Fever Pathophysiology By Lynn Babcock Cimpello, MD,

David L. Goldman, MD, and Hnin Khine, MD BRONX, NEW YORK

T HE ELEVATION of body temperature in association with infection is a primitive host response that is shown by animals separated from humans by millions of years of evolution. A febrile response to infection is observed even in

“cold-blooded” animals such as fish that swim in warm water and lizards that linger out in the sun to elevate their body tempera- tures in response to infection. 1 In humans, the febrile response is a complex, dynamically regulated process that is just beginning to be understood. Fever is part of an integrated, nonspecific response to a variety of insults to the human body including infection, inflammatory disorders, neoplastic diseases or im- mune-mediated illnesses. Pediatricians frequently evaluate and manage children with fever, often with little regard to the mech- anisms of fever. In this review, the authors present an overview of the current understanding of the pathogenesis of fever with an emphasis on its clinical relevance.

Normothermia

The human body has the remarkable ability to maintain a relatively constant temperature, despite wide fluctuations in sev- eral variables, including ambient temperature, energy expendi- ture, and energy intake. Thermoregulation is actively controlled by the thermoregulatory center within the hypothalamus. This center receives input from peripheral receptors and the temper- ature of the blood bathing the hypothalamus. Specialized neu- rons in the thermoregulatory center respond to various stimuli, including cold and warm temperatures, by altering their firing rates, This center can in turn act on autonomic, endocrine, and behavioral mechanisms to maintain body temperature at a par- ticular set point. When this set point is elevated, the result is fever. The maintenance of normothermia is a balance between heat production and heat loss (Table 1). Under normal condi- tions, metabolic activity generally produces more than sufficient heat to reach this set point, therefore, the maintenance of normal body temperature involves the regulation of heat loss. This is

84 FEVER PATHOPHYSlOLOGY / CIMPELLO, GOLDMAN, AND KHINE

FEVER PATHOPHYSlOLOGY / CIMPELLO, GOLDMAN, AND KHINE 85

TABLE I. Physiologic and Behavioral Mechanism of Body Temperature Regulation

Elevation of Body

Temperature

Reduction of Body

Temperature

Heat generation

Increased cell metabolism

Muscle activity

Involuntary shivering

Heat conservation

Vasoconstriction

Heat preference behavior

Heat loss

Obligate heat loss

Vasodilation

Sweating

Cold preference behavior

achieved primarily by altering blood flow to the skin through the control of the autonomic system. A decrease in sympathetic tone in the arterioles of the skin results in vasodilation and increased blood flow to the skin where heat loss can occur by either conduction, convection, or radiation. In addition, increasing perspiration, which is also under control of the autonomic system, can augment heat loss through the skin.

The hypothalamic set point normally maintains body temperature at about 37°C. Nevertheless “normal” temperature is best represented as a range of temperatures because there can be signif- icant variation in temperature between individuals. Confusion regarding the definition of “normal” tem- perature in the literature is compounded by differ- ences in observational techniques used in various studies, including methods of measurement, sites of measurement, and the time of day temperature was taken. Children, especially those younger than 1 year of age have been reported to have a slightly higher range of “normal” temperature.2 Body tem- perature varies during the day (circadian rhythm) with the peak occurring in the late afternoon (5:00 PM to 7:00 PM) and the trough early in the morning (2:00 AM to 6:00 AM).~ This circadian variation can differ significantly between individuals and can be as much as 1.3”C (2.4”F) or as little as O.l”C (0.2”F).3 This rhythm is less prominent during the first few months of life, and becomes established by the second year of life. The mechanisms of circa- dian variation are unclear, but this pattern appears to be a tightly regulated process. Circadian varia- tion in body temperature can persist even during febrile illnesses, although it is absent in patients with hyperthermia.2

A working definition of fever as a rectal temper-

ature of 38°C (100.4”F) is commonly used by pedi- atricians. Of note, infants (especially those younger than 2 months) may have a blunted febrile response to infection and the absence of fever should not be taken as a criterion to exclude infection. In con- trast, toddlers typically have a very labile response to infection and may show exaggerated febrile re- sponses to infection.

The beneficial effects of fever have been sug- gested by physicians as far back as the ancient

The Function of Fever in Infection

Greeks. Hippocrates hypothesized that fever was the result of an imbalance of the four humors and that fever plays a role in burning off the excessive humor.4 At various times in history, physicians have attempted to exploit the beneficial effects of fever therapeutically. For example, before the de- velopment of antibiotics, fever therapy (induced by infecting patients with malaria or injecting killed typhoid bacilli) was used to treat syphilis.5 The fact that fever occurs in response to infection in many animal types (eg, insects, fish, amphibians, reptiles, birds, and mammals) has been used to support the argument that fever must be beneficial to the host.6 Furthermore, the production of fever in response to bacterial and viral infections in various animal models improves survival rates,7-9 whereas the sup- pression of the fever results in increased mortal- ity. 10.12

Recently, a number of studies have shown that moderate increases in temperature can directly en- hance both the specific and nonspecific arms of the immune response.13 Neutrophils are the first line of defense against a variety of pathogens. Fever en- hances neutrophil function by improving chemo- tactic responses14 and increasing microbial killing ability by increasing the production of superox- ide.15 Fever also increases the production of inter- ferons by lymphocytes16 and enhances their func- tion.17 Interferons have important antibacterial and antiviral activity and are now being used therapeu- tically for the treatment of certain infections. Fever augments T cell proliferative responses and B-cell antibody production by the action of T helper cells, and thereby enhances both cellular and humoral immune responses.18 The beneficial effects of tem- perature on the immune response are generally lost when the elevation in temperature is excessive, ie, greater than 4O”C.19

Fever can also have direct antimicrobial activity and can inhibit the growth of certain bacterial (in- cluding treponemes and neisseria), viral and fungal

86 FEVER PATHOPHYSlOLOGY / CIMPELLO, GOLDMAN, AND KHINE

pathogens2 The antimicrobial action of fever ap- pears to be in part related to its effects on iron metabolism. Iron is an essential cofactor for many metabolic processes for both humans and patho- gens. To this end, pathogens have evolved elaborate mechanisms to obtain iron from the host. Fever can increase the iron requirements of certain pathogens and at the same time inhibit their ability to obtain iron from the host20 Fever decreases the produc- tion of siderophores by bacteria. Siderophores are molecules secreted by bacteria that act as iron scavengers. In addition, the febrile response in- volves the production of acute phase reactants that decrease the availability of free iron to the invading microbe.

Despite these observations, clinical evidence to support the hypotheses that fever is beneficial dur- ing infection and that fever reduction is harmful remain elusive. There are several possible explana- tions for this. Fever is only part of a complex re- sponse that has a variety of redundant mechanisms, therefore, the clinical effects associated with elim- ination of fever may not be significant. Further- more, certain pathogens are more susceptible to temperature elevation than others. Fever may be especially beneficial in infections caused by these pathogens. On the other hand, fever may actually be detrimental to the hosts in certain circum- stances. Sustained increases in body temperature result in a dramatic increase (10% to 12% percent per degree centigrade) in metabolic activity that is associated with increases in oxygen consumption and carbon dioxide production. Fever is also asso- ciated with a substantial increase in heart rate (ap- proximately 10 to 15 beats per minute/degree cen- tigrade).*iJ2 These physiologic changes could be potentially detrimental to patients with pre-existing pulmonary or cardiac conditions or patients that are in extremis.

Acute Phase Changes

In addition to the production of an elevation in body temperature, the febrile response is associ- ated with a cascade of physiologic changes known as acute phase changes. These changes occur in response to a variety of stressful situations, includ- ing infection, burns, inflammatory conditions, and neoplasia. The role of these changes remains to be clearly defined. Nevertheless, evidence suggests that this response can enhance the host’s ability to eradicate infection. These changes include the pro- duction of acute phase reactants, alterations in me- tabolism, and alterations in endocrine function.23

Acute phase reactants consist of a series of pro- teins that are synthesized during infection and in response to other injuries to the body. Increased synthesis of acute phase reactants occurs in the liver within 8 to 12 hours of infection. Acute phase proteins (APP) include ceruloplasmin, haptoglobin, C-reactive protein (CRP), amyloid A, complement, and fibrinogen. Concomitant with an increase in the production of APP is a decrease in the synthesis of certain proteins, such as albumin. The synthesis of APP is regulated by hormones and cytokines, some of which are endogenous pyrogens, (eg, inter- leukin-6 [IL-61 and tumor necrosis factor [TNF]). During the febrile response, serum levels of some APP are increased by only several-fold (haptoglobin and ceruloplasmin), whereas other APP serum lev- els can be increased by l,OOO-fold (CRP and amy- loids A).

The functions of APP are incompletely under- stood. CRP was initially identified for its ability to bind the polysaccharide capsule of pneumococcus and can act as an opsonin. CRP can be easily mea- sured in most laboratories and is often used as a marker of disease process. Another marker of dis- ease processes, the erythrocyte sedimentation rate, is a result of increased plasma concentration of APP, glycoproteins, and globulins. APP help the body to destroy damaged tissue structures, control infection, and aid in wound healing. APP also prob- ably help contain pathogens and their toxins, inac- tivate both microbial proteases, and highly reactive oxygen metabolites. Some APP bind to divalent cat- ions, such as zinc and iron, and lead to decreased levels of the cations in the plasma.

During the febrile response, organs such as mus- cle and bone undergo catabolism. The overall pro- cess results in a negative nitrogen balance and weight loss. Amino acids liberated from proteolysis are channeled toward gluconeogenesis, and the synthesis of APP and reparative proteins. In addi- tion to these metabolic changes, the acute phase response is often accompanied by glucose intoler- ance and the reduction of lipolysis as a result of a reduction in lipoprotein lipase synthesis in the liver. Fever also increases oxygen consumption and carbon dioxide production, along with increases in requirements of fluids and calories.

The activation of stress responses by the host organism is also part of the febrile response. This is associated with an increase in corticotropin releas- ing hormone secretion, which in turn increases corticotropin and subsequently glucocorticoid se- cretion. Increases in secretion of growth hormone and aldosterone occur, along with decreases in se- cretion of vasopressin.

FEVER PATHOPHYSIOLOGY I CIMPELLO, GOLDMAN, AND KHINE 87

The Febrile Response

Fever results when the thermoregulatory set point is elevated above the normal set point. The hypothalamus sensing that the current temperature is below the new set point, produces physiological changes designed to elevate the body temperature. These changes involve endocrine, metabolic, auto- nomic, and behavioral processes that in turn pro- duce the signs and symptoms associated with fever (Table 1). For example, the diversion of blood from vessels supplying the skin to more central vessels produces cool extremities, but helps to elevate core temperature, by decreasing heat loss. Shivering in- creases metabolic activity and increases heat pro- duction. The affected person may feel cold and display behavioral changes (eg, putting on more clothing, seeking a warmer environment and curl- ing up in a fetal position) which prevent heat loss. Once these processes have resulted in an increase in core temperature to approximate the elevated set point, the thermoregulatory center acts to maintain this temperature as it does during normothermia.

When the thermoregulatory point is reset in as- sociation with the resolution of an infection, the hypothalamus senses that the current temperature is above the set point and produces physiological changes designed to decrease the core temperature. These changes can include an increase in perspira- tion that results in heat loss. For example, the resolution of pneumococcal pneumonia in the pre- antibiotic era was typically associated with a crisis characterized by increased perspiration and a rapid decline in fever. Other physiological changes that decrease core temperature include dilation of cuta- neous vessels and the sensation of feeling hot which may produce behavioral changes such as the re- moval of clothes.

Hyperthermia

Pediatricians may occasionally encounter a pa- tient with an elevated body temperature that is due to hyperthermia. Hyperthemia must be distin- guished from fever because the pathophysiology and management of these two entities differs greatly. In contrast to fever, hyperthermia results from an unregulated rise in body temperature to a level above the hypothalamic set point. Hyper- themia can result from an excessive production of heat (eg, thyroid storm) or a reduced ability to dissipate heat (eg, anhidrotic ectodermal dyspla- sia). A combination of these two mechanisms may also result in hyperthermia (eg, exercise in hot,

humid environment). In patients with hyperther- mia, body temperature can reach extreme heights (eg, 45.6%) and can produce multiorgan dysfunc- tion leading to death.

Overview of Proposed Pathway

The febrile response is a dynamically regulated process, controlled by a central thermostat (ther- moregulatory center) within the hypothalamus (Fig 1). During infection, microbial products (exogenous pyrogens) induce the production of certain cyto- kines (endogenous pyrogens), which through the action of prostaglandins, turn up the thermostat. In addition to providing the signal to raise the ther- mostat, EPs play an essential role in regulating the inflammatory and acute phase responses. Once raised, the thermostat produces fever through a variety of mechanisms, involving the following sys- tems: autonomic, behavioral, metabolic, and endo- crine. Concomitant with the production of EPs, the body produces substances known as endogenous cryogens that counteract the effect of EPs and pre- vent extreme and potentially harmful elevations of the core body temperature.

Exogenous Pvroeens

Any substance that causes fever is termed a py- rogen. Exogenous pyrogens come from outside the body and can be viruses, microbes, microbial prod- ucts, or toxins. Examples of exogenous pyrogens include the endotoxin found in cell membrane of Gram-negative bacteria, and the toxins from cer- tain bacteria, such as Staphylococcus aureus and Groups A and B streptococci. Following phagocyto- sis of exogenous pyrogens, host cells, especially monocyteslmacrophages, produce numerous cyto- kines, including endogenous pyrogens (EPs).

Endogenous Pvroeens

EPs are cytokines that are induced in response to a variety of exogenous pyrogens. Production of EPs can also be induced by endogenously produced molecules such as antigen-antibody complexes, certain androgenic steroid metabolites, inflamma- tory bile acids, and complement components. EPs are virtually undetectable in the circulation of healthy subjects. EPs can induce fever by their action on the hypothalamus (through prostaglan- dins) and do not require intermediary cytokines. In addition to their pyrogenic properties, EPs have many

88 FEVER PATHOPHYSIOLOGY I CIMPELLO, GOLDMAN, AND KHINE

Figure I. Proposed pathway by which exogenous pyro- gens produce fever.

EXOGENOUS PYROGENS Bacteria, virus, tingi, endotoxins

OTHER INDUCERS OF ENDOGENOUS PYROGENS

Toxins, antibody-antigen complexes, complement components, inflammatory bile acids, lymphocyte products, certain androgenic steroids

HOST INFLAMMATORY CELL Monocyte, macrophage, endothelial cells,

B-lymphocytes, mesangial cells, keratinocytes, epithelial cells, astrocytes, glial cells

4 ENDOGENOUS PYROGENS

IL-l, IL-6, TNF, IFN

+ CIRCULATION

f PREOPTIC AREA OF THE

ANTERIOR HYPOTHALAMUS

INCREASED PROSTOGLANDIN SYNTHESIS PGE2

I”:“““:“” Via physiological and behavioral responses

biological activities, including the regulation of the acute phase and inflammatory responses.24 The pro- tean effects of EPs highlights the intricate connection between fever and the host immune response. A va- riety of inflammatory cells, in particular circulating monocytes and tissue macrophages, produce EPs. In the brain, astrocytes and microglia are responsible for the production of EPs. The regulation of EP produc- tion is complex and contains both positive and nega- tive feedback systems. Individual EPs can regulate their own expression as well as the expression of other EPs. EPs exert their effects through interactions with their own specific receptor. Recently, a common receptor known as gp 130 has been described to in- teract with a group of EPs.

The first EP to be identified, IL-l, was initially isolated from activated leukocytes in a rabbit model of sterile peritonitis.25 More recently, two forms of interleukin-1 (IL-la and IL-l@ have been identi-

fied. Both of these cytokines show extensive biolog- ical activities and possess considerable proinflam- matory properties. Early investigators were unclear as to whether the pyrogenic properties of IL-l were related to impurities, but the availability of recom- binant IL-1 has helped resolve this issue. When human subjects are injected with either form of recombinant IL-l, fever and chills occur in nearly all subjects.26 IL-1 is an extremely potent pyrogen, producing fever in humans at a dose as low as 1 rig/kg. The febrile response to IL-1 is dose-related and at high doses, significant hypotension can oc- cur.27,2s Some of the other physiological responses seen after injection with IL-1 include increases in cortisol, adrenocorticotropic hormone and thyroid- stimulating hormone levels, and decreases in serum glucose and testosterone level.28 Table 2 shows some of the immunologic properties of IL-l.

TNF is also a product of activated macrophages

FEVER PATHOPHYSlOLOGY I CIMPELLO, GOLDMAN, AND KHINE 89

TABLE 2. Biologic Activities of the Currently Recognized Pyrogenic Cytokines

IL-I IL-6 TNF IFN

Activates T cells Activates B cells Induces B cell immunoglobulin

synthesis Enhances phagocyte microbial

killing Stimulates hepatic acute phase

protein synthesis Decreases albumin synthesis Activates hematopoietic stem

cells Activates endothelial cells Stimulates synovial cells Stimulates bone resorption Induces IL-l, TNF, IL-6 Induces septic shock Induces sleep Induces anorexia Accelerates wound healing

Activates B cells Induces B cell immunoglobulin

synthesis Stimulates hepatic acute phase

protein synthesis Decreases albumin synthesis Enhances megakaryocyte

maturation Stimulates neuronal

differentiation Stimulates hematopoietic stem

cell proliferation

Activates T cells Activates B cells Induces B cell immunoglobulin

synthesis Enhances phagocyte microbial

killing Stimulates hepatic acute phase

protein synthesis Decreases albumin synthesis Activates endothelial cells Activates synovial cells Stimulates bone resorption Induces IL-l, TNF, and IL-6

production Induces shock syndrome Induces sleep Induces anorexia Stimulates tumor killing and

necrosis

Primes macrophages Antiviral activity Enhances natural

killer activity Stimulates hepatic

protein synthesis Induces IL-I and

TNF production Induces sleep

and was initially identified for its direct toxic effects diotropin, and oncostatin M. Among these cyto- on certain tumor cells and its ability to induce kines, the greatest amount of data exists for IL-6. cachexia. TNF shares many of the biological/proin- IL-6 injection produces fever in rabbits but at much flammatory properties of IL-l (Table 2) including higher concentration than IL-l. IL-6 expression is the ability to induce fever. Nevertheless, TNF and greatly enhanced by TNF and IL-l. Elevated levels IL-l do not share significant amino acid sequence of IL-6 have been found in various body fluids, homology and bind to different receptors. The fever including plasma, cerebrospinal fluid, and joint pattern produced by injection of recombinant TNF fluid of patients with arthritis, septic shock, infec- is indistinguishable from that of IL-1.29 Both in tious diseases, kidney transplants, and burns.34335 vitro and in vivo studies indicate that TNF can In contrast to IL-l and TNF, IL-6 does not appear to induce IL-1 production and that IL-l can induce possess proinflammatory properties. Nevertheless, TNF production, leading some to suggest that these IL-6 appears to play a central role in inducing the cytokines work synergistically to produce fever.30 production of acute phase reactants.35,36

Interferons were initially recognized for their an- tiviral activities31 and were the first cytokines to be used therapeutically in humans. Fever is noted con- sistently with the administration of recombinant interferon (IFN) to humans. All subtypes of IFN, (a, p, -y) have been shown to possess varying degrees of pyrogenic activities.z2 The fever pattern induced by IFN (eg, rate of rise and time of peak temperature elevation) differ from that of IL-l and TNF, but all are considered EPs.

IL-2 has also been implicated as an EP. Admin- istration of recombinant IL-2 causes fever in humans,37 as well as increases in levels of adreno- corticotropic hormone, prolactin, and growth hor- mone.3s The half-life of IL-2 is very short and serum levels may be very low and are generally undetect- able by the time the fever is present. IL-2 may induce fevers indirectly, possibly through other cy- tokines such as IL-l and TNF.

Numerous other cytokines have been implicated in fever production. Recently, a common receptor, gp 130, which can bind a group of pyrogenic cyto- kines has been discovered.33 The gp 130 receptor triggering cytokines include IL-6, IL-2, leukemic inhibitory factor, ciliary neurotropic factor, car-

The Hypothalamus in Fever Production

Circulating EPs do not readily cross the blood- brain barrier. Instead, EPs are believed to act indi- rectly on the thermoregulatory set point by their

90 FEVER PATHOPHYSlOLOGY I CIMPELLO, GOLDMAN, AND KHINE

actions within the organum vasculosum of the lam- ina terminalis (OVLT).39-40 This region of the hy- pothalamus is located near the preoptic area and is a circumventricular organ. Fenestrated capillaries that supply blood to this area of the brain allow the neurons of this region to be in close contact with cytokines in the circulation. Injection of EPs into the OVLT of cats and rabbits produced fever.41,4* Ablation of this area reduced the ability of these animals to produce fever after injection with endo- toxin or EPs.43~44

Within the OVLT, arachidonic acid metabolites especially prostaglandin E, (PGE,), have been impli- cated for their role in producing fever (Fig 2). PGE, levels are consistently elevated in the brains of ani- mals injected with EPs. 45 Glial cells and neurons around the site of OVLT produce the enzyme cyclo- oxygenase which is involved in the production of PGE2.46 The greatest number of PGE, receptors within the brain is found near the OVLT.47 Additional evidence supporting the role of PGE, in producing fever comes from the observation that inhibition of cyclooxygenase by the administration of agents such as aspirin and acetominophen result in the reduction of fever.

The exact mechanism by which PGE, produc- tion results in fever is uncertain. It is believed that PGE, probably modifies the activity of the thermo- sensitive neurons in the OVLT to raise the set point. It is not clear if PGE, acts directly or through another neurotransmitter such as cyclic adenosine monophosphate, which is induced by PGEa.48 Once the set point is raised, the hypothalamus is respon- sible for coordinating the autonomic, endocrine, and behavioral components of the febrile response. This requires sending signals to different parts of

Membrane Phospholipids

jLipoxygenase[

\ Leukotrienes

Prostacyclins *m--es

Figure 2. Pathway describing the production of prostaglandins by endogenous pyrogens.

the hypothalamus and the brain stem to achieve an integrated response. The rapid speed at which fever occurs after injection of cytokines suggests that it occurs by intrinsic neuronal pathways rather than diffusion of PGE, or other mediators.49

The Upper Limit of Fever

Although mild to moderate elevations in body temperature can be beneficial to the host, severe elevations are likely to be detrimental. It is not surprising that the body possesses mechanisms to down-modulate fever and to limit the maximal tem- perature associated with the febrile response. Sev- eral clinical and laboratory observations support the notion of an upper limit to the febrile response, however the exact limit in humans has not been precisely defined. In the preantibiotic era, it was rare to see a patient’s temperature rise above 42”C.j’J Today, with the advent of antimicrobial therapies and antipyretic agents it is rare to see a patient’s temperature persist above 41°C with most febrile illnesses. Most of the clinician’s understand- ing of the effect of extreme temperature elevations in humans has been extrapolated from fatal cases of heatstroke. In patients with heatstroke, tempera- tures can rise as high as 45°C due to a failure of the thermoregulatory center and heat loss mecha- nisms. Temperature elevations of this extreme pro- duce widespread organ dysfunction and damage including acid-base disturbances, disseminated in- travascular coagulation, thrombocytopenia, hemor- rhage, and organ congestion.51

Several mechanisms of maintaining an upper limit to the febrile response have been proposed including the production of antipyretics, also known as endog- enous cryogens. The existence of endogenous cryo- gens was initially suggested by studies with pregnant ewe and their offspring. 52 These animals were found to have blunted febrile responses to endotoxin in as- sociation with high levels of circulating arginine vaso- pressin (AVP).j3 Subsequent studies support the role of AVP as an endogenous cryogen, although the mechanism of action of this peptide remains un- known. Microinjections of AVP into the ventral septal area of sheep’s brain results in a reduction of endo- toxin-induced fever.54 Conversely, conditions that cause decreased levels of AVP are associated with increased fevers.55

Another proposed endogenous cryogen is a-MSH, a small peptide which is found in various regions of the brain. Injections of (-w-MSH attenuate the pyrogen-induced febrile response in animals.56 Furthermore, injection of rabbits with antiserum to

FEVER PATHOPHYSIOLOGY / CIMPELLO, GOLDMAN, AND KHINE 91

a-MSH results in significantly higher and longer temperature elevations after pyrogen injections compared with control rabbits.57 a-MSH production appears to be enhanced by IL-1 and IL-2 in vitro58 suggesting the possibility of a negative feedback system to regulate the febrile response.

In addition to enhancing the production of en- dogenous cryogens, EPs may also down-modulate fever by inhibiting the production of pyrogenic cy- tokines at high temperatures and eliminating pyro- genie cytokines via a negative feedback system.59,60 For example, induction of IL-1 production by the endotoxin lipopolysaccharide is also associated with the production of a soluble receptor antago- nist. This is known as IL-1 receptor antagonist, which inhibits the action of IL-l.60 TNF, another EP, may also act as an endogenous cryogen under certain circumstances. In rats, pretreatment with anti-TNF antibodies as compared with controls re- sulted in significantly higher fevers with lipopoly- saccharide challenge.6l

Numerous other neurochemicals are believed to have a role in limiting the febrile response. Cortico- tropin-releasing hormone and glucocorticoids limit fever by their inhibitory effects on both prostaglandin synthesis and on EP production.62,63 Thyrotropin-re- leasing hormone, gastric inhibitory peptide, neu- ropeptide Y and bombesin are other neuropeptides shown to have an inhibitory effect on febrile response under certain conditions5r

In addition to these mechanisms, some investi- gators have proposed that the thermoregulatory neurons in the hypothalamus possess special prop- erties that limit the febrile response.51 Above 42”C, the thermosensitive neurons may be incapable of providing additional neural signals to regulate the body temperature, thus limiting the response.

Summary

In summary, the production of fever involves a cascade of events that can be initiated by a variety of insults. The febrile response is a dynamic process which is part of a larger host response designed to assist the host in limiting infections. The febrile response involves the production of a variety of endogenous pyrogens which, through actions on hypothalamus, are primarily responsible for the production of fever. This process is actively regu- lated and is limited by intrinsic processes including the production of endogenous cryogens to avoid detrimental effects associated with extreme tem- perature elevation.

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