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Fever

Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using values between 37.2 and in humans. The increase in set point triggers increased muscle contractions and causes a feeling of cold. This results in greater heat production and efforts to conserve heat. When the set point temperature returns to normal, a person feels hot, becomes flushed, and may begin to sweat. Rarely a fever may trigger a febrile seizure, with this being more common in young children. Fevers do not typically go higher than 41 to.A fever can be caused by many medical conditions ranging from non-serious to life-threatening. This includes viral, bacterial, and parasitic infections—such as influenza, the common cold, meningitis, urinary tract infections, appendicitis, COVID-19, and malaria. Non-infectious causes include vasculitis, deep vein thrombosis, connective tissue disease, side effects of medication, and cancer. It differs from hyperthermia, in that hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss.Treatment to reduce fever is generally not required. Treatment of associated pain and inflammation, however, may be useful and help a person rest. Medications such as ibuprofen or paracetamol (acetaminophen) may help with this as well as lower temperature. Measures such as putting a cool damp cloth on the forehead and having a slightly warm bath are not useful and may simply make a person more uncomfortable. Children younger than three months require medical attention, as might people with serious medical problems such as a compromised immune system or people with other symptoms. Hyperthermia does require treatment.

Fever is one of the most common medical signs. It is part of about 30% of healthcare visits by children and occurs in up to 75% of adults who are seriously sick. While fever evolved as a defense mechanism, treating fever does not appear to worsen outcomes. Fever is often viewed with greater concern by parents and healthcare professionals than is usually deserved, a phenomenon known as fever phobia.

Associated symptoms

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

Diagnosis



A range for normal temperatures has been found. Central temperatures, such as rectal temperatures, are more accurate than peripheral temperatures. 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 – An ear (tympanic) or forehead (temporal) temperature may also be used.
  • Temperature in the mouth (oral) is at or over 37.2 C in the morning or over 37.7 C in the afternoon
  • Temperature under the arm (axillary) is at or over 37.2 C

    In adults, the normal range of oral temperatures in healthy individuals is 33.2 –, while when taken rectally it is 34.4 –, for ear measurement it is 35.4 –, and for armpit (axillary) measurement it is 35.5 –. Harrison's Principles of Internal Medicine defines a fever as a morning oral temperature of >37.2 °C (>98.9 °F) or an afternoon oral temperature of >37.7 °C (>99.9 °F) although normal daily temperature variation has been described as 0.5 °C (0.9 °F). 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.

    Hyperthermia

    Hyperthermia is an increase in body temperature over the temperature set point, due to either too much heat production or not enough heat loss. It is an example of a high temperature phenomenon that is not a fever; rather, it occurs from a number of causes including heatstroke, neuroleptic malignant syndrome, malignant hyperthermia, as well as in response to stimulants such as substituted amphetamines and cocaine, and in idiosyncratic drug reactions, and serotonin syndrome. Hyperthermia differs from hyperpyrexia, see section following.

    Types



    Various patterns of measured patient temperatures have been observed, some of which may be indicative of a particular medical diagnosis:
  • Continuous fever, where temperature remains above normal throughout the day and does not fluctuate more than in 24 hours (e.g. in lobar pneumonia, typhoid, meningitis, urinary tract infection, or typhus);
  • Intermittent fever, where the temperature elevation is present only for a certain period, later cycling back to normal (e.g., in malaria, leishmaniasis, pyemia, or sepsis);
  • Remittent fever, where the temperature remains above normal throughout the day and fluctuates more than in 24 hours (e.g., in infective endocarditis, or brucellosis).

    Among the types of intermittent fever are ones specific to cases of malaria caused by different pathogens. These are:
  • Quotidian fever, with a 24-hour periodicity, typical of malaria caused by Plasmodium knowlesi (P. knowlesi);
  • Tertian fever, with a 48-hour periodicity, typical of later course malaria caused by P. falciparum, P. vivax, or P. ovale;
  • Quartan fever, with a 72-hour periodicity, typical of later course malaria caused by P. malariae.

    In addition, there is disagreement regarding whether a specific fever pattern is associated with Hodgkin's lymphoma—the Pel–Ebstein fever, with patient's argued to present high temperature for one week, followed by low for the next week, and so on, where the generality of this pattern is debated.

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

    An old term, febricula, has been used to refer to 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 an extreme elevation of body temperature which, depending upon the source, is classified as a core body temperature greater than or equal to 40.0 or; the range of hyperpyrexias include cases considered severe (≥ 40 °C) and extreme (≥ 42 °C). It differs from hyperthermia in that ones thermoregulatory system's set point for body temperature is set above normal, then heat is generated to achieve it (versus body temperature rising above its set point due to outside factors. The high temperatures of hyperpyrexia are considered medical emergencies, as they may indicate a serious underlying condition or lead to severe morbidity (including permanent brain damage), or to mortality. A common cause of hyperpyrexia is an intracranial hemorrhage. Other causes in emergency room settings include sepsis, Kawasaki syndrome, neuroleptic malignant syndrome, drug overdose, serotonin syndrome, and thyroid storm.

    Differential diagnosis

    Fever is a common symptom of many medical conditions:

  • Infectious disease, e.g., COVID-19, Dengue, Ebola, gastroenteritis, HIV, influenza, Lyme disease, malaria, mononucleosis, as well as infections of the skin, e.g., abscesses and boils.
  • Immunological diseases, e.g., relapsing polychondritis, autoimmune hepatitis, granulomatosis with polyangiitis, Horton disease, inflammatory bowel diseases, Kawasaki disease, lupus erythematosus, sarcoidosis, and Still's disease;
  • Tissue destruction, as a result of cerebral bleeding, crush syndrome, hemolysis, infarction, rhabdomyolysis, surgery, etc.;
  • Cancers, most commonly kidney cancer, leukemia, and lymphomas;
  • Metabolic disorders, e.g., gout, and porphyria; and
  • Inherited metabolic disorder, e.g., Fabry disease. Adult and pediatric manifestations for the same disease may differ; for instance, in COVID-19, one metastudy describes 92.8% of adults versus 43.9% of children presenting with fever.

    In addition, fever can result from a reaction to an incompatible blood product.

    Teething is not a cause of fever.

    Selective advantage





    Scholars viewing fever from an organismal and evolutionary perspective note the value to an organism of having a fever response, in particular in response to infective disease. On the other hand, while fever evolved as a defense mechanism, treating fever does not appear to worsen outcomes. Studies using warm-blooded vertebrates suggest that they recover more rapidly from infections or critical illness due to fever. Other studies suggest reduced mortality in bacterial infections when fever was present. Fever is thought to contribute to host defense, as the reproduction of pathogens with strict temperature requirements can be hindered, and the rates of some important immunological reactions} are increased by temperature. Fever has been described in teaching texts as assisting the healing process in various ways, including: :* increased mobility of leukocytes; :* enhanced leukocyte phagocytosis; In the presence of an infectious agent, such as bacteria, viruses, viroids, etc., the immune response of the body is to inhibit their growth and eliminate them. The most common pyrogens are endotoxins, which are lipopolysaccharides (LPS) produced by Gram-negative bacteria such as E. coli. But pyrogens include non-endotoxic substances (derived from microorganisms other than gram-negative-bacteria or from chemical substances) as well. The types of pyrogens inlcude internal (endogenous) and external (exogenous) to the body.

    The "pyrogenicity" of given pyrogens varies: in extreme cases, bacterial pyrogens can act as superantigens and cause rapid and dangerous fevers.

    Endogenous

    Endogenous pyrogens are cytokines released from monocytes (which are part of the immune system). In general, they stimulate chemical responses, often in the presence of an antigen, leading to a fever. Whilst they can be a product of external factors like exogenous pyrogens, they can also be induced by internal factors like damage associated from molecular patterns such as cases like rheumatoid arthritis or lupus.

    Major endogenous pyrogens are interleukin 1 (α and β) and interleukin 6 (IL-6). Minor endogenous pyrogens include interleukin-8, tumor necrosis factor-β, macrophage inflammatory protein-α and macrophage inflammatory protein-β as well as interferon-α, interferon-β, and interferon-γ. Tumor necrosis factor-α (TNF) also acts as a pyrogen, mediated by interleukin 1 (IL-1) release. These cytokine factors are released into general circulation, where they migrate to the brain's circumventricular organs where they are more easily absorbed than in areas protected by the blood–brain barrier. The cytokines then bind to endothelial receptors on vessel walls to receptors on microglial cells, resulting in activation of the arachidonic acid pathway.

    Of these, IL-1β, TNF, and IL-6 are able to raise the temperature setpoint of an organism and cause fever. These proteins produce a cyclooxygenase which induces the hypothalamic production of PGE2 which then stimulates the release of neurotransmitters such as cyclic adenosine monophosphate and increases body temperature.

    Exogenous

    Exogenous pyrogens are external to the body and are of microbrial origin. In general, these pyrogens, including bacterial cell wall products, may act on Toll-like receptors in the hypothalamus and elevate the thermoregulatory setpoint.

    An example of a class of exogenous pyrogens are bacterial lipopolysaccharides (LPS) present in the cell wall of gram-negative bacteria. According to one mechanism of pyrogen action, an immune system protein, lipopolysaccharide-binding protein (LBP), binds to LPS, and the LBP–LPS complex then binds to a CD14 receptor on a macrophage. The LBP-LPS binding to CD14 results in cellular synthesis and release of various endogenous cytokines, e.g., interleukin 1 (IL-1), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNFα). A further downstream event is activation of 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 (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.

    Management

    Fever does not necessarily need to be treated, and most febrile cases 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 40.6 °C (105 °F). Treating fever in people with sepsis does not affect outcomes.

    Conservative measures

    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 (generally produced mechanically via conduction by applying numerous ice packs across most of the body or direct submersion in ice water). In general, people are advised to keep adequately hydrated. Whether increased fluid intake improves symptoms or shortens respiratory illnesses such as the common cold is not known.

    Medications

    Medications that lower fevers are called antipyretics. 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.

    Using both paracetamol and ibuprofen at the same time or alternating between the two is more effective at decreasing fever than using only paracetamol or ibuprofen. It is not clear if it increases child comfort. Response or nonresponse to medications does not predict whether or not a child has a serious illness.

    With respect to the effect of antipyretics on the risk of death in those with infection, studies have found mixed results as of 2019. Animals models have found worsened outcomes with the use of antipyretics in influenza as of 2010 but they have not been studied for this use in humans.

    Epidemiology

    Fever is one of the most common medical signs. It is part of about 30% of healthcare visits by children, and occurs in up to 75% of adults who are seriously sick. About 5% of people who go to an emergency room have a fever.

    History

    A number of types of fever were known as early as 460 BC to 370 BC when Hippocrates was practicing medicine including that due to malaria (tertian or every 2 days and quartan or every 3 days). It also became clear around this time that fever was a symptom of disease rather than a disease in and of itself.

    Society and culture

    Fever is often viewed with greater concern by parents and healthcare professionals than might be deserved, a phenomenon known as fever phobia, which is based in both caregiver's and parents' misconceptions about fever in 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. 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. 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. Fever can also be behaviorally induced by invertebrates that do not have immune-system based fever. For instance, some species of grasshopper will thermoregulate to achieve body temperatures that are 2–5 °C higher than normal in order to inhibit the growth of fungal pathogens such as Beauveria bassiana and Metarhizium acridum. Honeybee colonies are also able to induce a fever in response to a fungal parasite Ascosphaera apis.