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| {{Infobox_Disease |
| | #redirect:[[Fever]] |
| Name = Fever |
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| ICD10 = {{ICD10|R|50||r|50}} |
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| ICD9 = {{ICD9|780.6}} |
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| ICDO = |
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| Image = Clinical thermometer 38.7.JPG|
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| Caption = An analogue [[medical thermometer]] showing the temperature of 38.7 °C|
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| OMIM = |
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| MedlinePlus = |u
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| eMedicineSubj = med |
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| eMedicineTopic = 785 |
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| DiseasesDB = 18924 |}}
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| {{SI}}
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| {{CMG}}
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| {{EH}}
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| ==Overview==
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| '''Fever''' (also known as '''pyrexia''', or a '''febrile response''' from the [[Latin]] word ''[[febris]]'', meaning fever, and archaically known as '''ague''') is a frequent [[medicine|medical]] [[symptom]] that describes an increase in internal [[body temperature]] to levels that are 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]], which is an increase in body temperature over the body’s thermoregulatory set-point (due to excessive heat production or insufficient [[thermoregulation]], or both). [[Carl Reinhold August Wunderlich|Carl Wunderlich]] discovered that fever is not a disease but a symptom of disease.
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| The elevation in thermoregulatory set-point means that the previous "normal body temperature" is considered [[hypothermia|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.
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| When a patient has or is suspected of having a fever, that person's body temperature is measured using thermometer. At a first glance, fever is present if:
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| * temperature in the anus (rectum/rectal) or in the ear (otic) is at, or higher than 38 degrees Celsius (100.4 degrees Fahrenheit)
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| * oral temperature (in the mouth) is at, or higher than 37.5 degrees Celsius (99.5 degrees Fahrenheit)
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| * axillary temperature (underarm) is at, or higher than 37.2 degrees Celsius (99 degrees Fahrenheit)
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| 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, drunk, or smoked anything in at least the previous fifteen minutes.
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| Body temperature normally fluctuates over the day, with the lowest levels at 4A.M. and the highest at 6P.M. Therefore, an oral temperature of 37.5C would strictly be a fever in the morning, but not in the afternoon. Normal body temperature may differ as much as 0.4C (0.7F) between individuals or from day to day. In women, temperature differs at various points in the [[menstrual cycle]], and this can be used for [[fertility awareness|family planning]] (although it is only one of the variables of temperature). Temperature is increased after meals, and psychological factors (like the first day in the hospital) also influence body temperature.
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| There are different locations where temperature can be measured, and these differ in temperature variability. [[Tympanic membrane]] [[thermometer]]s measure radiant heat energy from the tympanic membrane (infrared). These may be very convenient, but may also show more variability.
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| 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]].
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| ==Mechanism==
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| 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.
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| [[Image:fever-conceptual.svg|thumb|right|400px|'''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.<br />'''Hypothermia''': Characterized in the center: Normal body temperature (thermoregulatory set-point) 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.<br />'''Fever''': Characterized on the right: Normal body temperature (thermoregulatory set-point) 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.]]
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| ===Pyrogens===
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| Substances <!--"which" incorrect: NOT ALL substances induce fever; a distinction is to be made-->that induce fever are called ''pyrogens''. These are both [[internal]] or [[endogenous]], and ''external'' or ''exogenous'', such as the bacterial substance [[lipopolysaccharide|LPS]].
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| ====Endogenous====
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| 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]].
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| These cytokine factors are released into general circulation where they migrate to the circumventricular [[organ (anatomy)|organ]]s of the [[brain]], where the [[blood-brain barrier]] is reduced. The cytokine factors bind with [[endothelium|endothelial receptor]]s on vessel walls, or interact with local [[microglial cell]]s. When these cytokine factors bind, they activate the [[arachidonic acid]] pathway.
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| ====Exogenous====
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| One model for the mechanism of fever caused by exogenous pyrogens includes [[lipopolysaccharide]] (LPS), which is a cell wall component of [[Gram-negative|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.
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| ===PGE2 release===
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| PGE2 release comes from the [[arachidonic acid]] pathway. This pathway (as it relates to fever), is mediated by the [[enzyme]]s [[phospholipase|phospholipase A2]] (PLA2), [[cyclooxygenase|cyclooxygenase-2]] (COX-2), and [[prostaglandin E2 synthase]]. These enzymes ultimately mediate the synthesis and release of PGE2.
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| 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 EP3 subtype of PGE receptors and the 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]].
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| ===Hypothalamus response===
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| The brain ultimately orchestrates '''heat effector mechanisms'''. These may be
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| * increased heat production by increased [[muscle tone]], [[shivering]] and hormones like epinephrine.
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| * prevention of heat loss, such as [[vasoconstriction]].
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| 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.
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| ==Types==
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| Pyrexia (fever) can be classed as
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| * [[low-grade fever|low grade]]: 38 - 39 °C (100.4 - 102.2 °F)
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| * moderate: 39 - 40 °C (102.2 - 104 °F)
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| * high-grade: > 40 °C (> 104 °F)
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| * [[Hyperpyrexia]]: > 42 °C (> 107.6 °F)
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| The last is clearly a [[medical emergency]] because it approaches the upper limit compatible with human life.
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| 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]]:
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| * Pel-Ebstein fever is 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 ([http://content.nejm.org/cgi/content/short/333/1/66]) whether this pattern truly exists.
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| * Continuous fever: temperature remains above normal throughout the day and does not fluctuate more than 1 degree C in 24 hours. Eg: [[lobar pneumonia]], [[typhoid]], [[urinary tract infection]], [[brucellosis]], [[typhus]], etc. [[Typhoid fever]] may show a specific fever pattern, with a slow stepwise increase and a high plateau.
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| *Intermittent fever: temperature is present only for some hours of the day and becomes normal for remaining hours.Eg: [[malaria]], [[kala-azar]], [[pyaemia]], [[septicemia]] etc 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 vivax''). These patterns may be less clear in travelers.
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| *Remittent fever: temperature remains above normal throughout the day and fluctuates more than 1 degree C in 24 hours.Eg: [[ infective endocarditis]] etc
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| Febricula<ref name=biologyonline>Febricula, definition from [http://www.biology-online.org/ Biology-Online.org], consulted June 7, 2006 [http://www.biology-online.org/dictionary/Febricula http://www.biology-online.org/dictionary/Febricula]</ref> is a mild fever of short duration, of indefinite origin, and without any distinctive pathology.
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| ==Differential diagnosis of causes of fever==
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| Fever is a common [[symptom]] of many medical conditions:
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| * [[infectious disease]], e.g. [[influenza]], [[common cold]], [[HIV]], [[malaria]], [[infectious mononucleosis]], [[gastroenteritis]], ''etc.''.
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| * Various skin [[inflammation]]s such as [[boils]], [[pimples]], [[acne]], [[abscess]], etc.
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| * [[Immunology|Immunological]] diseases like [[lupus erythematosus]], [[sarcoidosis]], [[inflammatory bowel disease]]s, ''etc.''.
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| * Tissue destruction, which can occur in [[hemolysis]], [[surgery]], [[infarction]], [[crush syndrome]], [[rhabdomyolysis]], [[cerebral hemorrhage]], ''etc.''.
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| * [[Drug fever]]
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| ** directly caused by the drug (e.g. [[lamictal]], [[progesterone]], [[chemotherapeutics]] causing [[tumor]] [[necrosis]])
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| ** as an adverse reaction to drugs (e.g. [[antibiotic]]s, [[Sulfonamide (medicine)|sulfa drug]]s, ''etc.'')
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| ** after drug discontinuation, like with [[heroin]] withdrawal
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| * [[Cancer]]s such as [[Hodgkin disease]] (with [[Pel-Ebstein fever]])
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| * [[Metabolic disorder]]s like [[gout]], [[porphyria]], ''etc.''.
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| * Thrombo-embolic processes (i.e. [[pulmonary embolism]], [[deep venous thrombosis]])
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| Persistent fever which cannot be explained after repeated routine clinical inquiries, is called [[fever of unknown origin]].
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| ==Usefulness of fever==
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| There are arguments for and against the usefulness of fever, and the issue is controversial<ref name=Schaffner>Schaffner A. Fever--useful or noxious symptom that should be treated? ''Ther Umsch'' 2006; '''63''': 185-8. PMID 16613288</ref><ref name=value>Soszynski D. The pathogenesis and the adaptive value of fever. ''Postepy Hig Med Dosw'' 2003; '''57''': 531-54. PMID 14737969</ref>. There are studies using [[warm-blooded]] [[vertebrates]]<ref name=VUB>Su F, Nguyen ND, Wang Z, Cai Y, Rogiers P, Vincent JL. Fever control in septic shock: beneficial or harmful? ''Shock'' 2005; '''23''': 516-20. PMID 15897803</ref> and [[human]]s <ref name=humans>Schulman CI, 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</ref> ''[[in vivo]]'', with some suggesting that they recover more rapidly from infections or critical illness due to fever.
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| Theoretically, fever has been conserved during evolution because of its advantage for host defense<ref name=Schaffner>Schaffner A. Fever--useful or noxious symptom that should be treated? ''Ther Umsch'' 2006; '''63''': 185-8. PMID 16613288</ref>. There are certainly some important immunological reactions that are sped up by temperature, and some [[pathogen]]s with strict temperature preferences could be hindered<ref name=Fischler>Fischler MP, Reinhart WH. Fever: friend or enemy? ''Schweiz Med Wochenschr'' 1997; '''127''': 864-70. PMID 9289813</ref>. The overall conclusion seems to be that both aggressive treatment of fever<ref name=humans>Schulman CI, 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</ref> and too little fever control<ref name=Schaffner>Schaffner A. Fever--useful or noxious symptom that should be treated? ''Ther Umsch'' 2006; '''63''': 185-8. PMID 16613288</ref> can be detrimental. This depends on the clinical situation, so careful assessment is needed.
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| 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.
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| ==Treatment==
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| 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.
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| 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.
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| 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.
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| Treatment of fever should be based primarily on lowering the setpoint, but facilitating heat loss may also contribute. The former is accomplished with [[antipyretic]]s. 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.
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| ==References==
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| ===Articles===
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| <references/>
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| ===Books===
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| * 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
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| * Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL. ''[[Harrison's Principles of Internal Medicine]]''. New York: McGraw-Hill, 2005. ISBN 0-07-139140-1.
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| == External links ==
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| * [http://www.seattlechildrens.org/child_health_safety/health_advice/fever.asp What to do if your child has a fever] from Seattle Children's Hospital
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| * [http://kidshealth.org/parent/general/body/fever.html Fever and Taking Your Child's Temperature]
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| * [http://www.nlm.nih.gov/medlineplus/ency/article/003090.htm US National Institute of Health factsheet]
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| * [http://hcd2.bupa.co.uk/fact_sheets/html/fever.html BUPA factsheet]
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| {{SIB}}
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| [[ar:حمى]]
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| [[bn:জ্বর]]
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| [[bg:Треска (болест)]]
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| [[ca:Febre]]
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| [[cs:Horečka]]
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| [[da:Feber]]
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| [[de:Fieber]]
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| [[es:Fiebre]]
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| [[eo:Febro]]
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| [[eu:Sukar]]
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| [[fr:Fièvre]]
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| [[io:Febro]]
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| [[it:Febbre]]
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| [[he:חום (תסמין למחלה)]]
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| [[la:Febris]]
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| [[ln:Fɛ́fɛlɛ]]
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| [[ms:Demam]]
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| [[nl:Koorts]]
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| [[ja:発熱]]
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| [[no:Feber]]
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| [[nn:Feber]]
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| [[ps:تبه]]
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| [[pt:Febre]]
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| [[qu:Ruphariy]]
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| [[ru:Лихорадка]]
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| [[si:උණ]]
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| [[simple:Fever]]
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| [[fi:Kuume]]
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| [[sv:Feber]]
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| [[ta:காய்ச்சல்]]
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| [[uk:Лихоманка]]
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| [[yi:פיווער]]
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| [[zh:发热]]
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| [[Category:Signs and symptoms]]
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| [[Category:Infectious disease]]
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| [[Category:Primary care]]
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| [[Category:Emergency medicine]]
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| [[pl:Gorączka]]
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