Fever: Evidence Based Practice

Fever is a common alteration of the vital signs, and fever is a very common complication of infectious diseases. Fever can also be caused by non-infectious diseases, inflammation, injury, and drugs. Many hospitalized patients will present with a fever; many patients develop a fever at some point during their hospital stay ^{(Chiumello et al., 2016; Doyle et al., 2016; Nakajima, 2016; Dai et al., 2012)}. Fever is also one of the most common signs of illness in children^{(Peetom et al., 2016)}, and the care and treatment of patients with fever occupy a considerable amount of time for many nurses.

But despite this extensive experience, there are important questions about fever that are unanswered, and even healthcare professionals have misconceptions about the adverse effects of a fever and disagree about when and how a fever should be treated ^{(Brick et al., 2017; Lava et al., 2016; Schortgen et al., 2012)}. In most cases, a fever will not cause harm, and it may be helpful. In addition, fever reduction is often not needed and may be harmful. In certain clinical situations, fever reduction can be beneficial, and nurses need to know when and how fever reduction should be done. For very young children who are febrile and the elderly patient who has a fever, the evaluation process must consider specific information about the risks of fever and signs and symptoms that are specific to those groups.

Fever is an elevation of body temperature at or above a specific point. The definition of a fever varies depending on the source, the patient's age, time of day, and how temperature is measured. Several definitions of fever are provided in Table 1 (Smitherman et al., 2017; Ward, 2016; Kasper et al., 2016).

Fever is an elevated body temperature with a specific cause distinct from other mechanisms that increase body temperature. Also, in certain clinical situations, a body temperature of < 38°C should be considered a fever. This point will be discussed later in the course.

The letter C indicates that the temperature was measured using the Celsius scale; the letter F indicates that the temperature was measured using the Fahrenheit scale. Either scale can be used, but the Celsius scale is more commonly used by medical personnel than the Fahrenheit. Celsius will be used in this course when referring to body temperature. Conversion tables or calculations are available by internet search.

To convert Fahrenheit to Celsius:

• Subtract 32 from the temperature in degrees Fahrenheit
• Multiply the result from step 1 by 5
• Divide the result from step 2 by 9

Example:

• 100°F – 32 = 68
• 68 x 5 = 340
• 340 ÷ 9 = 37.7°C

To convert Celsius to Fahrenheit:

• Multiply the temperature in degrees Celsius by 9
• Divide the result from step 1 by 5
• Add 32 to the result from step 2

Example:

• 36°C x 9 = 324
• 324/5 = 64.8
• 64.8 + 32 = 96.8°F

Normal body temperature ranges from >37.2°C/98.9°F in the morning and >37.7°C/99.9°F in the evening. This variation is due to variation in the hypothalamic set point. Children normally have a higher body temperature than adults. Menstruating women have a greater variation in the range of body temperature than other adults, especially in the two weeks before and during ovulation. Older adults typically have a lower body temperature than adults and children. During strenuous exercise, the body temperature can be as high as 40°C, and strenuous exercise can increase heat production to 20 times the normal level.

Measurement of body temperature is an attempt to determine the core temperature. Core temperature is the temperature of the organs and structures deep within the body. Normal temperature is where the body functions best. Body temperature can be measured invasively or non-invasively. Body temperature methods are all accurate and consistent if done correctly, but they are all subject to operator error.

• Oral measurement is usually an accurate and reliable method of determining body temperature, and it is convenient. Oral temperature readings are lower than the core temperature, and many variables can affect the reliability and accuracy. Oral temperatures are usually lower than rectal temperatures.
• Rectal measurement is the commonly used method that most accurately and consistently reflects core temperature.
• Tympanic temperature measures the heat of the tympanic membrane, and the ear canal, and they are typically lower than the rectal temperature. A tympanic thermometer is less accurate in children less than three months old if it is not placed properly in the ear canal or if excessive cerumen is present (Treitz et al., 2016).
• Axillary measurement is typically lower than an oral or rectal temperature.
• Temperature strips (Tempa•Dot™) are small plastic strips placed in the mouth, on the forehead, or under the axilla.
• Skin temperature sensors placed over the carotid artery accurately measure core temperature. This method provides accurate and consistent readings, albeit slightly lower than rectal measurements (Imani et al., 2016).
• Temporal artery thermometers measure heat emitted from the temporal artery. The temporal artery is highly perfused. This method of obtaining a temperature is an accurate way of estimating core temperature. It compares well with other methods.
• Bladder temperature sensors provide an accurate measurement of body temperature. A small study found that a urinary bladder sensor was more accurate than rectal or axillary body temperature measurements.
• Esophageal temperature probes provide an accurate measurement of core temperature, but the accuracy is very dependent on the proper positioning of the probe (Snoek et al., 2016).
• An invasive cardiovascular catheter sensor is done via a pulmonary artery catheter. The temperature measured by a sensor in a pulmonary artery catheter is considered to reflect core temperature most closely.

The method that should be used will depend on the clinical situation. When done correctly, all methods will consistently provide a measurement of the body temperature that accurately reflects the core temperature within their limits. The cardiovascular catheters, the bladder temperature sensors, and the esophageal temperature probes provide the closest approximation of core temperature. However, in almost all clinical situations in which a patient's temperature must be measured, or when a patient with a fever needs constant temperature monitoring, using the axillary, oral, or rectal methods is appropriate, accurate, and consistent.

Body temperature represents the balance between heat production and heat loss. Body heat is produced by the metabolic activity of organs such as the brain, heart, liver, and muscular activity, involuntary or voluntary. These processes generate heat as a byproduct of their functions. Body heat is lost by radiation, conduction, convection, and evaporation. Small amounts of body heat are also lost by defecation, respiration, and urination.

• Radiation is the movement of heat from one object to another colder one; in this case, the body to the environment.
• Conduction is the transfer of heat between objects with different temperatures in contact with each other.
• Evaporation is heat loss caused by water vaporization: Evaporation happens by sweat and insensible water loss. Insensible water loss occurs from the lungs, skin, excretion, and respiratory tract.
• Convection causes heat loss by cold air moving past and over the body. The surface temperature is lowered, blood vessels dilate to bring more heat to the skin, and heat is lost from the circulating blood.

Humans can maintain body temperature at an optimal point, increasing or decreasing heat production, and increasing or decreasing heat loss. This process is called thermoregulation. Thermoregulation is activated and maintained through a brain structure called the hypothalamus.

The hypothalamus contains a group of heat-sensitive neurons collectively called the temperature-regulating center. The hypothalamus's heat-sensitive neurons receive input from the blood's temperature as it passes through the hypothalamus. The heat-sensitive neurons also receive afferent messages from peripheral temperature receptors in the skin, deep tissues, and spinal cord.

The hypothalamus' thermoregulatory center can be usefully thought of as a thermostat. It has a "setpoint" of body temperature that it tries to maintain in response to internal and external environmental conditions. If the body temperature is too high, the hypothalamus heat-sensitive neurons initiate cooling mechanisms:

• Vasodilation
• Shunting blood from the core to the periphery
• Increased heart rate and cardiac output
• Decreasing the metabolic rate
• Decreasing muscular activity and
• Increased sweating

If the body temperature is too low, heat conservation mechanisms are initiated:;

• Sweating is decreased
• Blood vessels are constricted
• Muscular activity is increased, causing shivering
• The metabolic rate is increased

Table 2: Heat Loss and Heat Conservation

These mechanisms for heat loss and heat conservation are usually coordinated and balanced, and despite changes in the internal and external environment, normal body temperature is maintained.

Infection usually causes fever due to a micro-organism. The bacteria or the virus or other pathogens act as pyrogens and stimulate monocytes, macrophages, and Kupffer cells to produce and release cytokines^{(Doyle et al., 2016; Ward, 2016)}. Cytokines are small proteins produced by cells of the immune system. Cytokines perform many complex activities, but they typically are involved in generating an immune response to illness or infection. These cytokines interferon, interleukin-1, interleukin-6, and tumor necrosis factor act as endogenous pyrogens. They stimulate the hypothalamus to produce an elevated level of prostaglandin E2 (PGE2) (Doyle et al., 2016). An elevated level of PGE2 causes the "setpoint" of the temperature regulation center in the hypothalamus to be elevated, causing fever.

When this setpoint is changed upwards, the thermoregulatory center senses incorrectly that body temperature is too low. Heat production and heat conservation mechanisms are activated, and the patient develops a fever (Kasper et al., 2016). Elevated levels of PGE2 are also produced in the peripheral tissues that account for the arthralgias and myalgias, aka the aches and pains, which are often part of a febrile illness.

Is fever helpful or harmful? Should it be treated, and if so, when, how, and in whom? Fever is one of the most common signs of illness, but even with years of experience and research, the answers to these questions are not clear (Doyle et al., 2016). Fever has long been considered by lay people to be dangerous (Kelly et al., 2016). At times, healthcare professionals are apprehensive and misinformed about fever's consequences and implications (Ward, 2016; Rafaelli et al., 2016).

Nevertheless, fever is a self-limiting phenomenon, and in many situations, it is not harmful and is probably helpful (Doyle et al., 2016). A fever can be directly toxic to the bacteria, viruses, and other pathogens that cause fever, and fever can also inhibit growth. Fever increases the expression and activity of heat shock proteins (HSPs), proteins that protect the host's cells and tissues against heat stress. Fever reduces the expression and activity of intracellular proteins produced in response to heat stress. These proteins can be damaging to the host. Unless hyperthermia feedback mechanisms cause elevated body temperature, prevent body temperature from rising to levels that cause systemic damage. Hyperthermia is discussed later in this course. Fever can also be used as a diagnostic and prognostic tool.

The cells and organs' basic enzymatic processes do not function optimally if the body temperature is abnormally elevated. Generating a fever requires the body to increase its metabolic rate six times beyond baseline. Increasing body temperature from 37°C to 39°C increases the metabolic rate by approximately 25%, increasing cardiac output, heart rate, and oxygen demand.

For most people who have a fever caused by a self-limiting infectious process, the body temperature will not be that high. The fever will be unpleasant, but of no consequence. However, a fever can be a significant stressor if a febrile patient has a chronic illness such as cardiovascular disease, diabetes, or pulmonary disease. In some clinical situations, cerebral hemorrhage, or septic shock, lowering a fever can decrease the mortality rate.

Infection is the most likely source of a fever, but auto-immune disorders, drugs, endocrine disorders, inflammatory reactions, malignancies, and vascular disorders can also cause fever (Bond, 2017). Examples of non-infectious causes of fever include:

• Sarcoidosis
• Thyrotoxic storm
• Acute respiratory distress syndrome
• Lymphomas
• Cerebral infarction
• Sympathomimetic drugs

Because of their basic pharmacologic effects, certain drugs can increase body temperature when taken in excess amounts. These medications increase body temperature by the following mechanisms or a combination of the following mechanisms:

• Dramatically increasing the metabolic rate
• Intensely increasing muscular activity
• Depressing heat loss mechanisms
• Stimulating an immune response.

Nonsteroidal anti-inflammatory drugs such as ibuprofen and corticosteroids such as prednisone can decrease the fever response to an infection. The following are examples of commonly used drugs that can increase body temperature in these ways (Hoffman et al., 2015).

Another non-infectious source of fever is drug fever. Drug fever is a febrile response caused by administering a therapeutic dose of a medication. The elevated temperature coincides with drug administration, and the body temperature returns to normal when the drug is discontinued. Antimicrobials, anticonvulsants, and antiarrhythmics are drugs that commonly cause drug fever. However, many medications can cause drug fever.

Drug fever can happen at any time. It is not uncommon for drug fever to begin weeks, months, or even years after a medication has been first prescribed (Bor, 2016), but 7-10 days after starting medication therapy is the median time of onset. At least five mechanisms can cause drug fever; a hypersensitivity reaction is the most common. Drugs that have been commonly associated with drug fever are listed in Table 4 (Bor, 2016).

Metal fume fever is a febrile illness caused by inhaling fumes containing metal particles. Metal fume fever can happen when galvanized metal is being burned or welded, and the person or persons doing the work is not wearing a respirator.

Persons with metal fume fever typically have a fever, and they complain of a headache, malaise, and muscle aches. Metal fume fever is self-limiting; there should be no sequelae, and the illness resolves with time and supportive care, although severe cases may take several weeks to resolve (Greenberg et al., 2015). The pathogenesis of metal fume fever is not completely understood, but the disorder is probably caused by an inflammatory reaction and the release of cytokines and neutrophil activation (Greenberg et al., 2015).

Polymer fume fever is caused by the inhalation of fumes produced when polymer-containing compounds such as Teflon® are heated. The pathogenesis of polymer fume fever is not understood, but it is thought to be the same as that of metal fume fever (Greenberg et al., 2015).

There is essentially no difference in the clinical presentation between metal fume fever and polymer fume fever. It is a self-limiting illness, but long-term pulmonary sequelae are possible (Greenberg et al., 2015). The treatment is symptomatic and supportive.

The typical signs of fever are chills, diaphoresis, flushing, shivering, and tachycardia. Arthralgias, malaise, and myalgias are also common. Most people who have a simple febrile illness such as influenza will be uncomfortable, and they may not feel well enough to work, but they will perform basic activities of daily living.

Someone who has a fever will have noticeable signs and symptoms. The patient looks and feels sick, and there a body temperature that is > 38°C. However, a febrile illness presentation can be vastly different and less obvious in two populations: the elderly and the young. There is also a complication of febrile illnesses, febrile seizures, which happens only to children; this will be discussed separately.

Three clinical conditions can cause a very elevated body temperature distinct from the infectious processes and non-infectious medical conditions that were previously discussed. These conditions are hyperthermia, malignant hyperthermia, and neuroleptic malignant syndrome.

These conditions differ from the typical febrile illness in the following ways:

1. They are not mediated by the effects of cytokines on the hypothalamus, so antipyretics are not useful
2. The body temperature is often much higher than a fever caused by an infection
3. Associated with high rates of morbidity and mortality

When and how should a fever be treated? The only reasonable answer is it depends. Fever reduction should not be routinely done, and fever reduction should be subject to the same considerations as any therapy. There should be an indication for fever reduction. The patient should be considered individually to determine if he will benefit or suffer from fever reduction. The advantages and potential adverse effects of fever reduction should be factored into using or not using cooling techniques.

Most patients who have a fever, either adults or children, have an infectious illness quickly diagnosed and treated. They have a non-serious, self-limiting illness such as influenza. In the first case, specific therapies are more important than fever reduction, and in the second case, the illness, and the fever last at most a few days, and neither the illness nor the fever require specific therapies. There is no evidence that treating fever in either of these situations will decrease the illness's length. There is some evidence that suggests that antipyretics and cooling techniques may prolong the course of illness. So, treating a fever would be a comfort measure and not a vital part of these patients' therapy.

Nevertheless, there can be times when reducing a fever can be beneficial. Treating a fever can increase patient comfort, and that can be helpful. If the patient has a fever and has chronic cardiac or pulmonary disease, fever reduction should be considered. These patients have limited physical reserves, and the increased metabolic demand and oxygen consumption caused by a fever could be harmful. The use of fever reduction in specific clinical situations is described below.

A child who has a fever and is three months old or younger is more likely to have a serious bacterial infection (SBI) than an older child; the incidence of SBI neonates has been estimated to be 12% (Starr, 2016). The most common source of SBI in children aged 90 days and younger is a urinary tract infection, but sepsis, meningitis, cellulitis, sinusitis, and pneumonia are possible, as well ^{(Smitherman et al., 2017; Starr, 2016)}. These illnesses are serious in this age group because children who are three months old or younger have a relatively weak immune response to infection and fewer barriers against pathogens.

Risk factors for an SBI are this population include: (Smitherman et al., 2017)

• Age, especially < 28 days old
• Antibiotic use in the recent past
• No immunizations
• An ill-appearing child
• Fever > 38.6°C/101.5°F
• Maternal infections, e.g., genital herpes
• Prematurity

Evaluation of the presence of an SBI in these patients is complicated. Criteria that can be used to distinguish febrile children 90 days old and younger who have an SBI from those who simply have a self-limiting viral illness have been developed, e.g., Boston, Milwaukee, Philadelphia, and Rochester criteria. However, these criteria do not have good specificity, and they require extensive laboratory testing (Smitherman et al., 2017). Smitherman et al. (2017) recommend that instead of using these tools, the following approach should be applied.

The evaluation aims to determine which febrile children have an SBI and need testing and treatment and which children have a simple, self-limiting viral illness. The evaluation is particularly difficult because of the child's age and level of behavioral development.

Evaluation of any febrile child 90 days old or younger should begin with assessing the vital signs. The child should then be completely undressed, and a physical exam performed. Take special note of skin color and temperature, activity level, responsiveness, and lack of responsiveness to touch or handling, and examine the child carefully for local infection signs. After the vital signs and physical exam have been done, ask about the child's health and activity during the febrile illness. Has the child been especially agitated or lethargic? Has oral intake been significantly decreased, or does the child not tolerate feedings? Has the child been coughing or having difficulty breathing? If a cough has been present, ask about the duration and quality of the cough. Have the child's bladder or bowel habits been abnormal?

The child's prenatal and birth history should be reviewed, and the history of the child's health before the febrile illness should be reviewed. Ask the mother if she has had or has hepatitis B or C, infection with HIV, or a sexually transmitted disease. Ask the parent/parents if the child has been exposed to any adults or animals with an illness or recently arrived from another country.

Extensive evaluation depending on the child's:

• Age
• Clinical condition
• Temperature
• Findings of the physical examination
• Medical conditions
• Previous state of health

In the case of a well looking but febrile infant 29-60 days old with no focal bacterial infection, no risk factors for or findings of a herpes simplex virus infection, and a rectal temperature of <38.6°C (101.5°F) – the following tests should be done.

• Blood culture
• Chest radiograph in patients with signs of a respiratory illness
• Complete blood count (CBC) with differential
• C-reactive protein (CRP), but only if results are rapidly available, e.g., within 60 minutes
• Procalcitonin (PCT), but only if results are rapidly available, e.g., within 60 minutes)
• Urinalysis
• Urine culture (by transurethral bladder catheterization or suprapubic aspiration)

A lumbar puncture should be performed depending on these tests' results, and empirical antibiotic therapy started.

Febrile illnesses in adults are often self-limiting viral illnesses, or there is a clear cause for the fever, or the cause can be quickly determined. If the febrile illness persists and, despite a complete evaluation, no cause is found, this is called fever of unknown origin (FUO).

FUO is usually caused by a common disease or disorder, but the presentation is atypical. The most common causes of FUO are: (Kasper et al., 2016; Bor, 2016)

• Infections such as abscesses, diverticulitis, osteomyelitis, and tuberculosis
• Malignancies such as malignant lymphoma
• Non-infectious inflammatory diseases such as sarcoidosis
• Connective tissue diseases such as rheumatoid arthritis or systemic lupus erythematosus

Neutropenic states, drug fever, and healthcare-associated infections should be considered. An FUO for which no cause can be found is very unusual (Bor, 2016).

Assessment of a patient who has FUO should begin with history taking and a physical examination. This point seems obvious, but as noted in Kasper et al. (2016), the diagnostics' most important step is searching for potential diagnostic clues (PDCs) through complete and repeated history taking and physical examination. Be sure to ask the patient about exposure to animals, travel experiences, recent or past use of drugs, prescription, illicit, or over-the-counter, use of supplements, or alternative medicines.

Suppose no cause can be found after the history and physical examination or from the results of basic laboratory/diagnostic tests (e.g., blood cultures, complete blood count, chest radiography, urinalysis). In that case, the following tests should be done: (Bor, 2016)

• Antinuclear antibodies
• Creatine phosphokinase
• CT scan of the abdomen
• CT scan of the chest
• Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)
• Heterophile antibody test in children and young adults
• HIV antibody assay and HIV viral load for patients at high risk
• Rheumatoid factor
• Serum lactate dehydrogenase
• Serum protein electrophoresis
• Three routine blood cultures drawn from different sites for at least several hours without administering antibiotics, if not already performed
• Tuberculin skin test or interferon-gamma release assay

If there is a strong suspicion that the patient has an illness such as tuberculosis, then empiric treatment can be started. Antipyretics should be used cautiously as they may make finding the cause of an FUO more difficult. (Bor, 2016)

Fever reduction can be done using antipyretics drugs, physical cooling techniques, or both. Antipyretics drugs reset the temperature-regulating center of the hypothalamus. Physical cooling techniques encourage heat loss. Both methods are effective. Physical cooling techniques work faster, but they are more complex and time-consuming to initiate and monitor than using antipyretics.

Many laypersons have misconceptions about fever. They believe a fever is dangerous; the higher the temperature, the greater the danger; fever can cause brain damage, and a fever will almost always cause febrile seizures (Elkon-Tamier et al., 2017; Purssell et al., 2016). Misconceptions about fever and how to treat it are also common among healthcare professionals (Martins et al., 2016).

These beliefs can be very upsetting at the least and, at worst, can cause non-productive behaviors and are occasionally harmful (Peetoom et al., 2016). Emergency rooms see many patients who have a simple viral syndrome because of concern about high fever. Patients and parents may overuse antipyretics and over-the-counter cough and cold preparations. Therapeutic overuse of acetaminophen can cause liver damage. The excessive dosing of cough and cold preparations used to treat febrile illness can cause serious harm (Acheampong et al., 2016; Bertille et al., 2016; Lancaster et al., 2015). Patient education about fever can avoid this emotional distress and encourage sensible treatment of a fever.

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