Fever
Encyclopedia
Fever is a common medical sign
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....

 characterized by an elevation of temperature above the normal range of 36.5 – due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone
Muscle tone
In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...

 and shivering
Shivering
Shivering is a bodily function in response to early hypothermia in warm-blooded animals. When the core body temperature drops, the shivering reflex is triggered to maintain homeostasis. Muscle groups around the vital organs begin to shake in small movements in an attempt to create warmth by...

.

As a person's temperature increases, there is, in general, a feeling of cold
Cold
Cold describes the condition of low temperature.Cold may also refer to:*Common cold, a contagious viral infectious disease of the upper respiratory system*Chronic obstructive pulmonary disease...

 despite an increasing body temperature. Once the new temperature is reached, there is a feeling of warmth. A fever can be caused by many different conditions ranging from benign to potentially serious. There are arguments for and against the usefulness of fever, and the issue is controversial. With the exception of very high temperatures, treatment to reduce fever is often not necessary; however, antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 medications can be effective at lowering the temperature, which may improve the affected person's comfort.

Fever differs from uncontrolled hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...

, in that hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production and/or insufficient thermoregulation
Thermoregulation
Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different...

.

Definition

A wide range for normal temperatures
Normal human body temperature
Normal human body temperature, also known as normothermia or euthermia, is a concept that depends upon the place in the body at which the measurement is made, and the time of day and level of activity of the person...

 has been found.
Fever is generally agreed to be present if the elevated temperature is caused by a raised set point and:
  • Temperature in the anus
    Anus
    The anus is an opening at the opposite end of an animal's digestive tract from the mouth. Its function is to control the expulsion of feces, unwanted semi-solid matter produced during digestion, which, depending on the type of animal, may be one or more of: matter which the animal cannot digest,...

     (rectum/rectal) is at or over 37.5 –
  • Temperature in the mouth (oral) is at or over 37.7 °C (99.9 °F)
  • Temperature under the arm (axillary) or in the ear
    Ear
    The ear is the organ that detects sound. It not only receives sound, but also aids in balance and body position. The ear is part of the auditory system....

     (otic) is at or over 37.2 °C (99 °F)


In healthy adult men and women, the range of normal, healthy temperatures
Normal human body temperature
Normal human body temperature, also known as normothermia or euthermia, is a concept that depends upon the place in the body at which the measurement is made, and the time of day and level of activity of the person...

 for oral temperature is 33.2 –, for rectal it is 34.4 –, for tympanic membrane (the ear drum) it is 35.4 –, and for axillary (the armpit) it is 35.5 –.

Normal body temperatures vary depending on many factors, including age, sex, time of day, ambient temperature, activity level, and more. A raised temperature is not always a fever. For example, the temperature of a healthy person rises when he or she exercises, 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 37.3 °C (99.1 °F) may represent a clinically significant fever.

Types

The pattern of temperature changes may occasionally hint at the diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

:
  • Continuous fever: Temperature remains above normal throughout the day and does not fluctuate more than in 24 hours, e.g. lobar pneumonia
    Lobar pneumonia
    Lobar pneumonia is a form of pneumonia that affects a large and continuous area of the lobe of a lung.It is one of the two anatomic classifications of pneumonia .- Symptoms :...

    , typhoid, urinary tract infection
    Urinary tract infection
    A urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...

    , brucellosis
    Brucellosis
    Brucellosis, also called Bang's disease, Crimean fever, Gibraltar fever, Malta fever, Maltese fever, Mediterranean fever, rock fever, or undulant fever, is a highly contagious zoonosis caused by ingestion of unsterilized milk or meat from infected animals or close contact with their secretions...

    , or typhus
    Typhus
    Epidemic typhus is a form of typhus so named because the disease often causes epidemics following wars and natural disasters...

    . Typhoid fever
    Typhoid fever
    Typhoid fever, also known as Typhoid, is a common worldwide bacterial disease, transmitted by the ingestion of food or water contaminated with the feces of an infected person, which contain the bacterium Salmonella enterica, serovar Typhi...

     may show a specific fever pattern, with a slow stepwise increase and a high plateau. (Drops due to fever-reducing drugs are excluded.)
  • Intermittent fever: The temperature elevation is present only for a certain period, later cycling back to normal, e.g. malaria
    Malaria
    Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

    , kala-azar, pyaemia
    Pyaemia
    Pyaemia is a type of septicaemia that leads to widespread abscesses of a metastatic nature. It is usually caused by the staphylococcus bacteria by pus-forming organisms in the blood. Apart from the distinctive abscesses, pyaemia exhibits the same symptoms as other forms of septicaemia...

    , or septicemia. Following are its types
    • Quotidian fever, with a periodicity of 24 hours, typical of Malaria
    • Tertian fever (48 hour periodicity), typical of Malaria
    • Quartan fever (72 hour periodicity), typical of Plasmodium malariae
      Plasmodium malariae
      Plasmodium malariae is a parasitic protozoa that causes malaria in humans. It is closely related to Plasmodium falciparum and Plasmodium vivax which are responsible for most malarial infection. While found worldwide, it is a so-called "benign malaria" and is not nearly as dangerous as that...

      .
  • Remittent fever: Temperature remains above normal throughout the day and fluctuates more than in 24 hours, e.g., infective endocarditis
    Infective endocarditis
    Infective endocarditis is a form of endocarditis, or inflammation, of the inner tissue of the heart, such as its valves, caused by infectious agents. The agents are usually bacterial, but other organisms can also be responsible....

    .
  • Pel-Ebstein fever
    Pel-Ebstein fever
    Pel-Ebstein fever is a rarely seen condition noted in patients with Hodgkin's lymphoma in which the patient experiences fevers which cyclicly increase then decrease over an average period of one or two weeks...

    : A specific kind of fever associated with Hodgkin's lymphoma
    Hodgkin's lymphoma
    Hodgkin's lymphoma, previously known as Hodgkin's disease, is a type of lymphoma, which is a cancer originating from white blood cells called lymphocytes...

    , 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.


A neutropenic fever, also called febrile neutropenia
Febrile neutropenia
Febrile neutropenia is the development of fever, often with other signs of infection, in a patient with neutropenia, an abnormally low number of neutrophil granulocytes in the blood. The term neutropenic sepsis is also applied, although it tends to be reserved for patients who are less well...

, 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; this fever is, therefore, usually considered to require urgent medical attention. This kind of fever is more commonly seen in people receiving immune-suppressing chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....

 than in apparently healthy people.

Febricula is an old term for a low-grade fever, especially if the cause is unknown, no other symptoms are present, and the patient recovers fully in less than a week.

Hyperpyrexia

Hyperpyrexia is a fever with an extreme elevation of body temperature greater than or equal to 41.5 °C (106.7 °F). Such a high temperature is considered a medical emergency
Medical emergency
A medical emergency is an injury or illness that is acute and poses an immediate risk to a person's life or long term health. These emergencies may require assistance from another person, who should ideally be suitably qualified to do so, although some of these emergencies can be dealt with by the...

 as it may indicate a serious underlying condition or lead to significant side effects. The most common cause is an intracranial hemorrhage
Intracranial hemorrhage
An intracranial hemorrhage is a hemorrhage, or bleeding, within the skull.-Causes:Intracranial bleeding occurs when a blood vessel within the skull is ruptured or leaks. It can result from physical trauma or nontraumatic causes such as a ruptured aneurysm...

. Other possible causes include sepsis
Sepsis
Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues...

, Kawasaki syndrome, neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...

, drug effects, serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...

, and thyroid storm. Infections are the most common cause of fevers, however as the temperature rises other causes become more common. Infections commonly associated with hyperpyrexia include: roseola
Roseola
Exanthema subitum , also referred to as roseola infantum , sixth disease and baby measles, or three-day fever, is a disease of children, generally under two years old, although it has been known to occur in eighteen year olds, whose manifestations...

, rubeola and enteroviral infections. Immediate aggressive cooling to less than 38.9 °C (102 °F) has been found to improve survival. Hyperpyrexia differs from hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...

 in that in hyperpyrexia the body's temperature regulation mechanism sets the body temperature above the normal temperature, then generates heat to achieve this temperature, while in hyperthermia the body temperature rises above its set point.

Hyperthermia

Hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...

 is an example of a high temperature that is not a fever. It occurs from a number of causes including heatstroke, neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...

, malignant hyperthermia
Malignant hyperthermia
Malignant hyperthermia or malignant hyperpyrexia is a rare life-threatening condition that is usually triggered by exposure to certain drugs used for general anesthesia; specifically, the volatile anesthetic agents and the neuromuscular blocking agent, succinylcholine...

, stimulants such as amphetamine
Amphetamine
Amphetamine or amfetamine is a psychostimulant drug of the phenethylamine class which produces increased wakefulness and focus in association with decreased fatigue and appetite.Brand names of medications that contain, or metabolize into, amphetamine include Adderall, Dexedrine, Dextrostat,...

s and cocaine
Cocaine
Cocaine is a crystalline tropane alkaloid that is obtained from the leaves of the coca plant. The name comes from "coca" in addition to the alkaloid suffix -ine, forming cocaine. It is a stimulant of the central nervous system, an appetite suppressant, and a topical anesthetic...

, idiosyncratic drug reaction
Idiosyncratic drug reaction
Idiosyncratic drug reactions, also known as type B reactions, are drug reactions that occur rarely and unpredictably amongst the population. This is not to be mistaken with idiopathic, which implies that the cause is not known...

s, and serotonin syndrome
Serotonin syndrome
Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs...

.

Signs and symptoms

A fever is usually accompanied by sickness behavior
Sickness behavior
thumb|350px|right|[[Michael Peter Ancher|Ancher, Michael]], "The Sick Girl", 1882, [[Statens Museum for Kunst]]Sickness behavior is a coordinated set of adaptive behavioral changes that develop in ill individuals during the course of an infection....

, which consists of lethargy, depression
Depression (mood)
Depression is a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Depressed people may feel sad, anxious, empty, hopeless, helpless, worthless, guilty, irritable, or restless...

, anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...

, sleepiness, hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...

, and the inability to concentrate.

Differential diagnosis

Fever is a common symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

 of many medical conditions:
  • Infectious disease
    Infectious disease
    Infectious diseases, also known as communicable diseases, contagious diseases or transmissible diseases comprise clinically evident illness resulting from the infection, presence and growth of pathogenic biological agents in an individual host organism...

    , e.g., influenza
    Influenza
    Influenza, commonly referred to as the flu, is an infectious disease caused by RNA viruses of the family Orthomyxoviridae , that affects birds and mammals...

    , HIV
    HIV
    Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...

    , malaria
    Malaria
    Malaria is a mosquito-borne infectious disease of humans and other animals caused by eukaryotic protists of the genus Plasmodium. The disease results from the multiplication of Plasmodium parasites within red blood cells, causing symptoms that typically include fever and headache, in severe cases...

    , infectious mononucleosis
    Infectious mononucleosis
    Infectious mononucleosis is an infectious, widespread viral...

    , or gastroenteritis
    Gastroenteritis
    Gastroenteritis is marked by severe inflammation of the gastrointestinal tract involving both the stomach and small intestine resulting in acute diarrhea and vomiting. It can be transferred by contact with contaminated food and water...

  • Various skin inflammation
    Inflammation
    Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

    s, e.g., boils, or abscess
    Abscess
    An abscess is a collection of pus that has accumulated in a cavity formed by the tissue in which the pus resides due to an infectious process or other foreign materials...

  • Immunological
    Immunology
    Immunology is a broad branch of biomedical science that covers the study of all aspects of the immune system in all organisms. It deals with the physiological functioning of the immune system in states of both health and diseases; malfunctions of the immune system in immunological disorders ; the...

     diseases, e.g., lupus erythematosus
    Lupus erythematosus
    Lupus erythematosus is a category for a collection of diseases with similar underlying problems with immunity . Symptoms of these diseases can affect many different body systems, including joints, skin, kidneys, blood cells, heart, and lungs...

    , sarcoidosis
    Sarcoidosis
    Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...

    , inflammatory bowel disease
    Inflammatory bowel disease
    In medicine, inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis.-Classification:...

    s, Kawasaki disease
    Kawasaki disease
    Kawasaki disease , also known as Kawasaki syndrome, lymph node syndrome and mucocutaneous lymph node syndrome, is an autoimmune disease in which the medium-sized blood vessels throughout the body become inflamed. It is largely seen in children under five years of age...

  • Tissue destruction, which can occur in hemolysis
    Hemolysis
    Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...

    , surgery
    Surgery
    Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...

    , infarction
    Infarction
    In medicine, infarction refers to tissue death that is caused by a local lack of oxygen due to obstruction of the tissue's blood supply. The resulting lesion is referred to as an infarct.-Causes:...

    , crush syndrome
    Crush syndrome
    Crush syndrome is a medical condition characterized by major shock and renal failure after a crushing injury to skeletal muscle...

    , rhabdomyolysis
    Rhabdomyolysis
    Rhabdomyolysis is a condition in which damaged skeletal muscle tissue breaks down rapidly. Breakdown products of damaged muscle cells are released into the bloodstream; some of these, such as the protein myoglobin, are harmful to the kidneys and may lead to kidney failure...

    , cerebral hemorrhage, etc.
  • Reaction to incompatible blood products
  • Cancer
    Cancer
    Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...

    s, most commonly kidney cancer
    Kidney cancer
    Kidney cancer is a type of cancer that starts in the cells in the kidney.The two most common types of kidney cancer are renal cell carcinoma and urothelial cell carcinoma of the renal pelvis...

     and leukemia
    Leukemia
    Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...

     and lymphoma
    Lymphoma
    Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

    s
  • Metabolic disorders, e.g., gout
    Gout
    Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

     or porphyria
    Porphyria
    Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway . They are broadly classified as acute porphyrias and cutaneous porphyrias, based on the site of the overproduction and accumulation of the porphyrins...

  • Thrombo-embolic processes, e.g., pulmonary embolism
    Pulmonary embolism
    Pulmonary embolism is a blockage of the main artery of the lung or one of its branches by a substance that has travelled from elsewhere in the body through the bloodstream . Usually this is due to embolism of a thrombus from the deep veins in the legs, a process termed venous thromboembolism...

     or deep venous thrombosis


Persistent fever that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin
Fever of unknown origin
Fever of unknown origin , pyrexia of unknown origin or febris e causa ignota refers to a condition in which the patient has an elevated temperature but despite investigations by a physician no explanation has been found....

.

Pathophysiology

Temperature is ultimately regulated in the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

. A trigger of the fever, called a pyrogen, causes a release of prostaglandin E2 (PGE2). PGE2 then in turn acts on the hypothalamus, which generates a systemic response back to the rest of the body, causing heat-creating effects to match a new temperature level.

In many respects, the hypothalamus works like a thermostat
Thermostat
A thermostat is the component of a control system which regulates the temperature of a system so that the system's temperature is maintained near a desired setpoint temperature. The thermostat does this by switching heating or cooling devices on or off, or regulating the flow of a heat transfer...

. When the set point is raised, the body increases its temperature through both active generation of heat and retaining heat. Vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...

 both reduces heat loss through the skin and causes the person to feel cold. If these measures are insufficient to make the blood temperature in the brain match the new setting in the hypothalamus, then shivering
Shivering
Shivering is a bodily function in response to early hypothermia in warm-blooded animals. When the core body temperature drops, the shivering reflex is triggered to maintain homeostasis. Muscle groups around the vital organs begin to shake in small movements in an attempt to create warmth by...

 begins in order to use muscle movements to produce more heat. When the fever stops, and the hypothalamic setting is set lower; the reverse of these processes (vasodilation, end of shivering and nonshivering heat production) and sweating are used to cool the body to the new, lower setting.

This contrasts with hyperthermia
Hyperthermia
Hyperthermia is an elevated body temperature due to failed thermoregulation. Hyperthermia occurs when the body produces or absorbs more heat than it can dissipate...

, 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 (heat stroke) or an adverse reaction to drugs. Fever can be differentiated from hyperthermia by the circumstances surrounding it and its response to anti-pyretic medications.

Pyrogens

A pyrogen is a substance that induces fever. These can be either internal (endogenous
Endogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...

) or external (exogenous
Exogenous
Exogenous refers to an action or object coming from outside a system. It is the opposite of endogenous, something generated from within the system....

) to the body. The bacterial substance lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...

 (LPS), present in the cell wall of some bacteria, is an example of an exogenous pyrogen. Pyrogenicity can vary: In extreme examples, some bacterial pyrogens known as superantigens can cause rapid and dangerous fevers. Depyrogenation
Depyrogenation
Depyrogenation refers to the removal of pyrogens from solution, most commonly from injectable pharmaceuticals.A pyrogen is defined as any substance that can cause a fever. Bacterial pyrogens include endotoxins and exotoxins, although many pyrogens are endogenous to the host...

 may be achieved through filtration
Filtration
Filtration is commonly the mechanical or physical operation which is used for the separation of solids from fluids by interposing a medium through which only the fluid can pass...

, distillation
Distillation
Distillation is a method of separating mixtures based on differences in volatilities of components in a boiling liquid mixture. Distillation is a unit operation, or a physical separation process, and not a chemical reaction....

, chromatography
Chromatography
Chromatography is the collective term for a set of laboratory techniques for the separation of mixtures....

, or inactivation.

Endogenous
In essence, all endogenous pyrogens are cytokines, molecules that are a part of the innate immune system
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...

. They are produced by phagocytic cells and cause the increase in the thermoregulatory set-point in the hypothalamus. Major endogenous pyrogens are interleukin 1 (α and β), interleukin 6
Interleukin 6
Interleukin-6 is a protein that in humans is encoded by the IL6 gene.IL-6 is an interleukin that acts as both a pro-inflammatory and anti-inflammatory cytokine. It is secreted by T cells and macrophages to stimulate immune response, e.g. during infection and after trauma, especially burns or other...

 (IL-6) and tumor necrosis factor-alpha. Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-α, tumor necrosis factor-β, macrophage inflammatory protein
Macrophage Inflammatory Protein
Macrophage Inflammatory Proteins belong to the family of chemotactic cytokines known as chemokines. Macrophage inflammatory protein-1 , MIP-1 and MIP-1 are chemokines crucial for immune responses towards infection and inflammation. In humans, there are two major forms, MIP-1α and MIP-1β that are...

-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...

.

These cytokine factors are released into general circulation, where they migrate to the circumventricular organs of the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...

 due to easier absorption caused by the blood-brain barrier
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...

's reduced filtration action there. The cytokine factors then bind with endothelial receptor
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...

s on vessel walls, or interact with local microglial cells. When these cytokine factors bind, the arachidonic acid pathway is then activated.

Exogenous
One model for the mechanism of fever caused by exogenous pyrogens includes LPS, which is a cell wall component of gram-negative bacteria
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...

. An immunological protein called lipopolysaccharide-binding protein
Lipopolysaccharide-binding protein
Lipopolysaccharide-binding protein is a protein that in humans is encoded by the LBP gene.LBP is a soluble acute-phase protein that binds to bacterial lipopolysaccharide to elicit immune responses by presenting the LPS to important cell surface pattern recognition receptors called CD14 and...

 (LBP) binds to LPS. The LBP–LPS complex then binds to the CD14
CD14
Cluster of differentiation 14 also known as CD14 is a human gene.The protein encoded by this gene is a component of the innate immune system. CD14 exists in two forms. Either it is anchored into the membrane by a glycosylphosphatidylinositol tail or it appears in a soluble form...

 receptor of a nearby macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

. This binding results in the synthesis and release of various endogenous cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 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
Arachidonic acid
Arachidonic acid is a polyunsaturated omega-6 fatty acid 20:4.It is the counterpart to the saturated arachidic acid found in peanut oil, Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega-6 fatty acid 20:4(ω-6).It is the counterpart to the saturated arachidic acid found in peanut oil,...

 pathway. This pathway (as it relates to fever), is mediated by the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s phospholipase A2
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...

 (PLA2), cyclooxygenase-2
Cyclooxygenase
Cyclooxygenase is an enzyme that is responsible for formation of important biological mediators called prostanoids, including prostaglandins, prostacyclin and thromboxane. Pharmacological inhibition of COX can provide relief from the symptoms of inflammation and pain...

 (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
Preoptic area
The preoptic area is a region of the hypothalamus. According to the MeSH classification, it is considered part of the anterior hypothalamus. There are four nuclei in this region, according to Terminologia Anatomica .-Functions:The preoptic area is responsible for thermoregulation and receives...

 (POA) through the prostaglandin E receptor 3
Prostaglandin E receptor 3
Prostaglandin E receptor 3, also known as EP3, is a prostaglandin receptor, encoded by the PTGER3 gene.-Further reading:...

 (EP3). EP3-expressing neurons in the POA innervate the dorsomedial hypothalamus (DMH), the rostral raphe
Raphe
Raphe has several different meanings in science. Pronounced .In botany and planktology it is commonly used when describing a seam or ridge on diatoms or seeds....

 pallidus nucleus in the medulla oblongata
Medulla oblongata
The medulla oblongata is the lower half of the brainstem. In discussions of neurology and similar contexts where no ambiguity will result, it is often referred to as simply the medulla...

 (rRPa), and the paraventricular nucleus
Paraventricular nucleus
The paraventricular nucleus is a neuronal nucleus in the hypothalamus. It contains multiple subpopulations of neurons that are activated by a variety of stressful and/or physiological changes. Many PVN neurons project directly to the posterior pituitary where they release oxytocin or vasopressin...

 (PVN) of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...

 . Fever signals sent to the DMH and rRPa lead to stimulation of the sympathetic
Sympathetic nervous system
The sympathetic nervous system is one of the three parts of the autonomic nervous system, along with the enteric and parasympathetic systems. Its general action is to mobilize the body's nervous system fight-or-flight response...

 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
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...

 and various endocrine organs.

Hypothalamus

The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous system
Autonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...

. These may be:
  • Increased heat production by increased muscle tone
    Muscle tone
    In physiology, medicine, and anatomy, muscle tone is the continuous and passive partial contraction of the muscles, or the muscle’s resistance to passive stretch during resting state. It helps maintain posture, and it declines during REM sleep.-Purpose:Unconscious nerve impulses maintain the...

    , shivering
    Shivering
    Shivering is a bodily function in response to early hypothermia in warm-blooded animals. When the core body temperature drops, the shivering reflex is triggered to maintain homeostasis. Muscle groups around the vital organs begin to shake in small movements in an attempt to create warmth by...

    , and hormones like epinephrine
  • Prevention of heat loss, such as vasoconstriction
    Vasoconstriction
    Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...

    .

In infants, the autonomic nervous system may also activate brown adipose tissue
Brown adipose tissue
Brown adipose tissue or brown fat is one of two types of fat or adipose tissue found in mammals....

 to produce heat (non-exercise-associated thermogenesis
Thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs mostly in warm-blooded animals, but a few species of thermogenic plants exist.-Types:...

, also known as non-shivering thermogenesis). Increased heart rate and vasoconstriction contribute to increased blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...

 in fever.

Usefulness

There are arguments for and against the usefulness of fever, and the issue is controversial. There are studies using warm-blooded
Warm-blooded
The term warm-blooded is a colloquial term to describe animal species which have a relatively higher blood temperature, and maintain thermal homeostasis primarily through internal metabolic processes...

 vertebrates and human
Human
Humans are the only living species in the Homo genus...

s in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

, with some suggesting that they recover more rapidly from infections or critical illness due to fever. A Finnish study suggested reduced mortality in bacterial infections when fever was present.

In theory, fever can aid in host defense. There are certainly some important immunological reactions that are sped up by temperature, and some pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...

s with strict temperature preferences could be hindered. Fever in children is believed to train the immune system and prevent asthma.
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
    Endotoxin
    Endotoxins are toxins associated with some Gram-negative bacteria. An "endotoxin" is a toxin that is a structural molecule of the bacteria that is recognized by the immune system.-Gram negative:...

     effects decreased
  • Increased proliferation of T cells

Management

Fever should not necessarily be treated. Most people recover without specific medical attention. Although it is unpleasant, fever rarely rises to a dangerous level even if untreated. Damage to the brain generally does not occur until temperatures reach 42 °C (107.6 °F), and it is rare for an untreated fever to exceed 105 °F (40.6 °C).

In general, people are advised to keep adequately hydrated, as the most significant risk of complications is dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

. Water is generally used for this purpose. The risk of hyponatremia induced by increased fluid intake can be reduced through the use of appropriately formulated oral rehydration solutions. Other options include ice pop
Ice pop
An ice pop, also referred to in the United States as a popsicle, and in the United Kingdom as an ice lolly, lolly ice or ice lollipop, is a frozen, water-based dessert. It is made by freezing flavored liquid around a stick. Often, the juice is colored artificially...

s, juice, and other non-alcoholic drinks.

Some limited evidence supports sponging or bathing feverish children with tepid water. The use of a fan or air conditioning may somewhat reduce the temperature and increase comfort. If the temperature reaches the extremely high level of hyperpyrexia, aggressive cooling is required.

Medications

The antipyretic
Antipyretic
Antipyretics ; an-tee-pahy-ret-iks; from the Greek anti, against, and pyreticus, are drugs or herbs that reduce fever. Normally, they will not lower body temperature if one does not have a fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature...

 ibuprofen
Ibuprofen
Ibuprofen is a nonsteroidal anti-inflammatory drug used for relief of symptoms of arthritis, fever, as an analgesic , especially where there is an inflammatory component, and dysmenorrhea....

 is effective in reducing fevers in children. It is more effective than acetaminophen (paracetamol) in children. Ibuprofen and acetaminophen may be safely used together in children with fevers. The efficacy of acetaminophen by itself in children with fevers has been questioned. Ibuprofen is also superior to aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 in children with fevers. Additionally, aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...

 is not recommended in children and young adults (those under the age of 16 or 19 depending on the country) due to the risk of Reye's syndrome
Reye's syndrome
Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar . The classic features are liver damage, aspirin use and a viral infection...

.

Fever phobia

Fever phobia is the name given by medical experts to parents' misconceptions about fever in their children. Among them, many parents incorrectly believe that fever is a disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...

 rather than a medical sign
Medical sign
A medical sign is an objective indication of some medical fact or characteristic that may be detected by a physician during a physical examination of a patient....

, that even low fevers are harmful, and that any temperature even briefly or slightly above the oversimplified "normal" number marked on a thermometer is a clinically significant fever. They are also afraid of harmless side effects like febrile seizure
Febrile seizure
A febrile seizure, also known as a fever fit or febrile convulsion, is a convulsion associated with a significant rise in body temperature...

s and dramatically overestimate the likelihood of permanent damage from typical fevers. The underlying problem, according to professor of pediatrics Barton D. Schmitt, is "as parents we tend to suspect that our children’s brains may melt".

As a result of these misconceptions, parents are anxious, give the child fever-reducing medicine when the temperature is technically normal or only slightly elevated, and interfere with the child's sleep to give the child more medicine.

Etymology

Pyrexia is from the Greek pyretos meaning fire. Febrile is from the Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

 word febris
Febris
In Roman mythology, Febris was the goddess who embodied, but also protected people from fever and malaria. Febris had three temples in ancient Rome, of which one was located between the Palatine and Velabrum. She may have originated from the Etruscan god Februus...

, meaning fever, and archaically known as ague.

In other animals

Fever is an important feature for the diagnosis
Medical diagnosis
Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

 of disease in domestic animals
Veterinary medicine
Veterinary Medicine is the branch of science that deals with the prevention, diagnosis and treatment of disease, disorder and injury in non-human animals...

. The body temperature of animals, which is taken rectally, is different from one species to another. For example, a horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

 is said to have a fever above .

In species that allow the body to have a wide range of "normal" temperatures, such as camel
Camel
A camel is an even-toed ungulate within the genus Camelus, bearing distinctive fatty deposits known as humps on its back. There are two species of camels: the dromedary or Arabian camel has a single hump, and the bactrian has two humps. Dromedaries are native to the dry desert areas of West Asia,...

s, it is sometimes difficult to determine a febrile stage.

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

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
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