Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
w w w . r b h h . o r g
Case
report
Hemophagocytic
lymphohistiocytosis:
a
case
series
of
a
Brazilian
institution
Daniela
Guimarães
Rocha
Ferreira,
Paulo
do
Val
Rezende,
Mitiko
Murao,
Marcos
Borato
Viana,
Benigna
Maria
de
Oliveira
∗UniversidadeFederaldeMinasGerais(UFMG),BeloHorizonte,MG,Brazil
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t
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c
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e
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n
f
o
Articlehistory:
Received4October2013 Accepted27January2014 Availableonline17July2014
Keywords:
Hemophagocytic lymphohistiocytosis Visceralleishmaniasis Therapeutics
Bonemarrowtransplantation
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b
s
t
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c
t
Objective:To describe the clinical and laboratory presentation of hemophagocytic lymphohistiocytosisinchildrentreatedatareferralinstitution.
Methods:Aretrospectivedescriptivestudywascarriedoutofsevenchildrendiagnosedwith hemophagocytic lymphohistiocytosisbetween2010and2012.The criteriafordiagnosis werethoseproposedbytheHistiocyteSociety.Whenindicated,immunochemotherapywas prescribedaccordingtotheHLH94andHLH2004protocolsoftheHistiocyteSociety.
Results:Thepatients’agesatdiagnosisrangedfromonemonthtonineyears.Allpatients hadsplenomegaly,fever,anemia,thrombocytopenia,hyperferritinemiaand hypertriglyc-eridemia. Bone marrow hemophagocytosis was detected in six patients. In six cases, infectiousdiseasestriggeredthesyndrome.Intwocases,associatedwithvisceral leishman-iasis,remissionwasachievedaftertreatmentoftheunderlyinginfection.Threepatients, who had Epstein–Barr-relatedhemophagocytic lymphohistiocytosis,required treatment with immunochemotherapy. They are alive and in remission; one patient had symp-tomsofjuvenilerheumatoidarthritisandanother,whowassuspectedofhavingprimary hemophagocyticlymphohistiocytosis,enteredintoremissionafterbonemarrow transplan-tation.Twodeaths(28.6%)occurredinpatientswithsuspectedprimaryhemophagocytic lymphohistiocytosis;onewhoseclinicalpicturewastriggeredbycytomegalovirusinfection didnotrespondtoimmunochemotherapyandtheotherdiedbeforeanyspecifictreatment wasprovided.
Conclusion: Asreportedbefore, hemophagocyticlymphohistiocytosis hasa multifaceted presentationwithnonspecificsignsandsymptoms.Insecondaryforms,remissionmay beachievedbytreatingtheunderlyingdisease.Intheprimaryforms,remissionmaybe achievedwithimmunochemotherapy,butbonemarrowtransplantationisrequiredforcure. ©2014Associac¸ãoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.Published byElsevierEditoraLtda.Allrightsreserved.
∗ Correspondingauthorat:UniversidadeFederaldeMinasGerais(UFMG),Av.AlfredoBalena,190,sala267,Centro,30130-100Belo
Hori-zonte,MG,Brazil.
E-mailaddress:[email protected](B.M.deOliveira). http://dx.doi.org/10.1016/j.bjhh.2014.07.003
438
revbrashematolhemoter.2014;36(6):437–441Introduction
Hemophagocytic lymphohistiocytosis (HLH) is an immune hyperactivationsyndromecharacterizedbyclinicalsignsand symptomsofsevereuncontrolledinflammation.1
Diagnosis is based on combined clinical, laboratory, genetic,andmorphologicalcriteria.Accordingtothe Histio-cyteSociety,2 intheabsence offamilyhistoryorofspecific
genetictests,fiveoutofeightcriteriamustbepresentinorder toestablishadiagnosisandinitiatetreatment(Table1).
Common findings in HLH includepersistent fever, hep-atosplenomegaly, cytopenia,decreased activity ofcytotoxic T lymphocytes and natural killer cells (NK), as well as widespreadaccumulationoflymphocytesandmacrophages thatcarryouthemophagocytosis.3
HLHisincludedinthedifferentialdiagnosisofanumber ofdiseases commonly found in children, such as autoim-munediseases,primaryimmunodeficiencies,malignancies, andinfectiousdiseases.3
Therearetwomainforms,primaryorfamilialHLHand sec-ondaryHLH.SecondaryHLHcanbeassociatedwithinfections, autoimmunedisordersormalignancies.Despiteattemptsto differentiatebetweenprimaryandsecondaryformsofHLH, theirclinicalfeaturesareverysimilar.4,5
Remission may be achieved in primary HLH with immunochemotherapy and in cases of secondary HLH by treatingtheunderlyingdisease.6–8However,allpatientswith
thefamilialformofHLHrelapsedordieduntiltreatmentusing allogeneicbonemarrowtransplantation(BMT)startedtobe used.2,6
GivenitsrarityandthescarcityofdataintheBrazilian lit-erature,thisretrospectivestudywascarriedouttodescribe theclinical and laboratorypresentationofHLH inchildren followedattheHematologyServiceoftheHospitaldas Clini-cas,UniversidadeFederaldeMinasGerais(HC-UFMG)between January2010andJuly2012.
Table1–Criteriaforthediagnosisofhemophagocytic lymphohistiocytosis.
A.Moleculardiagnosiscompatiblewithhemophagocytic lymphohistiocytosis
OR
B.Atleastfiveoutoftheeightfollowingcriteria:
1.Fever 2.Splenomegaly
3.Cytopenias(twoormorelineages)
-Hemoglobin<9g/dLor<10g/dLinnewbornbabies -Platelets<100×109/L
-Neutrophils<1.0×109/L
4.Hypertriglyceridemia(>265mg/dL)orhypofibrinogenemia (<150mg/dL)
5.Hemophagocytosisinbonemarrow,spleen,lymphnodesor liverwithoutanyevidenceofmalignancy
6.Decreasedorabsentactivityofnaturalkillercells 7.Serumferritin>500g/L
8.IncreasedsolubleCD25(>2400U/mL)
ModifiedfromHenteretal.2
ThestudywasapprovedbytheInstitution’sResearchEthics Committee(protocolno.05683012.9.0000.5149),andpatients andguardianswereaskedtosigninformedconsentforms.
Case
report
Sevenchildrenwereincluded.Ageatdiagnosisrangedfrom onemonthtonineyears,withamedianof13 months.All patientspresentedwithsplenomegalyandfever.Other clin-icalmanifestationsareshowninTable2.Onlyonecase(#7) hadafamilyhistorysuggestingHLH.
Allchildrenhadanemia,thrombocytopenia, hypertriglyc-eridemia, and hyperferritinemia at the time of diagnosis. Hypofibrinogenemia was observed in six cases (85.7%). Hemophagocytosisfeatureswerevisibleinthebonemarrows ofsixpatients(85.7%)atdiagnosis(Table2).Lumbar punc-turewithcerebrospinalfluid(CSF)analysiswasperformedin twocases;bothhadpleocytosis.Cranialcomputed tomogra-phywasperformedinonepatient(#4)whichrevealeddiffuse corticalatrophy.
Theestimatedtimebetweentheonsetofsymptomsand HLHdiagnosisrangedfrom10to60days(medianof50days). Theinitialinvestigationshowedthatinsixcases(85.7%) theclinicalpicturewaspromptedbyinfectiousdiseases,two of which (33.3%)were secondary to visceralleishmaniasis, three(50%)afterinfectionswithEpstein–Barrvirus(EBV)and one(16.7%)triggeredbycytomegalovirus(Table2).
Fourcaseswereconsideredsecondaryforms:twohad vis-ceral leishmaniasis (#1and #3) andentered into remission aftertheinfectionwastreatedwithliposomalamphotericin BbutwithoutspecifictherapyforHLH.Theinitialclinical pic-tureofthepatientwithpositiveserology(IgM)forEBVwas severe; hereceived inductiontherapy followingthe HLH94 protocol,andenteredinto remissionaftereightweeks(#5). Thelastpatient(#6)hadapriordiagnosisofjuvenile rheuma-toidarthritisanddevelopedHLHsecondarytotheunderlying disease(macrophage activationsyndrome)triggeredbyEBV infection.Thechildreceivedinductiontherapyfollowingthe HLH2004 protocol and entered into remission after eight weeks.Thesecondaryformcasesarecurrentlybeingfollowed asoutpatientsandcontinueinremission.
Afteraretrospectivereview,theotherthreecaseswere con-sideredlikelytohavebeenprimaryformsofHLH.Datathat contributedtothissuspicionwere:ageatdiagnosis(allwere infants),noresponsetoimmunochemotherapy(intwocases), and inthe thirdcase,historyofsiblingsdyingwithsimilar clinicalpresentations.
Two patients(#2and#4)receivedimmunochemotherapy (Histiocyte Society HLH2004 and HLH94 protocols)2,7,8 and
failed to achieve remission after the induction and main-tenance phases.Thefirst patient(#2)underwent unrelated allogeneicbonemarrowtransplantationandrespondedwell. Heiscurrentlybeingfollowedintheoutpatientclinic.After aseven-monthfollow-up,thesecondpatient(#4)diedfrom severesepsisofapulmonaryfocuswithactivedisease.
bras
hema
tol
hemoter.
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0
1
4;
3
6(6)
:437–441
439
# Gender Ageat
diagnosis
Enlarged lymphnodes
Cutaneous rash
Jaundice Fibrinogen (mg/dL)
Hemophagocytosis inbonemarrow
Spinalfluid exam
Infectionsand associateddiseases
Typeof immunochemother-apy/presentclinical
status
1 F 5months No No Yes 89 No ND Visceralleishmaniasis ND/Aliveinremission
2 M 13months No No No >400 Yes Pleocytosis Epstein–Barrvirus HLH2004/Bonemarrow
transplantationinJuly2012; aliveinremission
3 M 5months No No No 97 Yes ND Visceralleishmaniasis ND/Aliveinremission
4 M 16months Yes Yes Yes 131 Yes ND Cytomegalovirus HLH1994/Noremission.
Deathaftersepsis
5 M 3years Yes No Yes 59 Yes ND Epstein–Barrvirus HLH1994/Aliveinremission
6 F 9years No Yes Yes 94 Yes Pleocytosis Epstein–Barr
virus/Juvenile RheumatoidArthritis
HLH2004/Aliveinremission
7 M 1month No No No 35 Yes ND Noneproven ND/Deathafter48hfrom
hospitaladmission
440
revbrashematolhemoter.2014;36(6):437–441tostartspecifictreatment.Resultsfromtheautopsysuggested HLH.
Mortalityamongpatientsinthestudywas28.6%(2/7)and bothdeathsoccurredinpatientssuspectedofhavingprimary HLH.
Discussion
HLH hasmultifacetedpresentationswith nonspecificsigns andsymptomsthatarefoundinotherclinicalconditions.In thepresentstudythemostfrequentclinicalandlaboratory findingsatdiagnosiswereprolongedfever,splenomegaly,and cytopenias,particularlyanemiaandthrombocytopenia,ashas alreadybeendescribedintheliterature.3
Hemophagocytosis,thephenomenonthatlendsitsname tothenosological entity,isnotaprerequisiteforthe clini-caldiagnosis ofHLH.6Thisphenomenonwasobservableat
somepointduringthefollow-up inall butonecaseofthis series.Nevertheless,absenceofhemophagocytosisshouldnot delay the diagnosis whenthe initialclinical picture fulfills theothercriteria.3Thismorphologicalphenomenoncanalso
beinducedbyothereventssuchasbloodtransfusion, infec-tion,autoimmunediseases,andsometypesofbonemarrow failure.6
Despite the limited access to more complex laboratory tests,commontomanyinstitutionswheremoleculargenetic studiesandassessmentofNKcellactivityandsolubleCD256
are notavailable,HLH diagnosis was possibleinthe seven reportedcasesbecauseeachfulfilledatleastfiveoftheeight criteriadescribed bytheHistiocyteSociety.2 Theabsenceof
molecular studies,however, prevented confirmation ofthe diagnosisofprimaryHLHcases,essentialforpredictingthe riskofrecurrenceandfordefiningdiseasepredispositionin asymptomaticfamilymembers.6
Inthiscaseseries,onlythreepatientsunderwent investiga-tionforchangesinthecentralnervoussystem(CNS).Intwo ofthesecases,theCSFwasexamined,andpleocytosiswas detectedinboth,withatypicalcells presentinone. Neuro-logicalabnormalitiesareaprominentfeatureofthisdisease. CNSinvolvementcancausesevereandirreversibledamage. Itisrecommendedthatallpatientsshouldbesubmittedto neurologicalevaluations withlumbar puncture evenwhen asymptomatic.6,9
FamilialHLHisconsideredanautosomalrecessivegenetic disorderwithanestimatedprevalenceof1/50,000livebirths. Approximately 70–80% of patients with familial HLH have symptomsinthefirstyearoflife.3Althoughcaseswith
docu-mentedgeneticdefectsare,bydefinition,primary,infectious processesappearasthetriggerinthemajorityofthese chil-dren.Becauseitisarecessivedisorder,negativefamilyhistory iscommonandresultsinsuchcasesarewronglydefinedas secondary,especiallywheninitialtreatmentinduces satisfac-toryclinicalremission.5Thus,theuseofthetermsprimary
andsecondaryHLHisnotideal.
Inthepresentstudy,patientswithsuspectedfamilialHLH manifestedsymptomswithinthefirsttwoyearsoflife.Intwo cases,arelatedinfectiousdiseasewasidentified.Thepatient whosediagnosiswasestablishedinthesecondmonthoflife wasthe mostseverecaseand rapidlyprogressedtodeath.
Asdescribedintheliterature,theyoungerthepatientisat diagnosis,thegreatertheseverityofthepresentation.2,6,8
Sixcaseswere relatedtoinfections,which alsoconcurs withdescriptionsinseveralreviewsonthetopic.2,4,6,7
Accord-ing to theHistiocyte Society study HLH94and many other studies,the mostcommon infectioustrigger istheEBV; in thesecases,theinitialclinicalpictureistypicallysevere.6,7,10
However,therearereportsthatclinicalpresentationofHLH secondarytoEBVinfectionisveryvariable,rangingfrom spon-taneously resolved inflammationtoextremelyseverecases that require immunochemotherapy10 followed bystem cell
transplantation.2Amongthepatientsinthissamplewhohad
EBV-relatedHLH,allhadverysevereinitialclinical presenta-tionsandrequiredimmunochemotherapytocontrolsignsand symptoms.
Inthisseries,twocaseswereassociatedwithvisceral leish-maniasis.BothachievedHLHremissionaftertheunderlying infection wastreatedandrequirednoanti-inflammatoryor cytotoxictherapies,alsoinagreementwiththeliterature.Itis importanttonote,however,thatwithouttreatingthe under-lyinginfection,themortalityrateisveryhigh.3
Macrophageactivationsyndromeoccurredinonepatient previouslydiagnosedwithjuvenilerheumatoidarthritis,the autoimmune diseasemostcommonlyassociatedwithHLH. Thepatientinitiallypresentedwithseverehepatitisand coag-ulopathy, very common findings in this specific group of patients.3
TheimmediategoaloftreatmentofpatientswithHLHis tosuppressthehyperinflammation,responsibleforthe symp-tomsthatputthepatient’slifeatrisk.Thus,chemotherapeutic and/or immunosuppressive agents such as corticosteroids, cyclosporin,andimmunoglobulinareused.InfamilialHLH, theultimategoalshouldbestemcelltransplantationto substi-tutethedefectiveimmunesystemwithproperlyfunctioning effectorcells.Withouttreatment,uncontrolled hyperinflam-mation leads to persistent neutropenia and death from repeated fungal and bacterial infections or multiple organ failure.4,8
A retrospective reviewofthis series revealed that com-plete response after immunochemotherapeutic treatment wasachievedonlyinpatientswithadiagnosisofsecondary HLH.Althougheffectiveinprolongingthesurvivalofpatients with familial HLH,it is known that immunochemotherapy alonecannotcurethisformofthedisease.6
Themortalityrateinourstudywas28.6%,lowerthanthe deathratedescribedbytheHistiocyteSociety,whichisaround
50%.2,6,7Thenumberofcasesinourseries,however,isvery
small.Ifweconsiderthatalldeathsoccurredinpatientswith primaryHLHandofthose,onlytheonewhounderwentBMT isalive,thedatafromthisstudyisinagreementwiththe lit-erature,whichgivesa100%mortalityrateforpatientswith primaryHLHwhoarenotsubmittedtoBMT.3,6,10
counseling.Weshouldemphasizethe needforprospective andcooperativestudiesinordertoenhanceunderstanding aboutHLHinBrazil,soastoimproveitsclinicalmanagement.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
Acknowledgements
Theauthors wishtothankMárciaKanadaniCampos,M.D., andGustavoMachadoTeixeira,M.D.,oftheUFMGUniversity Hospital,fortheirclinicalhelpinthisstudy.
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