Fever is a kind of hyperthermia where the physiological “set point” in the brain has been increased and the body attempts to maintain a high temperature (>38.3°C or 101°F) as though it were normal body temperature. Other kinds of hyperthermia i.e. heat stroke, malignant hyperthermia, etc. are increases in body temperature despite efforts by the thermoregulatory centres of the body trying to cool it down.
Fever is a kind of hyperthermia characterized by an increase in the “set point”.
Most of this post comes from excellent articles on Medscape, Wikipedia and the chapter on fever from Harrison’s Principles of Internal Medicine.
Temperature is regulated in the hypothalamus by temperature sensing neurons that detect blood temperature and skin temperature. The signals are integrated and appropriate responses are generated to keep the body at the “set point” temperature. This is 35.5°C – 37.5°C which varies depending on the person, the time of day, ambient conditions, and (importantly) method of measurement. The body is usually colder in the morning and hotter at night. Oral temperatures are typically about 0.4°C colder than rectal and tympanic membrane temperatures are about 0.8°C colder than rectal.
Heat is lost in 5 ways: radiation, convection, evaporation, respiration, and conduction (in decreasing order). Radiation contributes about 40% to heat loss. Heat loss can be mitigated by increasing metabolic rate, increasing skeletal muscle activity (including shivering), and behavioural modifications. An enlightening discussion about the difference between radiation, conduction, and convection can be found here.
If the body is too hot, behavioural responses might be triggered to turn down the heat, take that sweater off, or turn a fan on. Physiological responses might also be triggered involving vasodilation to increase circulation to the skin where heat can be lost by radiation and convection. Sweat production can be triggered to induce heat loss by evaporation. If the body is too cold, behavioural responses might include putting a hat on or getting under a blanket. Physiological responses might include increasing metabolic rate, eating, exercise, vasoconstriction to prevent blood from flowing near the skin, and shivering.
If core body temperature is over 38.3°C it is considered hyperthermia. Fever is one of several types of hyperthermia where the “set point” circuitry in the hypothalamus has been affected (by an infection for example) such that it is attempting to set the temperature of the body higher than normal. A temperature 41.5°C or higher is considered life-threatening.
Examples of non-fever causes of hyperthermia are malignant hyperthermia, heatstroke, and depending on who you ask … neuroleptic malignant syndrome and serotonin syndrome (whether the set point is affected or not in these syndromes is unclear, UpToDate suggests the set point is NOT affected in serotonin syndrome). These are generally quite emergent conditions because they do not respond to anti-pyretics and some can quickly be fatal.
As we’ve been saying, the pathogenesis of fever involves a change to the thermoregulatory set-point in the hypothalamus. This can be the result of “pyrogenic” substances from endogenous or exogenous sources. Lipopolysaccharide is the endotoxin produced by gram negative bacteria which happens to be a powerful pyrogen. Some naturally produced interleukins (IL) and tumor necrosis factors (TNF) are pyrogens as well. Thus infection and inflammation can produce fever. The exact way in which the set point is modified involves increased prostaglandin E2 (PGE2) production in the hypothalamus.
Working up a patient with hyperthermia involves trying to deduce the cause. Many causes will be obvious, but there can be some sinister sources which may not even be obvious to the patient. Checking your SIRS (Systemic Inflammatory Response Syndrome) criteria is usually a good start as these patients can be the sickest and need to be identified quickly. These would be patients with:
Temperature >38°C or <36°C
Heart rate >90
Resp rate >20
Arterial CO2 <32 mmHg
White blood cell count >12,000/µL or <4,000/µL or >10% immature band cells
Any 2 of these SIRS criteria in a patient is concerning for sepsis. A good septic workup should be performed and would include: chest x-ray, urinalysis with culture, complete blood count, electrolytes, lactate, creatinine, blood culture, nasopharyngeal swab, and lumbar puncture (especially in neonates).
On physical exam make sure to examine the neck for meningitis symptoms, look in the ears and pharynx. Palpate the abdomen for abscesses. Look at the groin for things like Fournier gangrene (which surprisingly some patients don’t even realize they have!). Palpate joints and bones to look for septic joints, discitis, and similar pathologies. Ask specifically about joint replacements, rods, pins, and other orthopedic devices. These can be important seeding grounds for infection. Finally, heart diseases like endocarditis can be hidden sources of infection. In a world where rates of diabetes are skyrocketing, neuropathies can impair a patient’s ability to feel pain despite serious tissue damage.
In terms of treatment for fever, essentially all anti-pyretic drugs inhibit cyclooxygenase enzymes (which take arachidonic acid from cell membranes and metabolize it into prostaglandin). Inhibiting this reaction lowers prostaglandin production and thus prevents elevation of the set point. Examples include NSAIDs, aspirin, and acetaminophen (which has no cyclooxygenase inhibiting activity itself, but is metabolized into something that does). One of the benefits of acetaminophen is that its metabolite inhibits the cyclooxygenase COX-3 which is only found in the CNS thus making it very specific and immune to the side effects of other cyclooxygenase inhibitors like NSAIDs and aspirin which can cause bleeding problems due to their COX-1 and COX-2 effects.
With a fever, the question is always whether to treat or not. It’s very rare for a body to generate a fever with a temperature in the life threatening range. Fevers make you feel horrible, but aren’t necessarily dangerous (except in the very young, very old, or chronically ill). Fevers are generally self-limiting as well.
One final thing that I found really interesting is that one of the reasons you feel cold with a fever is due to the shunting of blood away from the skin as a heat conserving measure. The skin feels cold and the thermoreceptors in the skin report that they are cold. Thus despite having a high core temperature you still feel cold!
Here is a link to the relevant chapter in Harrison’s which is excellent if you have access to it
Dinarello CA, Porat R. Fever. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 19e. New York, NY: McGraw-Hill; 2015. http://accessmedicine.mhmedical.com.libaccess.lib.mcmaster.ca/content.aspx?bookid=1130&Sectionid=79724479. Accessed October 01, 2016.
This is a link to a wonderful post on Medscape
And as always, Wikipedia has a great page