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SleepandInfection
NoSnooze,YouLose?
PenelopeA.Bryant,PhD,NigelCurtis,PhD PediatrInfectDisJ.201332(10):11351137.

Introduction
Youaremorelikelytocatchacoldifyouaretired:factorfiction?Thereisinfactasurprisinglylargebodyofevidence tosupportthewidelyheldbeliefthatsleepdeprivationincreasessusceptibilitytoinfection.[1]Thelinkbetweensleep andtheimmunesystemhasimportantimplicationsforbothindividualsandthepopulation,astherehasbeenasteady declineoverthelastfewdecadesinindividuals'averagedurationofsleep.[2]Hereinwereviewtheevidencethatthereis arelationshipbetweensleep,immunityandinfection,includingthesmallamountofdatainchildren. Ofthe2phasesofsleep,rapideyemovementsleepisthoughttobetherestorativephase.Nonrapideyemovement sleep,andtheslowwavesleepcomponentinparticular,isbelievedtobeinvolvedininformationprocessing.

DoInfectionsInfluenceSleepDuration?
ExperimentalInfectionsinAnimalsandHumans

Studiesinbothanimalsandhumansshowevidencethatavarietyofviralandbacterialinfectionsleadtoincreased sleep.[3,4]Forexample,inhumansexperimentallyinfectedwithinfluenza,sleepdurationdecreasesduringincubation andincreasesduringthesymptomaticphase.[3]

ClinicalInfectionsinAdultsandChildren

Infantsrecoveringfromupperrespiratorytractinfectionshowimpairedarousalfromsleepcomparedwithhealthy controls,suggestinganexplanationfortheassociationbetweeninfectionandsuddeninfantdeathsyndromeobserved insomestudies.[5]Arecentreviewofrandomizedcontroltrialsofoseltamivirversusplaceboinadultsandadolescents withinfluenzashowedasignificantlyfasterreturntobaselinesleepdurationswithtreatment,supportingthenotionthat itwasthevirusthatcausedincreasedsleep.[6] SleephasbeenstudiedextensivelyinHIVinfectedadultsandadolescentscomparedwithhealthycontrolswithwidely varyingresults,onlypartiallyexplainedbytheuseofdifferentsleepassessmenttoolsandmeasuresofsleep.Children withHIVhavelesssleepandaremoretiredthanhealthycontrols.[7]ArecentstudyinadolescentsfoundthatHIV infectionwasassociatedwithchangesinsleeppattern,withconcomitantsignificantdifferencesinbloodcytokine levels.[8]
CytokinesandSleep

Cytokinestudieshaveledtothehypothesisthatpathogeninducedhostimmunefactorsarethemeansbywhich infectioninfluencessleep.Studiesinbothanimalsandhumanshaveshowndifferenteffectsofcytokinesonsleep, especiallyTNF,IL1andIL6(Table,SupplementalDigitalContent1,http://links.lww.com/INF/B690).However,no singlecytokineisconsistentlyassociatedwithsleep,andthismayexplainwhydifferentinfectionsareassociatedwith differentpatternsofsleepdisruption. Theregulationofendogenouscytokinesduringthesleep/wakecyclealsoprovidessomeintriguinginsights.Circadian rhythmicityisclearlyanimportantaspectofsleep,andtheparadigmforcircadianregulationistheendocrinesystem. Thereisawellrecognizedrelationshipbetweentheneuroendocrineandimmunesystems,andstudiessuggestthat

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theyinteracttoinfluencesleep(Fig.1andTable,SupplementalDigitalContent1,http://links.lww.com/INF/B690).The samecytokinesareinvolvedinbothphysiologicalsleepandtheeffectsofinfectiononsleep.

Figure1. Theproposedinteractionbetweensleepandimmunity,andothersystemsandprocesses(adaptedfromBryantetal).1 Becauseinfectiongenerallyincreasessleepduration,andbecausecytokinesarephysiologicallyregulatedduringsleep, ithasbeensuggestedthatsleepisrestorativetoimmunefunction.Sleepdeprivationstudiesaredesignedto investigatethishypothesis.

DoesSleepDurationInfluencetheImmuneResponse?
SleepDeprivationStudiesinHumans

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Animalandhumanstudiesshowthatsleepdeprivationhasdetrimentaleffectsonimmunecellsandcytokines.[1]In humans,numbersofThelpercellsandnaturalkillercellsdecreaseafteronenight'ssleepdeprivation.[9]Both endogenouscytokinelevelsandcytokineresponsestolipopolysaccharidestimulationarealsoaffected(Table, SupplementalDigitalContent1,http://links.lww.com/INF/B690). Althoughtheconceptofasinglemediatorofsleepandinfection,"sleepamine,"isattractive,itismorelikelythata combinationofimmuneregulatorymoleculesmediatestherelationshipbetweensleepandtheimmuneresponse necessitatingaglobalapproachtoinvestigatingthislink.Arecentstudyusedmicroarraystocompareglobalgene expressioninvolunteersaffordedinsufficientsleepfor7nights(mimickingchronicpartialsleeploss)withexpressionin thesameindividualsafteradequatesleep.[10]Insufficientsleepledtoupordownregulationofgeneexpression,lossof circadianrhythmicityanddecreasedamplitudeofcircadianregulatedexpression.Clustersofgenesinvolvedinimmune andinflammatoryresponses,cytokineactivityandnuclearfactorkappaBsignalingpeakedintheirendogenous expressioninthebiologicalday,andsleepdeprivationledtolossofcircadianrhythmicityanddecreasedamplitudeof expression.Significantincreasesininterleukin(IL)6andIL1receptorexpressionwereseenaftersleepdeprivation, parallelingfindingsfromotherstudies(Table,SupplementalDigitalContent1,http://links.lww.com/INF/B690).
ClinicalSleepDeprivation

Inchildren,obstructivesleepapneahasbeenconsideredbysomeresearcherstoprovideaclinicalscenarioinwhich theeffectsofchronicpartialsleeplosscanbeinvestigated.[11]Severalstudieshaveinvestigatedinflammatory pathwaysinobstructivesleepapnea,showingincreasesinplasmaproinflammatorycytokines,suchastumornecrosis factorandIL6.[12,13]However,obstructivesleepapneaisnotuniversallythoughttobeassociatedwithsleep deprivation,anditisdifficulttoseparatethepotentialconfoundingeffectsofhypoxia.Thesameistrueininfective exacerbationsincysticfibrosis:theseareassociatedwithdecreasedrapideyemovementsleep,whichresolveswith antibiotics.[14]Chronicinsomniainadultswithouthypoxia,however,isalsoassociatedwithchangesincytokines, includingdecreasedIFNglevels.[15]Chronicfatiguesyndrome,whichmayfollowanacuteinfection,showsdisordered sleeparchitecturewithdisruptednonrapideyemovementsleep.Althoughstudieshaveshownanalteredcytokine profileinsomeindividualswithchronicfatigue,includingincreasesincellularproductionoftumornecrosisfactorandIL 6,whetherthisisacausalrelationshipisuncertain.[16]

IstheEffectofSleepontheImmuneSystemClinicallyRelevant?
FunctionalEffectsofSleepDeprivation

Aretheobservedeffectsontheimmuneresponseinducedbysleepdeprivationimportantintheclinicalsetting?The immuneresponsetoimmunizationprovidesanopportunitytoinvestigatethis.Akeystudyshowedthathealthyadults immunizedagainstinfluenzaAduringpartialsleepdeprivationdevelopedantibodytitershalfthelevelofthoseinwell restedcontrols(levelIII).[17]Asinglenight'stotalsleepdeprivationhasrecentlybeenshowntoadverselyaffect antibodytitersearlyinresponsetoH1N1vaccinationinmales,althoughnotfemales(levelIII).[18]Interestinglyinboth studiestheeffectwasonlyshownatseveraldayspostimmunizationandthedifferencewasnolongersignificantaftera fewweeks,suggestingboththatsleepisimportantintheearlyadaptiveresponseandthatsubsequentrestorativesleep reversestheeffect.DecreasedsleepalsolowerstheantibodyresponsetohepatitisA(levelIII)[19]andhepatitisB vaccines(levelIII).[20]Conversely,afterimmunizationagainsthepatitisA,sleeppromotesTh1adaptiveresponsesand immunologicalmemory.[19] Therehavebeensurprisinglyfewstudiesinhumansthathavedirectlyaddressedwhethersleepdeprivationincreases susceptibilitytoorseverityofinfections,astheyhavenotinvestigatedtheinfectionrateintheperiodaftersleep deprivation.Inaddition,moststudieshaveinvestigatedonlyhealthysubjectsandonlyshortperiodsofsleep deprivation.Ofgreaterrelevancetosocietyisthechronicpartialsleeplossthatistypicalinshiftworkers(whoin studiesreportmoreinfectionsthannonshiftworkers)[21]andalsorelevanttothepopulationingeneral.Arecentstudy directlyaddressedtherateofinfectioninthiscircumstance.Volunteerswereaskedtorecordtheirdailysleepduration andefficiencyfor14daysandwerethenquarantinedfor14daysandchallengedwithintranasalrhinovirus(levelIII).[22]

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Intriguinglytherewasa"doseresponse"relationship,withthoseindividualswhohadlessthan7hoursaveragesleep beingalmost3timesmorelikelytodevelopacoldthanthosewhohad8hoursormore.Poorersleepefficiencythe proportionoftimeinbedactuallyasleepshowedasimilareffect,andpotentialconfoundingfactorswereexcluded. Thisisthebestevidenceyettosupportthenotionthatyouaremorelikelytocatchacoldwhenyouaretired. Theeffectsofchronicpartialsleepdeprivationmayhavesignificanteffectsonotherconditionsinwhichimmunitymay playarole.Disorderedsleepandcytokineabnormalitieshavealsobeenshownininflammatoryboweldiseaseand cancer. Inlightoftheincreasingevidenceforaneffectofsleep,andmoreimportantlythelackofsleep,ontheimmunesystem, andsomeevidencethatthismightbefunctionallyimportant,canwedoanythingaboutit?Ononelevel,the documenteddecreasingmediansleepdurationinthepopulationoverthelastfewdecadesmightbeseenasapublic healthissue.Onanindividuallevel,1interestingstudyinpatientsonhemodialysisshowedthatcognitivebehavioral therapyismoreeffectivethansimplesleephygieneadviceinimprovingsleepdisturbance,andatthesametime,it reducedplasmaCreactiveproteinandIL18.[23]Thissuggeststhatsleepdisturbanceanditseffectsontheimmune systemareamenabletochange. Recognizingsleepasacrucialcomponentoftheimmunesystemnotonlygivesinsightsintotheimmuneresponsebut alsoraisesawarenessabouttheimportanceofsleepforsocietyasawholeandforpatients.Perhapsasclinicianswe shouldatleastrecognizethepotentialdetrimentaleffectsofsleepdisruptiononpatientsinbusywardsandintensive care.
References

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