Fever

Fever (also known as pyrexia or controlled hyperthermia ) is a common medical sign 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 and shivering.

As a person's temperature increases, there is, in general, a feeling of cold 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 medications can be effective at lowering the temperature, which may improve the affected person's comfort.

Fever differs from uncontrolled hyperthermia, 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.

Definition
A wide range for normal temperatures 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 (rectum/rectal) is at or over 37.5 –
 * Temperature in the mouth (oral) is at or over 37.7 C
 * Temperature under the arm (axillary) or in the ear (otic) is at or over 37.2 C

In healthy adult men and women, the range of normal, healthy temperatures 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 may represent a clinically significant fever.

Types
The pattern of temperature changes may occasionally hint at the diagnosis:


 * Continuous fever: Temperature remains above normal throughout the day and does not fluctuate more than $38.7 °C$ 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. (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, kala-azar, pyaemia, 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).
 * Remittent fever: Temperature remains above normal throughout the day and fluctuates more than $101.7 °F$ in 24 hours, e.g., infective endocarditis.
 * 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.

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; 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 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. Such a high temperature is considered a medical emergency as it may indicate a serious underlying condition or lead to significant side effects. The most common cause is an intracranial hemorrhage. Other possible causes include sepsis, Kawasaki syndrome, neuroleptic malignant syndrome, drug effects, serotonin syndrome, 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, rubeola and enteroviral infections. Immediate aggressive cooling to less than 38.9 C has been found to improve survival. Hyperpyrexia differs from hyperthermia 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 is an example of a high temperature that is not a fever. It occurs from a number of causes including heatstroke, neuroleptic malignant syndrome, malignant hyperthermia, stimulants such as amphetamines and cocaine, idiosyncratic drug reactions, and serotonin syndrome.

Signs and symptoms
A fever is usually accompanied by sickness behavior, which consists of lethargy, depression, anorexia, sleepiness, hyperalgesia, and the inability to concentrate.

Differential diagnosis
Fever is a common symptom of many medical conditions:
 * Infectious disease, e.g., influenza, HIV, malaria, infectious mononucleosis, or gastroenteritis
 * Various skin inflammations, e.g., boils, or abscess
 * Immunological diseases, e.g., lupus erythematosus, sarcoidosis, inflammatory bowel diseases, Kawasaki disease
 * Tissue destruction, which can occur in hemolysis, surgery, infarction, crush syndrome, rhabdomyolysis, cerebral hemorrhage, etc.
 * Reaction to incompatible blood products
 * Cancers, most commonly kidney 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 that cannot be explained after repeated routine clinical inquiries is called fever of unknown origin.

Pathophysiology


Temperature is ultimately regulated in the hypothalamus. 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. When the set point is raised, the body increases its temperature through both active generation of heat and retaining heat. Vasoconstriction 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 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, 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) or external (exogenous) to the body. The bacterial substance lipopolysaccharide (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 may be achieved through filtration, distillation, chromatography, or inactivation.

In essence, all endogenous pyrogens are cytokines, molecules that are a part of the innate immune system. 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 (IL-6) and tumor necrosis factor-alpha. Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-α, tumor necrosis factor-β, macrophage inflammatory protein-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ.
 * Endogenous

These cytokine factors are released into general circulation, where they migrate to the circumventricular organs of the brain due to easier absorption caused by the blood-brain barrier's reduced filtration action there. The cytokine factors then bind with endothelial receptors on vessel walls, or interact with local microglial cells. When these cytokine factors bind, the arachidonic acid pathway is then activated.

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.
 * Exogenous

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 (PVN) of the hypothalamus. 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
The brain ultimately orchestrates heat effector mechanisms via the autonomic nervous system. These may be: In infants, the autonomic nervous system may also activate brown adipose tissue to produce heat (non-exercise-associated thermogenesis, also known as non-shivering thermogenesis). Increased heart rate and vasoconstriction contribute to increased blood pressure in fever.
 * Increased heat production by increased muscle tone, shivering, and hormones like epinephrine
 * Prevention of heat loss, such as vasoconstriction.

Usefulness
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. 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 pathogens 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 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.

In general, people are advised to keep adequately hydrated, as the most significant risk of complications is dehydration. 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 pops, 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 ibuprofen 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 in children with fevers. Additionally, aspirin 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.

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 rather than a medical sign, 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 seizures 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 word febris, meaning fever, and archaically known as ague.

In other animals
Fever is an important feature for the diagnosis of disease in domestic animals. The body temperature of animals, which is taken rectally, is different from one species to another. For example, a horse is said to have a fever above $1 °C$ ($1 °C$).

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.