Understanding Fever in Children: Causes and Management

1. Fever Assoc. Prof. Dr. Suat Biçer Yeditepe University, Faculty of Medicine Child HealthandPediatricsDepartment

2. AMAÇLAR Çocukluk çağında ateş nedenleri konusunda bilgi sahibi olabilmek, Ne zaman ateş ciddi hastalık belirtisidir sorusunu yanıtlayabilmek, Ateşli çocuğa yaklaşım konusunda bilgi sahibi olmak, Yineleyen ateşte etiyolojik faktörler ve tedavi yöntemleri konusunda bilgi sahibi olmak, Ateşli çocuğa müdahale yöntemleri ve antipiretikler konusunda bilgi sahibi olmak.

3. What is thedefinition of fever in children? ≥ 39°C > 39°C ≥ 40°C ≥ 38°C > 38°C > 37.9°C > 37°C ≥ 36.5°C >36.5°C

4. What is thedefinition of hyperpyrexia in children? • Thesamedefinitionforfever, • ≥ 38°C • > 39°C • > 37.9°C • > 37°C • ≥ 36.5°C • > 36.5°C • ≥ 39°C • > 38°C • > 37.9°C • > 37°C • ≥ 36.5°C • > 36.5°C • > 40.5°C

5. Definition • Fever is defined as a rectaltemperature ≥38°C, and a value≥ 41°C is calledhyperpyrexia. • Body temperaturefluctuates in a defined normal range (36.6°C-37.9°C rectally), sothatthehighestpoint is reached in earlyeveningandthelowestpoint is reached in themorning. • Anyabnormalrise in body temperatureshould be considered a symptom of an underlyingcondition.

6. Where is regulatedthe body temperature? Body temperature is regulatedbythermosensitiveneuronslocated in thesupraopticandposteriorhypothalamusthatrespondtochanges in bloodtemperatureas well as coldandwarmreceptorslocated in capillaryandvenousvessels. Body temperature is regulatedbythermosensitiveneuronslocated in thepreopticoranteriorhypothalamusthatrespondtochanges in bloodtemperatureas well as coldandwarmreceptorslocated in skin andmuscles.

7. Pathogenesis • Thermoregulatoryresponsesincluderedirectingbloodtoorfromcutaneousvascularbeds, increasedordecreasedsweating, regulation of extracellularfluidvolumeviaargininevasopressin, andbehavioralresponses, such as seeking a warmerorcoolerenvironmentaltemperature.

8. FEVER RESPONSE Infection, toksins, injury, inflamation, immunolojic reactions, Fever Vasomotor area Monocyt, neutrophil, lymphocyt, endotel,glial, mesenchimal cells Increased set point Monoaminsand Calcium cAMP Prostoglandin E2 Pyrojeniccytokins, IL-1, TNF, IFN, IL-6 Circulation Endotel Circumventricular area

9. Whichmechanisms can producefever? • Pyrogens, • Heatproductionexceedingloss, • Defectiveheatloss

10. ThefirstmechanisminvolvesendogeneousandexogenouspyrogensthatraisetheThefirstmechanisminvolvesendogeneousandexogenouspyrogensthatraisethe hypothalamic temperature set point. • Endogenouspyrogensincludethecytokines • interleukin 1 (IL)-1 and IL-6, • tumornecrosisfactor-α (TNF-α), and • interferon (IFN)-β and IFN-γ. • Stimulatedleukocytesandothercellsproducelipidsthatalsoserve as endogenouspyrogens.

11. Thebest-studiedlipidmediator is ................., whichattachestothe ................. receptors in the ................. toproducethenewtemperature set point. Thebest-studiedlipidmediator is prostaglandin (PG)E2, whichattachestotheprostaglandinreceptors in thehypothalamustoproducethenewtemperature set point. Exogenouspyrogensorsubstancesthatcomefromoutsidethe body includemainlyinfectiouspathogensanddrugs. Microbes, microbialtoxins, orotherproducts of microbesarethemostcommonexogenouspyrogensandstimulatemacrophagesandothercellstoproduceendogenouspyrogens.

12. Some substances produced within the body are not pyrogens but are capable of stimulating endogenous pyrogens. Such substances include antigen-antibody complexes in the presence of complement, complement components, lymphocyte products, bile acids, and androgenic steroid metabolites.

13. Endotoxin is one of the few substances that can directly affect thermoregulation in the hypothalamus as well as stimulate endogenous pyrogen release. Many drugs cause fever, and the mechanism for increasing body temperature varies with the class of drugs. Drugs that are known to cause fever include vancomycin, amphotericin B, and allopurinol. Along with infectious diseases and drugs, malignancy and inflammatory diseases can cause fever through the production of endogenous pyrogens.

14. Secondandthirdmechanismsthat leads to fever: Heat production exceeding heat loss is the second mechanism that leads to fever, with examples including salicylate poisoning and malignant hyperthermia. Defective heat loss is the third mechanism of fever genesis, for example, in children with ectodermal dysplasia or victims of severe heat exposure.

15. Etiology Whatarethecauses of fever? (organized into 4 main categories) 1- Infections 2- Inflammatorydiseases 3- Neoplasticdiseaes 4- Miscellaneous Whatare the most common causes of acute fever and hyperpyrexia? 1- Self-limitedviralinfections (commoncold, gastroenteritis) 2- Uncomplicatedbacterialinfections (otitismedia, pharyngitis, sinusitis)

16. What is the limit of fever? 40°C 41°C 42°C 43°C 45°C

17. The body temperature should not rise above potentially lethal levels (41.7°C) in the neurologically intact child unless extreme hyperthermic environmental conditions are present or other extenuating circumstances exist, such as underlying malignant hyperthermia or thyrotoxicosis.

18. The pattern of the fever can provide clues to the underlying etiology. Viral infections typically are associated with a slow decline of fever over a week, whereas bacterial infections are associated with a prompt resolution of fever after effective antimicrobial treatment is employed. Although administration of antimicrobial agents can result in a very rapid elimination of bacteria, if tissue injury has been extensive, the inflammatory response and fever can continue for days after all microbes have been eradicated.

19. Intermittent fever is an exaggerated circadian rhythm that includes a period of normal temperatures on most days; extremely wide fluctuations may be termed septic or hectic fever. Sustained fever is persistent and does not vary by more than 0.5°C/day. Remittent fever is persistent and varies by more than 0.5°C/day.

20. Relapsing fever is characterized by febrile periods that are separated by intervals of normal temperature; tertian fever occurs on the first and third days (malaria caused by Plasmodium vivax), and quartan fever occurs on the first and fourth days (malaria caused by Plasmodium malariae).

21. Diseasescharacterizedbyrelapsingfeversshould be distinguishedfrominfectiousdiseasesthathave a tendencytorelapse. Biphasicfeverindicates a singleillnesswith 2 distinctperiods (camelbackfeverpattern); poliomyelitis is theclassicexample. A biphasiccourse is alsocharacteristic of otherenteroviralinfections, leptospirosis, denguefever, yellowfever, Colorado tickfever, spirillaryrat-bite fever(Spirillumminus),andtheAfricanhemorrhagicfevers (Marburg, Ebola, and Lassa fevers).

22. Thetermperiodicfever is usednarrowlytodescribefeversyndromeswith a regularperiodicity (cyclicneutropeniaand PFAPA [periodicfever, aphthousstomatitis, pharyngitis, andadenopathy]) ormorebroadlytoincludedisorderscharacterizedbyrecurrentepisodes of feverthat do not follow a strictlyperiodicpattern (familialMediterraneanfever, Hibernianfever, TNF-receptor–associatedperiodicsyndrome [TRAPS], hyper-IgDsyndrome, theMuckle-Wellssyndrome). Factitiousfever, or self-inducedfever, may be causedbyintentionalmanipulation of thethermometerorinjection of pyrogenicmaterial.

24. NONINFECTIOUS CAUSES

25. PERIODIC FEVER SYNDROMES

26. Thedoublequotidianfever (orfeverthatpeakstwice in 24 hours) is classicallyassociatedwithinflammatoryarthritis. In general, a singleisolatedfeverspike is not associatedwith an infectiousdisease. Such a spike can be attributedtotheinfusion of bloodproductsandsomedrugs, as well as tosomeprocedures, ortomanipulation of a catheter on a colonizedorinfected body surface.

27. Temperatures in excess of 41°C aremostoftenassociatedwith a noninfectiouscause. Causesforveryhightemperatures (>41°C) includecentralfever (resultingfromcentralnervoussystem (CNS) dysfunctioninvolvingthehypothalamus), malignanthyperthermia, malignantneurolepticsyndrome, drugfever, orheatstroke.

28. Hypothermia Temperaturesthatarelowerthan normal (<36°C) can be associatedwithsepsis but aremorecommonlyrelatedtocoldexposure, hypothyroidism, oroveruse of antipyretics.

29. ClinicalFeatures Theclinicalfeatures of fever can rangefromnosymptoms at alltoextrememalaise. Childrenmightcomplain of feeling hot orcold, displayfacialflushing, andexperienceshivering. Fatigueandirritabilitymay be evident. Parentsoftenreportthatthechildlooksillorpaleand has a decreasedappetite.

30. Theunderlyingetiologyalsoproducesaccompanyingsymptoms. Althoughtheunderlyingetiologies can manifest in variedwaysclinically, therearesomepredictablefeatures. Forinstance, feverwithpetechiaein an ill-appearingpatientindicatesthehighpossibility of life-threateningconditionssuch as meningococcemia, RockyMountainspottedfever, oracutebacterialendocarditis.

31. Changes in heart rate, mostcommonlytachycardia, accompanyfever. Relativetachycardia, whenthepulse rate is elevatedout of proportiontothetemperature, is usuallyduetononinfectiousdiseasesorinfectiousdiseases in which a toxin is responsiblefortheclinicalmanifestations.

32. Relativebradycardia (temperature-pulsedissociation), whenthepulse rate remainslow in the presence of fever, can accompanytyphoidfever, brucellosis, leptospirosis, ordrugfever. Bradycardia in the presence of feveralsomay be a result of a conductiondefectresultingfromcardiacinvolvementwithacuterheumaticfever, Lymedisease, viralmyocarditis, orinfectiveendocarditis.

33. Evaluation Mostacutefebrileepisodes in a normal host can be diagnosedby a carefulhistoryandphysicalexaminationandrequirefew, ifany, laboratorytests. Becauseinfection is themostlikelyetiology of theacutefever, theevaluationshouldinitially be gearedtodiscovering an underlyinginfectiouscause. Thedetails of thehistoryshouldincludetheonsetandpattern of feverandanyaccompanyingsignsandsymptoms.

34. Thepatientoftendisplayssignsorsymptomsthatprovidecluestothecause of thefever. Exposurestootherillpersons at home, daycare, andschoolshould be noted, alongwithanyrecenttravelormedications. Thepastmedicalhistoryshouldincludeinformationaboutunderlyingimmunedeficienciesorothermajorillnessesandreceipt of childhoodvaccines.

35. Intheacutelyfebrilechild, thephysicalexaminationshouldfocus on anylocalizedcomplaints, but a completehead-to-toescreen is recommended, becausecluestotheunderlyingdiagnosismay be found. Forexample, palmand sole lesionsmay be discoveredduring a thorough skin examinationandprovide a clueforinfectionwithcoxsackievirus. Vitalsignsshouldincludepulseoximetry, becausehypoxiaindicateslowerrespiratorytractdisease.

36. EVALUATION OF ACUTE FEVER

37. EVALUATION OF ACUTE FEVER

38. If a fever has an obviouscause, thentheevaluation is complete, nofurthertesting is advised, andcare is tailoredtotheunderlyingdiagnosiswith as-needed re-evaluation. Ifthecause of thefever is not apparent, thenfurtherdiagnostictestingshould be considered on a case-by-casebasis. Thehistory of presentationandabnormalphysicalexaminationfindingsguidetheevaluation. Thechildwithrespiratorysymptomsandhypoxia can require a chestradiographorrapidantigentestingfor RSV orinfluenza. Thechildwithpharyngitis can benefitfromrapidantigendetectiontestingforgroup A Streptococcusand a throatculture.

39. Dysuria, backpain, orhistory of vesicoureteralrefluxshouldprompt a urinalysisandurineculture, andbloodydiarrheashouldprompt a stoolculture. A completebloodcountandbloodcultureshould be considered in theill-appearingchild, alongwithcerebrospinalfluidstudiesifthechild has neckstiffness. Well-definedhigh-risk groupsrequire a more-extensiveevaluation on thebasis of age, associateddisease, orimmunodeficiencystatusandmightwarrantpromptantimicrobialtherapybefore a pathogen is identified.

40. Treatment Althoughfear of fever is a commonparentalworry, evidence is lackingtosupportthebeliefthathighfever can result in braindamageorotherbodilyharm, except in rareinstances of febrilestatusepilepticusandheatstroke. Treatingfever in self-limitingillnessesforthe sole reason of bringingthe body temperaturebackto normal is not necessary in theotherwisehealthychild.

41. Increasesneutrophilmigration, • Antibacterial agents such as released from neutrophils superoxide anion production increases. • Increases the production of interferon • Enhances the antiviral and antitumor activity of interferon. • Activation of T-helper cells, and cytotoxic activity of expression increases. • Promotes the release of lactoferrin.Accelerate the killing of intracellular bacteria.Increases the bactericidal activity of antimicrobial agents. Most evidence suggests that fever is an adaptive response and should be treated only in selected circumstances. In humans, increased temperatures are associated with decreased microbial replication and an increased inflammatory response.

42. - oxygenconsumption, - carbondioxideproduction, - cardiacoutput Althoughfever can havebeneficialeffects, it also - increases Fever can exacerbate; - cardiacinsufficiency in patientswithheartdiseaseorchronicanemia (e.g., sicklecelldisease), - pulmonaryinsufficiency in patientswithchroniclungdisease, - metabolicinstability in patientswithdiabetesmellitusorinbornerrors of metabolism.

43. Basal metabolic rate leads to a six-fold increase, Body temperature increase from 38 to 41 ⁰ C with increasing oxygen consumption by 20%, The oxygen affinity of hemoglobin is reduced, Degrees above the normal body temperature of a need to keep the increase in the basal metabolic rate of 10-12.5%.

44. Childrenbetweentheages of 6 moand 6 yrare at increased risk forsimplefebrileseizures. Childrenwithidiopathicepilepsyalsooftenhave an increasedfrequency of seizuresassociatedwith a fever.

45. Fever withtemperatures <39°C in healthychildrengenerallydoes not requiretreatment. However, as temperaturesbecomehigher, patientstendtobecomemoreuncomfortable, andtreatment of fever is thenreasonable. If a child is included in one of thehigh-risk groupsorifthechild'scaregiver is concernedthatthefever is adverselyaffectingthechild'sbehaviorandcausingdiscomfort, treatmentmay be giventohastentheresolution of thefever.

46. Otherthanprovidingsymptomaticrelief, antipyretictherapydoes not changethecourse of infectiousdiseases. Encouraginggoodhydration is thefirst step toreplacefluidsthatarelostrelatedtotheincreasedmetabolicdemands of fever. Antipyretictherapy is beneficial in high-risk patientswhohavechroniccardiopulmonarydiseases, metabolicdisorders, orneurologicdiseasesand in thosewhoare at risk forfebrileseizures.

47. Hyperpyrexia (>41°C) indicatesgreater risk of hypothalamicdisordersor CNS hemorrhageandshould be treatedwithantipyretics. Somestudieshaveshownthathyperpyrexiamay be associatedwith a significantlyincreased risk of seriousbacterialinfection, but otherstudieshave not substantiatedthisrelationship. High feverduringpregnancymay be teratogenic.

48. Acetaminophen at a dose of 10-15 mg/kg/dose every 4 hr and ibuprofen in children older than 6 months at a dose of 5-10 mg/kg/dose every 8 hours are the most commonly employed antipyretics. Antipyretics reduce fever by reducing production of prostaglandins. If used appropriately, antipyretics are safe; potential adverse effects include liver damage (acetaminophen) and gastrointestinal or kidney disturbances (ibuprofen).

49. Toreducefevermostsafely, thecaregivershouldchooseonetype of medicationandclearlyrecordthedoseand time of administration, sooverdosagedoes not occur, especiallyifmultiplecaregiversareinvolved in themanagement.

50. Physicalmeasuressuch as tepidbathsandcoolingblanketsare not consideredeffectivetoreducefever. Evidence is alsoscarcefortheuse of complementaryandalternativemedicineinterventions. Fever duetospecificunderlyingetiologiesresolveswhenthecondition is properlytreated. Examplesincludeadministration of intravenousimmunoglobulintotreatKawasakidiseaseortheadministration of antibioticstotreatbacterialinfections.