Internal Medicine/Fever

The body's temperature is regulated by the hypothalamus, which acts as a thermostat. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two types of signals. One type comes from peripheral nerves that transmit information from skin receptors sensitive to warmth or cold. The other type of signal comes from the temperature of the blood flowing through these regions. The hypothalamus integrates these signals to maintain the body's temperature within a normal range of 36.5–37.5°C (97.7–99.5°F) when in a neutral environmental temperature.

In normal conditions, the human body produces more heat than is required to maintain its core temperature. This excess heat is generated through metabolic activity in muscles and the liver. Despite variations in the environment, the hypothalamus ensures that the core body temperature remains stable. A study involving over 35,000 individuals found that the average oral temperature is 36.6°C (95% confidence interval, 35.7–37.3°C). A temperature above 37.7°C (99.9°F), which represents the 99th percentile for healthy individuals, is considered a fever. It's important to note that higher ambient temperatures are associated with higher baseline body temperatures. Additionally, body temperatures vary throughout the day and across seasons, with lower levels in the morning and during the summer and higher levels in the afternoon and during the winter. Various factors such as age, demographics, and certain medical conditions can influence baseline temperatures. Interestingly, a slight increase in baseline temperature is associated with a higher risk of mortality, even after adjusting for other factors.

Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. This difference may be attributed to mouth breathing, especially in patients with respiratory infections and rapid breathing. Lower-esophageal temperatures closely reflect core temperature. Tympanic membrane thermometers measure radiant heat from the tympanic membrane and nearby ear canal. These measurements can vary and may not be as accurate as directly determined oral or rectal values. In women who menstruate, body temperature typically decreases during the two weeks before ovulation and then rises by about 0.6°C (1°F) during ovulation, remaining at that level until menstruation. The circadian rhythm of body temperature remains relatively constant during the luteal phase of the menstrual cycle.

Fever vs. Hyperthermia
Fever is an elevation of body temperature beyond the normal daily variation and is accompanied by an increase in the hypothalamic set point. This shift in the set point is similar to raising the thermostat setting in a room. Fever involves processes like vasoconstriction, shivering, and nonshivering heat production to raise body temperature, and it is generally characterized by an increase of 1–2°C. Fever management includes behaviors like adding clothing or bedding to raise body temperature.

Hyperpyrexia is an extremely high fever, with temperatures exceeding 41.5°C (106.7°F). This level of fever is rare but can occur in severe infections or central nervous system hemorrhages. Unlike fever, which involves raising the set point, hyperthermia is characterized by uncontrolled overheating of the body, exceeding its ability to dissipate heat. Hyperthermia can result from excessive heat production, such as intense physical exertion in a hot environment, and does not involve pyrogenic molecules. It is essential to distinguish between fever and hyperthermia because hyperthermia can be life-threatening and does not respond to antipyretic drugs like aspirin or acetaminophen.

Pathogenesis of Fever
Pyrogens are substances that cause fever, and they can be exogenous (derived from outside the body) or endogenous (produced within the body). Exogenous pyrogens include microbial products, toxins, and whole microorganisms. Examples include the endotoxin produced by gram-negative bacteria and toxins from gram-positive bacteria like Staphylococcus aureus. Pyrogenic cytokines, which include interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and others, are endogenous pyrogens that regulate immune and inflammatory processes. These cytokines can trigger fever when injected into humans at specific doses.

The elevation of the hypothalamic set point and the initiation of fever involve prostaglandin E2 (PGE2) levels increasing in hypothalamic tissue. Pyrogenic cytokines stimulate the production of PGE2. PGE2 in the brain side of the hypothalamic endothelium triggers the release of cyclic adenosine 5'-monophosphate (cAMP), a neurotransmitter. This process leads to changes in the hypothalamic set point, raising the core body temperature. Microbial products and pyrogenic cytokines can activate receptors on the hypothalamic endothelium, known as Toll-like receptors and IL-1 receptors, to induce PGE2 production and fever.

Cytokines produced within the brain may also contribute to hyperpyrexia in conditions like central nervous system infections, trauma, or hemorrhage. Viral infections of the brain can induce the production of cytokines in microglial and neuronal cells. These cytokines may lead to hyperpyrexia when injected directly into the brain or brain ventricles, bypassing the circumventricular organs. These hyperpyrexic states are not caused by pyrogenic molecules but result from abnormal cytokine production within the central nervous system.

In summary, fever is a regulated response to pyrogens, both exogenous and endogenous, involving changes in hypothalamic temperature set points and subsequent alterations in heat production and conservation to maintain the elevated body temperature. Hyperthermia, on the other hand, is uncontrolled overheating, typically due to excessive heat production or inability to dissipate heat effectively, and it does not involve pyrogenic molecules or changes in the hypothalamic set point.

Patient Evaluation for Fever
When assessing a patient with fever, it is essential to consider various disease processes that can manifest with fever as a primary symptom. A detailed patient history can help distinguish between these categories. The timing of events leading to fever, such as exposure to infected individuals or disease vectors, should be investigated. Electronic devices for temperature measurement, including oral, tympanic membrane, or rectal thermometers, are reliable, but it's crucial to consistently use the same site for monitoring fever. It's worth noting that certain populations, like newborns, the elderly, individuals with chronic liver or kidney issues, or those taking glucocorticoids or undergoing anticytokine therapy, might not exhibit fever despite having an underlying infection due to a blunted febrile response.

Laboratory Tests
In the evaluation of fever, conducting a complete blood count is typically necessary. A differential count should be performed to identify specific features in the blood that may suggest a bacterial infection, such as the presence of juvenile or band forms, toxic granulations, or Döhle bodies. Neutropenia, a low neutrophil count, can also be present in some viral infections.

Measuring circulating cytokine levels may not be useful in patients with fever because these levels often fall below the detection limit of assays or may not correlate with fever. Instead, when evaluating patients with low-grade fever or suspected underlying disease, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are valuable markers of inflammation. Circulating interleukin-6 (IL-6) levels, which induce CRP production, can also be informative. While IL-6 levels may fluctuate during a feverish disease, CRP levels typically remain elevated. These markers are part of the acute-phase reactants used in diagnosing and monitoring inflammatory processes.

Fever in Patients Receiving Anticytokine Therapy
Patients undergoing long-term anticytokine therapy may experience increased susceptibility to infections due to compromised host defenses. For instance, anti-TNF therapy can lead to the dissemination of latent Mycobacterium tuberculosis infection. As anticytokines are increasingly used in conditions like Crohn's disease, rheumatoid arthritis, or psoriasis to reduce the activity of IL-1, IL-6, IL-12, IL-17, or TNF, it's crucial to consider that these therapies may reduce the febrile response. Blunting the fever response can be a concern, especially when evaluating patients with low-grade fever or suspected underlying diseases in the context of anticytokine therapy.

Treatment of Fever
When deciding whether to treat fever, it's important to recognize that fever itself is not an illness but rather a normal response to various physiological disturbances. Most fevers are associated with self-limited infections, like common viral diseases. Antipyretics are not contraindicated in such infections and do not delay recovery or affect the resolution of infections significantly. However, in bacterial infections, withholding antipyretic therapy can be useful in assessing the effectiveness of a particular antibiotic, as it can unmask an inadequately treated bacterial infection.

Some infections follow specific fever patterns, with episodes of fever separated by intervals of normal temperature. Recognizing these patterns can help tailor diagnostic testing and treatment. While recurrent fevers can be seen in autoimmune diseases, autoinflammatory diseases, and periodic fever syndromes, they are especially characteristic of autoinflammatory conditions, which include rare diseases like familial Mediterranean fever and more common conditions like idiopathic pericarditis and gout. Many of these conditions respond well to anticytokine therapies like IL-1 blockers.

Mechanisms of Antipyretic Agents
Antipyretics aim to reduce fever by lowering the elevated hypothalamic set point and enhancing heat loss. Drugs like aspirin and NSAIDs work by inhibiting the enzyme cyclooxygenase, which is involved in prostaglandin synthesis. Prostaglandins, particularly PGE2, play a crucial role in raising the hypothalamic set point during fever. Acetaminophen, while not a strong cyclooxygenase inhibitor in peripheral tissues, acts as a more effective antipyretic in the brain. Glucocorticoids reduce fever by both inhibiting cyclooxygenase and blocking the transcription of mRNA for pyrogenic cytokines. The use of antipyretic agents does not affect normal core body temperature regulation.

Regimens for Fever Treatment
Oral acetaminophen is the preferred antipyretic due to its efficacy and safety profile. In children, oral ibuprofen is also a suitable option, while aspirin should be avoided due to the risk of Reye's syndrome. In cases where oral antipyretics cannot be taken, parenteral NSAIDs and rectal suppositories can be used. It's essential to treat fever in patients with preexisting cardiac, pulmonary, or CNS conditions, as fever increases oxygen demand. Additionally, children with a history of febrile or nonfebrile seizures should receive prompt treatment to reduce fever. In hyperpyrexia, cooling blankets can be used to lower temperature, but they should be combined with oral antipyretics. Cooling is particularly important in hyperpyretic patients with CNS conditions or trauma, as it helps mitigate the harmful effects of high temperature on the brain.