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ral Ulcers During the Course of Cytomegalovirus Infection inenal Transplant Recipients

.M. López-Pintor, G. Hernández, L. de Arriba, J.M. Morales, C. Jiménez, and A. de Andrés

ABSTRACT

Background. Cytomegalovirus (CMV) infection is frequent in kidney transplant recip-ients. Although involvement of the gastrointestinal tract with CMV has been described,intra-oral localization is rare. The aim of this study was to analyze the incidence, clinicalcharacteristics, treatment, and outcome of renal transplant recipients with oral lesions dueto CMV.Patients and Methods. We analyzed the records of 453 patients who underwent kidneytransplantation between February 1989 and March 2007. Incident cases and characteristicsof CMV oral lesions were ascertained retrospectively in the outpatient records.Results. The cumulative incidence of 6 cases with oral ulcerations was 1.32%. Themedian follow-up (n � 453) was 61.84 � 50.68 months. The interval for the incidence ofCMV oral ulcers after renal transplantation was 12.83 � 23.51 months. The affected orallocations included the buccal mucosa, hard palate, soft palate, tongue, and floor of themouth. CMV cases showed no significant difference with regard to gender distribution, ageat renal transplantation, renal transplant indication, type of immunosuppressive treatment,and donor/recipient CMV serological status before transplantation. The number of acuterejection episodes was significantly greater and time since transplantation was significantlyshorter in CMV cases.Conclusion. CMV infection, which is common in renal transplant recipients, only rarelyaffects the mouth. Herein we have reported 6 patients who suffered oral ulcers due toCMV infection. An early diagnosis of these lesions is important to a successful outcome for

these patients.

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PPORTUNISTIC infections are common among im-munosuppressed patients who have undergone renal

ransplantation. Cytomegalovirus (CMV) infection occursn 44%–85% of kidney transplant recipients, primarily inhe first 3 months posttransplantation, when immunosup-ression is most intense.1

CMV infection in renal transplant recipients exhibits aide range of clinical manifestations; it can affect any

egment of the gastrointestinal tract, including the esopha-us, stomach, and small and large intestines.1 Althoughnvolvement of the entire gastrointestinal tract with CMVas been described, intra-oral localization is rare. Oralucosa ulcerations have been attributed to CMV in pa-

ients with acquired immunodeficiency syndrome (AIDS),atients who received immunosuppressive chemotherapy,

eart transplant recipients, and patients after bone marrow C

2009 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 41, 2419–2421 (2009)

ransplantation2–6; cases of CMV oral ulcerations are raren renal transplant recipients. The aim of our study was tonalyze the incidence, clinical characteristics, treatment,

From the Department of Oral Medicine and Surgery (R.M.L.-P.,.H., L.d.A.), School of Dentistry; Department of Nephrology

J.M.M., A.d.A.), Hospital Universitario 12 de Octubre; andepartment of General and Digestive Surgery and Abdominalrgan Transplantation (C.J.), Hospital Universitario 12 de Oc-

ubre, Complutense University, Madrid, Spain.This study was supported by grant no. 5250425 from theutua Madrileña Foundation for Medical Research, Madrid.Address reprint requests to Prof. Gonzalo Hernández Vallejo,

ep. Estomatología III, Facultad de Odontología, Pza. Ramón y

ajal s/n, 28040 Madrid, Spain. E-mail: ghervall@odon.ucm.es

0041-1345/09/$–see front matterdoi:10.1016/j.transproceed.2009.06.053

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2420 LÓPEZ-PINTOR, HERNÁNDEZ, DE ARRIBA ET AL

nd outcome of renal transplant recipients with oral lesionsue to CMV.

ATIENTS AND METHODS

e analyzed the records of 453 patients who underwent kidneyransplantation between February 1989 and March 2007. Incidentases of CMV oral lesions were ascertained retrospectively in theutpatient records. Active CMV infection was defined as theetection of CMV pp65 antigenemia assay, which was performedsing immunofluorescence (MonoFluo kit CMV, Bio-Rad), ac-ording to the manufacturer’s instructions. The CMV oral lesionsere evaluated for response to antiviral treatment with no newlcerations after treatment.We reviewed the renal transplant outpatient database of cases

nd non-cases of CMV lesions with particular reference to age at

Table 1. Characteristics of Renal Tra

CaseNo. Gender

Age(y) IS Treatment Oral Ulcers Localization

1 F 65 Pred � Tacro � MMF Hard palateBuccal mucosa

2 F 49 Pred � CsA � MMF Buccal mucosaSoft palateFloor of the mouth

3 F 64 Pred � Tacro � MMF Buccal mucosa4 F 48 Pred � CsA � MMF Tongue

Soft palate5 M 48 Pred � CsA � Aza Buccal mucosa

Hard palate6 M 30 Pred � Tacro � MMF Floor of the mouth

Abbreviations: F, female; M, male; Pred, prednisone; Tacro, tacrolimus; Csressant; D/R CMV, donor/recipient CMV serology status before transplantatiollograft rejection; i.v., intravenous.

Table 2. Characteristics of Renal Transplan

Cases with Oral CM

ge (y) 50.83 � 12exMales 33.3%Females 66.7%

ime since transplant (mos) 12.83 � 23mmunossuppressant treatment

Pred � CsA � MMF 33.3%Pred � Tacro � MMF 50%Pred � CsAPred � CsA � Aza 16.7%Others

enal transplant indicationPolycystic kidney disease 66.67%Chronic glomerulonephritis 16.67%Diabetic nephropatyIgA nephropaty 16.67%Others

AR 66.7%CMVR� 66.7%R- 33.3%

Abbreviations: R CMV� recipient CMV serology status before transplant; AAR� a

ransplantation, immunosuppressive treatment, acute allograft re-ection episode, time since transplantation, and donor/recipientMV serological status before transplantation. Statistical analysisxamined differences between mean values and proportions bytudent t test and the chi-square test, respectively, with P � .05onsidered significant.

ESULTS

e identified 6 patients with oral lesions due to CMVTable 1). All were white and had received orthotopicadaveric renal transplants. The cumulative incidence ofral CMV lesions was 1.32% (n � 453). The clinical oral

ocations affected by CMV included the tongue (1 case),uccal mucosa (4 cases), hard palate (2 cases), soft palate (2ases), and floor of the mouth (2 cases).

nt Patients With CMV Oral Lesions

CMVTime of

Appearance AAR Treatment Others

/� 14 d � i.v. Ganciclovir Leukopenia

/� 2 mo � i.v. Ganciclovir

/� 45 d � i.v. Ganciclovir Diabetes/� 1 y � i.v. Ganciclovir Leukopenia

/� 22 d � i.v. Ganciclovir Oral candidiasisLip cancer

/� 5 y � i.v. Ganciclovir Varicella processChronic renal failure

losporin A; Aza, Azathioprine; MMF, mycophenolate mofetil; IS, immunosup-e of appearance, time of appearance after renal transplantation; AAR, acute

ients With and Without CMV Oral Lesions

� 6) Non-Cases (n � 447) P

53.44 � 13.39 0.5050159

61.5%38.5%

59.83 � 47.92 0.0370.999

20.4%40.7%

8.3%5.1%

25.5%0.948

12.8%11.6%

11%11%

53.6%16.6% 0.001

0.07989.3%10.7%

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ORAL ULCERS 2421

The median follow-up (n � 453) time was 61.84 � 50.68onths. The median interval for the incidence of CMV oral

lcers after renal transplantation was 12.83 � 23.51 months.he median age of patients with CMV oral ulcers atiagnosis was 50.83 � 12.82 years. CMV cases showed noignificant difference with regard to gender distribution, aget renal transplantation, renal transplant indication, type ofmmunosuppressive treatment, and donor/recipient CMVerological status before transplantation. The number ofcute rejection episodes was significantly greater in CMVases (P � .001). Time since transplantation was signifi-antly lower in patients with CMV oral lesions at diagnosisP � .037) (Table 2).

ISCUSSION

ral ulcerations due to CMV among renal transplantecipients have not been reported before. We observed 6enal transplant recipients who presented with oral ulcersuring the course of CMV disease.The appearance of oral CMV infection is highly variable,

ncluding deep and painful ulcers, mucosal erythema, androsions.2 In our study, the 6 patients with oral infectionsue to CMV suffered painful ulcers. The oral ulcers affectedhe tongue, buccal mucosa, hard and soft palate, and floorf the mouth.As soon as these types of ulcers are seen in any solid

ransplant recipient treated with immunosuppressive drugs,herpes simplex virus or CMV infection should be sus-

ected because early diagnosis of these conditions reducesatient morbidity.2 Clinical diagnosis of oral ulcers in

mmunosuppressed patients is often difficult because vari-us etiologic factors, such as infections, drugs, and tumors,ay produce similar lesions.Herpes simplex may cause cold sores or a gingivostoma-

itis often accompanied by fever, malaise, and lymphade-opathy. Mucosal vesicles may also be caused by Varicella-oster virus. The initial clinical picture may include vague

igns and symptoms, such as fever, cough, debilitation,rthralgias, myalgias, nausea, diarrhea, and abdominal pain,hich are common at the beginning of a human herpesvirus

nfection.7 In our case, active CMV infection was defined ashe detection of CMV pp65 antigenemia assay that wasositive in all cases.Oral ulcerations have been reported with various immu-

osuppressants, such as tacrolimus, sirolimus, and myco-

henolate mofetil.7 Several arguments suggest that these d

uccal ulcerations may result from drug toxicity, but severaltudies suggest that they could be caused by overimmuno-uppression, lack of steroids, or use of the oral formulationnstead of pills of sirolimus.1,7 The patients with CMV orallcers in our study had cyclosporine and tacrolimus blood

evels within the normal values, and the 6 patients wereaking prednisone. The good response to ganciclovir treat-ent excluded the possibility of drug toxicity.CMV has been isolated from a number of oral sites in

mmunosuppressed patients, such as oral healthy mucosa,aliva, and periodontal pockets.8,9 Periodontal pockets andaliva may be reservoirs for human CMV. Following trans-lantation, frequent monitoring of a recipient’s periodontalealth may reduce the risk of transplant complications dueo CMV.9

The early diagnosis of oral lesions due to CMV infections important because CMV infection causes infectious di-ease syndromes, increases immunosuppression, and isssociated with opportunistic infections and allograft rejec-ion episodes in renal transplant recipients.

EFERENCES

1. Ponticelli C, Passerini P: Gastrointestinal complications inenal transplant recipients. Transpl Int 18:643, 2005

2. Epstein JB, Sherlock CH, Wolber RA: Oral manifestations ofytomegalovirus infection. Oral Surg Oral Med Oral Pathol 75:443,9933. Schubert MM, Epstein JB, Lloid ME, et al: Oral infections

ue to cytomegalovirus in immunocompromised patients. J Oralathol Med 22:268, 19934. Ammatuna P, Campisi G, Giovannelli L, et al: Presence of

pstein-Barr virus, cytomegalovirus and human papillomavirus inormal oral mucosa of HIV-infected and renal transplant patients.ral Dis 7:34, 20015. Jones AC, Freedman PD, Phelan JA, et al: Cytomegalovirus

nfections of the oral cavity. A report of six cases and review of theiterature. Oral Surg Oral Med Oral Pathol 75:76, 1993

6. Correira-Silva JF, Victória JMN, Guimaraes ALS, et al:ytomegalovirus shedding in the oral cavity of allogeneicaematopoietic stem cell transplant patients. Oral Dis 13:163,0077. Hernández G, Jiménez C, Arriba L, et al: Resolution of oral

lcerations after decreasing the dosage of tacrolimus in a liverransplantation recipient. Oral Surg Oral Med Oral Pathol Oraladiol Endo 92:526, 20018. Nowzari H, Jorgensen MG, Aswad S, et al: Human

ytomegalovirus-associated periodontitis in renal transplant pa-ients. Transplant Proc 35:2949, 2003

9. Cappuyns I, Gugerli P, Mombelli A: Viruses in periodontalisease – a review. Oral Dis 11:219, 2005