Fevers

This is about the medical condition. For other uses, see Fever (disambiguation).

Symptom/Sign: Fever
Classifications and external resources

ICD-10	R50.
ICD-9	780.6
DiseasesDB	18924

An analogue medical thermometer showing the temperature of 38.7 °C

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 symptom that describes an increase in internal body temperature to levels above normal (the common oral measurement of normal human body temperature is 36.8±0.7 °C or 98.2±1.3 °F). Fever is most accurately characterized as a temporary elevation in the body\'s thermoregulatory set-point, usually by about 1–2°C. Fever differs from hyperthermia; 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 bodies mechanisms to try and neutralize the percieved threat inside the body be it bacteria or a virus.

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)

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

Body temperature normally fluctuates over the day, with the lowest levels at 4 a.m. and the highest at 6 p.m.^{[citation needed]} Therefore, an oral temperature of 37.5°C (99.5°F) would strictly be a fever in the morning, but not in the afternoon. Normal body temperature may differ as much as 0.4°C (0.7°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 meals, and psychological factors (like the first day in the hospital) also influence body temperature.

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

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

Contents 1 Mechanism 1.1 Pyrogens 1.1.1 Endogenous 1.1.2 Exogenous 1.2 PGE2 release 1.3 Hypothalamus response 2 Types 3 Causes 4 Usefulness of fever 5 Treatment 6 References 7 Further reading 8 External links

Mechanism

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

Hyperthermia: Characterized on the left. Normal body temperature (thermoregulatory set-point) is shown in green, while the hyperthermic temperature is shown in red. As can be seen, hyperthermia can be conceptualized as an increase above the thermoregulatory set-point.
Hypothermia: Characterized in the center: Normal body temperature is shown in green, while the hypothermic temperature is shown in blue. As can be seen, hypothermia can be conceptualized as a decrease below the thermoregulatory set-point.
Fever: Characterized on the right: Normal body temperature is shown in green. It reads "New Normal" because the thermoregulatory set-point has risen. This has caused what was the normal body temperature (in blue) to be considered hypothermic.

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.

Endogenous

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

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

Exogenous

One model for the mechanism of fever caused by exogenous pyrogens includes 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, pyrexia (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. Asher, Richard (July 6, 1995). "Making Sense". The New England Journal of Medicine 333. 
• 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.

FebriculaFebricula, definition from Biology-Online.org, consulted June 7, 2006 http://www.biology-online.org/dictionary/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 withdrawal.
• Cancers, e.g. Hodgkin disease.
• 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

"Give me a fever, and I can cure any illness." -- Hippocrates (ca. 400 BC)

There are arguments for and against the usefulness of fever, and the issue is controversial.Schaffner A. Fever—useful or noxious symptom that should be treated? Ther Umsch 2006; 63: 185-8. PMID 16613288Soszynski D. The pathogenesis and the adaptive value of fever. Postepy Hig Med Dosw 2003; 57: 531-54. PMID 14737969 There are studies using warm-blooded vertebratesSu, F.; Nguyen, N.D.; Wang, Z.; Cai, Y.; Rogiers, P.; Vincent, J.L. Fever control in septic shock: beneficial or harmful? Shock 2005; 23: 516-20. PMID 15897803 and humansSchulman, C.I.; Namias, N.; Doherty, J., et al. The effect of antipyretic therapy upon outcomes in critically ill patients: a randomized, prospective study. Surg Infect (Larchmt) 2005; 6:369-75. PMID 16433601 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.Fischler, M.P.; Reinhart, W.H. Fever: friend or enemy? Schweiz Med Wochenschr 1997; 127: 864-70. PMID 9289813 The overall conclusion seems to be that both aggressive treatment of fever and too little fever control can be detrimental. This depends on the clinical situation, so careful assessment is needed.

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

ResearchCraven, R and Hirnle, C. (2006). Fundamentals of nursing: Human health and function. Fourth edition. p. 1044 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 CellsLewis, SM, Heitkemper, MM, and Dirksen, SR. (2007). Medical-surgical nursing: Assessment and management of clinical problems. sixth edition. p. 212
• 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 for follow-up. Moreover, not all fevers are of infectious origin.

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

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

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

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

v • d • e Symptoms and signs (R00-R69, 780-789)
Circulatory and respiratory systems	abnormalities of heart beat (Tachycardia, Bradycardia, Palpitation) - Heart murmur - Gangrene - Epistaxis - Hemoptysis - Cough - abnormalities of breathing (Dyspnea, Orthopnoea, Stridor, Wheeze, Cheyne-Stokes respiration, Hyperventilation, Mouth breathing, Hiccup, Bradypnea, Hypoventilation) - Chest pain - Asphyxia - Pleurisy - Respiratory arrest - Sputum - Bruit/Carotid bruit - Rales
Digestive system and abdomen	Abdominal pain (Acute abdomen) - Nausea/Vomiting - Heartburn - Dysphagia - flatulence and related (Abdominal distension, Bloating, Burping, Tympanites) - Fecal incontinence (Encopresis) - hepatosplenomegaly (Hepatomegaly, Splenomegaly) - Jaundice - Ascites - Fecal occult blood - Halitosis
Skin and subcutaneous tissue	disturbances of skin sensation (Hypoesthesia, Paresthesia, Hyperesthesia) - Rash - Cyanosis - Pallor - Flushing - Petechia - Desquamation - Induration - Diaphoresis
Nervous and musculoskeletal systems	abnormal involuntary movements (Tremor, Spasm, Fasciculation, Athetosis) - Gait abnormality - lack of coordination (Ataxia, Dysmetria, Dysdiadochokinesia, Hypotonia) - Tetany - Meningism - Hyperreflexia
Urinary system	Renal colic - Dysuria - Vesical tenesmus - Urinary incontinence - Urinary retention - Oliguria - Polyuria - Nocturia - Extravasation of urine - Extrarenal uremia
Cognition, perception, emotional state and behaviour	Anxiety - Somnolence - Coma - Amnesia (Anterograde amnesia, Retrograde amnesia) - Dizziness/Vertigo - smell and taste (Anosmia, Ageusia, Parosmia, Parageusia)
Speech and voice	speech disturbances (Dysphasia, Aphasia, Dysarthria, Schizophasia) - symbolic dysfunctions (Dyslexia, Alexia, Agnosia, Apraxia, Acalculia, Agraphia) - voice disturbances (Dysphonia, Aphonia)
General symptoms and signs	Fever (Hyperpyrexia) - Headache - Chronic pain - Malaise/Fatigue (Asthenia, Debility) - Fainting (Vasovagal syncope) - Febrile seizure - Shock (Cardiogenic shock) - Lymphadenopathy - Edema (Peripheral edema, Anasarca) - Hyperhidrosis (Sleep hyperhidrosis) - Delayed milestone - Failure to thrive - Short stature (Idiopathic) - food and fluid intake (Anorexia, Polydipsia, Polyphagia) - Cachexia - Xerostomia - Clubbing - Tenderness

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