JPediatr(RioJ).2016;92(5):539---541
www.jped.com.br
LETTERS
TO
THE
EDITOR
Atypical
manifestations
of
Epstein-Barr
virus:
red
alert
for
primary
immunodeficiencies
夽Manifestac
¸ões
atípicas
do
vírus
de
Epstein-Barr:
alerta
vermelho
para
imunodeficiências
primárias
DearEditor,
The Jornal de Pediatria has published an elegant review paper entitled ‘‘Atypical manifestations of Epstein-Barr virus in children: a diagnostic challenge’’.1 The authors
performed a literature review includingthe last 30 years of publicationsonatypical manifestationsassociatedwith an Epstein-Barr virus (EBV) infection. However, I would like to complement their review by providing a partic-ularly important point of view related to atypical EBV infections.
EBV is a gamma-1 herpes virus restricted to primate hosts, characterized by its persistence in the B-lymphoid system, and its capacity to stimulate B-cells growth by coordinatingtheexpressionoflatentcyclegenes.2Most
EBV-infectedindividualsareasymptomaticorpresentinfectious mononucleosissyndrome with a benign course, especially teenagers and young adults.2,3 In its normal course, EBV
infects B-cells and the immune system controls the virus using a complex mechanism that involves NK, iNKT, CD4, andCD8cells.GeneticalterationsleadingtofunctionalNK orT-cellimpairmentmayleadtoafailureintheEBVcontrol mechanisms.3
Primary immunodeficiencies (PIDs) are a group of dif-ferentdiseases thatcausealterations in thedevelopment and/or function of the immune system, leading to an increased susceptibility to infections and, in some cases, increased incidence of autoimmune diseases and malig-nancies. Most PID cases are genetic diseases that follow
DOIoforiginalarticle:
http://dx.doi.org/10.1016/j.jped.2015.06.007 夽
Pleasecitethisarticleas:SegundoGR.Atypicalmanifestations ofEpstein-Barrvirus:redalertforprimaryimmunodeficiencies.J Pediatr(RioJ).2016;92:539---40.
simpleMendelianpatternsofinheritance,whileafew oth-ers are considered as complex disorders.4,5 The advance
inthe genetic approaches in the lastyears hasincreased the pace at which causative genes for PIDs are being discovered.5
Recently,PalendiraandRickson,inaeducationaland sim-plemethod,dividedPIDpatientsintogroupstoexplainthe susceptibilitytoEBVinfections:(1)PIDsthatareselectively susceptibletoEBV;(2)PIDswithbroadervirussusceptibility, butfrequentEBVdisease;(3)PIDsgenerallysusceptibleto viralandnonviralinfections;and(4)PIDswithaninherent susceptibilitytolymphoma.2
Group 1 includes the X-linked lymphoproliferative dis-easestype1,causedbySH2D1Agenemutations,andtype 2,associatedwithXIAP genemutations.In both diseases, patients could present severe infectious mononucleosis; and acute disease could result in a cytokine storm that causes macrophage activation and hemophagocytic lym-phohistiocytosis(HLH).2,4Inanotherreview,authorsadded
three different PIDs to this group, including mutations in the genes PRF1 (perforin deficiency, autosomal reces-sive(AR)),STXBP2(munc18-2deficiency, AR),andUNC13D (munc13-4deficiency, AR),which arealsoassociated with
HLH and the development of chronic and severe EBV
disease.6
Group2containsPIDscausedbymutationsingenesCD27 (CD27deficiency, AR),MAGT1 (XMENsyndrome,X-linked), ITK (ITK deficiency, AR), CORO1A (coronin-1A deficiency, AR),FCGR3 (CD16 deficiency, AR),and MCM4 (MCM4 defi-ciency,AR).2Thediseasesinthisgroupshowedanincreased
susceptibilitynotonlytoEBV,butalsotootherherpesvirus familyand,insomecases,toHPV.4
Group 3 has complex PIDs with different predisposi-tionsto severalmicroorganisms,including EBVinfections. ThePIDs included in thisgroupare resultofmutations in genesPIK3CD (Activated PI3-kinasedelta syndrome, auto-somaldominant(AD)), STK4 (MST1deficiency, AR),ZAP70 (Zap-70 deficiency, AR), CTPS1 (CTPS1 deficiency, AR), CARD11 (CARD11 deficiency, AR), LRBA (LRBA deficiency, AR),GATA2(monoMACsyndromeorGATA2deficiency,AD), LYST (Chediak-Higashi syndrome, AR), and hypomorphic mutationsinARTEMISandDNAligaseIV,bothassociatedwith Omennsyndrome.2,4,6
ThePIDsingroup4presentdifferentdegreesofimmune systemdeficiency,whicharealsoassociatedwithincreased
540 LETTERSTOTHEEDITOR
cancer incidence and the involvement of EBVin some of these tumors, especially lymphomas. This group includes PIDs with mutations in genes WAS (Wiskott---Aldrich syn-drome,X-linked),ATM(Ataxiatelangiectasiasyndrome,AR), andTNFRSF6(ALPS-FAS,ADandAR).2,4,6
ThemessageforallpediatriciansistoconsiderEBVasa causativeagentinclinicalpicturessimilartothosedescribed byBolisetal.Inadditiontotheimmunesystemimpairment associatedwithtreatmentforseveraldiseases,wemustalso considerthesesituationsasaredalertforprimary immuno-deficienciesinpediatricpatients.RecognizingPIDsmaybe essentialtoachieveabettermanagementforpatientswith atypicalEBVinfections.
Funding
C.H.I.L.D.R.E.N. initiative for primary immunodeficiency
researchoftheJeffreyModellFoundation;Postdoctoral
Fel-low abroad through Coordenac¸ão de Aperfeic¸oamentode
Pessoal deNível Superior ---CAPES (Higher Education
Per-sonnelImprovementCoordination).
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
References
1.BolisV,Karadedos C,Chiotis I,ChaliasosN,TsabouriS. Atypi-calmanifestationsofEpstein-Barrvirusinchildren:adiagnostic challenge.JPediatr(RioJ).2016;92:113---21.
2.Palendira U, Rickinson AB. Primary immunodeficiencies and thecontrol ofEpstein-Barr virus infection. Ann NY Acad Sci. 2015;1356:22---44.
3.MossDJ,LutzkyVP.EBV-specificimmuneresponse:earlyresearch and personal reminiscences. Curr Top Microbiol Immunol. 2015;390:23---42.
4.PicardC,Al-HerzW, BousfihaA, CasanovaJL,Chatila T, Con-leyME,etal.Primaryimmunodeficiencydiseases:anupdateon theclassificationfromtheInternationalUnionofImmunological SocietiesExpertCommitteeforPrimaryImmunodeficiency2015. JClinImmunol.2015;35:696---726.
5.Fodil N, Langlais D, Gros P. Primary immunodeficiencies and inflammatory disease: a growing genetic intersection. Trends Immunol.2016;37:126---40.
6.CohenJI.PrimaryimmunodeficienciesassociatedwithEBV dis-ease.CurrTopMicrobiolImmunol.2015;390:241---65.
GesmarR.S.Segundo
UniversidadeFederaldeUberlândia(UFU),Departamento dePediatria,Uberlândia,MG,Brazil
E-mail:gesmar@famed.ufu.br
http://dx.doi.org/10.1016/j.jped.2016.05.002
Authors’
reply:
Atypical
manifestations
of
Epstein---Barr
virus:
red
alert
for
primary
immunodeficiencies
夽Resposta
dos
autores:
manifestac
¸ões
atípicas
do
vírus
de
Epstein-Barr:
alerta
vermelho
para
imunodeficiências
primárias
DearEditor,
Humanprimaryimmunodeficiencydisease(PID) isa
condi-tion where mutations in single immune system genes
predispose individuals to certain infectious agents. The human herpesviruses are a challenge of immune compe-tence, since most of these agents are widespread in the population; they are often acquired silently or with mild symptomsinchildhoodandthencarriedforlifeas asymp-tomaticlatentinfections.PIDpatientsarethereforelikely tobeexposed totheseviruses relativelyearly in lifeand will have to deal with them both as a primary infection
DOIofreferstoarticle:
http://dx.doi.org/10.1016/j.jped.2016.05.002
夽 Please cite this article as: Bolis V, Karadedos C, Chiotis I,
Chaliasos N, Tsabouri S. Authors’ reply: Atypical manifestations ofEpstein---Barrvirus:redalertforprimaryimmunodeficiencies.J Pediatr(RioJ).2016;92:540---1.
and as a persistent condition.1 For individuals who are
immunocompromised,duetoageneticimmunodeficiencyor immunosuppressivedrugtherapy,viralinfectionsmayresult inseverecomplicationsandevenlife-threateningdisease.2
PID is considered a rare disease, with an overall inci-denceof4.6casesofPIDsper100,000person-yearsinthe last35years.3However,neitherthetrueincidencenorthe
true prevalence of PID are known. Although there have been estimates of these parameters from geographically limitedstudies, thoseestimates werebasedonly on diag-nosedcases.Therefore,PIDmaybefarmorecommonthan previouslyestimated.Surveyssuggestprevalenceratesfor diagnosedPIDas1:2000forchildren,1:1200forallpersons, and1:600households.4
Specificgenemutations inPID patients areresponsible forsusceptibilitytoEpstein---Barrvirus(EBV)infections,as highlightedinthelettertotheeditoroftheJornalde Pedia-triaentitled‘‘AtypicalmanifestationsofEpstein---Barrvirus: red alert for primary immunodeficiencies’’. Although PID and atypical complications of EBV infection are not very common, pediatriciansshould indeed correlate thesetwo conditions asmentioned in the previous letter, sinceEBV infectsmorethan95%oftheadultpopulationworldwide.5
PID incidence has increased in the last decades,3 and
patients with immunodeficiency are the group most
exposed to atypical complications of EBV among healthy people.
