The temperature of the human body is regulated mainly by the hypothalamus. This small region of the brain serves as the interface between the nervous and endocrine systems. One of its many tasks is to maintain body temperature within a relatively narrow range - between 95 and 100 degrees Fahrenheit. Below 95 F, a person rapidly develops hypothermia; above 100 F, a person becomes febrile and lethargic. Fevers of 105 or higher can lead to brain damage or even death if not brought under control. Most of the time, however, body temperature is maintained within this margin of safety.
Since the causes of hypothermia are usually obvious, for example prolonged exposure to freezing temperatures, this article will instead focus on fluctuations of body temperature within the normal range as well as the main causes of fever.
Temperature as a circadian rhythm - Body temperature rises and falls over a period of about 24 hours. In general, body temperature is lowest in the morning immediately upon awakening, probably because metabolism is slower during sleep than at any other time of the day. Body temperature rises throughout the day by one to two degrees Fahrenheit. Several other metabolic parameters such as blood pressure, heart rate, and cortisol levels exhibit similar circadian cycles. Most circadian rhythms seem to be coordinated by a small group of hypothalamic cells called the suprachiasmatic nucleus (SCN), which receives direct input from the retina. The SCN is thought to synchronize the body's internal clock with changes in day length.
Physical exertion, such as intense workout, may raise body temperature to 100 degrees F but seldom higher. The reason that strenuous physical activity at room temperature rarely results in fever is that the hypothalamus maintains an established set point for body temperature, much like a thermostat. When the hypothalamic neurons along with other thermoreceptors detect a rise in core body temperature, compensatory mechanisms, most notably sweating, dissipate the excess heat. Sweat glands are innervated by the sympathetic nervous system, the branch of the autonomic nervous system designed to carry out the fight or flight response. Sweating occurs almost exclusively as an involuntary reflex; it is common knowledge that strong emotions like arousal, fear, and anger can also trigger sweating.
Fever - Although people have associated fever with illness since time immemorial, the mechanisms underlying the febrile response remain incompletely understood. In many cases of infection, antigens from the infectious agents as well as the immune system's inflammatory response combine to produce fever. Interferons and cytokines like Interleukin-1 can induce fever, as can pyrogenic bacterial toxins. Viral infections like influenza or chicken pox can also cause fever; on the other hand, self limited viruses like the adenovirus strains responsible for the common cold rarely cause fever.
In addition to infectious agents, fever has many other etiologies. The most important ones include drug reactions, autoimmune diseases (systemic lupus, rheumatoid arthritis, thyroid storm); and the most dreaded diagnosis of all, cancer, particularly leukemia and lymphoma. The common thread in all of these disease states seems to be out of control immunological activity. In contrast, immune compromised patients, especially those with AIDS or advanced stage cancer, often remain afebrile even during an overwhelming infection, i.e. septic shock.
Drug reactions deserve special mention. Many adverse drug reactions occur idiosyncratically, meaning in a sporadic, unpredictable manner. This is often the case with a febrile response to antibiotics as well as certain other medications. Anesthetic agents like halothane can trigger a condition called malignant hyperthermia in susceptible patients. Antipsychotic drugs such as haloperidol can induce a similar condition called neuroleptic malignant syndrome (NMS), marked by tremors, muscle rigidity, and high fever. The underlying cause of malignant hyperthermia, and possibly NMS, seems to be an abnormal variant of a calcium channel gene expressed in skeletal muscle called the dihydropyridine receptor. For unclear reasons, exposure to halogenated anesthetic and/or neuroleptic agents causes uncontrolled calcium flow through this channel, resulting in prolonged muscle contractions, which generate excessive heat and subsequent fever.