Hyperreactive malarious splenomegaly and aids: a case report

braz j infect dis.2014;18(5):565–567

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

Case

report

Hyperreactive

malarious

splenomegaly

and

aids:

a

case

report

Zuleica

Naomi

Tano

_,

_Chafic

_Esper

_Kallas

_Filho

_,

_Regina

_Mitsuka

_Breganó

_,

Wander

Rogério

Pavanelli

_,

_Uheyna

_Gancedo

_Ruzon

a_{DepartamentodeClínicaMédica,UniversidadeEstadualdeLondrina,Londrina,PR,Brazil}

b_{UniversidadeEstadualdeLondrina,Londrina,PR,Brazil}

c_{DepartamentodeCiênciasPatologicas,UniversidadeEstadualdeLondrina,Londrina,PR,Brazil}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received21March2014 Accepted21April2014 Availableonline6June2014

Keywords:

Hyperreactivemalarious splenomegaly

Aids

a

b

s

t

r

a

c

t

MalariaisendemicintheNorthofBrazil.However,HyperreactiveMalariousSplenomegaly (HMS)hasbeenrarelydescribed.SplenomegalyinHIV/Aidsinfectionhasalargedifferential diagnosis,butmalariaisacauseofgrosssplenomegaly,regardlessoftheHIVstatus.Inthis paper,wereportthecaseofa50-year-oldman,HIVpositive,withmassivesplenomegaly andmultiplemalariainfectionsinthepast.HefulfilledthecriteriaforHMS,receivedashort courseofanti-malarialtreatmentandweeklyquimioprofilaticChloroquine.In9months, hehadgreatclinicalandlaboratorialimprovementconfirmingtheHMS,ararediagnosisin Brazil.

©2014ElsevierEditoraLtda.Allrightsreserved.

Introduction

Hyperreactivemalarioussplenomegaly(HMS),knownas Trop-ical Splenomegaly Syndrome,1 _{despite being common in}

malaria-endemicregionsandintravelersfromnon-endemic areas,2 _{haslowprevalenceinBrazil.}3_{TheHMSispresented}

asanexaggeratedimmuneresponsetoinfectionby

Plasmo-dium,resultinginnonspecific,hyper-immunoglobulinM(IgM)

polyclonal immunoglobulin production by B lymphocytes, andtheformationofimmunecomplexesthataredeposited in the spleen. The criteria for the diagnosis of HMS are: splenomegaly(>10cmbelowtheleftcostalmargin),increased IgM that exceeds twice the reference value, high titers of

∗ _{Correspondingauthor.}

E-mailaddresses:zntanno@terra.com.br,naomi.tano@gmail.com(Z.N.Tano).

antibodies specific against Plasmodium sp. and clinical-laboratory improvementafter treatmentwith anti-malarial drugs.4,5 _{Theassociation with HIVinfection ispoorly}

doc-umented, although HIV and malaria are endemicin many tropicalregions.

Case

report

A50-year-old manwasadmittedtotheinfectious diseases sectorofUHL(UniversityHospitalofLondrina,Brazil)in Febru-ary2012.Onadmission,hecomplainedofprogressiveweight loss, asthenia, and abdominal discomfortfor two months, associatedwithfeverforthreedays.

http://dx.doi.org/10.1016/j.bjid.2014.04.005

566

Physicalexaminationshoweddiscretehepatomegalyand significant splenomegaly,about 20cm belowthe left costal margin. He reported having lived in the cities of Lon-drina/PR and Itaituba/PA, where he worked in mining for about seven months a year. He had a previous his-tory of 20 episodes of malaria, and had been diagnosed with HIV in the past two years, with irregular use of antiretroviraltherapy.Laboratorytestsonadmissionshowed: Hb=5.6g/dL, platelets=61,000/mm3_{; leukocytes=4300/mm}3

(67%neutrophils),proteinelectrophoresiswith hypergamma-globulinemia=51%;albumin=2.5g/dL;IgM=1790mg/dL(NR: 57-212),CD4=115/mm3_{andviralload=2352copies/mL.}

Anti-body(indirectimmunofluorescence)anti-plasmodiumvivax was 1/1280 and anti-plasmodium falciparum=1/320. The directmethodforPlasmodiumsp.thick smearwasnegative, aswellaspolymerasechainreaction(PCR).Onadmission,the firstdiagnostichypothesiswassepsisafterurinarytract infec-tion.OnceE.colibacteriawereisolatedfrombloodandurine, thetreatmentwithCiprofloxacinhadgoodresponse,butthe urinaryinfectioncouldnotexplainthesplenomegaly.

MieloculturewasperformedandfungiandLeishmaniain twosamplesweresearched,bothturnedoutnegative,ruling outhistoplasmosisandvisceralleishmaniasis.Inoculationin micebonemarrowblood resultednegativeforLeishmania. Parasiticalexamswerenegativeinfeces.

On admission, serology for toxoplasmosis and cytomegalovirus had positive IgM for both microorgan-isms,whichultimatelyprovedtobefalse-positive.Likewise, anti-HCVwaspositiveatlowtiters,withnegativePCRforHCV. Abdominaltomographyshoweda3700mLspleenat admis-sionand 9monthsafterinitiation oftreatment,it reduced to 1358mL (64% reduction), demonstrating homogeneous parenchymal liver and spleenwithout portal hypertension

(Figs.1and2).

HavingdefinedthediagnosisofHMSthefirstcyclewith pri-maquineandchloroquinewascarriedoutfor7days,followed

Fig.1–CTabdomenatadmission.

Fig.2–CTabdomenninemonthsafterchloroquineuse.

Table1–Laboratorytests.

Admission 1month 9month

Hb(g/dL) 5.6 10.2 13.7 Platelets/mL 56,000 100,000 99,000 Leukocytes(␮/L) 4300 3500 5800 IgM(mg/dL) 1790 – 473 Proteinelectrophoresis (Hypergamma%) 51 35.8 30 Albumin(g/dL) 2.5 4.5 4.68 Spleenvolume CTabdomen(vol/mL) 3700 – 1358

bychloroquine300mg/week.Follow-upexamsinthefirstand ninthmonthareshowninTable1.

Discussion

and

conclusion

ThedevelopmentofHMSisassociatedwithtwomainfactors: repeated exposure to Plasmodium species and genetic pre-disposition.Countrieswithhighendemismformalariahave prevalenceofHMSrangingfrom1to2%inNigeriaand80%in certaintribesofNewPapuaGuinea.2_{InBrazil,theprevalence}

islowintheAmazonregion.3_Alecrim6_{examinedapopulation}

of890peoplelivinginahyper-endemicareaofManaus,and foundonly10peoplewithapersistentspleenenlargement.Of these,fourmetthecriteriaforTropicalSplenomegaly,asitwas knownatthetime,threeofthemwerebrothers,underscoring theimportanceofgeneticpredispositionintribalHMS.

The main genetic factors related to high population prevalence of HMS were HLA-DR2 and high levels of HLA heterozygous,4,7_{inadditiontothehighfrequencyofthe}

hap-lotypeIGHG3.8

Itis believedthat patients withHMS haveahyper pro-ductionofpolyclonalIgM,1 _{whichislinkedtosuppressorT}

lymphocytes(cytotoxicphenotype),causingtheelimination oftheparasite,aswellasgeneratingimmunecomplexesthat aredepositedinthespleen,thusresultinginsplenomegaly.

In this case, the overproduction of nonspecific poly-clonal IgM explains the false positive results for both

brazj infect dis.2014;18(5):565–567

567

Table2–Diagnosticfeatureofhyperreactivemalarious splenomegaly(HMS)–Fakunlecriteria.

Majorcriteria Minorcriteria

Splenomegaly>10cm Hepaticsinusoidal lymphocytosis IgM>2SDoflocalmean Hypersplenism Hightitersofantimalarial

antibodies

Lymphocyticproliferation Clinicalandimmunological

responsetoantimalarialdrug

Normalcellularandhumoral immuneresponsetoantigenic challengeexcluding

Plasmodium

Occurrencewithinfamiliesand tribes

cytomegalovirusandtoxoplasmosis,inadditiontohightiters ofIgM(oneofthediagnosticcriteria).

Thediagnosisoftropicalsplenomegalysyndromerequires exclusionofothercausesofmassivesplenomegaly.However, definitediagnosis dependson specificcriteria, such asthe Fakunle4,5,9_{criteriashowninTable2.Thesecriteriaare not}

differentforHIVpatients.10_{Inthecasehereinreported,the}

patientmetallmajorcriteriainadditiontohypersplenismas aminorcriterion,thusconfirmingthediagnosis.

AlthoughHIV/AIDSandmalariacoexistwithhigh preva-lenceinmanycountriesofsub-SaharanAfrica,fewcaseshave beenpublished linkingthetwo diseases.10,11 _{Inindividuals}

withAIDSthereisaninversionintheCD4/CD8ratiodueto decreaseinnumberandfunctionofCD4Tlymphocytes,while inHMS thereis anincrease inthis ratio duetodecreased number ofCD8T lymphocytes. One hypothesis isthat this differencemaypreventpatientswithHIVfrommanifesting HMSafterrepeatedMalaria infections,explainingtherefore thelownumberofcasesassociatingthetwodiseases. How-ever,furtherstudiesshouldbecarriedouttobetteridentify theimmunologicalrelationshipbetweenthem.

HMStreatmentconsistsofashortcycleofanti-malarial drug,andtheuseofchemoprophylaxis(chloroquineinthis case) fora periodof 9–26months inpatients who remain exposedtomalaria,topreventnewinfectionsandtohavethe describedimmunomodulatoryeffectofchloroquine.12

Therefore, we must be alert to cases of massive splenomegalyinpatientslivinginendemicareasofmalaria inBrazil,orthosewhomigratedfromtheseregions. Further-more,HMSneedstobeconsideredasadifferentialdiagnosis inpatientswithsplenomegalyandAIDS.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

Acknowledgment

WewouldliketothankAndréMachadoSiqueirafrom Univer-sidadeEstadualdoAmazonas(AmazonasStateUniversity)for thesuportinmalariaPCR.

r

e

f

e

r

e

n

c

e

s

1.BrycesonA,FakunleYM,FlemingAF,etal.Malariaand

splenomegaly(letter).TransRSocTropMedHyg.1983;77:

879.

2.CraneGG.Recentstudiesofhyperreactivemalarious

splenomegaly(tropicalsplenomegalysyndrome)inPapua

NewGuinea.PNGMedJ.1986;29:35–40.

3.Doenc¸asInfecciosaseParasitárias:Enfoque

Amazônico/RaimundoNonatoQueirozdeLeão

{coordenador}.Belém:Cejup,UEPA,InstitutoEvandro

Chagas;1997.

4.FakunleYM.Tropicalsplenomegaly.ClinHematol.

1981;10:963–75.

5.BatesI,Bedu-AddoG.Reviewofdiagnosticcriteriaof

hyperreactivemalarialsplenomegaly.Lancet.1997;349:

1179.

6.Alecrim,WD.Estudoclínicoeepidemiológicodamaláriano RioItuxi-Amazonas.1979.115p.Tese(mestrado).

UniversidadedeBrasiília,Brasília.1979.

7.BhatiaKK,CraneGG.HLAheterozygosityandhyperreactive

malarioussplenomegalyintheUpperWatutValleyofNova

Guinéa.PNGMedJ.1989;32:277–86.

8.KellyKM.IGHG3Gandthepathogenesisofhyperreactive

malarioussplenomegaly.MedHypotheses.1996;46:135–9.

9.RanjanK,Singh.Hyperreactivemalarialsplenomegalyin

expatriates.TravelMedInfectDis.2007;5:24–9.

10.DeIacoG,SaleriN,PerandinF,etal.CaseReport.

Hyper-reactivemalarialsplenomegalyinapatientwith

humanimmunodeficiencyvirus.AmJTropMedHyg.

2008;78:239–40.

11.LowenthalMN,HorowitzJ,GasparN,etal.Hyperreactive

malarialsplenomegalyandAIDS:proguanilprevents

recurrentpneumonia.TransRSocTropMedHyg.

1996;90:313–4.

12.HoffmanSL,PiessensWF,RatiwayantoS,etal.Reductionof

suppressorTlymphocytesinthetropicalsplenomegaly