conceptos en fiebre

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Concepts of Fever

Philip A. Mackowiak, MD

If asked to define fever, most physicians would offer a thermal definition, such as “fever is

a temperature greater than. . . .” In offering their definition, many would ignore the im-

portance of the anatomic site at which temperature measurements are taken, as well as the

diurnal oscillations that characterize body temperature.1 If queried about the history of clini-

cal thermometry, few physicians could identify the source or explain the pertinacity of the belief

that 98.6°F (37.0°C) has special meaning vis-à-vis normal body temperature. Fewer still could cite

the origin of the thermometer or trace the evolution of modern concepts of clinical thermometry.

Although many would have some knowledge of the fundamentals of thermoregulation and the role

played by exogenous and endogenous pyrogens in the induction of fever, few would have more

than a superficial knowledge of the broad biological activities of pyrogenic cytokines or know of

the existence of an equally complex and important system of endogenous cryogens. A distinct mi-

nority would appreciate the obvious paradoxes inherent in an enlarging body of data concerned

with the question of fever’s adaptive value. The present review considers many of these issues in

the light of current data. Arch Intern Med. 1998;158:1870-1881

The oldest known written reference to fe-ver exists in Akkadian cuneiform inscrip-tions from the sixth century BC, whichseem to have been derived from an an-cient Sumerian pictogramof a flaming bra-zier that symbolized fever and the localwarmth of inflammation.2 Theoretical con-structs concerned with the pathogenesisof fever did not emerge until several cen-turies later, when Hippocratic physiciansproposedthatbody temperature, andphysi-ologic harmony in general, involveda deli-cate balance among 4 corporeal humors—blood, phlegm, black bile, and yellow bile.3

Fever, it wasbelieved, resulted from an ex-

cess ofyellow bile, a concept consistent withthefact that many infections ofthat erawereassociated with fever and jaundice. Dur-ing the Middle Ages, demonic possessionwas added to the list of mechanisms be-lieved responsiblefor fever.By the18th cen-tury, Harvey’s discovery of the circulation

of blood and the birth of microbiology lediatrophysicists and iatrochemists to hy-pothesize, alternatively, that body heat andfever resultfrom friction associated with theflow of blood through the vascular systemandfrom fermentation andputrefaction oc-curring in the blood and intestines.4 Ulti-mately, thanks to the work of the greatFrench physiologist, Claude Bernard, themetabolic processes occurring within thebody finally came to be recognized as thesource of body heat. Subsequent work es-tablished that body temperature is tightlycontrolled withina narrowrangeby mecha-nisms regulating therate at which such heat

is allowed to dissipate from the body.The origin of the practice of moni-toring body temperature as an aid to di-agnosis is shrouded in uncertainty. Theoldest known references to devices used

From the Medical Care Clinical Center, Maryland Veterans Affairs Health CareSystem, Baltimore, and the Department of Medicine, University of Maryland School of Medicine, Baltimore.

This article is also available on our Web site: www.ama-assn.org/internal.

REVIEW ARTICLE

ARCH INTERN MED/ VOL 158, SEP 28, 19981870

©1998 American Medical Association. All rights reserved. on September 11, 2007www.archinternmed.comDownloaded from

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to measure temperature date to thefirst or second century BC, whenPhilo of Byzantium and Hero of Al-exandria are believed to have in-vented severalsuch devices.5 It isrea-s o n a b l y c e r t a i n t h a t G a l i l e omanufactured a primitive (air) ther-mometer at about the time he as-sumed the chair in mathematics atPadua in 1592.6 However,thermom-

etry was not fully assimilated intomedical practice until 1868, whenCarl Reinhold August Wunderlichpublished a magnum opus entitledDas Ver halten der Eigenwärme inKrankenheiten (The Course of Tem- perature in Diseases).7

Through Das Verhalten der Eigenwärme in Krankenheiten, Wun-derlich gave 98.6°F (37.0°C) its spe-cial meaning for normal body tem-perature.8 He described diurnalvariation of body temperature and,in the process, alerted clinicians tothe fact that “normal body tempera-ture” is actually a temperature rangerather than a specific temperature.In an analysis of a series of clinicalthermometric measurements, thesize of whichhasnever been equaled(estimated to have included some 1million observations in as many as25 000 subjects), Wunderlich estab-lished 100.4°F (38.0°C) as the up-per limit of the normal range and,in so doing, proffered one of thefirstquantitative definitions of fever.

Despite the fact that Wun-derlich’s work was published morethan a century ago and was basedprimarily on axillary measure-ments generally taken no more of-ten than twice daily, it has survivedalmost verbatim in modern day con-cepts of clinical thermometry. In-terestingly, recent tests conductedwith one of Wunderlich’s thermom-eters suggest that his instrumentsmay have been calibratedby as muchas 1.4°C to 2.2°C (2.6°F-4.0°F)higher than today’s instruments.8 As

a result, at least some of Wun-derlich’s cherished dictums aboutbody temperature (eg, the specialsignificance of 98.6°F[37.0°C]) haverequired revision.9

DEFINITIONS

Fever has been defined as “a state of elevated core temperature, which isoften, but not necessarily, part of the

defensive responses of multicellu-lar organisms (host) to the inva-sion of live (microorganisms) or in-animate matter recognized aspathogenic or alien by the host.”10

The febrile response (of which fe-ver is a component) is a complexphysiologic reaction to disease, in-volving a cytokine-mediated rise incore temperature, generation of

acute phase reactants, and activa-tion of numerous physiologic, en-docrinologic, and immunologic sys-tems. The rise in temperature duringfever is to be distinguished from thatoccurring during episodes of hyper-thermia. Unlike fever, hyperther-mia involves an unregulated rise inbody temperature in which pyro-genic cytokines are not directly in-volved and against which standardantipyretics are ineffective. It rep-resents a failure of thermoregula-tory homeostasis, in which there isuncontrolled heat production, in-adequate heat dissipation, or defec-tive hypothalamic thermoregula-tion.

In the clinical setting, fever istypically defined as a pyrogen-mediated rise in body temperatureabove the normal range. Althoughuseful as a descriptor for the febrilepatient, the definition ignores thefact that a rise in body temperatureis but one component of this mul-tifaceted response. This standardclinical definition is further flawed,because it implies that “body tem-perature” is a single entity, when infact, it is a pastiche of many differ-ent temperatures, each representa-tive of a particular body part andeach varying throughout the day inresponse to the activities of daily liv-ing and the influence of endoge-nous diurnal rhythms.

THERMOREGULATION

Heat is derived from biochemical re-

actions occurring in all living cells.

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At the mitochondrial level, energyderived from the catabolism of me-tabolites, such as glucose, is used inoxidative phosphorylation to con-vert adenosinediphosphate to aden-osine triphosphate. At rest, morethan half of the body’s heat is gen-erated as a result of the inefficiencyof the biochemical processes thatconvert food energy into the free en-

ergy pool (eg, adenosine triphos-phate). When no external work isperformed, the remainder of thebody’s heat (approximately 45%) isderived from the internal work in-volved in maintaining the struc-tural and functional integrity of thebody (ie, the use and resynthesis of adenosine triphosphate). When ex-ternal work is performed, a portion

of the latter heat (up to 25%) is gen-erated by skeletal muscle contrac-tions.

In adult humans and mostother large mammals, shivering isthe primary means by which heatproduction is enhanced. Nonshiv-ering thermogenesis is more impor-tant in smaller mammals, new-borns (including humans), andcold-acclimated mammals.11,12 Althoughseveral tissues (eg, the heart, respi-ratory muscles, and adipose tissue)may be involved, brown adipose tis-sue has been associated most closelywith nonshivering thermogenesis.This highly specialized form of adi-pose tissue located near the shoul-der blades, neck, adrenal glands, anddeep blood vessels is characterizedby its brownish color, a profuse vas-cular system, and an abundance of mitochondria.11,13

Heat, generated primarily by vi-talorgans lying deep within thebodycore, is distributed throughout thebody by the circulatory system. Inresponse to input from the nervoussystem, the circulatory system de-termines the temperature of thevarious body parts and the rate atwhich heat is lost from body sur-faces to the environment (via con-duction, convection, radiation, andevaporation).14 In a warm environ-ment or in response to an elevationin core temperature due to exer-cise, cutaneous blood flow in-creases so that heat is transportedfrom the core to be dissipated at theskin surface. In anesthetized ani-

mals, although discrete hypotha-lamic warming increases such cuta-neous blood flow, blood pressure ismaintained because of a concomi-tant reduction in gastrointestinalblood flow.15 In a cold environ-ment or in response to a decrease incore temperature, cutaneous bloodflow normally decreases as a meansof retaining heat within the bodycore.14





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No single center within thener-vous system controls body tempera-ture. Rather, thermoregulation is aprocess that involves a continuumof neural structures and connec-tions extending from the hypothala-mus and limbic system through thelower brainstem and reticular for-mation to the spinal cord and sym-pathetic ganglia (Figure 1).16 Nev-ertheless, an area of thebrain locatedin and near the rostral hypothala-mus seems to have a pivotal role inthe process of thermoregulation. Al-though generally referred to as the preoptic region, it actually includesthe medial and lateral aspects of thepreoptic area, anterior hypothala-mus, and septum. Numerous stud-ies extending more than 60 yearshave established that neurons lo-cated in this region are thermosen-sitive and exert at least partial con-trol over physiologic and behavioralthermoregulatory responses.14,17

Many, although not all, ther-mophysiologists believe that thetemperature-sensitive preoptic re-gion “regulates” body temperatureby integrating thermal input sig-

nals from thermosensors in the skinand core areas (including the cen-tral nervous system).18 One of themore widely held theories is thatsuch integration involves a desig-nated thermal set point for the pre-optic region that is maintained viaa system of negative feedback. Ac-cording to this theory, if the preop-tic temperature rises above its setpoint for whatever reason (eg, dur-

ing exercise), heat loss responses areactivated to lower body tempera-ture and return the temperature of thepreopticregion to thethermal setpoint(eg, 37.0°C).19 The thermal setpoint of a particular heat loss re-sponse is thus the maximum tem-perature toleratedby thepreopticre-gion before the response is evoked.If, on the other hand, the preoptic

temperature falls below its thermalset point (eg, as a result of cold ex-posure), various heat retention andheat production responses are acti-vated to raise body temperature andwith it the temperature of the pre-optic region to its thermal set point.The thermal set point of a particu-lar heat production response is thusthe minimum temperature toler-ated bythe preoptic region before theresponse is evoked.

Although useful in explainingthe elevationof thethermal setpointthat occurs during fever, the con-cept of a single central set point tem-perature is regarded by many ther-mal physiologists as oversimplified.At least some of these physiologistsprefer to think of body tempera-ture as regulated within a narrowrange of temperatures by a compos-ite set point of several thermosen-sitive areas and severaldifferent ther-moregulatory responses.20,21

A variety of endogenous sub-stances and drugs seem to affecttemperature regulation by alteringthe activity of hypothalamic neu-rons. Perhaps the best examples of such substances are the pyrogeniccytokines in the next section.These are released by phagocyticleukocytes in response to a widear r ay o f sti m uli and hav e thecapacity to raise the thermoregula-tory center’s thermal set point. Whet he r th ey cr oss th e bl ood-brain barrier to do so22,23 or act bycausing the release of other media-tors (eg, prostaglandin E2) in cir-

cumventricular organs, such as theorganum vasculosum laminae ter-minalis 22 is, as yet, uncertain. Whatever the precise endogenousmediators of fever, their primaryeffect seems to be to decrease thefi r i ng r ate o f pr eo pti c w ar m -sensitive neurons, leading to acti-vation of responses designed todecrease heat loss and increaseheat production.

ENDOGENOUS PYROGENS

Pyrogens traditionally have been di-vided into2 general categories: thosethat originate outside the body (ex-ogenous pyrogens) and those de-rived from host cells (endogenouspyrogens). Exogenouspyrogens are,for the most part, microbes, toxins,or other products of microbial ori-

gin,24 whereas endogenous pyro-gens are host cell–derived (pyro-g eni c) cy to ki nes that ar e theprincipal central mediatorsof the fe-brile response. According to cur-rent concepts, exogenous pyro-gens, regardless of physicochemicalstructure, initiate fever by induc-ing host cells (primarily macro-phages) to produce endogenouspyrogens. Such concepts notwith-standing, certain endogenous mol-ecules also have the capacity to in-duce endogenous pyrogens. Theseinclude, among others, antigen-antibody complexes in the pres-ence of complement,25,26 certainandrogenic corticosteroid metabo-lites,27-29 inflammatory bile acids,30

complement,31 and various lympho-cyte-derived molecules.32-34

Completeunderstanding of thefunction of individual pyrogenic cy-tokines has been hampered by thefact that one cytokine often influ-ences expression of other cyto-kines and/or their receptors and alsomay induce more distal comedia-tors of cytokine-related bioactivi-ties (eg, prostaglandins and platelet-aggregating factor).35 In short,cytokines function within a com-plex regulatory networkin which in-formation is conveyed to cells bycombinations and, perhaps, se-quences of a host of cytokines andother hormones.36 Like the words of human communication, individualcytokines are basic units of infor-mation. On occasion, a single cyto-kine, like a single word, may com-

municate a complete message. Moreoften, however, complete messagesreceived by cells probably re-semble sentences, in which combi-nations and sequences of cytokinesconvey information. Because of suchinteractions, it has been difficult toascertain the direct in vivo bioac-tivities of particular cytokines. Nev-ertheless, several cytokines have incommon the capacity to induce fe-

SeptalNucleus

PreopticNucleus

OVLT

AnteriorHypothalamus

RF

STt

Figure 1. Sagittal view of the brain and upper spinal cord showing the multisynaptic pathway of skin and spinal thermoreceptors through the spinothalamic tract (STt) and reticular formation (RF) to the anterior hypothalamus, preoptic region, and the septum. OVLT indicates organum vasculosum laminae terminalis.Adapted from Mackowiak and Boulant.16





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ver.Based on thischaracteristic, theyhave been codified as so-called py-rogenic cytokines.

The list of currently recog-nized pyrogenic cytokines in-cludes, among others, interleukin(IL)–1 (IL-1 and IL-1), tumornecrosis factor (TNF-), IL-6,and interferon gamma (IFN-)(Table 1).37-45 Even among these

few cytokines, complex relation-ships exist, with certain membersup-regulating expression of othermembers or their receptors undercertain conditions and down-regulating them under other condi-tions.35 The 4 pyrogenic cytokineshave monomeric molecular weightsthat range from 17 to 30 kd. Unde-tectable under basal conditions in

healthy subjects, they are pro-duced by many different tissues inresponse to appropriate stimuli.Once released, pyrogenic cyto-kines have short intravascular half-lives. They are pleiotropic: they in-teract with receptors present onmany different host cells. They areactive in picomolar quantities, in-duce maximal cellular responses

Table 1. Biological Characteristics of the Principal Pyrogenic Cytokines*

PyrogenicCytokine Aliases Cell Source

Expression Effect onOther

PyrogenicCytokines Biological Activities

Up-regulatedby

Down-regulatedby

IL-1 Endogenous pyrogenLeukocyte endogenous pyrogenLymphocyte-activating factorMononuclear factor

CatabolinOsteoclast-activating factorHematopoietin-1Melanoma growth inhibition factorTumor inhibitory factor-2

AstrocytesEndothelial cellsKeratinocytesMonocytes

MacrophagesDendritesFibroblasts

TNFIFN-GM-CSFZymosan

LPSIL-1C5aLeukotrienesPMA

IL-4IL-6IL-10TGF-

CorticosteroidsPGE2Retinoic acid

↑ IL-6↑ TNF↑ IL-1

IL-2 and IL-2R inductionThymocyte costimulationFibroblast activationInduce acute phase response

T-cell activationCostimulation of B-cell proliferation

and differentiationAugment CTL, LAK inductionInduce endothelial adhesion

moleculesEnhance phagocyte microbial killingAccelerate wound healing

TNF- Cachectin MonocytesMacrophagesEosinophilsNeutrophilsLymphocytesAstrocytesEndothelial cellsMast cellsKupffer cells

NK cellsCertain tumors

BacteriaVirusesFungiProtozoaLPSStaph TSSTIIL-1IL-2TNF

IFNsGM-CSFPAFSubstance PAnti-TCRTumor cellsPMA

CorticosteroidsCyclosporinePGE2IL-4IL-6IL-10TGF-Vitamin D3

↑ TNF↑ IL-1↑ IL-6

Septic shockEnhance phagocyte microbial killingTumor necrosisCachexiaAnorexiaEndothelial and epithelial MHC,

adhesion molecule inductionOsteoclast activationB-cell differentiation

CTL induction

IL-6 Interferon beta-2B-cell stimulatory factor-2Hybridoma or plasmacytoma

growth factorHepatocyte-stimulating factorCytotoxic T-cell differentiation

factorMacrophage granulocyte-inducing

factor 2A

MonocytesMacrophagesLymphocytesFibroblastsEndothelial cellsEpithelial cellsKeratinocytesBone marrow

stromaCertain tumors

LPSIL-1TNFIFN- Calcium

ionophoreMitogenic

lectin andPMA

Viruses

CorticosteroidsEstrogens

↓ TNF↓ IL-1

B-cell growth, differentiation, and IgGsynthesis

Myleoma proliferationCTL inductionAcute phase responseThymocyte costimulationWeak antiviral activityMegakaryocyte maturationNeuronal differentiationEnhance IL-3–dependent stem cell

proliferationIFN- Type II interferon

Immune interferonT cellsNK cells

Mitogeniclectins

IL-1IL-2

CorticosteriodsCyclosporineVitamin D3

↑ TNF↑ IL-1

Macrophage primingAntiviral activityEnhance TNF activityMHC inductionEnhance NK activityEnhance endothelial ICAM-1 expressionInhibit IL-4–induced B-cell responsesB-cell differentiation and IgG2a

secretion

*IL indicates interleukin; TNF, tumor necrosis factor; IFN, interferon; GM-CSF; granulocyte-macrophage colony-stimulating factor; LPS, lipopolysaccharide; C5a,complement component C5a; PMA, phorbol myristate acetate; TGF- , transforming growth factor ; PGE 2 , prostaglandin E 2 ; CTL, cytotoxic T lymphocytes; LAK,lymphocyte-activated killer; NK, natural killer; Staph TSSTI, staphylococcal toxic shock syndrome toxin-1; PAF, platelet-activating factor; TCR, T-cell receptor; MHC, major histocompatibility complex; and ICAM, intercellular adhesion molecule. An upward arrow indicates enhanced expression; a downward arrow, reduced expression. Adapted from Hasday and Goldblum cited in Mackowiak et al.35





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even at low receptor occupancy, andexert local (autocrine or paracrine)and systemic (endocrine) effects.35

It has been theorized, al-though not proved, that interac-tion between pyrogenic cytokinesand their receptors in the preopticregion of the anterior hypothala-mus activates phospholipase A2, lib-erating plasma membrane arachi-donic acid as substrate for thecyclooxygenase pathway. Some cy-tokines mightdo so by increasing cy-clooxygenase expression directly,causing liberation of the arachido-

nate metabolite, prostaglandin E2.Because this small lipid moleculeeasily diffuses across the blood-brain barrier, it might be the localmediator that actually activates ther-mosensitive neurons. Although notdiscussed in this article, recent stud-ies indicate that thermal informa-tion involved in the febrile re-sponse also might be transmittedfrom the periphery to the thermo-

regulatory center via peripheralnerves.46

Extensive work with pyro-genic cytokines during the last 2 de-cades has provided a hypotheticalmodel for the febrile response(Figure 2). Nevertheless, our un-derstanding of this process re-mains incomplete and largely specu-lative. As indicated, several issuesremain unresolved: (1) whether cir-culating cytokines cross the blood-brain barrier or have to be pro-duced within the central nervoussystem to activate thermosensitiveneurons; (2)whether each of the py-rogenic cytokines is capable of rais-ing the thermoregulatory set pointindependently or must exert this ef-

fect through some common path-way (eg, IL-6, as suggested by Din-arello24 ; Figure 2); (3) whetherprostaglandin E2 or other local me-diators are a sine qua non of the fe-brile response; (4) what deter-mines the magnitude of expressionof individual cytokines in responseto various stimuli; and (5) how theupper limit of the febrile range isset.35

Tumor necrosis factor andIL-1 have pivotal roles during thein-duction phase of the febrile re-sponse47 but also are expressedthroughout the response.48 A smallbut growing body of data suggeststhattemperatures nearthe upper endof the febrile range influence pro-duction of such cytokines.49-60 How-ever, such effects are highly depen-

dent on experimental conditions.

THE ACUTE PHASE RESPONSE

As noted, a cytokine-mediated risein core temperature is but one of many features of the febrile re-sponse. Numerous other physi-ologic reactions, collectively re-ferred to as the acute phase response,are mediated by members of thesame group of pyrogenic cytokinesthat activate the thermal response of fever.36 Such reactions include som-nolence, anorexia,changes in plasmaprotein synthesis, and altered syn-thesis of hormones such as cortico-tropin-releasing hormone, gluca-g o n , i n s u l i n , c o r t i c o t r o p i n ,hydrocortisone, adrenal catechol-amines, growth hormone, thyrotro-pin, thyroxine, aldosterone, and ar-ginine vasopressin. Inhibition of bone formation, negative nitrogenbalance, gluconeogenesis, and al-tered lipid metabolism also are seenduring the acute phase response, asare decreased serum concentra-tions of zinc and iron and in-creased serum concentrations of copper.Hematologic alterations61 in-clude leukocytosis, thrombocyto-sis, and decreased erythropoiesis(re-sulting in an “anemia of chronicinflammation”62). Stimuli capable of inducingan acute phase responsein-clude bacterial and, to a lesser ex-tent, viral infection, trauma, malig-nant neoplasms, burns, tissueinfarction, immunologically medi-ated and crystal-induced inflamma-

tory states, strenuous exercise,

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andchildbirth. Recent data also sug-gest that major depression,64 schizo-phrenia,65 and psychological stress66

are capable of inducing an acutephase response.

Traditionally, the phrase acute phase response has been used to de-note changes in plasma concentra-tions of a number of secretory pro-teinsderived from hepatocytes. Acute

Exogenous Pyrogen

Activated Leukocytes

Pyrogenic Cytokines(IL-1, TNF-α, IFN-γ )

IL-6

IL-6

Temperature-Dependent

Feedback onCytokine

Expression

Circumventricular Organs

PGE2

39.5°C (103.0°F)

Fever

Figure 2. Hypothetical model for the febrile response. IL indicates interleukin; TNF, tumor necrosis factor; IFN, interferon; and PGE 2 ,prostaglandin E 2 .

Table 2. The Acute PhaseProteins (ACPs)*

Positive ACPs†

C-reactive protein

Serum amyloid A

Haptoglobin

1-Acid glycoprotein

1-Protease inhibitor

Fibrinogen

CeruloplasminComplement (C3 and C4)

C1 esterase inhibitor

C4b binding protein

2-Macroglobulin

Ferritin

Phospholipase A2Plasminogen activator inhibitor-1

Fibronectin

Hemopexin

Pancreatic secretory trypsin inhibitor

Inter- protease inhibitor

Manose binding protein

Negative ACPs‡

Albumin

Transthyretin

Transferrin2-HS glycoprotein

*Adapted from Kushner and Rzewnicki.36

†Proteins exhibiting increased plasma concentrations during the acute phase response.

‡Proteins exhibiting decreased plasma concentrations during the acute phase response.





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phase proteins, of which there aremany (Table 2), 36 exhibit in-creased synthesis (positive acutephase proteins) or decreased synthe-sis (negative acute phase proteins)during the acute phase response.

Many of the acute phase pro-teins are believed to modulate in-flammation andtissue repair.67 Ama- jor function of C-reactive protein

(CRP), for example, is presumed toinvolve binding of phosphocholineon pathogenic microorganisms, aswellas phospholipid constituents ondamaged or necrotic host cells.Through such binding, CRP mightactivate the complement system andpromote phagocyte adherence,thereby initiating the process bywhich pathogenic microbes or ne-crotic cells are eliminated from thehost. Such activities are most likelypotentiated by CRP-induced pro-duction of inflammatory cyto-kines68 and tissue factor69 by mono-cytes. Nevertheless, the ultimatefunction of CRP is uncertain; sev-eral in vivo studies have shown it tohave anti-inflammatory proper-ties.70-72

The other major human acutephase protein, serum amyloid A, re-cently has been reported to poten-tiateadhesiveness and chemotaxis of phagocytic cells and lympho-cytes.73 There also is evidence thatmacrophages bear specific bindingsites for serum amyloid A, that se-rum amyloidA–rich, high-densityli-poproteins mediate transfer of cho-lesterol to macrophages at sites of inflammation,74 andthat serum amy-loid A enhances low-density lipo-protein oxidation in arterial walls.75

Complement components,many of which are acute phase re-actants, modulate chemotaxis, op-sonization, vascular permeability,and vascular dilatation and have cy-totoxic effects as well.36 Haptoglo-bin, hemopexin, and ceruloplas-

min all are antioxidants. It is,therefore, reasonable to assume that,like the antiproteases, -1-antichy-motrypsin and C1 esterase inhibi-tor, they have important roles inmodulating inflammation. How-ever, the functional capacity of suchproteins is broad.

Although closely associatedwith fever, the acute phase re-sponse is not an invariable compo-

nent of the febrile response.36 Somefebrile patients (eg, those with cer-tain viral infections) have normalblood levels of CRP. Moreover, pa-tients with elevated blood levels of CRPare not always febrile. The acutephase response, like the febrile re-sponse, is a complex response con-sisting of numerous integrated butseparately regulated components.

The particular components ex-pressed in response to a given dis-ease process more than likely re-flects the specific cytokines inducedby the disease.

ENDOGENOUS CRYOGENS

Hippocrates maintained that “Heatis the immortal substance of life en-dowed with intelligence. . . . How-ever, heat must also be refrigeratedby respiration and kept withinbounds if the source or principle of life is to persist; for if refrigerationis not provided, the heat will con-sume itself.”76 Modern day clini-cians also generally subscribe to thenotion that the febrile range has anupper limit,1 but do not agree on aprecise temperature defining thislimit. The lack of a consensus in thisregard is understandable, owing tothe factthat“body”temperaturepro-files exhibit considerable indi-vidual, anatomic, and diurnal vari-ability. For this reason, the upperlimit of the febrile range cannot bedefined as a single temperature ap-plicable to all body sites of all peopleat all times during the day. Never-theless, thefebrile responseis a regu-latedphysiologic response, in whichtemperature is maintained withincertain carefully controlled limits,the upper limit of which almostnever exceeds 41.0°C, regardless of the cause of the fever or site at whichtemperature measurements aretaken.77 The physiologic necessity of this upper limit is supported by con-

siderable experimental data demon-strating adverse physiologic effectsof core temperatures greater than41.0°C or 42.0°C.16

The mechanisms regulating fe-ver’s upper limit have yet to be fullydefined. They could lie with the in-trinsic properties of the neuronsthemselves or involve the release of endogenous antipyretic substancesthat antagonize the effects of pyro-

gens on thermosensitive neurons.For the former possibility, plots of the firing rates of neurons coordi-nating thermoregulatory responsesand heat production tend to con-verge at 42.0°C (Figure 3).16 At thistemperature, the long-term or ex-tended f i r i ng r ates o f w ar m -sensitive neurons reach their ze-nith and cannot be increasedfurther

in response to higher tempera-tures. Similarly, the firing rates of cold-sensitive neurons reach theirnadir at 42.0°C and cannot de-crease further evenif temperaturein-creases further. Thus, regardless of pyrogen concentration, thermosen-sitive neurons seem to be incapableof providing additional thermoregu-latory signals once the temperaturereaches 42.0°C.

These same thermosensitiveneurons are influenced by a varietyof endogenous substances, at leastsome of which seem to function asendogenous cryogens.16 Studies bynumerous investigators using a va-riety of animal models have estab-lished that arginine vasopressin ispresent in the fibers andterminals of the ventral septal area of the hypo-thalamus, is released into the ven-tral septal area during fever, and re-duces fever via its action at type 1vasopressin receptors when intro-ducedinto theventral septalarea and,when inhibited, prolongs fever.78-80

-Melanocyte-stimulating hor-mone (-MSH) is another neuro-peptide exhibiting endogenous an-tipyretic activity.81 Unlike someother antipyretic peptides, -MSHhas not been identified in fibers pro- jecting into the ventral septal area.82

It does, nevertheless, reduce pyro-gen-induced fever when adminis-tered to experimental animals indoses below those having an effecton afebrile body temperature.83-87

When given cent rally, -MSH ismore than 25 000 times more po-

tent as an antipyretic than acetami-nophen.81 Repeated central admin-istration of -MSH does not inducetolerance to its antipyretic effect.88

In addition, injection of anti–-MSH antiserum into the cerebralventricles augments the febrile re-sponse of experimental animals toIL-1.89

Numerous neurochemicalsseem to have the capacity to influ-





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ence hypothalamic control of bodytemperature. Because some lowerbody temperature even in the ab-sence of fever, they are more appro-priately termed hypothermic agentsthan antipyretic agents. In some of the earliest work in this area, Feld-berg and Meyers90 observed that in-tracerebroventricular injections of epinephrine and norepinephrine in

cats cause a fall in body tempera-ture, whereas injections of seroto-nin cause temperature to rise. Basedon these observations, they pro-posed that regulation of body tem-perature involves a balance be-tween the release of catecholamines(inducing heat loss) and serotonin(activating heat production) in theanterior hypothalamus. More re-cent data, including those consid-ered in the present article, suggestthat the basis of set-point determi-nation by the thermoregulatory net-work is considerably more com-plex.91

Glucocorticoids and their in-ducers(corticotropin-releasing hor-mone and corticotropin) inhibit syn-thesis of pyrogenic cytokines suchas IL-6 and TNF-.92-94 Throughsuch effects, they are believed to ex-ert inhibitory feedback on lipopoly-saccharide (LPS)–induced fever.95 Li-pocortin 1, a putative mediator of glucocorticoid function, also hasbeen shown to inhibit the pyro-genic actions of IL-1 and IFN.96 Cor-ticotropin-releasing hormone injected into the third ventricl e of experimental animals produces simi-lar antipyretic effects.97

Thyroliberin,98 gastric inhibi-tory polypeptide,99 neuropeptideY,100 and bombesin,101 likewise, ex-hibit cryogenic properties under ap-propriate conditions. Of these,bombesin is probably the most po-tent, because it consistently pro-duces hypothermia associated withchanges in heat dissipation and heat

production when injected into thepreoptic area/anterior hypothala-mus of conscious goats and rab-bits.101-103 Bombesin is believedto ex-er t i ts hy po ther m i c effect b yincreasing the temperature sensitiv-ity of warm-sensitive neurons.102

Pyrogenic cytokines, the me-diators of the febrile response,mightthemselves have a direct role in de-termining fever’s upper limit. There

is, for instance, experimental evi-dence indicating that under certainconditions TNF- lowers, ratherthan raises, body temperature.104,105

Thus, it is possible that, at certainconcentrations or in the appropri-ate physiologic milieu (eg, at 41.0°-42.0°C), pyrogenic cytokines func-tion paradoxically as endogenouscryogens.

A growing body of literature in-dicates that release of pyrogenic cy-tokines, such as IL-1, is followed byincreased shedding of soluble recep-

tors for such cytokines, which func-tion as endogenous inhibitors of thesepyrogens.106 In the case of IL-1,a 22- to 25-kd molecule identifiedin supernatants of human mono-cytes blocks binding of IL-1 to its re-ceptors.107 The IL-1 receptor antago-nist is structurally related to IL-1and IL-1108 and binds totype I andtype II receptors on various targetcells without inducing a specificbio-

logical response.109,110 Shedding of soluble circulating receptors of TNF- that bind to circulatingTNF- and thereby inhibit bindingto cell-associated receptors also hasbeen described.111-115 The precise bio-logical function of such circulatingreceptor antagonists and soluble re-ceptors is unknown. However, it ispossible, that 1 function is to serveas a natural braking system for thefebrile response.

RISK-BENEFIT

CONSIDERATIONS

Questions about fever’s risk-benefit quotient havegeneratedcon-siderable controversy in recentyears.116 The controversy arises be-cause of substantial data indicatingpotentiating and inhibitory effects of the response on resistance to infec-tion. As a result, there is no consen-sus about the appropriate clinical

Pyrogen

Maximum

N

P1

P2

N

P1P2

N

P1

P2

Th 37° 42°

Th 37° 42°

Th 37° 42°

FR

FR

Heat

Production

A

B

C

C

W

–

–

Figure 3. Model showing responses (A and B) of neuronal firing rates (FR) in the preoptic region and anterior hypothalamus and whole-body metabolic heat production (C) during changes in hypothalamic temperature (T h ). Thermosensitivity is reflected by the slope of each plot. The letters inside the cells indicate a warm-sensitive (w) neuron and a cold-sensitive (c) neuron. With increases in T h ,warm-sensitive neurons raise their FRs, and heat production decreases. Pyrogens inhibit (-) the FRs of warm-sensitive neurons, thereby resulting in accelerated FRs of cold-sensitive neurons and increased heat production. The plots show FR and heat production responses during normal conditions in the absence of pyrogens (N) and in the presence of low concentrations (P 1) and high concentrations (P 2 ) of pyrogens. The temperatures are given in degrees Celsius. Adapted from Mackowiak and Boulant.16





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situations (if any) in which fever ori ts m edi ato r s sho ul d b e sup-pressed.

Data illustrating fever’s benefi-cial effects originate from severalsources. Studies of the phylogeny of fever have shown the response to bewidespread within the animal king-dom.117 With few exceptions, mam-mals, reptiles, amphibians, and fish,

as well as several invertebrate spe-cies, have been shown to manifestfever in response to challenge withmicroorganisms or other known py-rogens. This fact has been viewed assome of the strongest evidence thatfever is an adaptive response, basedon the argument that the metaboli-cally expensive increasein body tem-perature that accompanies the fe-brile response would not haveevolved and been so faithfully pre-served within the animal kingdomunless fever had some net benefit tothe host.

Further evidence of fever’s ben-eficial effects can be found in nu-merous studies demonstrating en-hanced resistance of animals toinfection withincreases in body tem-perature within the physiologicrange.117 In classic studies involv-ing experimental infection of therep-tile Dipsosaurus dorsalis with Aeromonas hydrophila, Kluger et al118

and Bernheim and Kluger119 dem-onstrated a direct correlation be-tween body temperature and sur-vival. Bernheim and Kluger119 alsoshowed that suppression of the fe-brile response with sodium salicy-late results in a substantial increasein mortality. Covert and Rey-nolds120 corroborated these find-ings in an experimental model in-volving goldfish.

In mammalian experimentalmodels, increasing body tempera-ture by artificial means has been re-ported to enhance resistance of miceto herpes simplex virus,121 poliovi-

rus,

122

coxsackie B virus,

123

rabies vi-rus,124 and Cryptococcus neofor-mans,125 butto decrease resistance toStreptococcus pneumoniae.126 In-creased resistance of rabbits to S pneumoniae127 and C neoformans,128

dogsto herpesvirus,129 piglets to gas-troenteritis virus,130 and ferrets to in-fluenza virus131 also has been ob-served after induction of artificialfever. Unfortunately, because rais-

ing body temperature by artificialmeans does not duplicate the physi-ologic alterations that occur duringfever in homeotherms (and, in-deed, entails a number of oppositephysiologic responses132), data ob-tained using mammalian experimen-tal models have been less convinc-ing than those obtained usingreptiles or fish.

Clinical data supporting anadaptive role for fever have accu-mulated slowly. Like animal data,clinicaldatainclude evidence of ben-eficial effects of fever and adverse ef-fects of antipyretics on the out-come of infections. In a retrospectiveanalysis of 218 patients with gram-negative bacteremia, Bryant et al133

reported a positive correlation be-tween maximum temperature on theday of bacteremia and survival. Asimilar relationship has been ob-served in patients with polymicro-bial sepsis and mild (but not se-vere) underlying diseases.134 In anexamination of factors influencingthe prognosis of spontaneous bac-terial peritonitis, Weinstein et al135

identified a positive correlation be-tween a temperature reading of morethan 38°C and survival.

It has been reported that chil-dren with chicken pox who aretreated with acetaminophen have alonger time to total crusting of le-sions than placebo-treated controlsubjects.136 Stanley et al137 reportedthat adults infected with rhinovi-rus exhibit more nasal viral shed-ding when they receive aspirin thanwhen given placebo. Furthermore,Graham and colleagues138 reporteda trend toward longer duration of rhinovirus shedding in associationwithantipyretic therapy and showedthat the use of aspirin or acetami-nophen is associated with suppres-sion of the serum neutralizing anti-body response and with increasednasal symptoms and signs. These

data, like those reviewed in the pre-ceding paragraph, are subject to sev-eral interpretations anddo notprovea causal relationship between feverand improved prognosis during in-fection. Nevertheless, they are con-sistent with such a relationship, and,when considered in concert with thephylogeny of the febrile responseand the animal data summarizedherein, they constitute strong cir-

cumstantial evidence that fever is anadaptive response in most situa-tions.

Whereas the foregoing studiesfocused on the relationship be-tween elevation of core tempera-ture and the outcome of infection,others have considered the endog-enous mediators of the febrile re-sponse. In such studies, all 4 of the

major pyrogeniccytokineshave beenshown to have immune-potentiat-ing capabilities that might theoreti-cally enhance resistance to infec-tion (Table1).139 In vitro and in vivostudies of these cytokines have pro-vided evidence of a protective ef-fect of IFN, TNF-, and/or IL-1against Plasmodium organisms,140-142

Toxoplasma gondii,143 Leishmania major, 144 Trypanosoma cruzi,145 andCryptosporidium organisms.146

Several recent reports also haveshown enhancement of resistance toviral147-149 and bacterial150,151 infec-tions by pyrogenic cytokines. Treat-ment of healthy and granulocytope-nicanimalswith IL-1 hasbeen shownto prevent death in some gram-positive and gram-negative bacte-rial infections.151 However, IL-1 is ef-fective only if administered anappreciable time (eg, 24 hours) be-fore initiation of infections havingrapidly fatal courses.In less acute in-fections, IL-1 administration can bedelayed until shortly after the infec-tious challenge. Such observationssuggest thatthe physiologic effectsof fever that enhance resistance to in-fection might be limited to localizedinfections or systemic infections of only mild to moderate severity.

The potential of the febrile re-sponse for harm is reflected in a re-cent flurry of reports suggesting thatIL-1, TNF-, IL-6, and IFN mediatethe physiological abnormalities of certain infections. Although proof of an adverseeffectof fever on theclini-cal outcome of these infections has

yet to be established, the implica-tion is that if pyrogenic cytokinescontribute to the pathophysiologicburden of infections, the mediatorsthemselves and the febrile responseare potentially deleterious.

The most persuasive evidencederives from studies of gram-negativebacterialsepsis.152 Ithas longbeen suspected thatbacterial LPS hasa pivotal role in the syndrome. Puri-





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fied LPS induces a spectrum ofphysi-ological abnormalities that are simi-lar to those occurring in patients withgram-negative bacterial sepsis. In ex-perimental animals, challenge withLPS causes TNF- and IL-1 to be re-leased into the bloodstream coinci-dent with the appearance of signs of sepsis.153 Furthermore, patients withthe septic syndrome have detectable

levelsof circulatory TNF-, IL-1, andI L- 6 i ndependent o f cul tur e-documented infection,and such lev-els correlate inversely with sur-vival.154 Interleukin 1, alone or incombinationwithother cytokines, in-duces many of the same physiologi-cal abnormalities(eg, fever, hypogly-cemia, shock, and death) seen afteradministration of purified LPS.155 Ina murineexperimental modelfor sep-ticshock,IFNadministeredbeforeoras long as 4 hours after LPS chal-lenge increases mortality, whereaspretreatment with anti-IFN anti-body substantially reduces mortal-ity.156 In several recentstudies,the ad-verseeffectsofgram-negativebacterialsepsis, LPS injections, or both havebeen attenuated by pretreating ex-perimental animals with IL-1 antago-nists157,158 and monoclonal antibod-ies directed against TNF-.159,160

Furthermore, animals rendered tol-erant to TNF- by repeated injec-tions of therecombinant cytokine areprotectedagainstthe hypotension, hy-pothermia, and lethality of gram-negative bacterial sepsis.161

Together, these observationshave ledto a growing conviction thatpyrogenic cytokines are central me-diators of the clinical and humoralmanifestationsof gram-negativebac-terial sepsis and have generated in-tense interest, although littleprogress,162 in the clinical applica-tion of antagonists of such cyto-kines. Similar data suggest that py-rogenic cytokines might mediate atleast some of the systemic and local

manifestations of sepsis due to gram-positive bacteria,153,163,164 AIDS,165 spi-rochetal infections,166,167 meningi-tis,168 the adult respiratory distresssyndrome,165,169 suppurative arthri-tis,170 and mycobacteriosis.171

CONCLUSIONS

To fully appreciate the clinical im-plications of fever, one must take a

broad view that encompasses the fe-brile response in its entirety. Feveris mediated by a host of cytokinesthat not only cause the body’s ther-moregulatory set point to rise, butalso simultaneously stimulate pro-duction of a panoply of acute phasereactants (although, apparently notinvariably) and activate numerousmetabolic, endocrinologic, and im-

munologic systems. For these rea-sons, fever cannot be equated withhyperthermia. More important, ex-perimental models of “fever” inwhich body temperature is el-evated by external means or byagents that markedly increase heatproduction by uncoupling oxida-tive phosphorylation must be rec-ognized as having limited value inthe study of this physiologic re-sponse. Only if one views fever fromthe perspective of its relationshipwith thefebrile response, can one be-

gin to explain the apparent para-dox inherent in reports demonstrat-ing beneficial effectsof therapy withpyrogenic cytokines and their an-tagonists and, through such under-standing, take maximum advan-tage of the response to alleviate theburden of human disease.

Accepted for publication January 22,1998.

This work was supported by theDepartmentof Veterans Affairs, Wash-ington, DC.

I am indebted to Sheldon E.Greisman, MD, for his critical re-view of the manuscript.

Reprints: Philip A. Mackowiak,MD, Medical Care (111), VA Medi-cal Center, 10 N Greene St, Balti-more, MD 21201.

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