Introduction

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)

It is essential to 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.

Issues of Concern

An issue of concern that should be addressed when discussing the concept of fever is understanding that 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.

Cellular Level

Milton and Wendlandt 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]

Organ Systems Involved

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.[7]
• 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.[8]
• 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.[9]
• 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.[10]
• Hemostasis
  • Inhibition of platelet aggregation, spontaneous bleeding, increased clotting times, thrombocytopenia, and increased plasma fibrin degradation productions are classically seen in hyperthermic patients.[11]

Function

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]

Mechanism

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.[12] 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.[13]

Related Testing

A diagnostic approach to fever or hyperthermia includes the following:

Diagnostic Testing

• ESR and CRP
• Procalcitonin-elevated in certain bacterial infections
• Tuberculin skin test
• HIV
• Serum LDH
• Routine blood cultures
• RF, ANA, heterophile antibody in children and young adults
• CPK
• Serum protein electrophoresis
• Imaging studies based on history
• CNS signs should prompt lumbar puncture
• Patients with a travel history to malaria-endemic regions should be tested with thick and thin peripheral smears.
• Rule out thrombophlebitis and infective endocarditis in IV drug abuse

Several other specific tests can be performed based on the history and physical exam findings in patients of varying age groups. A detailed history and thorough physical examination of all body systems can help narrow the list of differential diagnoses.

Pathophysiology

Patients with fever usually exhibit warm, flushed skin, tachycardia, involuntary muscular contractions or rigors, and sweating or night sweats. Piloerection and positioning of the body to minimize exposed surface area are also seen. Occasionally these signs are absent or minimal, and dry, cold skin or extremities are detected despite a significant rise in core temperature.

• Fever occurs when either endogenous or exogenous pyrogens cause an elevation in the body's thermoregulatory set-point. In hyperthermia, the set-point is unaltered, and the body temperature becomes elevated in an uncontrolled fashion due to exogenous heat exposure or endogenous heat production.
• Hyperpyrexia is the term for exceptionally high fever (greater than 41 C), which can occur in patients with severe infections. Hyperpyrexia may also be seen in patients with CNS hemorrhages and is associated with a poor outcome.[14] Elevated brain temperature may lead to increased intracranial pressure, ischemic brain injury, exacerbation of cerebral edema, and death. 
• Inhibitors of cyclooxygenases, for example, aspirin and acetaminophen, can help reduce fever.[15]
• Observation of a pattern of fever can be helpful in certain conditions. For example, a fever that occurs every 48 to 72 hours occurs in certain types of malaria, and a fever that occurs predominately in the evening is typical of tuberculosis.
• The everyday highs and lows of typical temperatures are emphasized in many fevers. However, these variations might be turned around in typhoid fever and disseminated tuberculosis. Temperature-pulse dissociation occurs in typhoid fever, brucellosis, leptospirosis, some medication-prompted fevers, and factitious fever. In healthy individuals, the temperature-pulse relationship is directly proportional, with an expansion in the pulse of 4.4 beats/minute for each 1 degree C (2.44 beats/minute for each 1 degree F) increase in core temperature.
• During infections, fever may not be observed in babies, older adults, patients with chronic kidney disease, or patients taking corticosteroids; instead, hypothermia may be present.

The Most Common Causes of Fever in the Clinical Setting

• Sepsis accounts for up to 74% of fever in hospitalized patients.[16]
• Malignancy, tissue ischemia, and drug reactions account for most of the remainder of the fevers seen in the hospitalized setting.[17]
• Rare causes of fever include neurogenic fever and fevers associated with endocrinopathy.

Clinical Significance

While we have talked in detail about what constitutes a 'normal' and 'abnormal' temperature, given the many factors influencing the results of temperature measurements in humans, there can never be a single, universally accepted temperature cutoff defining a fever. This clinical reality, however, does not remove the need for precision in measuring and reporting fever. 

Instruments Used in Diagnosing Fever

• Digital sublingual thermometer
  • A temperature probe is placed under the patient's tongue, with the lips closed around the instrument. The patient should not have recently smoked or consumed hot or cold substances. Digital thermometers are recommended over glass thermometers, as they have a disposable probe cover and give results in approximately 10 to 20 seconds, as opposed to 3 to 5 minutes for a glass probe.[18]
• Digital rectal thermometer
  • They are indicated in children and patients who cannot fully cooperate. A lubricated blunt-tipped thermometer should be inserted approximately 4 to 5 cm into the anal canal at a 20-degree angle from the horizontal, with the patient in a prone position. A rectal temperature reading is the preferred method in patients suspected of hypothermia. A rectal probe and a thermocouple are essential for measuring temperatures as low as 25 C (77 F).[19]

Before each new measurement with a digital thermometer, the device should be reset to below 35 C (95 F).

• Infrared forehead thermometer
  • This method involves taking a temperature measurement a short distance from the frontal bone without contacting the skin. Devices such as these function by converting infrared radiation from the forehead into an electrical signal, which is then used to determine a temperature reading.[20] This is the preferred method for non-contact temperature readings, as it requires no cleaning between individual readings.
• Infrared tympanic thermometer
  • This method detects infrared radiation from the tympanic membrane and converts it into an electrical signal, which is then interpreted as a temperature reading. This method involves patient contact and requires cleaning after each patient.[20]
• Infrared temporal artery thermometer
  • This method utilizes a thermometer that records temperature by slowly moving the device from the center of the forehead over to the lateral hairline. This detects infrared radiation emitted from the skin over the superficial temporal artery. This thermometer takes up to 1,000 readings/second and reports the highest temperature.[21] An algorithm is used to adjust for ambient temperature and calculate the core temperature. 

Fever Suppression

• Fevers are typically managed with antipyretics, which work by inhibiting the enzyme cyclooxygenase (COX), thereby reducing the levels of PGE2 within the hypothalamus. Other mechanisms of antipyretics have been suggested, which include reduction in proinflammatory mediators and enhancement of anti-inflammatory signals at the site of injury. While one may feel inclined to give an antipyretic to all febrile patients, this is not recommended. Some antipyretics may cause patient discomfort, predispose patients to adverse effects from other medications ingested, or interfere with the accurate assessment of patients receiving antibiotics.[22] Over-the-counter antipyretics include acetaminophen and NSAIDs such as aspirin, naproxen, and ibuprofen. 

While most patients with an elevated body temperature have a typical fever, there are some instances in which the body temperature increases above the fever threshold, termed hyperthermia or hyperpyrexia. Hyperpyrexia may typically be seen in heat-related illnesses such as heat exhaustion and heat stroke, which are usually caused by overexertion and dehydration in a hot environment. Other causes include obesity, metabolic conditions, adverse drug reactions (malignant hyperthermia or neuroleptic malignant syndrome), and age, with individuals under four and greater than 65 years old at an increased risk for a heat-related illness.[23] In contradiction to fever, in hyperpyrexia, the thermoregulatory set-point remains unaltered at normothermic levels, while body temperature elevates in an uncontrolled manner and beyond the capacity to lose heat.[24]

Heat Exhaustion: Temperature above 38 degrees C (100 degrees F) in the presence of any of the following symptoms[25]

• Increased sweating
• Pale, clammy, cold skin
• Generalized weakness
• Tachycardia with weak pulse
• Nausea or vomiting
• Dizziness, lightheadedness, or fainting

Heat Stroke: Temperature above 40 degrees C (104 degrees F) in the presence of any of the following symptoms[26]

• Hot, red, dry skin
• Tachycardia with a strong pulse
• Delirium, convulsions, or coma