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igns and Symptoms of Cytomegalovirus Disease in Kidneyransplant Recipients

. Pour-Reza-Gholi, A. Labibi, F. Farrokhi, M. Nafar, A. Firouzan, and B. Einollahi

ABSTRACT

Purpose. To investigate the range of clinical presentations of cytomegalovirus (CMV)disease in kidney transplant recipients.Materials and methods. We retrospectively reviewed the records of hundred kidneyrecipients who developed CMV disease between 1984 and December 2002 for demo-graphic characteristics, laboratory findings, and presenting signs and symptoms.Results. The most common presentations were elevated serum creatinine in 74 patients,fever in 71, thrombocytopenia in 43, nausea in 32, vomiting in 25, elevated alkalinephosphatase in 24, leukocytosis in 22, and leukopenia in 21. Tissue involvement wasrelatively rare, but six patients had pneumonia, two had conjunctivitis, and one hadvascular dermatitis. Four percent of the patients had received intravenous ganciclovirprophylaxis, and 7% had received oral ganciclovir prophylaxis. Fever was associated withnumber of hospitalizations (P � .006), elevated creatinine (P � .006), nausea (P � .017),vomiting (P � .031), and previous posttransplantation infections (P � .001). All thepatients with conjunctivitis, pneumonia, pulmonary symptoms, and abnormal heart soundsand most of those with arthralgia, nausea, and vomiting were febrile during their CMVdisease course.Conclusion. Our findings showed that leukocytosis should be considered as much asleukopenia when CMV disease is suspected. CMV-induced pneumonia is not common inrenal transplant recipients compared to other organ transplant recipients. CMV invasionto other tissues is also rare. Finally, fever is a common symptom and important in assessing

the severity and prognosis of the disease.

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YTOMEGALOVIRUS (CMV) disease is the mostfrequent type of infection in kidney transplant recip-

ents.1,2 The prevalence of CMV infection, as signaled byetectable levels of anti-CMV immunoglobulin G antibod-

es in serum, increases with age in the general population,nd serological findings indicate that more than two-thirdsf donors and recipients have had this infection prior toransplantation.1 Association of CMV infection with graftutcome has been proven in many studies, which seems toe due to its additional immunosuppressive effects. Inddition its immunocompromising effects can lead to otherotential complications in recipients.3

The clinical manifestations of CMV disease in renalransplant patients often differ from those in the generalopulation. Consequently, in kidney recipients, it can beifficult to diagnose CMV infection based on clinical fea-

ures.4 Careful interpretation of presenting signs and symp- T

041-1345/05/$–see front matteroi:10.1016/j.transproceed.2005.07.051

056

oms of CMV infection is important in this patient group,ut the literature contains little information related to this.n attempt to expand knowledge in this area, we reviewedll cases of CMV disease that occurred in kidney recipientst our center in order to evaluate the signs and symptoms ofMV disease in this patient group.

ATERIALS AND METHODS

rom 1984 to December 2002, among 1925 patients who hadndergone kidney transplant surgery, 100 were diagnosed with

From the Urology and Nephrology Research Center, Shaheedabbafinejad Medical Center, Shaheed Beheshti University ofedical Sciences, Tehran, Iran.Address reprint requests to Farhat Farrokhi, Urology/Nephrol-

gy Research Center (UNRC), No. 44, 9th Boustan, Pasdaran,

ehran, 1666679951, Iran. E-mail: farrokhi@unrc.ir

© 2005 by Elsevier Inc. All rights reserved.360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 37, 3056–3058 (2005)

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SIGNS AND SYMPTOMS OF CMV DISEASE 3057

MV disease at some stage after transplantation. In each case,MV disease was diagnosed according to clinical features andetection of CMV antigen (pp65 antigenemia) in serum.The 100 cases were retrospectively investigated for details re-

ated to transplantation, demographic characteristics, as well ashysical examination and laboratory findings after hospitalizationor CMV disease.

The results were statistically analyzed with the chi-square andhe Student t tests to assess differences between subgroups ofatients, based on the presence of fever.

ESULTS

f the 100 kidney recipients with CMV disease, 62 wereen and 38 were women. The mean age at time of

ransplantation was 33.8 � 15.1 years. The median intervalrom transplantation to diagnosis with CMV was 3.4onths (range, 1 to 9 months). Prior to transplantation, theean dialysis duration for the group was 14.9 � 22.9onths. Seventy-seven patients had been on hemodialysis

nd four had been on peritoneal dialysis. The other 19atients had undergone preemptive transplantation. Ninety-our of the patients had received their first transplant, fivead received their second graft, and one had received ahird graft. Eighty-six of the transplants were from livingnrelated donors, 10 were from living related donors, andour were deceased donor grafts.

Thirty-seven patients had received intensive antirejectiongents after transplantation (pulse-steroid therapy in 27ases, antilymphocyte globulin in 10 cases).

The mean number of hospitalizations after transplanta-ion was 2.5 � 2.1. More than 90% of the recipients andonors were positive for CMV immunoglobulin G at theime of transplantation.

The following signs and symptoms were present duringospitalization for CMV disease: fever in 71 cases, nausea

n 32, vomiting in 26, pulmonary signs and symptoms in 20,rthralgia in 10, and ocular abnormalities in four.

CMV tissue invasion occurred in 16 patients, includingeart involvement (new abnormal heart sounds) in seven,neumonia in six, conjunctivitis in two, and dermal vascu-

itis in one.The abnormal laboratory findings were elevated creati-

Table 1. Laboratory Findings During CMV Clinical C

Mean � SD

hite blood cells 6820.4 � 3223.9/mm3

emoglobin 10.8 � 2.4 mg/dLematocrit 31.1 � 69%latelets 212189.7 � 88661.5/mm3

reatinine 2.4 � 1.8 mg/dLUN 60.5 � 38.1 mg/dLLT 26.8 � 33.9 IU/LST 23.8 � 16.1 IU/Llkaline phospatase 213.3 � 137.6 IU/L

BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate am

ine (71 cases), thrombocytopenia (43), leukocytosis (22), C

eukopenia (21), elevated alanine aminotransferase (19),nd elevated aspartate aminotransferase (15) (Table 1).

Analysis revealed associations between fever and numberf hospitalizations after transplantation (P � .006), ele-ated creatinine (P � .006), nausea (P � .017), vomitingP � .031), number of infection episodes after transplanta-ion (P � .001), and pulmonary symptoms (P � .002). All ofhe patients with conjunctivitis, pneumonia, pulmonaryymptoms, and abnormal heart sounds were febrile duringospitalization for CMV disease (Table 2).Eighty-eight of the patients had not been given CMV

rophylaxis. Of the remaining 12 patients, seven had re-eived a 12-week course of oral ganciclovir and four hadeceived a 2-week course of intravenous ganciclovir. Two ofhe patients who had been given oral prophylaxis and twoho had received intravenous prophylaxis had at least onepisode of fever. Of the 88 patients who had not receivedMV prophylaxis, 71.6% had at least one episode of fever,hile none of the patients who received prophylactic treat-ent developed fever (P � .018) or CMV tissue invasion.o deaths occurred and all of the patients responded to

reatment.

e for the 100 Kidney Recipients With CMV Disease

Increased (%) Decreased (%)

22 21— 59— 5411 4371 —67 —19 —15 —24 —

nsaminase.

Table 2. Association of Fever With Other Characteristicsof Patients and CMV Disease

Fever No fever P value

ge (y) 33.3 � 18.4 31.1 � 15.0 .60ialysis duration (months) 13.5 � 23.1 15.4 � 16.7 .71o. of hospitalizationsafter transplantation 2.9 � 2.2 1.5 � 1.5 .006

istory of dialysis 79.1% 84.6% .12LG/pulse 73.1% 58.4% .47osttransplant infections 71.6% 25.9% .001ausea 40.2% 14.8% .017omiting 32.8% 11.2% .031rthralgia 13.4% 3.7% .16ulmonary symptoms 28.3% 0% .002neumonia 8.9% 0% .10bnormal heart sounds 10.4% 0% .081asculitis 1.5% 0% .52onjunctivitis 2.9% 0% .38

ALG, antilymphocyte globulin.

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*Administration of antilymphocyte globulin or steroid-pulse therapy beforeMV disease.

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3058 POUR-REZA-GHOLI, LABIBI, FARROKHI ET AL

ISCUSSION

n kidney recipients, CMV infection most often occurs inhe first few months after transplantation.1 In the 100 casesn our study, the median interval from transplantation toiagnosis with CMV was 3.4 months, findings consistentith those reported by Abbott and colleagues.5 They found

hat 79% of hospitalizations for CMV infection in kidneyecipients occurred in the first 6 months after transplanta-ion. Farrugia and Schwab identified fever, malaise, myal-ia, leukopenia, and elevated transaminase levels as theost common manifestations of CMV disease in kidney

ecipients.6 Ranked in descending order, the most commonanifestations of CMV in our series were fever, elevated

reatinine, thrombocytopenia, nausea, vomiting, leukocyto-is, leucopenia, and pulmonary signs and symptoms. In atudy conducted by Durlik et al on clinical manifestationsnd diagnosis of CMV infection in renal allograft recipi-nts, the most frequent clinical manifestations of CMVisease were fever (91%), leukopenia (82%), and thrombo-ytopenia (27%).7 Compared with these rates, our fre-uency of fever was lower (71%) and our rate of leukocy-osis was high (22%), which is a considerable finding.

Elevated serum creatinine was a considerable finding inur series; however, not all these patients were investigatedith renal biopsy to assess for CMV-induced glomerulone-hritis8 or other potential renal impacts of CMV.Our data indicate that fever is associated with more

evere forms of CMV disease. This is in line with findingsrom other studies; for instance, fever was present in all ofur cases complicated with pneumonia and in 91% ofneumonia cases of the study of Uchida and coworkerstudy.9 Thus, when fever is present, a more serious clinicalourse of CMV disease should be anticipated.

Tissue invasion is one of the characteristic features ofMV infection in transplant recipients and pneumonia isne of the most frequent forms of CMV organ involve-ent.6,9 Viral invasion of tissues in our series occurred in 16

ases, and the clinical course of these conditions was

oderate to severe. pneumonia, which occurred in six Z

atients, represented an incidence lower than rates docu-ented in other studies. Abbott and coworkers reported

neumonia in 17% of their 422 kidney transplant patients.5

nother study on clinical manifestations of CMV in kidneyecipients revealed a 9% pneumonia rate.7

Most of the signs and symptoms in kidney recipients withMV were not specific for CMV infection, thus diagnostic

esting is essential. At our hospital, we investigated alluspect CMV cases with the CMV antigenemia assaypp65). On the other hand, Durlik and colleagues found notatistical correlation between a positive result on this testnd clinical manifestations of CMV in kidney recipients (P

.98).7 This suggests that clinical findings are generally noteliable for diagnosing CMV in this patient group and moreccurate laboratory investigations are needed to identifyhether the nonspecific manifestations are due to CMV.

EFERENCES

1. Rubin RH: Infectious disease complications of renal trans-lantation. Kidney Int 44:221, 19932. Brennan DC: Cytomegalovirus in renal transplantation. J Am

oc Nephrol 12:848, 20013. Nett PC, Heisey DM, Fernandez LA, et al: Association of

ytomegalovirus disease and acute rejection with graft loss inidney transplantation. Transplantation 78:1036, 20044. Lautenschlager I: Cytomegalovirus and solid organ transplan-

ation: an update. Curr Opin Transplant 8:269, 20035. Abbott KC, Hypolite IO, Viola R, et al: Hospitalizations for

ytomegalovirus disease after renal transplantation in the Unitedtates. Ann Epidemiol 12:402,20026. Farrugia E, Schwab TR: Management and prevention of

ytomegalovirus infection after renal transplantation. Mayo Clinroc 67:879, 19927. Durlik M, Siennicka J, Litwinska B, et al: Clinical manifesta-

ions and diagnosis of cytomegalovirus infection in renal allograftecipients. Transplant Proc 33:1237, 2001

8. Onuigbo M, Haririan A, Ramos E, et al: Cytomegalovirus-nduced glomerular vasculopathy in renal allografts: a report of twoases. Am J Transplant 2:684, 2002

9. Uchida K, Nakayama H, Yoshida K, et al: Opportunisticneumonia after kidney transplantation. Nihon Kokyuki Gakkai

asshi 39:166, 2001