The science of fever

Q: Can you provide any evidence to prove that the current diagnosis of fever is according to modern science?

Krishna:Another Q I received is: “ Can you provide any evidence to prove that the current definition of fever is according to modern science?” Both the questions are not very clear to give a specific answer. Anyway, let me explain it in the way it can be done.

The straight answer to your Q is ‘Yes, it is”.

Fever, or pyrexia, is the elevation of an individual's core body temperature above a 'set-point' regulated by the body's thermoregulatory center in the hypothalamus. This increase in the body's 'set-point' temperature is often due to a physiological process brought about by infectious causes or non-infectious causes such as inflammation, malignancy, or autoimmune processes. These processes involve the release of immunological mediators, which trigger the thermoregulatory center of the hypothalamus, leading to an increase in the body's core temperature.

The normal temperature of the human body is approximately 37 degrees Celsius (C), or 98.6 degrees Fahrenheit (F), and varies by about 0.5 C throughout the day.(1) This variation in the core body temperature results from normal physiological processes throughout the human body, including metabolic changes, sleep/wake cycles, hormone variability, and changing activity levels. However, in the case of a fever, the increase in the core body temperature is often greater than 0.5 C and is attributed to a fever-inducing substance (pyrogen).

While these numbers may vary slightly based on the source, below is a summary of how to categorize fever.(2)

• Low-grade: 37.3 to 38.0 C (99.1 to 100.4 F)
• Moderate-grade: 38.1 to 39.0 C (100.6 to 102.2 F)
• High-grade: 39.1 to 41 C (102.4 to 105.8 F)
• Hyperthermia: Greater than 41 C (105.8 F)

Please understand that the definition of fever is not the same as that of hyperthermia (hyperpyrexia). In fever, there is an increase in the 'set-point' temperature brought about by the hypothalamus, enabling the body to maintain a controlled increase in the core temperature and general functionality of all organ systems. In hyperthermia, however, the rise in the body's core temperature is beyond the confines of the set-point temperature and regulation of the hypothalamus.

Moreover, the site of measurement influences body temperature readings.

The average axillary temperature reading is 35.97 degrees C (96.75 degrees F), oral is 36.57 degrees C (97.83 degrees F), urine is 36.61 degrees C (97.90 degrees C), tympanic is 36.64 degrees C (97.95 degrees F), and rectal is 37.04 degrees C (98.67 degrees F).(3)

It is also important to consider the patient's normal baseline body temperature. If a patient typically runs "cold" or "hot," then their baseline body temperature may be decreased or elevated above what is considered "normal" and does not necessarily indicate a fever or febrile illness.

A final issue of concern is that, while patients can state they have a fever because they "feel warm," it is noted that the diagnosis of fever based on palpation is unreliable and inaccurate in up to 40% of individuals. If a fever is suspected, an official reading should be obtained.

Researchers demonstrated that fever is mediated by the pyrogenic activity of prostaglandins (PGs), specifically PGE2. The synthesis of PGE2 begins with membrane phospholipids being converted to arachidonic acid (AA) by phospholipase A2 (PLA2). AA is then converted to PGH2 via cyclooxygenase (COX), after which PGH2 undergoes isomerization to PGE2 by PGE synthase. PGE2 acts via the EP3 receptor to affect specific neurons within the hypothalamus that aid in thermoregulation. Medications that inhibit COX are a mainstay of treatment for fevers, as it halts the conversion of AA into PGE2 and, thus, other prostanoids that can lead to fever.

The action of PGE2 begins when exogenous pyrogens (e.g., bacteria, viruses) stimulate endogenous pyrogens such as IL-1, IL-6, tumor necrosis factor (TNF), and interferon (IFN) to alter the hypothalamic set point via the organum vasculosum of the lamina terminalis (OVLT) and raise the core body temperature. Endogenous pyrogens also act to trigger an immune and inflammatory response. The immune response includes leukocytosis, T cell activation, B cell proliferation, NK cell killing, and increased white blood cell adhesion. The inflammatory response includes increased acute phase reactants, increased muscle protein breakdown, and increased synthesis of collagen.(4)

Fever induction in humans occurs at a high metabolic cost, such that only a 1 C rise in body temperature requires a 10–12.5% increase in metabolic rate.(5)

Metabolic effects associated with a febrile state: 

• Increased oxygen demand

  • Increased heart rate
  • Increased respiratory rate
• Increased use of body proteins as an energy source
• Metabolism switches from utilizing glucose (an excellent medium for bacterial growth) to utilizing the breakdown products of protein and fat
• Enhanced immune function

  • Increase in the motility and activity of white blood cells
  • Stimulates interferon production and activation of T cells
• Growth inhibition of specific microbial agents

  • Many microbial agents that cause infection tend to grow at normal body temperatures

A sustained, severely elevated fever can lead to lethal effects within multiple organ systems:

• Brain

  • Acute neurologic and cognitive function may occur after an episode of hyperthermia, with approximately 50% of heatstroke survivors experiencing chronic neurologic damage. Specifically, the Purkinje cells in the cerebellar cortex are sensitive to heat damage, which can lead to long-lasting cerebellar dysfunction.(6)
• Cardiovascular

  • Acutely, a hyperthermic patient will tend to be hypotensive with a high cardiac output due to blood redistribution and nitric-oxide-induced vasoconstriction. In severe fever, such as heatstroke, an electrocardiogram may show T-wave abnormalities, QT and ST changes, and conduction defects. In addition, serum troponin I levels may be significantly raised.(6)
• Gastrointestinal

  • Above 40 C (104 F), there is a reduction in blood flow to the GI tract. In addition, oxidative stress, denatured proteins, and damaged cell membranes are evident, increasing the potential for releasing pro-inflammatory cytokines, GI inflammation, and edema.(6)
• Liver

  • Elevated liver enzymes (AST/ALT) are observed in individuals with body temperatures above 40 C, with severe cases leading to permanent hepatocellular damage requiring a liver transplant. It is important to note that liver function may continue to decline even after correcting hyperthermia. For this reason, a clinician should trend the patient's liver enzymes to ensure no ongoing liver damage exists.(6)
• Kidney

  • Patients with an increased body temperature are at a significantly greater risk for acute kidney injury (AKI). An increase in body temperature by only 2 C leads to a decrease in the glomerular filtration rate (GFR), which continues to fall with a further rise in temperature. Lab studies will show an increase in plasma creatinine and urea. Additionally, a hyperthermic state stimulates the renin-angiotensin-aldosterone system (RAAS), leading to a subsequent reduction in blood flow to the kidney.(6)
• Hemostasis

  • Inhibition of platelet aggregation, spontaneous bleeding, increased clotting times, thrombocytopenia, and increased plasma fibrin degradation productions are classically seen in hyperthermic patients.(6)

  The fever response is a systemic reaction to an infection that has evolved in warm-blooded animals for over 600 million years. An increase in core body temperature is known to improve survival and resolve infections. While an increased body temperature subsequently leads to an increased metabolic cost, it is known that the survival benefits outweigh the metabolic cost associated with a fever. An increase in core body temperature acts as an alert system to activate immune surveillance via different cell types, including natural killer cells, dendritic cells, macrophages, T and B lymphocytes, neutrophils, and vascular endothelial cells.(5)

  The mechanism of initiation of fever results from complex interactions between cells in the periphery that are then transmitted centrally to the hypothalamus, specifically to the ventral medial preoptic (VMPO) area. Multiple studies showed that the VMPO houses fever-activated neurons, specifically localized near the vascular organ of lamina terminalis (VOLT), which lacks a blood-brain barrier (BBB). This lack of a BBB allows circulating substances access to the brain, which includes fever-related molecules from the immune system.(6)A recent study has stated that VMPO neurons' primary function during infection is to translate immune signals from the periphery into changes within brain activity to ultimately bring about symptoms of illness.

  If all this is not scientific what is it?

I hope you got your answer now.

Footnotes:

1. Del Bene VE. Temperature. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Butterworths; Boston: 1990. [PubMed]
2. Islam MA, Kundu S, Alam SS, Hossan T, Kamal MA, Hassan R. Prevalence and characteristics of fever in adult and paediatric patients with coronavirus disease 2019 (COVID-19): A systematic review and meta-analysis of 17515 patients. PLoS One. 2021;16(4):e0249788. [PMC free article] [PubMed]
3. Geneva II, Cuzzo B, Fazili T, Javaid W. Normal Body Temperature: A Systematic Review. Open Forum Infect Dis. 2019 Apr;6(4):ofz032. [PMC free article] [PubMed]
4. Conti B. Prostaglandin E2 that triggers fever is synthesized through an endocannabinoid- dependent pathway. Temperature (Austin). 2016 Jan-Mar;3(1):25-7. [PMC free article] [PubMed]
5. Evans SS, Repasky EA, Fisher DT. Fever and the thermal regulation of immunity: the immune system feels the heat. Nat Rev Immunol. 2015 Jun;15(6):335-49. [PMC free article] [PubMed]
6. https://www.ncbi.nlm.nih.gov/books/NBK562334/#:~:text=Introduction,....