Approach to Fever or Suspected Infection in the Normal Host

Definition

The traditional definition of a normal temperature as 98.6° F (37.0° C) came from a study more than 150 years ago, when 98.6° F (37.0° C) was the mean temperature from over 1 million axillary temperature measurements in 25,000 patients. Multiple more recent studies show contemporary axillary temperatures to be lower, with a mean axillary temperature of 96.75° F (36° C) and a mean oral temperature of about 36.5° C or 98° F. ^,

Human temperature also varies by time of day, with mean nadir temperatures in the early morning (i.e., 6 am ) and mean zenith temperatures in the late afternoon and early evening (i.e., 4 to 6 pm ). Mean oral temperatures are below 37° C for all types of individual. In one study of healthy volunteers, the maximum normal oral temperature, as defined by the 99th percentile, was 98.9° F (37.2° C) at 6 am and 99.9° F (37.7° C) at 4 pm . By this definition, any temperature greater than 99° F (37.2° C) at 6 am or 100° F (37.8° C) any time of day can be considered a fever.

Some studies have suggested that older individuals have lower mean temperatures than younger persons, but other studies have found that older persons’ mean core temperatures are no different. Similarly, data in women as compared with men are inconsistent. Overall, any differences in normal mean temperatures by age and sex are negligible and not clinically significant.

Epidemiology

Most infections are transmitted from person to person to person by direct contact (e.g., hands, fomites), emanate from a common source (e.g., food, water), are spread by aerosols or respiratory droplets (e.g., viral respiratory infections), or are transmitted by vectors (e.g., mosquitos), often as zoonoses ( Chapter 303 ). Infections also can be caused by breaches in skin integrity or self-injection. However, the source is often unknown. Risk factors therefore include contact with other sick individuals, exposure to contaminated food or water, proximity to animals, mosquito bites, and injection drug use ( Chapter 365 ). Geographic exposures also vary, even in developed countries, where diseases such as histoplasmosis (Central and Eastern United States; Chapter 308 ), coccidioidomycosis (Southwestern United States; Chapter 308 ), Lyme disease ( Chapter 296 ), babesiosis ( Chapter 324 ), and ehrlichiosis ( Chapter 302 ) are seen in certain geographic areas. Prior vaccination reduces the risk of many infections ( Chapter 15 ), but immunity to many of those infections wanes over time.

Pathobiology

Multiple temperature sensors throughout the body are thought to provide feedback via neural pathways to a dynamic federation of independent thermoeffector loops within the preoptic anterior hypothalamus. Each controller has its own threshold for signaling its effector to modulate the transfer of heat. These independent controllers and effectors work in a coordinated and, as appropriate, additive fashion to achieve the desired body temperature.

The generation of fever involves exogenous pyrogens, of which bacterial endotoxin (lipopolysaccharide) from the outer membrane of gram-negative bacteria is a classic example, and endogenous pyrogens or pyrogenic cytokines. Exogenous pyrogens bind to pattern recognition receptors expressed by cells of the innate immune system. This binding triggers gene expression and synthesis of pyrogenic cytokines, such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ, as well as many other molecules fundamental to the febrile response. IL-6 is in turn integral to the production of many acute-phase reactants. The binding of lipopolysaccharide to pattern recognition receptors on pulmonary and hepatic macrophages also activates enzymes required for synthesis of prostaglandin E ₂ , which is critical to the generation of fever by its interaction with the thermoregulatory system. Medications such as nonsteroidal anti-inflammatory drugs and aspirin block the activity of enzymes involved in the synthesis of prostaglandin E ₂ .

When patients fail to develop a fever despite severe bacterial infection, morbidity and mortality tend to be higher. This phenomenon suggests that fever may either inhibit the multiplication of some pathogens or increase the entry of neutrophils into inflammatory sites.

Clinical Manifestations

Fever is typically associated with relative or absolute tachycardia of about 2 to 5 beats per minute per 1° F increase in temperature. Temperature-pulse dissociation, which is the absence of this response, is classically found in typhoid fever ( Chapter 284 ), leptospirosis ( Chapter 298 ), rickettsiosis ( Chapter 302 ), dengue ( Chapter 352 ), legionellosis ( Chapter 290 ), and babesiosis ( Chapter 324 ).

The peripheral vasodilation in response to fever contributes to the relative tachycardia and may blunt the increase in blood pressure that typically accompanies adrenergic activation. Relative or absolute hypotension can auger the development of septic shock ( Chapter 94 ), which portends a poor prognosis.

The source of fever is often suggested by accompanying symptoms or signs, including headache or altered mental status in meningitis ( Chapter 381 ) or encephalitis ( Chapter 383 ), sore throat in pharyngitis ( Chapter 397 ), ear pain in otitis ( Chapter 394 ), upper respiratory symptoms in tracheitis ( Chapter 84 ) or sinusitis ( Chapter 394 ), cough and sputum in pneumonia ( Chapter 85 ), abdominal pain in visceral abdominal infections ( Chapters 128 and 141 ), diarrhea in enteric infections ( Chapter 262 ), and pelvic pain in pelvic inflammatory disease ( Chapter 264 ). However, localizing symptoms may be absent in infectious endocarditis ( Chapter 61 ) and sepsis ( Chapter 94 ). Elderly individuals and patients with diabetes mellitus are more likely to develop severe infections.

Diagnosis

Just as there is no single definition of fever, there is no single approach to the evaluation of a febrile patient. An individualized approach is warranted. Most febrile patients have common, self-limited processes; some warrant further evaluation with laboratory testing and imaging, and a smaller subset have potentially serious or life-threatening conditions. A thoughtful history (including information about exposures, travel, concurrent medical problems, medications, allergies, and prior vaccinations) and a careful physical examination are always important.