Temperature Regulation and the Pathogenesis of Fever

According to Wunderlich and Seguin, “When the organism (man) is in a normal condition, the
general temperature of the body maintains itself at the physiologic point: 37° C = 98.6° F.” [48]
Although several subsequent investigations have recorded mean temperatures of normal adult
populations closer to 36.6° C (98.0° F), [59] Wunderlich’s intimation that 37° C (98.6° F) is the most
normal of temperatures [60] persists to this day in lay thinking, although to a lessening extent in the
thinking of health care workers. The special significance formerly accorded 37° C (98.6° F) is
perhaps best illustrated by the 1990 edition of Stedman’s Medical Dictionary, which defines fever
as “a body temperature above the normal of 37° C (98.6° F).” [61] In the 2000 edition, fever is
defined as “A complex physiologic response to disease mediated by pyrogenic cytokines and
characterized by a rise in core temperature, generation of acute-phase reactants and activation of
immunological systems.” [62]
The data reviewed earlier suggest that 37° C (98.6° F) has no special significance vis-à-vis body
temperature in healthy young adults when such temperature is measured orally using modern
thermometers. In the population examined, 37° C (98.6° F) was not the overall mean temperature,
the mean temperature of any of the time periods studied, the median temperature, or the single
most frequent temperature recorded. Furthermore, it did not fall within the 99.9% confidence limits
for the sample mean (36.7° to 36.8° C; 98.1° to 98.2° F).
Wunderlich identified 38.0° C (100.4° F) as the upper limit of normal body temperature in his
patient population and, therefore, regarded any temperature greater than 38.0° C (100.4° F) as
fever. [48] However, the upper limit of normal body temperature varies among individuals, thereby
limiting the applicability of mean values derived from population studies (even those as large as
Wunderlich’s) to individual subjects. However, the maximal temperature, like the mean
temperature, exhibited by a population varies according to the time of day and the site at which
temperature measurements are taken. Because of such variability, no single temperature can be
designated as the upper limit of normal. In the study population considered earlier, 37.2° C (98.9° F)
was the maximal oral temperature (i.e., the 99th percentile) recorded at 6 AM, whereas at 4 PM, the
maximal oral temperature observed reached 37.7° C (99.9° F). Thus, these data suggest that when
modern thermometers are used to monitor oral temperature in young or middle-aged adults, fever
is roughly defined as an early-morning temperature of 37.2° C (99.0° F) or greater or a temperature
of 37.8° C (100° F) or greater at any time during the day.
Wunderlich wrote in 1868 that “[temperature] oscillates even in healthy persons according to time
of day by 0.5° C = 0.9° F.” The next year, Wunderlich and Reeve wrote, “The lowest point is
reached in the morning hours between two and eight, and the highest in the afternoon between
four and nine.” [63] Modern authorities have generally concurred with these observations. However,
Tauber has suggested that the amplitude of diurnal variation might be as high as 1° C (1.8° F). [64]
The data described earlier are more consistent with the views of Wunderlich and colleagues.
Nevertheless, the subjects examined in that study exhibited considerable individual variability,
some having daily temperature oscillations as wide as 1.3° C (2.4° F) and others having
oscillations as narrow as 0.1° C (0.2° F).
According to Wunderlich and Seguin, women have slightly higher normal temperatures than men
and often show greater and more sudden changes of temperature. [48] In a study of nine healthy