Fever: Evidence Based Practice

An elevated body temperature characterizes a fever and is often said to be a protective response by the body's immune or inflammatory system. Fevers can also result from medications or injury (Mackowiak et al., 2021). Interestingly enough, most vital signs have established upper and lower limits of what is considered “normal,” except temperature. Temperatures can vary based on the type/location of temperature, age, time of day, race, etc. (Mackowiak et al., 2021). Fevers are one of the most common symptoms of illness, especially in children. Febrile illness can pose a risk to many, given its range of severity and potential complications (Heidari & Saidi, 2023).

Though a normal body temperature can have different variances, the average is 98.6 degrees Fahrenheit. This may fluctuate because of differing factors, such as age, time of day, etc. For example, some older adults may have a temperature of 96 or 97 degrees Fahrenheit, which is completely normal. A good rule of thumb for determining if a fever is present is a temperature of 100.4 degrees or higher. Also, remember that humans may have an elevated body temperature in response to inflammation or an infection (National Library of Medicine, 2023).

Temperature can be checked in a variety of ways, such as (National Library of Medicine, 2024):

• Orally- 98.6 degrees is the average normal temperature when using this method.
• Axillary- This typically has a measurement of 0.5°F (0.3°C) to 1°F (0.6°C) below an oral temperature.
• Rectally-Rectal temperature is the most accurate representation of the core measurement and is usually 0.5°F (0.3°C) to 1°F (0.6°C) higher than an oral temperature reading.
• Skin/ forehead thermometer—These are commonly seen in clinics, but they often read lower than an oral temperature.
• Ear- Also commonly seen in clinics, this method is similar to a forehead thermometer, calculating a temperature lower than oral as well.
• Temporal artery thermometers detect heat emitted from the temporal artery, which is highly perfused. This method is reliable for estimating core temperature and demonstrates strong accuracy compared to other temperature measurement methods.
• Bladder temperature sensors offer precise body temperature measurements. A small study indicated that urinary bladder sensors are more accurate than rectal or axillary temperature measurements.
• Esophageal temperature probes measure core temperature accurately, though their reliability depends heavily on proper probe placement (Kovacs & Deutch, 2022).
• Invasive cardiovascular catheter sensors, such as those in pulmonary artery catheters, provide temperature readings that are widely regarded as the most accurate reflection of core temperature.

Maintaining a normal body temperature is essential for optimal physiological function (Lim, 2020).

Heat Production:

Muscular activity, whether voluntary (e.g., exercise) or involuntary (e.g., shivering), significantly contributes to heat production.

Heat Loss Mechanisms:

The body employs several methods to dissipate excess heat:

• Radiation: The emission of infrared heat from the body's surface to the cooler surrounding environment.
• Conduction: Heat transfer between skin to object contact.
• Convection: Heat loss facilitated by the movement of air or water molecules across the skin, enhancing the transfer of heat away from the body.
• Evaporation: Heat loss that occurs when sweat on the skin surface evaporates, consuming energy and thereby cooling the body. Insensible water loss, which includes evaporation from the respiratory tract and skin, also contributes to this process.
• Urination: Minor heat loss can often occur with physiological processes, such as urination.

Thermoregulatory Control:

The area in the brain known as the hypothalamus is responsible for regulating body temperature. It functions analogously to a thermostat, maintaining a setpoint temperature by integrating inputs from:

• Central Thermoreceptors: Detect changes in the temperature of blood flowing through the hypothalamus.
• Peripheral Thermoreceptors: Located in the skin, deep tissues, and spinal cord, these receptors sense external temperature variations and relay information to the hypothalamus.

Responses to Temperature Deviations:

Heat exposure: When body temperature rises above the hypothalamic setpoint, the following cooling mechanisms are activated:

• Vasodilation: Widens the blood vessels, which increases blood flow.
• Peripheral Blood Shunting: Redistribution of blood from the core to the body's surface to enhance heat loss.
• Increased Sweating: Activation of sweat glands to promote evaporative cooling.
• Elevated Heart Rate and Cardiac Output: Enhancement of circulatory efficiency to transport heat to the periphery.
• Reduced Metabolic Rate and Muscular Activity: Decreasing internal heat production by lowering metabolic and muscular activities.

Cold Exposure: Conversely, when body temperature falls below the setpoint, heat conservation mechanisms are initiated:

• Vasoconstriction: Narrowing of blood vessels to reduce blood flow to the skin, minimizing heat loss.
• Decreased Sweating: Reduction in sweat production to conserve heat.
• Shivering: Involuntary muscle contractions that generate additional heat.
• Increased Metabolic Rate: Elevation of metabolic processes to produce more heat.

By helping the body maintain a normal body temperature, we help the body maintain homeostasis (Lim, 2020).

Fever can be both beneficial and harmful, depending on the situation. The same applies to its treatment. As a common response to infection, fever can be protective by supporting the immune system. Still, it may also cause harm in certain circumstances, creating confusion among the medical community and patients. While the typical response to fever is to treat it, it often signals that the immune system is working effectively to combat an infection (Wrotek et al., 2020).

Fever can directly harm bacteria, viruses, and other pathogens by being toxic to them and inhibiting their growth. It also enhances the expression and activity of heat shock proteins (HSPs), which help protect the host's cells and tissues from heat-related stress. At the same time, fever reduces the expression and activity of intracellular proteins that could otherwise damage the host under heat-stress conditions. Unless feedback mechanisms associated with hyperthermia cause body temperature to rise excessively, the body generally prevents fever from reaching levels that result in systemic harm. Hyperthermia will be discussed later in this course. Fever can also be a diagnostic and prognostic tool in clinical practice (Wrotek et al., 2020).

While fever helps fight infection, the body's basic enzymatic processes in cells and organs do not function optimally when the temperature is abnormally elevated. Producing a fever significantly increases the metabolic rate—up to six times the baseline level. For example, raising the body temperature from 37°C to 39°C increases the metabolic rate by approximately 25%, leading to higher cardiac output, heart rate, and oxygen demand(Wrotek et al., 2020).

Body temperature does not reach dangerously high levels for most individuals with a fever caused by a self-limiting infectious process. Although the fever may be unpleasant, it typically has no serious consequences. However, fever can impose significant stress on individuals with chronic illnesses such as cardiovascular disease, diabetes, or pulmonary conditions. In some clinical scenarios, such as cerebral hemorrhage or septic shock, reducing fever may improve outcomes and lower mortality rates (Wrotek et al., 2020).

The typical signs of fever include chills, sweating, flushing, shivering, and an increased heart rate (tachycardia). Common symptoms also include joint pain (arthralgias), fatigue (malaise), and muscle aches (myalgias). Individuals with a straightforward febrile illness, such as influenza, may feel uncomfortable and unwell, potentially unable to work, but they are often still capable of performing basic daily activities.

Common interventions for fevers may include antipyretics, such as acetaminophen or NSAIDs. NSAIDS have more of an anti-inflammatory role than other medication classes but could produce a higher risk of infection when used (Wrotek et al., 2020).

Noticeable signs and symptoms usually accompany fever; the patient appears and feels sick, with a body temperature exceeding 38°C. However, the presentation of a febrile illness can vary significantly and may be less obvious in two specific populations: the elderly and young children. Additionally, febrile illnesses in children can sometimes lead to febrile seizures, a complication that will be addressed separately.

A temperature elevation is often a sign of an immune response. Microorganisms such as viruses, bacteria, and other pathogens are responsible for producing infections. These pathogens act as pyrogens, triggering monocytes, macrophages, and Kupffer cells to produce and release cytokines. Cytokines are small proteins produced by immune system cells that are key in coordinating the immune response to illness or infection. Specific cytokines, including interferon, interleukin-1, interleukin-6, and tumor necrosis factor, function as endogenous pyrogens. They stimulate the hypothalamus to increase the production of prostaglandin E2, leading to a rise in body temperature (Santacrose et al., 2023).

An increased level of PGE2 raises the "setpoint" of the temperature regulation center in the hypothalamus, leading to the onset of fever. When the setpoint is elevated, the thermoregulatory center mistakenly perceives the body's temperature as too low. This triggers mechanisms for heat production and conservation, resulting in the development of a fever. Increased levels of PGE2 are also produced in peripheral tissues, contributing to the arthralgias and myalgias—commonly known as aches and pains—that frequently accompany a febrile illness (Santacrose et al., 2023).

While infection is the most common cause of fever, other factors such as autoimmune disorders, medications, endocrine conditions, inflammatory responses, malignancies, and vascular disorders can also lead to elevated body temperature.

Due to their pharmacologic effects, certain drugs can raise body temperature when taken in excessive amounts. This increase occurs through one or more of the following mechanisms:

• Significantly elevating the metabolic rate
• Intensely stimulating muscular activity
• Suppressing heat loss mechanisms
• Triggering an immune response

Conversely, medications like nonsteroidal anti-inflammatory drugs (e.g., ibuprofen) and corticosteroids (e.g., prednisone) can suppress the fever response to infection. Below are commonly used medications that can elevate body temperature through these mechanisms (Hoffman et al., 2015).

Medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are often used to manage fevers. Aspirin is rarely used as an antipyretic due to specific risks, which will be discussed later.

NSAIDs reduce fever by inhibiting cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes, decreasing prostaglandin production. This results in the re-adjustment of the hypothalamic temperature setpoint to normal levels. The exact mechanism by which acetaminophen reduces fever is not fully understood, but it likely involves its effects on the hypothalamic temperature-regulating center (Mehmood et al., 2024).

Both ibuprofen and acetaminophen are effective for fever reduction, though ibuprofen has been shown to be slightly more effective. The safety profiles of the two drugs are generally similar, but there are notable differences. Ibuprofen is more likely to cause gastrointestinal discomfort and should be used with caution in individuals who are dehydrated or have renal impairment.

Acetaminophen, while generally well-tolerated, is a leading cause of liver failure when taken in therapeutic overdoses.

Alternating acetaminophen and ibuprofen is sometimes recommended for managing fever in children, but there is no definitive evidence that this approach is more effective than a single medication.

Cooling blankets and sponge baths are non-pharmacological interventions often recommended for fever management (Mehmood et al., 2024).

Evaluating neonates and infants is a higher priority than simply reducing the fever, but it is not without challenges. Assessing neonates and infants is difficult because of their young age and inability to communicate when something is wrong. This makes diagnosing illnesses in this population more difficult compared to older children. Additionally, fever in neonates and infants is more likely to be associated with a serious bacterial infection (SBI). Components that providers should include in their assessment include (Smitherman et al., 2024):

• Assessing for a change in behavior
• Elevated rectal temperature
• Prematurity history
• Other comorbid conditions
• Related symptoms
• Recent exposures
• Socioeconomic status/ social determinants of health

Viral illness is the most common cause of fever in infancy, with the most common viruses being (Smitherman et al., 2024):

• Herpes Simplex Virus (HSV)
• Varicella-Zoster
• Enterovirus
• Influenza
• Adenovirus
• Respiratory Syncytial Virus (RSV)
• Covid-19

Bacterial infections are less common reasons for fever in this age group but may refer to bacteremia, bacterial meningitis, pneumonia, osteomyelitis, soft tissue infections, septic arthritis, and even bacterial gastroenteritis. The most common pathogens responsible for bacterial infections may include (Smitherman et al., 2024):

• Escherichia Coli (E. Coli)
• Listeria monocytogenes
• Staphylococcus Aureus
• Streptococcus pneumoniae
• Salmonella
• Enterococcus faecalis
• Enterobacter cloacae
• Moraxella catarrhalis
• Klebsiella
• Citrobacter

Infections occurring within the first week of life are often the result of vertical transmission from the mother.

Febrile seizures are a common complication of febrile illnesses in children and represent the most frequent cause of seizures in the pediatric population. A febrile seizure occurs in a child aged 6 to 60 months with a body temperature of ≥38°C (100.4°F), without a central nervous system infection, metabolic disturbance, or a prior history of afebrile seizures. Most febrile seizures will occur within the first 24 hours of an illness. Symptoms of a febrile seizure may include (National Institute of Neurological Disorders and Stroke, 2024):

• Loss of consciousness
• Uncontrollable shaking/jerking/stiffness
• Abnormal eye movements
• Loss of bodily functions, such as urinating

Febrile seizures are the most common type of seizures occurring in children, though the exact incidence is uncertain. These seizures are most frequently linked to common infectious illnesses, such as otitis media and upper respiratory infections.

Age is the strongest risk factor for febrile seizures, but several other factors may also increase the risk, including (National Institute of Neurological Disorders and Stroke, 2024):

• Antenatal complications
• Daycare attendance
• Developmental delays
• Family history of febrile seizures
• Male gender
• High peak body temperature
• Hypocalcemia
• Hypoglycemia
• Deficiencies in iron, selenium, and zinc
• Microcytic hypochromic anemia

Childhood vaccinations have been suspected to be associated with febrile seizures, but health experts state this is extremely rare. The fever, not the vaccination, likely precipitates children who develop a febrile seizure after receiving a vaccine (National Institute of Neurological Disorders and Stroke, 2024).

The majority of febrile seizures are classified as simple febrile seizures. These seizures are generalized, last less than 15 minutes, occur only once within 24 hours, and have no post-seizure complications or lasting effects. Additionally, children experiencing simple febrile seizures typically have no prior history of neurological disease (National Institute of Neurological Disorders and Stroke, 2024).

While rare, serious neurological complications can occasionally occur following a simple febrile seizure, particularly if the seizure was prolonged or severe, the child had an exceptionally high fever, or the seizure was linked to infections such as measles or salmonella (National Institute of Neurological Disorders and Stroke, 2024).

Infants up to 90 days old are at a heightened risk of serious bacterial infections (SBI) and require a comprehensive evaluation by a healthcare provider. Their immune systems are still underdeveloped at this age, and many have not yet received vaccinations, leaving them with reduced protective defenses against infections (Smitherman et al., 2024).

Upon evaluation, providers should pay close attention to physical appearance, vital signs, and information shared by the responsible guardian. Oftentimes, several diagnostic studies may be performed, such as (Smitherman et al., 2024):

• Blood culture
• Chest radiograph in patients with signs of a respiratory illness
• Complete blood count (CBC) with differential
• C-reactive protein (CRP)
• Procalcitonin (PCT)
• Urinalysis
• Urine culture (by transurethral bladder catheterization or suprapubic aspiration.

Depending on the results of these tests, a lumbar puncture should be performed, and empirical antibiotic therapy should be started (Smitherman et al., 2024).

In adults, febrile illnesses are often self-limiting viral infections, have an identifiable cause, or can be quickly diagnosed. However, if a fever persists despite a thorough evaluation and the cause remains undetermined, it is classified as a fever of unknown origin (FUO). Criteria for this determination include a temperature greater than 38ºC on multiple occasions, lasting at least three weeks, and with an unclear source of an infection/trigger for the fever (Haidar & Singh, 2022).

Infection is a common cause of illness and fever in older adults. However, advancing age increases the likelihood that a fever may result from a non-infectious source, a medical condition, or a medication.

An important consideration is that older adults may not always develop a fever when infected. Up to 50% of elderly patients with severe infections, such as bacteremia or meningitis, may not develop a fever. Since an older adult’s baseline core temperature is often lower than average, even slight elevations may not meet the standard definition of fever. This altered febrile response is well-documented, but its exact cause remains unclear. Possible explanations include reduced hypothalamic sensitivity, diminished production or activity of endogenous pyrogens, or insufficient levels of prostaglandin E2.

Older adults presenting with a fever may not have other symptoms that often accompany a fever, such as chills, sweating, or flushing. Instead, signs like confusion, shortness of breath, reduced activity, or impaired mobility may suggest an illness. To ensure timely intervention, it is important to consider the possibility of an infectious process when an older adult experiences a sudden change in mental or physical function.

The Infectious Diseases Society of America criteria for defining fever in the elderly population include (O’Grady et al., 2023):

• A single oral temperature > 37.8°C (100°F)
• Multiple oral temperatures > 37.2°C (99°F) or rectal temperatures > 37.5°C (99.5°F)
• Persistent tympanic temperature > 37.2°C (99°F)
• An increase of > 1.1°C (2°F) above the baseline temperature

Fever is characterized by an elevated body temperature and is commonly regarded as a protective response by the body’s immune or inflammatory systems. The hypothalamus in the brain regulates body temperature, similar to a thermostat, and factors such as muscular activity and cytokine production play significant roles in heat generation and the immune response. It is particularly prevalent in children and is one of the most common symptoms of illness. While the threshold for treating a fever is often set at 100.4°F, the primary goal is not to eliminate the fever but to ensure the child’s comfort and promote oral intake. Although infections are the most frequent cause of fever, other conditions like autoimmune disorders, medications, and malignancies can also result in an elevated body temperature. Symptoms often include chills, sweating, joint pain, fatigue, and muscle aches. While fever can have protective effects, it can also be harmful in certain situations, and medications like NSAIDs are typically preferred for treatment in children over acetaminophen. Education on proper fever management, especially regarding avoiding aspirin in children, is crucial for families. Additionally, rare conditions such as malignant hyperthermia, which is linked to anesthesia, require special attention.

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