giant cell myocarditis in a 12-year-old girl with common variable immunodeficiency

Mayo Clin Proc, January 2002, Vol 7792 Common Variable Immunodeficiency and Myocarditis

Mayo Clin Proc. 2002;77:92-96 92 © 2002 Mayo Foundation for Medical Education and Research

Case Report

Giant Cell Myocarditis in a 12-Year-Old Girl WithCommon Variable Immunodeficiency

HELMUT LAUFS; PETER ANDRIJA NIGROVIC, MD; LYNDA C. SCHNEIDER, MD; HANS OETTGEN, MD, PHD;PEDRO DEL NIDO, MD; IVAN P. G. MOSKOWITZ, MD, PHD; ELIZABETH BLUME, MD;AND ANTONIO R. PEREZ-ATAYDE, MD

From the Department of Cardiovascular Surgery (H.L., P.d.N.), De-partment of Medicine (Division of Immunology) (P.A.N., L.C.S.,H.O.), Department of Pathology (I.P.G.M., A.R.P.-A.), and Depart-ment of Cardiology (H.L., E.B.), The Children’s Hospital and HarvardMedical School, Boston, Mass. Mr Laufs, a medical student at theMedical University of Lübeck, Germany, contributed to this workwhile participating in a student clerkship.

Individual reprints of this article are not available. Address corre-spondence to Antonio R. Perez-Atayde, MD, Department of Pathol-ogy, The Children’s Hospital, 300 Longwood Ave, Boston, MA02115 (e-mail: antonio.perez-atayde@ tch.harvard.edu).

Giant cell myocarditis (GCM) is a rare and often fataldisease that infrequently affects children. Common variableimmunodeficiency (CVID) describes a heterogeneous groupof disorders characterized by hypogammaglobulinemia andpoor specific antibody responses. To our knowledge, CVIDand GCM have not been reported together in 1 patient. Wedescribe a 12-year-old girl with CVID who developed acutesevere GCM that necessitated cardiac transplantation. His-topathological and immunohistochemical studies of theendomyocardial biopsy specimen and the explanted heart

CVID = common variable immunodeficiency; GCM = giantcell myocarditis; IVIG = intravenous immunoglobulin

revealed numerous histiocytes, eosinophils, T cells, andmultinucleated giant cells. Both CVID and GCM arethought to involve dysregulation of T-cell function and havebeen associated with a similar spectrum of autoimmuneconditions. The coincidence of CVID and GCM in a singlepatient may reflect a pathophysiologic connection.

Mayo Clin Proc. 2002;77:92-96

Giant cell myocarditis (GCM) is an idiopathic condi-tion defined pathologically by myocyte necrosis in

the presence of an inflammatory infiltrate featuring multi-nucleated giant cells.1,2 Since tissue destruction is typicallyextensive, the prognosis of GCM is generally worse thanthat of lymphocytic myocarditis.3 In the largest reportedseries, 70% of 63 patients died or required transplantationwithin 1 year of diagnosis.1 Although the etiology of GCMremains obscure, it has been associated in 20% of caseswith disorders of dysregulated immunity, including inflam-matory bowel disease, Hashimoto thyroiditis, and rheuma-toid arthritis.1 We report what we believe to be the first caseof GCM associated with another disorder that is oftenpresumed to involve T-cell dysfunction, common variableimmunodeficiency (CVID).

REPORT OF A CASEA 12-year-old girl with a history of CVID presented to theemergency department after 3 days of fatigue, chest pain,mild exertional dyspnea, and an episode of near-syncopewhile showering. No viral prodrome had been noted. She

was tachycardic with a heart rate of 150 beats/min, her bloodpressure was 90/54 mm Hg, and she had an oxygen satura-tion of 99% by pulse oximetry. Findings on physical exami-nation were remarkable for hepatomegaly and a third heartsound. Electrocardiography revealed sinus tachycardia withlow voltages throughout and T-wave inversions in leadsI through III and V4 through V6. Chest radiography showedinterval cardiac enlargement compared with the appearanceon a chest x-ray film taken a few months earlier. Echo-cardiography showed a thickened, nondilated myocardiumwith severe left ventricular dysfunction, and she was ad-mitted to the cardiac intensive care unit with presumedmyocarditis.

She had been diagnosed as having CVID at the age of 6years during evaluation for recurrent sinopulmonary infec-tions. Initial serum immunoglobulin studies showed lowIgG, low IgM, and undetectable IgA levels but adequatespecific antibody responses (Table 1). Several months later,IgG and IgA levels were undetectable, IgM levels had de-clined, and her specific antibody responses had deteriorated.T-cell function as measured by blastogenesis to tetanus andcandida was normal, but the CD4+:CD8+ ratio was abnormalat almost 9:1. Treatment with intravenous immunoglobulin(IVIG) was begun, and she showed some clinical improve-ment, although persistent sinusitis ultimately necessitatedsurgery. Anti-IgA antibodies measured at the age of 8 yearswere undetectable. Her medical history was otherwise no-table for diffuse mild cutaneous ichthyosis with nail pittingbut no frank psoriasis. A younger brother had borderline-lowIgG levels but was clinically well. There was no familyhistory of autoimmunity or cardiac disease. Her only medi-

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Mayo Clin Proc, January 2002, Vol 77 93Common Variable Immunodeficiency and Myocarditis

Table 1. Immunologic Evaluation*

Initial diagnosis Follow-up studies GCM admissionat age 6 y at age 7 y at age 12 y

Immunoglobulins (mg/dL)IgG 278 (low) <89 639 (on IVIG)IgA <18 <19 <5IgM 27 (low) 11 (low) <7IgE ND 2 ND

Specific antibody titersTetanus (IU/mL) 0.63 (normal) 0.12 (low) NDPRP (µg/mL) 1200 (normal) 300 (low) ND

Lymphocyte markers (%)CD3 ND 81 89CD4 ND 71 75CD8 ND 8 15CD19 ND 14 5CD16 ND ND 6

T-cell proliferation (patient/control)Mitogens ND ND Bkg 565/824

ConA 72576/97909PHA 82076/167871PWM 87710/44153

Antigens ND ND Bkg 580/1729Diph 13489/22368Tet 9775/63900

HIV (antibody) Negative ND Negative

*Immunologic evaluation of the patient at presentation with common variable immunodeficiency, onreevaluation 5 months later, and on presentation with giant cell myocarditis (GCM). Initialhypogammaglobulinemia with preserved specific antibodies decayed to near-agammaglobulinemiawith poor antibody responses. No vaccine challenge was performed. T-cell proliferation responseswere essentially intact. Bkg = background; ConA = concanavalin A; Diph = diphtheria; HIV = humanimmunodeficiency virus; IVIG = intravenous immunoglobulin; ND = not done; PHA = phyto-hemagglutinin; PRP = polyribosylribitol phosphate; PWM = pokeweed mitogen; Tet = tetanus toxin.

cations were budesonide nasal spray daily and IVIG, 20 g(approximately 500 mg/kg) infused every 3 weeks.

Repeat studies on day 2 of her hospitalization revealedan immunoglobulin pattern and lymphocyte subset distri-bution as had been noted previously (Table 1). Mitogen andantigen testing again showed generally intact T-cell func-tion. She underwent cardiac catheterization and receivedIVIG, 2 g/kg, based on a standard treatment protocol forpresumed lymphocytic myocarditis.2 Biopsy of the rightventricle suggested eosinophilic myocarditis, without evi-dent giant cells. Her highest peripheral eosinophil countwas 940 × 109/L (reference range, 0-400 × 109/L). Viralcultures remained negative. Therapy with pulse cortico-steroids was begun.

On the night of her second hospital day, she developedventricular tachycardia and cardiac arrest. Cardioversionwas unsuccessful, and she was managed with cardiopulmo-nary resuscitation during cannulation for extracorporealmembrane oxygenation. She was listed for urgent trans-plantation and within 12 hours received a donor heart. Herpostoperative course was unremarkable, and she was dis-

charged on hospital day 22 on a standard regimen ofcyclosporine-based triple immunosuppression.

PATHOLOGIC FINDINGSThe initial endomyocardial biopsy confirmed the diagnosisof diffuse acute myocarditis, with a marked mixed inflam-matory infiltrate of lymphocytes, eosinophils, and histio-cytes associated with extensive myocyte damage and necro-sis. Eosinophils were numerous and formed small focalcellular aggregates. The cardiectomy specimen exhibited asoftened myocardium with increased thickness of the ven-tricular walls. On cut section, the myocardium appearedmottled with widespread light tan nodules measuring up to 3mm (Figure 1). There were areas of hemorrhage and geo-graphic necrosis. Histopathologically, the findings weresimilar to the endomyocardial biopsy, but in addition therewere numerous multinucleated giant cells diagnostic ofGCM and extensive areas of necroinflammatory activity andcoagulative necrosis (Figure 1). There was no evidence ofvasculitis or granuloma formation. Special staining withGram stain and methenamine silver revealed no evidence of



microorganisms. Immunoperoxidase studies performed onthe endomyocardial biopsy specimen revealed that the lym-phocytic infiltrate was composed predominantly of T cells(CD3+) and rare B cells (CD20+) (Figure 2). Subtyping re-vealed an even mixture of CD4+ and CD8+ lymphocytes.Enteroviral polymerase chain reaction analysis and tissuecultures for viral and bacterial pathogens remained negative.

Figure 1. Left, Cut section of explanted heart with thickened and mottled myocardium, widespread light tannodules measuring up to 3 mm (arrows), and focal areas of necrosis and hemorrhage. Center and right, Idiopathicgiant cell myocarditis with a prominent inflammatory infiltrate consisting of mononuclear cells, lymphocytes,numerous eosinophils forming small cellular aggregates, and multinucleated giant cells (arrows, right) (hematoxylin-eosin stain).

HLA typing showed the following specificities: A2,A11, B8, B35, BW6, CW4, CW7, DQ2, DQ5, DR103,DR17, DR52.

DISCUSSIONGiant cell myocarditis is an often fulminant form of myo-cardial inflammation with a high mortality rate. Most re-

Figure 2. Immunoperoxidase reaction of the myocardial biopsy specimen with markers for CD68 (antihistiocyteantibody), CD3 (common T-cell antibody), and CD20 (anti–B-cell antibody). Prominent CD68+ histiocyticinfiltrate, including CD68+ giant cells (CD68, arrows), numerous T cells (CD3), and rare B cells (CD20, arrows)(hematoxylin counterstain).


Mayo Clin Proc, January 2002, Vol 77 95Common Variable Immunodeficiency and Myocarditis

ported cases have occurred in adults. The largest seriesdescribed 63 patients ranging in age from 15 to 69 years(median, 43 years), with equal incidence in males andfemales.1 Although rare, GCM accounted for 22% of allcases of biopsy-verified myocarditis diagnosed at 1 majoracademic center during a 131/2-year period.3 No data areavailable about the epidemiology of GCM in children.Only 9 patients aged 19 years or younger have been re-ported, of whom only 3 were younger than 15 years,1,4-8

including a newborn infant.4

Patients with GCM present with congestive heart fail-ure, conduction disturbance, ventricular arrhythmia, or,rarely, a syndrome mimicking acute myocardial infarc-tion.1 Diagnosis is by endomyocardial biopsy, which has asensitivity of approximately 85% compared with the “goldstandard” of open heart biopsy, cardiectomy, or autopsy.9

No controlled clinical trial has compared different treat-ment regimens. Retrospective analysis suggests thatmultidrug immunosuppression is more effective than treat-ment with corticosteroids alone, although outcomes withmedical treatment remain poor.1 Transplantation is thetherapy of choice for severe disease, although GCM recurs inthe transplanted heart in about a quarter of the cases (9 of 34patients in the only large series).1 These recurrences gener-ally respond to increased immunosuppression, such thatlong-term outcome after transplantation for GCM is similarto transplantation for other causes of cardiomyopathy.9

The etiology of GCM is unknown. No viral trigger hasbeen demonstrated, although a neonate with GCM in thesetting of congenital herpes simplex virus infection has beenreported.4 Myocarditis resembling human GCM can be in-duced in the Lewis rat by immunization with cardiacmyosin, supporting the suspicion of an autoimmune mecha-nism.10 The principal infiltrating lymphocyte in experimen-tal GCM is the CD4+ T cell, unlike murine viral myocarditisin which the CD8+ T cell is predominant.11 In human acuteGCM, CD8+ cells outnumber CD4+ cells, but the CD4+:CD8+

ratio can vary with the stage of disease, perhaps accountingfor the equal numbers of CD4+ and CD8+ cells in ourpatient.12 Prominent eosinophilia is common in acute hu-man GCM.12 Experimental GCM can be transferred intohealthy syngenic rats by infusion of concanavalin A–stimulated lymphocytes from myosin-immunized animals.Transfer via serum or IgG fractions is unsuccessful, imply-ing a central role for T cells in initiating myocardialdamage.11 The hypothesis that human GCM is also of au-toimmune etiology is supported by reports of frequent as-sociation with autoimmune or inflammatory conditions inup to 20% of cases, including ulcerative colitis, Crohndisease, Hashimoto thyroiditis, myasthenia gravis, and dif-ferent forms of inflammatory arthritis (Table 2).1,9 In addi-tion, GCM has been noted to accompany hypersensitivity

reactions and cancers, including lymphoma, sarcoma, lungcancer, and thymoma.9,17

Common variable immunodeficiency is a heterogeneouscondition characterized by hypogammaglobulinemia, poorspecific antibody responses, and recurrent infections. Mul-tiple clinical subtypes have been observed, reflecting theprobable diversity of underlying pathophysiologic mecha-nisms.18,19 Although primary B-cell dysfunction may be in-volved in some cases, most CVID probably results fromdefective T-cell help, since B cells from CVID patients cangenerally be driven to make antibody adequately in vitro.20 Tcells from some patients with CVID have been observed toinhibit antibody production by lymphocytes from healthydonors.21 Additionally, T-cell responses to mitogen and anti-gen stimulation have been observed to be deficient in asubstantial proportion of patients with CVID.13 While ourpatient’s T cells proliferated normally, her CD4+:CD8+ ratiowas abnormal at 5:1 to 9:1 (Table 1), and her poor immuno-globulin production suggests a more subtle functional defect.

Perhaps as a consequence of problems with T-cell func-tion, CVID is prominently associated with autoimmunity,including inflammatory bowel disease,13 rheumatoid andjuvenile arthritis,13 systemic lupus erythematosus,13,14 au-toimmune hemolytic anemia,13,16 thrombocytopenia,13,16

and alopecia13,16 (Table 2). Thymoma13 and malignant neo-plasms13,16 have also been reported. The major histocom-patibility complex supratype A1, Cw7, B8, C4AQO,

Table 2. Diseases Involving Immune DysregulationAssociated With GCM and CVID*

Conditions associated with

GCM† CVID‡

CVID (this case) GCM (this case)Ulcerative colitis1,9 Ulcerative colitis13

Crohn disease1,9 Crohn disease13

Thyroid disease1,9 Thyroid disease13

Rheumatoid arthritis9 Rheumatoid arthritis13,16

Pernicious anemia9 Pernicious anemia13

Alopecia totalis vitiligo9 Alopecia13,16

Thymoma1,9 Thymoma13

Lymphoma9 Lymphoma16

Other cancers9 Other cancers13

*CVID = common variable immunodeficiency; GCM = giant cellmyocarditis.

†Other associations with GCM: myasthenia gravis,9 Takayasuarteritis,9 orbital and skeletal myositis,9 after mitral valve surgery,9

and mitral stenosis.9

‡Other associations with CVID: systemic lupus erythematosus,13,14

immune thrombocytopenic purpura,13 autoimmune hemolyticanemia,13,15 anti-IgA antibody,13 hepatitis,13,15 chronic malab-sorption,13,16 idiopathic thrombocytopenia,15 secretory diarrhea,15

diabetes mellitus,13 sicca syndrome,13 Guillain-Barré syndrome,15

psoriasis,16 parotitis,1 primary biliary cirrhosis,13 sarcoidosis,13 andhypersensitivity reaction.9,17



C4B1, BfS, DR3 is associated both with CVID and withcertain autoimmune conditions,18,22 although our patient didnot have this supratype. Up to 10% of CVID patients mayultimately develop an autoimmune condition.19 In a seriesdescribed by Hausser et al,16 9 of 30 children with CVIDhad an associated autoimmune disorder, and in anotherseries, Conley et al15 described 16 different autoimmunediseases diagnosed in 8 children with CVID. The overlapwith conditions associated with GCM is striking (Table 2),although authorities on the 2 diseases have not encounteredthem together (C. Cunningham-Rundles, L.T. Cooper, Jr,oral communication, July 2000). The case we report hereinsuggests that GCM should be added to the list of CVID-associated autoimmune diseases.

The pathologic findings of a prominent eosinophilicinfiltrate and multiple giant cells raise other diagnosticpossibilities. Eosinophilic myocarditis is an independententity that may be associated with drug hypersensitivity,parasitic infections, and Churg-Strauss vasculitis.23 Periph-eral eosinophilia is common but not invariable.23 More than20 different drugs have been implicated in eosinophilicmyocarditis,23 although giant cells are not typically found,and our patient was not taking any of the associated medi-cations. Cardiac sarcoidosis is associated with the presenceof giant cells, but granulomas are uniformly present andinfiltrating eosinophils are generally absent.12 We are un-able to exclude the possibility that the patient’s myocarditisresulted from inadequate defense against an undeterminedinfectious agent, rather than from an autoimmune mecha-nism. It is also possible that hypersensitivity contributed toher pathology, whether in response to an environmentalstimulus or to her IVIG. A case of eosinophilic myocarditiswithout giant cells has been reported in the setting of IVIGtherapy for Guillain-Barré syndrome, although the patientalso received phenytoin, known to be associated with hy-persensitivity myocarditis.24

CONCLUSIONTo our knowledge, this is the first case of GCM reported ina patient with CVID, and this patient is one of the youngestdescribed with GCM. Since both disorders are thought torepresent disordered T-cell function and have been encoun-tered with similar autoimmune conditions, it may be thattheir association in this case reflects an underlying patho-physiologic connection. Confirmation of this hypothesiswill require the identification of other examples of theassociation of these 2 disorders and better understanding oftheir pathogenesis.

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giant cell myocarditis in a 12-year-old girl with common variable immunodeficiency

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