Fever

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Fever (also known as pyrexia, 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 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 Wunderlich discovered that fever is not a disease but a symptom of disease.

There are many variations in normal body temperature, and this needs to be considered when measuring fever.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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:

• 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)

Mother’s touch can diagnose fever among children according to a systematic review.^[1] The sensitivity was 89% and specificity was 50%.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There are many variations in normal body temperature, and this needs to be considered when measuring fever.

Body temperature normally fluctuates over the day, with the lowest levels at 4 a.m. and the highest at 6 p.m. 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. 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.

In women, temperature differs at various points in the menstrual cycle, and this can be used for 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.

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.

Abnormal patterns include^[1]:

• Hectic “when the difference between peak and trough temperature is great (1.4°C or more)”
• Sustained when “here is little change (0.3°C or less) in the elevated temperature during a 24-hour period”
• Remittent is when “the temperature falls each day but not to normal”
• Intermittent is then the fever is normal at least part of each day
• Relapsing fever is “a variant of the intermittent pattern, fever spikes are separated by days or weeks of intervening normal temperature”
  • This pattern may occur in “rat-bite fever, malaria, cholangitis, infections with Borrelia recurrentis, Hodgkin’s disease (Pel-Ebstein fever), and other neoplasms… Fever at 48-hour intervals suggests Plasmodium vivax or P. ovale; 72-hour intervals suggest P. malariae, while P. falciparum often has an unsynchronized intermittent fever”

Arthropathy, when prominent, suggests Parvovirus B19.

Myalgias, when prominent, suggests Dengue fever.

Headache, when prominent, suggests West Nile Virus.

The “pulse rate rises about 15 beats/min for each degree centigrade of fever”Closing </ref> missing for <ref> tag Relative bradycardia suggests an intracellular organism such as salmonella, legionella, and chlamydia.^[2] Other causes include Sandfly fever, Dengue fever, and maybe some cases of drug induced fever^[3].

The distinction between serotonin syndrome, neuroleptic malignant syndrome, malignant hyperthermia, and toxicity from cholinergic agents has been reviewed (see chart).^[4] The most difficult distinction is between serotonin syndrome and neuroleptic malignant syndrome as patients may be on drugs that could cause either disorder.

• Serotonin syndrome shows hyperkinesia, hyperreflexia, and hyperactive bowel sounds
• Neuroleptic malignant syndrome shows bradykinesia, bradyreflexia and normal or diminished bowel sounds.

A helpful guide is that “dopamine antagonists [such as used to sedate a psychosis] produce bradykinesia, whereas serotonin agonists [such as used to activate a depression] produce hyperkinesia”.^[4] Lastly, neuroleptic malignant syndrome may develop over several days while serotonin syndrome develops faster.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

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.

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.

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 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 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.

The brain ultimately orchestrates heat effector mechanisms. 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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pyrexia (fever) can be classed as:

• Low grade: 38–39°C (100.4–102.2°F)
• Moderate: 39–40°C (102.2–104.0°F)
• High-grade: 40–42°C (104.0–107.6°F)
• Hyperpyrexia: Over 42°C (107.6°F)

Febricula is a mild fever of short duration, of indefinite origin, and without any distinctive pathology.^[1]

• Sustained fever: the fluctuation in temperature during a 24-hour period is 0.3 °C (0.5 °F) or less.
• Remittent fever: the temperature is elevated, and it falls each day, but not to normal, remaining 37.3 °C (99.2 °F) or above. The excursion in temperature is more than 0.3 °C (0.5 °F) and less than 1.4 °C (2.5 °F).
• Intermittent fever: the temperature is elevated but falls to normal (37.2 °C [99 °F] or below) each day. The excursion in temperature is more than 0.3 °C (0.5 °F) and less than 1.4 °C (2.5 °F).
• Hectic fever: remittent or intermittent fever, with a difference of 1.4 °C (2.5 °F) or more between peak and trough.^[2]

The periodicity of fever generally offers little diagnostic value in ascertaining the etiology of fever. Characteristic fever patterns include:^[3]

• Sustained fever (suggestive of brucellosis, drug fever, lobar pneumonia, tularemia, typhoid, typhus)
• Remittent fever (suggestive of tuberculosis, mycoplasma pneumonia, malaria, legionellosis)
• Intermittent fever (suggestive of malaria, kala-azar, pyaemia)

• Double quotidian fever (suggestive of Still’s disease, legionellosis, miliary tuberculosis, kala-azar)
• Quotidian fever (suggestive of Plasmodium falciparum or Plasmodium knowlesi malaria)
• Tertian fever (suggestive of Plasmodium vivax or Plasmodium ovale malaria)
• Quartan fever (suggestive of Plasmodium malariae malaria)
• Alternate-day fever (suggestive of response to antipyretic dosage schedule)

• Hyperpyrexia (suggestive of intracranial hemorrhage, septicemia, Kawasaki disease, thyroid storm, drug fever)
• Hectic or spiking pattern (suggestive of biliary or urinary tract infection, endocarditis)
• Morning temperature spikes (s/o typhoid fever, tuberculosis, polyarteritis nodosa)
• Relapsing pattern (suggestive of Borrelia recurrentis, typhoid fever, malaria, brucellosis, rat-bite fever)
• Irregular pattern (suggestive of factitious fever)
• Pel-Ebstein pattern (suggestive of Hodgkin’s lymphoma)
• Picket fence pattern (suggestive of acute mastoiditis complicated by transverse sinus thrombosis)
• Saddleback pattern (suggestive of dengue fever, leptospirosis, poliomyelitis, human granulocytic ehrlichiosis)
• Wunderlich curve pattern (suggestive of typhoid fever)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

There are arguments for and against the usefulness of fever, and the issue is controversial.^[1][2] There are studies using warm-blooded vertebrates^[3] and humans^[4] in vivo, with some suggesting that they recover more rapidly from infections or critical illness due to fever.

Theoretically, fever has been conserved during evolution because of its advantage for host defense.^[1] There are certainly some important immunological reactions that are sped up by temperature, and some pathogens with strict temperature preferences could be hindered.^[5] The overall conclusion seems to be that both aggressive treatment of fever^[4] and too little fever control^[1] 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.

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