Chronic granulomatous disease associated with common variable

Pleasecitethisarticlein pressas:PachecoC,etal.Chronicgranulomatousdiseaseassociatedwithcommonvariable immunodeficiency---2clinicalcases.RevPortPneumol.2014.http://dx.doi.org/10.1016/j.rppneu.2013.09.005

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CASE

REPORT

Chronic

granulomatous

disease

associated

with

common

variable

immunodeficiency

---

2

clinical

cases

C.

Pacheco

,

A.

Morais

,

R.

Rolo

,

L.

Ferreira

,

R.

Nabic

¸o

,

J.

Cunha

a_{Servic¸odePneumologia,HospitaldeBraga,Braga,Portugal}

b_{Servic¸odePneumologia,CentroHospitalardeSãoJoão;FaculdadedeMedicinadaUniversidadedoPorto,Porto,Portugal} c_{Servic¸odeMedicinaInterna,HospitaldeBraga,Braga,Portugal}

Received13May2013;accepted9September2013

KEYWORDS Commonvariable immunodeficiency; Granulomas; Sarcoidosis; Granulomatous disease

Abstract

Introduction:Chronic granulomatousdisease associated with commonvariable immunodefi-ciency(GD-CVID),althoughwelldocumented,israre.Granulomatouslesionscanaffectseveral organsandarehistologicallyindistinguishablefromsarcoidosis.

Clinicalcases: Case 1: A 39-year-old male patient with CVID, asymptomatic although with thrombocytopeniaandmediastinal-hilaradenopathies.GD-CVIDwasdiagnosedbybonemarrow biopsy.Progressiveclinicalandradiologicalimprovementwasobtainedwithcorticotherapy.

Case2: A38-year-old malepatient withCVID,sufferedfromasthenia,anorexia,myalgia, lowerlimbsedemas,anddrycough.Hehadmediastinalandbilateralhilaradenopathieswithin whichbiopsyrevealednon-necrotizinggranulomatousinfiltrate.Aspontaneousresolutionwas detectedafter9monthsofevolution.

Conclusion: GD-CVIDisrareandcanmimetizeotherpathologies,namely,sarcoidosis;itshould thereforebepublicizedanddiscussedsothatitbecomesageneralclinicalknowledge. © 2013SociedadePortuguesa dePneumologia. Publishedby Elsevier España,S.L. Allrights reserved.

PALAVRAS-CHAVE Imunodeficiência comumvariável; Granulomas; Sarcoidose; Doenc¸a granulomatosa

Doenc¸agranulomatosacrónicaassociadacomaimunodeficiênciacomumvariável -2casosclínicos

Resumo

Introduc¸ão: Adoenc¸agranulomatosacrónicaassociadaàimunodeficiênciacomumvariável (DG-IDCV),apesar debemdocumentada,érara.Aslesõesgranulomatosaspodem afectarvários orgãosesãohistologicamenteindistinguíveisdaquelasquecaracterizamasarcoidose.

Casosclínicos:Caso1:Doentedosexomasculino,39anos,comdiagnósticodeimunodeficiência comumvariável,clinicamenteassintomático,comtrombocitopeniaeadenopatiaspré-traqueais ehilaresdenovo.OdiagnósticodeDG-IDCVfoi obtidoporbiópsiademedulaóssea. Iniciou tratamentocomcorticoterapiacommelhoriaclínicaeradiológicaprogressiva.

∗_{Correspondingauthor.}

E-mailaddress:ceciliafpacheco@gmail.com(C.Pacheco).

Pleasecite thisarticleinpressas: PachecoC,etal.Chronicgranulomatousdiseaseassociatedwithcommonvariable immunodeficiency---2clinicalcases.RevPortPneumol.2014.http://dx.doi.org/10.1016/j.rppneu.2013.09.005

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Caso2:Doentedosexomasculino,38anos,comdiagnósticodeimunodeficiênciacomum var-iável,comqueixasdeastenia,anorexia,mialgias,edemasdosmembrosinferioresetosseseca. Adenopatiasmediastínicasehilaresbilateraiscujabiopsiarevelouinfiltradogranulomatosonão necrotizante.Observou-seumaresoluc¸ãoespontâneaapósnovemesesdeevoluc¸ão.

Conclusão:A doenc¸agranulomatosacrónicaassociada aimunodeficiênciacomum variávelé rara.Dadoqueestaentidadepodemimetizaroutraspatologias,nomeadamenteasarcoidose, oscasosclínicosquesereferemàmesmadevemserpublicadosediscutidosparaconhecimento clínicogeral.

©2013SociedadePortuguesa dePneumologia.Publicado porElsevier España,S.L.Todosos direitosreservados.

Introduction

Commonvariableimmunodeficiency(CVID)isarareprimary immunodeficiency syndrome characterized by impaired B-cell differentiation with inaccurate immunoglobulin production.1 _{It is defined by markedly reduced serum}

concentrations of IgG, combined with low levels of IgA and/or IgM, poor or absent response to immunizations in a patient without any other signs of immunodeficiency. The prevalence in Europe is estimated to be around 1:50,000---1:200,000.2 _{The etiology is stillunknown,but it}

appearstoresultfromavarietyofgenedefects(e.g.,ICOS, TACI,BAFF-R,CD19,CD20,CD21,andCD81),mostofwhich aresporadicratherthanfamiliar.2---4

Although rare, systemicgranulomatous disease related to CVID is well documented (>50 case reports). Granulo-matousnon-caseous lesions can be detected in the lung, liver,spleen,gastrointestinaltract,lymphnodes,skinand eye in almost 10% of the patients with CVID.2,5 _Some

of them also show clinical manifestations similar to sar-coidosis, with symptoms like dyspnea, persistent cough, asthenia,anorexiaandarthralgia.6,7_{Granulomatouslesions}

inCVID maynot onlyaffect the sameorgans as sarcoido-sis but also be histologically indistinguishable.8---11 _{As a}

consequence, sarcoidosisis often incorrectly diagnosedin GD-CVID patients, with GD-CVID considered as a distin-guishedentity.12---15

TheauthorspresenttwoclinicalcasesofCVIDwith sys-temicinvolvementbynon-caseousgranulomas.

Clinical

cases

1stcase

A 39-year-old male, mechanic engineer, non-smoker, had been diagnosed with CVID 4 years ago, under treatment withintravenous IgG. He had previously had several res-piratory infections since childhood. In November 2009, after a routine chest X-ray with mediastinum enlarge-ment, a thoracic CT scan was performed and numerous adenopathies in the prevascular, pretracheal as well as intheright pulmonary hilumwereobserved. Additionally, diffuse peribronchovascular micronodules were detected in lung parenchyma (Fig. 1 and 2). The patient had no

relevantclinicalcomplaintsoralterationsatphysical exam-ination. Besides hypogammaglobulinemia (IgG 287mg/dL; IgM 8mg/dL; IgA 6mg/dL) and slight thrombocytopenia (platelets127×103␮L),nootherserumrelatedalterations

werenoticed.Lungfunctiontestsrevealedamild obstruc-tive pattern.A bronchoscopywith bronchoalveolarlavage (BAL)wasperformed.Itshowedlymphocyticalveolitis(28%) withaslightincreaseinCD4/CD8ratio(2.2),andno microor-ganism was isolated or malignant cell detected. A bone marrow biopsy was also performed, which showed non-caseousgranulomas.Therewerenoclinicalorimagiological indications of other organinvolvement.At thisstage, the patient was started on oral corticotherapy which led to progressiveclinicalandradiologicalimprovementendingin totaldisease resolutionwhichcontinued afterthepatient comeoffmedication.

2ndcase

A 38-year-old male nurse, a non-smoker, had been diag-nosed with CVID a year earlier, treated with intravenous IgG. Previously, he had had several respiratory infections since childhood. In February 2010, he began to suffer from asthenia, anorexia, and erythema nodosum. A tho-racicCTscanshowedmediastinalandbilateralsymmetrical hilaradenopathies.Lungfunctiontestswerenormal. Bron-choscopy with BAL revealed lymphocytosis (35%) with a slight increase in CD4/CD8 ratio (2.6) and no microor-ganism or malignant cells were detected. Endobronchial ultrasound biopsy showed non-necrotizing granulomatous infiltration. There wereno signsof extrathoracic involve-ment. After diagnosis, he was prescribed symptomatic therapy only (antitussives and anti-inflammatories). After 6 months, therewasa spontaneousresolution of the dis-ease,thatistosay,thepatientbecameasymptomaticand noimagiologicalterationsorsignsofrecurrencehavebeen detectedsofar.

Discussion

Pleasecitethisarticlein pressas:PachecoC,etal.Chronicgranulomatousdiseaseassociatedwithcommonvariable immunodeficiency---2clinicalcases.RevPortPneumol.2014.http://dx.doi.org/10.1016/j.rppneu.2013.09.005

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Chronicgranulomatousdiseaseassociatedwithcommonvariableimmunodeficiency 3

Figure1and2 ThoracicCTscanfrompatient1,November2009,showingdiffuseperibronchovascularmicronodulesdetectedin lungparenchyma.

granulomatous inflammation (GD-CVID).5,16---18 _Although

GD-CVIDis welldocumented,theetiologyis stillunknown andtreatmentundefined.18

The link between CVID andthe granulomatous disease seemslogical accordingtotheimmunologicalmechanisms thatareimpliedintheCVIDpathophysiology.However,the absenceofgranulomatousdiseaseinother immunodeficien-cies(ashypogammaglobulinemiarelatedtoX)suggeststhat GD-CVIDisnotcaused byrecurrent/persistentinfections.6

A recent hypothesis is that high levels of tumor necrosis factor(TNF)mightberelatedtothedevelopmentof granu-lomasinthesepatients.6,12

Non-caseous granulomatous lesions that affect CVID patients are histologically indistinguishable from thoseof sarcoidosis. The patient’s age and sex, diminished cellu-lar immunity, the systemic involvement, and high levels of angiotensin-converting enzyme are common features for the two pathologies, so a previous story of recur-rent/persistent bacterial infections should raise suspicion of CVID.6,7 _{However, in a case---control study comparing}

GD-CVIDpatientsandpatientswithpulmonarysarcoidosis, certaindifferencesweredetected,suchasarandomversus perilymphaticmicronodulardistributiononlungCTscanin GD-CVIDpatients,besidesthehigherfrequencyof consoli-dationswithairbronchogram,bronchiectasis,orhalosigns. BiologicaldatashowedthatBALCD4/CD8ratiowas signifi-cantlylowerinGD-CVID.Thereisageneralagreementthat thepresenceoflung involvementisassociatedwithabad prognosisinCVID,includingwhenaGD-CVIDoccurs. How-ever Bouvryetal.in theircase---controlstudydidnotfind GD to be a criticaldeterminant of prognosis but found a worseoutcometobelinkedtotheclassicalcomplicationsof CVIDsuchaslymphoma,infectionorobstructivelungdisease secondarytobronchiectasis.1

The clinical presentations of the two reportedclinical cases,asymptomaticmediastinalandhilaradenopathiesand erythema nodosum,areamongthemost frequent presen-tationsofsarcoidosis.InadditionCVIDwasalreadyknown inbothpatients;howeverGD-CVIDcan,althoughrarely,be the presentation of the disease. The random distribution ofthelungmicronodulesinthefirstpatientandtheslight BAL CD4/CD8 increase are in line with previous reports. However,thetherapeuticstrategy towardthis granuloma-tous disease has diverged. Although corticotherapy is not universallyaccepted asamandatorytreatment,12,15_itwas

prescribed for the first patient because of the systemic

involvement,namely,thecytopeniasecondarytothebone marrowinvolvement.Thesecondpatientdidnotreceiveany therapydirectedattheGD.However,bothofthemimproved inclinical,analytical,andradiologicalterms,whichisinline withthefavorableevolutionreportedbyBouvryetal.1_The

appropriatetreatmentforGD-CVIDpatientshasnotyetbeen established.6,7,12,15

There are no protocols regarding diagnosis, treatment and follow-up, nor prognosis for GD-CVID patients. Many of these patients are followed individually and in a non-standardizedway.Allcliniciansshouldbefamiliarwiththis pathology because so many organs and systems can be affected.7,8,17

Ethical

disclosures

Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.

Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdataandthatallthepatientsincludedinthe studyreceivedsufficientinformationandgavetheirwritten informedconsenttoparticipateinthestudy.

Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Conflicts

of

interest

Theauthorshavenoconflictsofinteresttodeclare.

References

1.BouvryD,MouthonL,Pierre-YvesB,KambouchnerM,DucroixJ, etal.Granulomatosis-associatedcommonvariable immunode-ficiencydisorder:acase---controlstudyversussarcoidosis.Eur RespJ.2013;41:115---22.

Pleasecite thisarticleinpressas: PachecoC,etal.Chronicgranulomatousdiseaseassociatedwithcommonvariable immunodeficiency---2clinicalcases.RevPortPneumol.2014.http://dx.doi.org/10.1016/j.rppneu.2013.09.005

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RPPNEU-196; No.ofPages4

4 C.Pachecoetal.

3.Salzer U, Unger S, Warnatz K. Common variable immun-odeficiency (CIVD): exploring the multiple dimensions of a heterogeneousdisease.AnnNYAcadSci.2012;1250:41---9. 4.Park JH, Resnick ES, Cunningham-Rundles C. Perspectives

on common variable immune deficiency. Ann N Y Acad Sci. 2011;1246:41---9.

5.Aghamohammadi A, Abolhassani H, Rezaei N, Kalantari N, TamizifarB,CheraghiT,etal.Cutaneousgranulomasincommon variableimmunodeficiency: casereportand reviewof litera-ture.ActaDermatovenerolCroat.2010;18:107---13.

6.Naveen K, Ryland P, Cheryl L, Thomas M, Johnson C. Noncaseating granulomatous disease in common variable immunodeficiency.SouthMedJ.2000;93:631---3.

7.ArnoldDF,WigginsJ,Cunningham-RundlesC,MisbahSA,Chapel HM. Granulomatous disease: distinguishing primary antibody diseasefromsarcoidosis.ClinImmunol.2008;128:18---22. 8.RoelandtPR,BlockmansD.Commonvariableimmunodeficiency

(CIVD):casereportandreviewoftheliterature.ActaClinBelg. 2009;64:355---60.

9.ViallardJF,Bloch-MichelC,CaubetO,ParrensM,Texier-Maugein J,Neau-CransacM,etal.␥␦Tlymphocytosisassociatedwith granulomatous disease in a patient with common variable immunodeficiency.ClinInfectDis.2002;35:134---7.

10.Ardeniz O, Cunningham-Rundles C. Granulomatous dis-ease in common variable immunodeficiency. Clin Immunol. 2009;133:198---207.

11.HampsonFA,ChandraA,ScreatonNJ,CondliffeA,Kumararatne DS, Exley AR, et al.Respiratorydisease incommon variable

immunodeficiencyandotherprimaryimmunodeficiency disor-ders.ClinRadiol.2012;67:587---95.

12.ThatayatikomA, Thatayatikom S,WhiteAJ. Infliximab treat-ment for severe granulomatous disease in common variable immunodeficiency:acasereportandreviewoftheliterature. AnnAllergyAsthmaImmunol.2005;95:293---300.

13.Artac H, Bozkurt B, Talim B, Reisli I. Sarcoid-like granulo-mas in common variable immunodeficiency. Reumathol Int. 2009;30:109---12.

14.SutorGC,FabelH.Sarcoidosisand commonvariable immun-odeficiency. A case of a malignant course of sarcoidosis in conjunctionwithsevereimpairmentofthecellularandhumoral immunesystem.Respiration.2000;67:204---8.

15.FasanoMB,SullivanKE,SarpongSB,WoodRA,JonesSM,Johns CJ,etal.Sarcoidosisandcommonvariableimmunodeficiency. Reportof8casesandreviewoftheliterature.Medicine (Balti-more).1996;75:251---61.

16.Vultaggio A, Matucci A, Parronchi P, Rossi O, Filì L, Giudizi MG,etal.Associationbetween‘‘sarcoidosis-like’’diseaseand commonvariable immunodeficiency(CVI):a newCVI variant showinganactivationoftheimmunesystem.SarcoidosisVasc DiffuseLungDis.2007;24:127---33.