180MedicalClassicsHerricksaccountofsicklecellsselfhadthoughtthatthislocationofthelesionsmighthavebeenduetothebruisesandscratchesthatwerefrequentlyproducedasheranaboutabarefootboythroughthestreets ID: 248453
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YALEJOURNALOFBIOLOGYANDMEDICINE74(2001),pp.179-184.CopyrightK)2001.Allrightsreserved.CLASSICSOFBIOLOGYANDMEDICINEPeculiarElongatedandSickle-shapedRedBloodCorpusclesinaCaseofSevereAnemiaaJamesB.Herrick,M.D.1013StateStreet,Chicago,IllinoisThiscaseisreportedbecauseoftheunusualbloodfindings,noduplicateofwhichIhaveeverseendescribed.Whetherthebloodpicturerepresentsmerelyafreakishpoikilocytosisorisdependentonsomepeculiarphysicalorchemicalcondi-tionoftheblood,orischaracteristicofsomeparticulardisease,Icannotatpresentanswer.Ireportsomedetailsthatmayseemnon-essential,thinkingthatifasim-ilarbloodconditionisfoundinsomeothercaseacomparisonofclinicalconditionsmayhelpinsolvingtheproblem.HISTORYThepatientwasanintelligentnegroof20,whohadbeenintheUnitedStatesthreemonths,duringwhichtimehewasastudentinoneoftheprofessionalschoolsinChicago.HisformerresidencehadbeenGrenada,WestIndies,wherehehadbeenbornandbroughtup,oneofafamilyoffourchildren,allliving,andallwellwiththeexceptionofhimself.Hismotherwaslivingandingoodhealth;hisfatherhaddiedofaccident.Attheageof10thepatienthadhadyaws.Thiswasacommondiseaseinthelocalitywherehelived.Thelesions,ashedescribedthem,hadbeenpustular,withformationofulcersandscabs.Onhealing,scars,manyofwhichhepointedout,wereleft.Someoftheulcershadbeenaslargeasasilverquarterofadollar.Thediseaselastedaboutoneyearandduringthistimehehadfeltsomewhatweakandindisposed.Mostoftheulcershadbeenonthelegsandthepatienthim-aEditor'sNote:FromtimetotimetheJournalwillre-publishclassicpapersofbiologyandmedicinefromsourcesthatmaybehardtofindorunavailableinmanylibraries.This1910articlebytheChicagophysician,Dr.JamesB.Herrick,describesthefirstrecognitionofsicklecellanemia.Herrick'sclinicaldescriptionisclearandhisintuitionastotheunderly-ingcauseoftheabnormalsicklecellsisstrikingtothemodernreader.HistoricalanalysisofthisworkisfoundinrecentpublicationsofToddSavitt:'Theinvisiblemalady:sicklecellanemiainAmerica,1910-1970."J.Natl.Med.Assoc.73:739-46,1981;(withM.F.Goldberg)"Herrick's1910casereportofsicklecellanemia:therestofthestory."JAMA261:266-271,1989;and'Thesecondreportedcaseofsicklecellanemia.Charlottesville,Virginia,1911."Va.Med.Q.124:84-92,1997.Subsequentpathophysiologicalclassicsonsicklecellhemo-globininclude:LinusPauling,HarveyItano,S.JonSinger,and1.C.Wells,"Sickle-cellane-mia:amoleculardisease."Science110:543-548,1949;andVernonIngraham,"Genemuta-tioninhumanhemoglobin:thechemicaldifferencebetweennormalandsickle-cellhemo-globin."Nature180:326-328,1957.179 180MedicalClassics:Herrick'saccountofsicklecellsselfhadthoughtthatthislocationofthelesionsmighthavebeenduetothebruisesandscratchesthatwerefrequentlypro-ducedasheranabout,abarefootboy,throughthestreetsandthebrush.Hewassurehehadneverhadground-itch,thoughhesaiditwasnotuncommoninGrenada.Hehadattendedschooluptotheageof17.Sinceleavingschool,thatis,forthepastthreeyears,hehadfeltadisinclina-tiontotakeexercise.Foraboutayearhehadnoticedsomepalpitationandshort-nessofbreathwhichhehadattributedtoexcessivesmoking.Therehadbeentimeswhenhethoughthewasbiliousandwhenthewhitesoftheeyeshadbeentingedwithyellow.Atsuchtimeshehadnothadanypain,chillorfever.Threeyearsprevi-ouslyhehadhadapurulentdischargefromtherightearlastingsixmonths.Hehadhadnodiarrheaandnohemorrhagesatanytime.Hedeniedsyphilisandgonor-rhea.Therewasneveranyrheumatismorotherjointtrouble.OnlandinginNewYorkinSeptember,1904,hehadasoreononeankleforwhichheconsultedaphysi-cian.Tinctureofiodinwasappliedandinaweek,thesorehealed,leavingascarsimilartotheothersonthelimbs.Forthepastfiveweekshehadbeencoughing.Twodayspriortoexaminationhehad"takencold,"hiscoughhadgrownworseandhehadhadaslightchill,followedbyfever.Itwasthiscoughandfeverforwhichhewishedtreatmentatthehospital,andofwhichhechieflycomplained,thoughhementionedalsothathefeltweakanddizzy,hadheadacheandcatarrhofthenose.PHYSICALEXAMINATIONThisshowedhimtobeayoungmanoftypicalnegrofacies,withblack,curlyhair.Hewasfairlywelldevelopedphysi-callyandwasbrightandintelligent.Therewasatingeofyellowinthescleraandthevisiblemucousmembraneswerepale.Theeyeswerenormal;thepupilsshowedpromptreactiontolightandinaccommo-dation.Thehearingwasgood;therewasnodischargefromtheear.Thenoseshowedchronicandacuterhinitis.Thetonguewascoated,thepharynxslightlyreddened;noscarsorotherlesionswerefoundhere.Thecervicalglandsweredef-initelyenlarged,hardandnotpainful.Theaxillary,inguinalandepitrochlearglandswerealsoenlarged,someintheaxillabeingofthesizeofalmonds.Overthechestandabdomenwereseveralgood-sizedleukodermatouspatches,theinter-veningskinbeingratherdeeplypigment-ed.Thescarstowhichbehadreferredwerenearlyalllocatedonthelegsandthighs,someintheformerlocationbeingasmuchas3cm.indiameter.Therewereperhapstwentyscarsinall.Theywereroundedoroval,sometimesofirregularcontour,theedgesclean-cut;somewereliketissuepaperorthinparchmenttothetouchandwerelighterincolorthanthesurroundingskin.Theywerestrikinglylikescarsoftenseenastheresultofsyphilis.Thechestwaswellformed.Therewasfairexpansion.Numerousrales,mostlyofthemoistvariety,wereheardscatteredthroughoutthechest,espe-ciallyposteriorly.Therewasaslightrela-tivedulnessoverthebaseofeitherlungbehind.Theheartwasenlargedtotheleft,theapeximpulsebeinginthesixthinter-spaceoneinchtotheleftoftheleftmam-millaryline.Therewasbutaslightincreaseinthedullnesstotheright.Asoftsystolicmurmur,notwelltransmittedinanydirection,washeardoverthebaseoftheheart.Afaintsystolicmurmur,orper-hapsitwouldbebettertocallitanimpurefirsttone-washeardattheapex.Theheart'sactionremindedoneofaheartunderstrongstimulation,thoughnohisto-ryofingestionofastimulantofanykindwasobtainable.Basedow'sfindingswerenottobemadeout.Thepulsewasofgoodqualityandoffairvolume.Theabdomen MedicalClassics:Herrick'saccountofsicklecells181wasnotdistendednorwasittender.Neitherspleennorlivercouldbepalpated.Therewasnotendernessoverthegall-bladderregion.Thegenitaliawerenormal.Thepatellarreflexesweresluggish.Therewasnoataxiaandtherewerenosensorydisturbances.Thetemperatureonadmissionwas101°F.Itvariedbetween990and1010forfourdays,thengraduallysubsided,thoughforthenextthreeweeksitwasoftenfoundbetween99and100F.,thoughwithnoregularity.Thepulsevariedfrom64to104.averagingabout80.Therewasneveranyrapidbreathing.URINEANDSPUTUMTheurinewasamberincolor,specif-icgravity1.010to1.014,slightlyincreasedinamount-2,000c.c.-acid,containedadistincttraceofserum-albu-min,afewgranularandhyalinecasts.Thisrepresentstheaverageofseveralexamina-tions.Theurineonadmissionhadatraceofbile.December28,urinaryexamina-tionsforhemoglobinandhematopor-phyrinweremadeandnonefound.Testsweremadeforparamidophenol,butnonewasfound.Notuberclebacilliwerediscoveredinthesputum.BLOODEXAMINATIONTheblood-countonDec.26,1904,was:Redcorpuscles,2,570,000;whitecorpuscles,40,000;hemoglobin(Dare)40percent.colorindex,0.78.December31thecountwasasfollows:Erythrocytes,2,880,000.Leukocytes,15,250.Hemoglobin,50percent.(Dare).Theredcorpusclesvariedmuchinsize,manymicrocytesbeingseenandsomemacrocytes.Polychromatophilia.waspresent.Nucleatedredswerenumer-ous,74beingseeninacountof200leuko-cytes,therebeingabout5,000tothec.mm.Theshapeoftheredswasveryirregular,butwhatespeciallyattractedattentionwasthelargenumberofthin,elongated,sickle-shapedandcrescent-shapedforms.Thesewereseeninfreshspecimens,nomatterinwhatwaythebloodwasspreadontheslideandtheywereseenalsoinspecimensfixedbyheat,byalcoholandether,andstainedwiththeEhrlichtriacidstainaswellaswithcontrolstains.Theywerenotseeninspecimensofbloodtakenatthesametimefromotherindividualsandpre-paredunderexactlysimilarconditions.Theyweresurelynotartefacts,norweretheyanyformofparasite.Instainingreac-tionstheywereexactlyliketheirneigh-bors,theordinaryredcorpuscles,thoughmanytookthestainheavily.Inafewoftheelongatedformsanucleuswasseen.Inthefreshspecimenwheretherewasaslightcurrentinthebloodbeforeithadbecomeentirelyquiet,alloftheredcorpuscles,theelongatedformsaswellasthoseofordi-naryform,seemedtobeunusuallypliableandflexible,bendingandtwistinginaremarkablemannerastheybumpedagainsteachotherorcrowdedthroughanarrowspaceandseemingalmostrubber-likeintheirelasticresumptionofthefor-mershape.Onereceivedtheimpressionthattheflattenedreddiscsmightbyreasonofunusualpliabilityberolledupasitwereintoalongnarrowbundle.OnceortwiceIsawacorpuscleofordinaryformturninsuchawayastobeseenonedge,whenitsappearancewassuggestiveofthesepecu-liarforms.Thewhitecorpusclesweremadeupofpolymorphonuclearneutrophils72percent.,smallmononuclearlymphocytes15percent.,largemononuclearforms7percent.,polymorphonucleareosinophils5percent.,myelocytes(?)1percent.Manypolymorphonuclearcellsandsomemononuclearformscontainedbasophilicgranules(Neusser'sperinuclearbasophils[?]).Inoverheatedspecimensespecially,a 182MedicalClassics:Herrick'saccountofsicklecellsnumberofcellswithshadowyoutlinesandstainingbutslightlywereseen.Theseresembledwhitecells.STOOLSThestoolswereexaminednotonlyasamatterofroutine,butbecauseofthepos-sibilityofdetectingthepresenceofsomeparasitethatmightexplaintheeosinophil-ia,leukocytosisandanemia,apossibilitynotatallunlikelyinonecomingfromthetropicsandwhohadlivedwhereground-itchwasacommonoccurrence.Manystoolswerethoroughlystudied.Considerablemucuswasfoundinsomeofthestoolspassedsoonafteradmission,andsomeofthemucuswasblood-stained.Nobloodwasfoundintheinteriorofthefecalmasses.Ontwooccasionsprecedingthegivingofthethymol,abodywasfoundresemblingalmosttypicallytheeggofAnkylostomaduodenale.Portionsofthestoolswereincubated,butnoembryosweretobemadeout.Thymolwasgiven,butneithereggsnorembryoscouldbefoundinthestools,followingitsadminis-tration.TREATMENTANDCOURSEOFDISEASEUndertreatment,consistingofrest,nourishingfoodandsyrupoftheiodidofiron,thefeverandralesdisappeared,theglandsbecamesmaller,thebloodimprovedinqualityandthepatientleftthehospitalafterafour-weeks'stay,declaringthathefeltwell.Thepossibletherapeuticinfluenceofthethymolmustalsonotbeoverlooked.Thebloodatthistimeshowed3,900,000redcorpuscles,15,000white,58percent.hemoglobin.Therewasstilltobeseenatendencytothepeculiarcres-cent-shapeintheredcorpusclesthoughthiswasbynomeanssonoticeableasbefore.Nucleatedredswerepresent,thoughinsmallernumbers.Eosinophilswerefoundasbefore,makingupabout5petcent.ofthetotalnumberofleukocytes.Wewereatalosstoaccountforthispeculiarcomplexusofsymptoms,acondi-tionevidentlychronicasrevealedbythehistoryofthepastthreeyears,withyawsandsuppuratingotitisaspredecessors,yetwithacuteexacerbations,aconditionnotclearlyexplainedonthebasisofanorgan-iclesioninanyoneorgan,yetshowingcardiacenlargement,albuminuriaandcylindruria,generaladenopathy,icterus,withasecondaryanemianotremarkableforthegreatreductioninredcorpusclesorhemoglobin,butstrikinglyatypicalinthelargenumberofnucleatedredcorpusclesofthenormoblastictypeandintheten-dencyoftheerythrocytestoassumeaslen-dersickle-likeshape.Theleukocytosiswitharatherhigheosinophilcountwasalsotobenoted.Anattemptwasmadetokeeptrackofthepatient,andwhilehewasneverafter-wardundermyprofessionalcarehewastwiceseenbymyselfandseveraltimesbyDr.E.E.Irons,whosenotesandblood-examinationsareheregiven:January,1906:Patientinahospitalforafewdayswithbronchitis.Rapidrecovery.March7,1906:Patientinbedwithfever,bronchitis;feelsweak,Nodiarrhea.Redbloodcorpuscles2,700,000,whites30,500;hemoglobin55percent.Bloodshowsmanyelongatederythrocytes,afewmicrocytes.Theelongatedandspindle-formsseemedtostainmoredarklythanthenormalroundredcor-puscles.Noparasiteswereseen.Thediffer-entialcountofthewhitecellsshowedpolynuclearneutrophils58,largemononu-clear12,smallmononuclear22,eosinophils7,myelocytes1.Therewere2,279nor-moblaststothecubicmillimeter.AcountonMarch14,1906,showedanincreaseinthereds,alesseningofthewhites,butwasinotherrespectspracticallythesame.Thestoolwasnormalinappearance,formed,yellowishbrown,andnobloodoreggswerefound.Theurinewasacid,clean,withnobloodorabnormalpigment.Therewasatrace MedicalClassics:Herrick'saccountofsicklecells183ofalbumin,andseveralgranularandhyalinecastswerefound.InMay,1906,thepatientwasseenbyDr.Irons,whofoundhimwithsomefluidintheleftknee-joint;thetemperaturewas100.Gonorrheawasdenied.Thepatientascribedthejointtroubletoawrenchofthekneeafewdaysbefore.Herecoveredaftertendaysofrestinbed.InApril,1907,theyoungmanreport-edthatbehadbeenlaidupinahospitalfromDec.26,1906,toFeb.26,1907,withwhathecalledmuscularrheumatism.Hisillnesshadbegunwithmalaise,painintheback,themusclesofthelegsandarms.Hehadhadaslightfeverandwaspale.Afewdaysbeforethisillnesshehadsufferedfromoneofhis"bilious"attacks,inwhichhehadhadquitesevereepigastricpain,hadvomitedandhadlaternoticedthattheurinewasdarkandthatthescelerewereyellowish,thoughhewasinclinedtothinktheicterichuehadbeenpresentbeforetheonsetofthepain.Hewasstill,hesaid,somewhatshortofbreath,butinotherrespectsfeltquitewell.SincethenIhaveneverseenorheardfromhim.COMMENTNoconclusionscanbedrawnfromthiscase.Notevenadefinitediagnosiscanbemade.Syphilisissuggestedbymanyofthefacts,suchasadenopathyandthecon-ditionoftheheartandkidneys;itmightexplaintheanemia,thearthritisandper-hapsalsothetemperature,coughandattacksofpainresemblinghepaticorgall-bladderdisease,forasiswellknown,vis-ceralsyphilismayfurnishamostbizarregroupofsymptoms.TheWassermanntestwasnotinuseatthistime.ThescarssaidL,-v:...................................~~~~...............I~~~~~I...X...........Figure1.Thesephotomicrographsshowthepeculiarelongatedformsoftheredcor-puscles.Occasionalshadowformsareseenwithafewnucleatedreds.Thevariationsinshapeandsizearebestmadeoutinthelow-powerfigure.Therelativelynumberofwhitecorpusclesandofnormoblastsisnotshownbytheseparticularfigures. 184MedicalClassics:Herrick'saccountofsicklecellstohavebeenduetoyawswerelikethoseleftbysyphilis.Thepatientcomingfromthetropics,onethoughtofintestinalparasitessuchasuncinariaasapossibleexplanationoftheanemiaandtheeosinophilia.Whatwerethoughttobeeggswerefoundononeoccasiononly,andafterthymoltherewastemporaryimprovement.Theoddbloodpicturemadeoneexamineforpossibletoxiceffectsofthecoal-tarpreparations,butneitherfromthehistorynorfromtheexaminationoftheurinewasthereanyevidencethatsuchdrugswerehabituallytaken.Wewereatthistimeparticularlyinterestedinthesub-jectofchronicacetanilidintoxicationaswellasinuncinariasis,havingjusthadacaseofeachoftheseinterestingconditionsunderobservation,sothatwewereonthelookoutforsuchout-of-the-waydiseases.Thequestionofdiagnosismustremainanopenoneunlessreportsofothersimilarcaseswiththesamepeculiarblood-pictureshallclearupthisfeature.Schleip,inhis"Atlas,"picturesfreshunstainedpreparationsofredblood-cor-pusclesmadebyhismethodofdilutingtheblood1to10withphysiologicsaltsolu-tionandexaminingwiththeaidofthehangingdropchamber.Someofthecor-pusclesremindonealittleoftheseformsIhavedescribed.Yettheyarenotexactlythesame.ProfessorHektoenshowedmeaspec-imenthathehadencounteredinthecourseofsomeofhishematologicwork,whichmostnearlyresemblestheseforms.Thispreparationwasoneinwhichwashedhumancorpusclesweresuspendedinaone-eighth-normalsolutionofcane-sugar.ButneitherDr.HektoennorIhavebeenabletoreproducetheexactpictureagain,thoughusingcanesugarsolutionofthesamestrength.This,whilesuggestingthatthechemicalcompositionofthefluidsus-pendingthecorpusclesmayhavesome-thingtodowiththesepeculiarformations,perhapssuggestsmorestronglythatsomeunrecognizedchangeinthecompositionofthecorpuscleitselfmaybethedeter-miningfactor.Reprintedfrom:Arch.Int.Med.5:517,1910.