or typhus. Typhoid fever may show a specific fever pattern, with a slow stepwise increase and a high plateau.
• Intermittent fever: Elevated temperature is present only for some hours of the day and becomes normal for remaining hours, e.g. malaria, kala-azar, pyaemia, or septicemia. 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 malariae). These patterns may be less clear in travelers.
• Remittent fever: Temperature remains above normal throughout the day and fluctuates more than 1°C in 24 hours, e.g. infective endocarditis.

A neutropenic fever, also called febrile neutropenia, is a fever in the absence of normal immune system function. Because of the lack of infection-fighting neutrophils, a bacterial infection can spread rapidly and this fever is therefore usually considered a medical emergency. This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy than in apparently healthy people.

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:

• Infectious disease, e.g. influenza, common cold, HIV, malaria, infectious mononucleosis, or gastroenteritis
• Various skin inflammations, e.g. boils, pimples, acne, or abscess
• Immunological diseases, e.g. lupus erythematosus, sarcoidosis, inflammatory bowel diseases
• Tissue destruction, which can occur in hemolysis, surgery, infarction, crush syndrome, rhabdomyolysis, cerebral hemorrhage, etc.
• Drug fever
• directly caused by the drug, e.g. lamictal, progesterone, or chemotherapeutics causing tumor necrosis
• as an adverse reaction to drugs, e.g. antibiotics or sulfa drugs.
• after drug discontinuation, e.g. heroin or fentanyl withdrawal
• Cancers, most commonly renal cancer and leukemia and lymphomas
• Metabolic disorders, e.g. gout or porphyria
• Thrombo-embolic processes, e.g. pulmonary embolism or 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 can aid in 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, causing 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.

Research has demonstrated that fever has several important functions in the healing process:

• increased mobility of leukocytes
• enhanced leukocytes phagocytosis
• endotoxin effects decreased
• increased proliferation of T Cells
• enhanced activity of interferon

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 to govern medical treatment and gauge its effectiveness. 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 electrolyte-replacing 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 is normally done by lowering the set-point, but facilitating heat loss may also be effective. The former is accomplished with antipyretics such as ibuprofen or acetominophen (aspirin can be given to adults, but can cause Reye's Syndrome in children). Heat removal is generally by wet cloth or pads, usually applied to the forehead, but also through bathing the body in tepid water. This is particularly important for babies, where drugs should be avoided. However, using water that is too cold can induce vasoconstriction, and reduce effective heat loss.

Heat loss may also be accomplished by heat conduction, convection, radiation, or evaporation (sweating, perspiration), or a combination of these.

Fever in domestic animals

Fever is also an important feature for the diagnosis of disease in domestic animals. The body temperature of animals, which is always taken rectally, is different from one species to another. For example, a horse is said to have a fever at 38.5°C, while a cow is said to have a fever at 39.6°C.

In species that allow the body to have a wide range of "normal" temperatures, such as camels, it is sometimes difficult to determine a febrile stage.

Diseases called "fever"

As fever is a prominent symptom of many diseases, in humans and animals, it will often appear in the common appellation of diseases.

in humans

• Ebola fever
• Puerperal fever
• Yellow fever
• Scarlet fever

in animals

• East Coast fever (an African disease of cattle)
• Malignant catarrhal fever (a world-wide disease of cattle)
• Milk fever (a metabolic illness of cattle with hypothermia)
• Rift valley fever (an African disease of sheep)

References

Further reading

• Rhoades, R. and Pflanzer, R. Human physiology, third edition, chapter 27 Regulation of body temperature, p. 820 Clinical focus: pathogenesis of fever. ISBN 0-03-005159-2
• Kasper, D.L.; Braunwald, E.; Fauci, A.S.; Hauser, S.L.; Longo, D.L.; Jameson, J.L. Harrison's Principles of Internal Medicine. New York: McGraw-Hill, 2005. ISBN 0-07-139140-1.

External links

• What to do if your child has a fever from Seattle Children's Hospital
• Fever and Taking Your Child's Temperature
• US National Institute of Health factsheet
• BUPA factsheet