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linical Manifestation, Laboratory Findings, and the Response ofreatment in Kidney Transplant Recipients With CMV Infection

. Razeghi, A. Hadadi, M. Mansor-Kiaei, M. Molavi, P. Khashayar, and G. Pourmand

ABSTRACT

Objectives. To report clinical manifestations, laboratory findings, and treatment outcomesof in kidney transplant recipients who had cytomegalovirus (CMV) infections.Methods. This retrospective study evaluated the records of kidney transplant recipientsfollowed regularly from 2001 to 2006. In some patients information was also gatheredthrough a telephone call or physical examination. The CMV infection diagnosis was alsomade by detecting PP.65 antigen per 50,000 peripheral blood leukocytes.Results. Of the 200 kidney transplant recipients, 66 were infected with CMV including42 men and 24 women. The mean patient age was 40 � 13 years (range, 14 to 67 years).Seventy-nine percent of the infected patients were diagnosed during the first 6-monthsafter transplantation. All except 22 patients (33%) had constitutional complaints. Feverwas present in 65% of patients, abdominal pain in 21%, diarrhea in 20%, and vomiting in15%. Likewise, pulmonary complaints including cough and dyspnea were reported by 32%and 23%, respectively. However, 20% of patients were completely asymptomatic. Hema-tologic laboratory data showed anemia (64%), thrombocytopenia (47%), and leukopenia(21%). Seventy eight percent of patients had a serum creatinine �2 mg/dL beforeinfection, but it was �2 in just 26% at the time CMV was diagnosed and 60% aftertreatment. Antiviral therapy included intravenous gancyclovir in 80% of patients andgancyclovir plus oral acyclovir in 20%. Corticosteroid pulse therapy was also administeredin 78% of patients. No statistically significant correlation was observed between CMVantigen load and the severity of clinical manifestations or the time of response to treatmentor the recurrence prognosis. In our series, 1 patient died, 28 treated patients (42%)experienced CMV recurrence, and 37 (56%) showed no recurrence.Conclusions. CMV infection should be considered in any renal transplant recipient whohas a rise in creatinine even if symptom-free. Despite the results of other studies, we found

no prognostic value for the viral antigen load.

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YTOMEGALOVIRUS (CMV) infection continues tobe a major clinical problem after solid organ trans-

lantation with significant morbidity and mortality. Itauses symptomatic disease in 35% and death in 2% ofenal transplant recipients.1

In the general population, exposure to the virus, asndicated by the presence of detectable IgG anti-CMVntibodies in the plasma, increases with age. It is present inore than two thirds of donors and recipients before

ransplantation. Thus, transplants between donors who areeropositive for CMV and recipients who are seronegativeD�/R�) have the highest incidence (60% to 80%) of

ubsequent CMV infections.5 T

2007 by Elsevier Inc. All rights reserved.60 Park Avenue South, New York, NY 10010-1710

ransplantation Proceedings, 39, 993–996 (2007)

CMV disease usually is manifested within 2 to 6 monthsfter renal transplantation. The clinical manifestation in-lude signs and symptoms: fatigue, aching joints, headaches,

From the Department of Nephrology, (E.R.), the Department ofnfection (A.H.) the Kidney Transplantation Research Center (M.M-K.,

.M.), the Research Center, Tehran University of Medical Sciences,ina Hospital; Research Center (P.K.), Sina Hospital, Medical Sci-nces, University of Tehran; and the Department of Urology (G.P.),ina Hospital, Medical Sciences, University of Tehran, Tehran, Iran.Address reprint requests to E. Razeghi, Department ofephrology, Sina Hospital, Imam Khomeini St, 11367-46911,

ehran, Iran. E-mail: Effat162@yahoo.com

0041-1345/07/$–see front matterdoi:10.1016/j.transproceed.2007.02.014

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994 RAZEGHI, HADADI, MANSOR-KIAEI ET AL

igh temperature, leukopenia, anemia, thrombocytopenia,typical lymphocytosis, and deranged liver function tests.1

CMV infection can be identified by several methods,ncluding pp-65 antigen detection on leukocytes, polymer-se chain reaction (PCR) to detect CMV DNA in plasmandicating active viral replication, viral culture, seroconver-ion with the appearance of anti-CMV IgM antibodies; aourfold increase in preexisting anti-CMV IgG titers forualitative detection of CMV.3

The clinical presentation, laboratory findings, and treat-ent outcomes in kidney transplant recipients with CMV

nfection in our center have not been studied extensively.e therefore conducted a retrospective analysis to examine

he incidence, clinical pattern of symptomatic CMV infec-ion, and factors affecting its presentation and treatmentutcomes in our renal patients.

ETHODS

e retrospectively reviewed the records of all renal transplant pa-ients in our center from 2001 to 2006. Criteria for the diagnosis ofymptomatic CMV infection included the presence of symptoms andigns or laboratory abnormalities plus detectable pp-65 antigen–ositive cells per 50,000 peripheral blood leukocytes. Although PCRethods are emerging as the most clinically useful diagnostic methodith high sensitivity and specificity combined with rapid availability of

esults. We used the pp-65 antigen to detect this disease because PCRas not yet standardized in all laboratories in Iran and the pp-65ntigen test is less expensive and more accessible.

Depending on the organs or systems involved, the presentationsere divided into (1) fever (�38°C); (2) hematologic involvementith either leukopenia (WBC � 4300/L) or thrombocytopenia

platelets �100,000/L) or anemia (significant decrease in hemoglo-in); (3) a 25% rise in serum creatinine; (4) liver functionerangement (ALT or AST � 40 IU/L); (4) pneumonitis; (5)astrointestinal tract involvement; or (6) others. Patients fulfillingriteria for diagnosis of symptomatic CMV infection were enrolledn this study.

For statistical analysis, the �2 test was used to compare differ-nces in proportions, and student’s t test was used to compareean values.

ESULTS

here was evidence of CMV disease in 66 of 200 (33%)atients, which was diagnosed at a median time of 9.7onths (just after transplant to 10 years) posttransplanta-

ion; 52 (79%) diagnoses were made within 6 monthsosttransplantation. There were 42 males and 24 femaleffected of overall mean age of 40 � 13 years (range, 14 to7 years).It is interesting to note that all donors and recipients

nrolled in our study had previous exposure to CMV. Afterhe diagnosis of CMV, the mean duration of pp65 antigen-mia was 13.8 days (range, 1 to 10 weeks). The clinical andaboratory manifestations are shown in Table 1. All 27atients who were referred due to symptoms related toneumonia had normal chest x-rays.A history of antilymphocyte globulin therapy was present

n 29 (44%) of the patients. The correlation between viral b

oad and days needed for the patient to be cured was notignificant (P � .082).

Patients were treated with intravenous gancyclovir: oralcyclovir was added in 12 (18%) patients. Pulse therapy wasone in 50(76%).Twenty-eight cases of recurrence and one death were

eported during this study. The estimated mean creatininealue was higher among the patients who experienced infec-ions (3.3) compared with the value estimated before diagnosis2.1) and after treatment (2.4). The difference in the meanreatinine before, at the time of CMV detection, and uponure was statistically significant (P � .001). Seventy- eightercent of patients had a creatinine � 2 mg/dL before the

nfection; creatinine remained � 2 in only 26% when CMVas diagnosed, and in 60% after the treatment.

ISCUSSION

t is well known that CMV infections are common among inenal transplant recipients.4 Symptomatic CMV infectionsnclude a heterogeneous group of clinical features andaboratory findings, ranging from mild infection to severeisease. The incidence of symptomatic CMV disease in ourenter was 33%. The median time to diagnosis was 9.7onths posttransplant, 79% displayed symptomatic CMV

nfections within the first 6 months. This period representshe maximal immunosuppression for prevention and treat-ent of acute rejection.Recently, attention has been focused on the role of the

uantitative CMV viral load as an accurate diagnostic testor CMV. Although in general, CMV viral load correlatesith viral disease, CMV disease can occur in the setting oflow viral load. In many studies, viral load was reported as

n optimal parameter for monitoring responses to antiviralherapy, whereas in our study there was no correlationetween viral load and days needed for cure.3

CMV disease most commonly presents as a febrile illness,

Table 1. Clinical and Laboratory Manifestation of CMV inThis Study

Frequency (%)

Constitutional complaints 44 (67)Hematologic abnormalities

Anemia 42 (64)Leukopenia 14 (21)Thrombocytopenia 31 (47)

Fever 43 (65)GI effects

Abdominal pain 14 (21)Diarrhea 13 (20)Vomiting 10 (15)

PneumonitisCough 21 (32)Sputum 9 (14)Dyspnea 15 (23)

Abnormal liver tests 14 (21)Asymptomatic 13 (20)

ut can present with only blood abnormalities (leukopenia,

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KIDNEY RECIPIENTS WITH CMV INFECTION 995

hrombocytopenia, anemia, elevated liver enzymes) or withymptoms of solid organ involvement (pneumonia, retinitis,olitis).2 The clinical presentation in this study was similaro other studies. Constitutional complaints were the mostommon presentation, followed by leukopenia, anemia,hrombocytopenia, fever, gastrointestinal tract involvement,neumonia, and abnormal liver function. However, pneu-onitis, a severe complication, was rarely reported in other

tudies.1 Some of the clinical manifestations could be theesult of CMV infection and the side effect of the drugs, buts in our study they disappeared after the cure, suggestingMV infection to be the main cause.Although mycophenolate mofetil has been shown inany studies to be the agent responsible for increasing the

ncidence CMV infection,5 our study reported that theombination of mycophenolate mofetil, cyclosporine Ne-ral, and prednisolone used after the transplant in ourenter, has made the manifestation of CMV disease milder;n other words organ involvement seemed to occur lessrequently after using this combination (data not shown).rophylactic, deferred treatment, and preemptive treat-ent strategies have been described in renal transplanta-

ion but not compared adequately to determine the besttrategy.5 In our center, prophylactic treatment included 2eeks of gancyclovir in patients who needed ALG or ATG

o prevent rejection or as induction therapy.In the literature, patients were treated for CMV disease

t the discretion of the attending clinician with intravenousancyclovir for a course of 10 to 14 days followed by 3onths of oral acyclovir with a temporary reduction in

mmunosuppression. Oral valgancyclovir was also indicatedor a 3-month course in patients with less severe symptoms.5

ur patients were treated with intravenous gancyclovirntil a week after disappearance of CMV antigen. A smallroportion of patients (12%) required treatment using oralcyclovir (400 to 800 mg four times a day) plus gancyclovirepending on the patient’s compliance and the severity ofhe disease. The reason for giving the additive drug was torevent recurrence. Valgancyclovir was not prescribed inny patient because it is too expensive and not available forll. In addition, there was no relation between the type ofrug and the duration of treatment.Although a history of receiving antilymphocyte globulin

as present in 29 (43.9%) of the patients; there wasn’t aignificant relation between receiving antilymphocyte glob-lin and viral load in these patients. In a study performed inngland, the difference in incidence of acute rejectionetween patients experiencing no infection (7.1%) andhose experiencing disease (35%) was clinically but nottatistically significant due to the small number of patientsn each group. One can speculate that the increased inci-ence of acute rejection among patients experiencing CMVisease is the cause of worse renal function at the first yearollowing transplantation. In our study, 50 of 66 patientseeded pulse therapy due to evidence of possible rejectiony a raised creatinine in the remaining group, there was no

vidence of rejection. Various studies have reported relapse d

f CMV infection after treatment with gancyclovir is moreikely to occur if gancyclovir is discontinued while viraleplication is ongoing. Therefore, it has been recommendedo continue gancyclovir until viral replication is no longervident.2

As a result of the widespread use of antiviral prophylaxisnd preemptive therapy, the incidence and severity of CMVisease and its indirect effects are significantly reduced.owever, there is the increasing recognition of gancyclovir-

esistant CMV infection. The overall incidence of gancyclovir-esistant CMV infection is 2.1%, which varies widely amongransplant groups, with the highest incidence among recip-ents of lung and combined kidney- pancreas transplants.

ancyclovir-resistant CMV infection has been observed in%, 0.3%, 1%, 9%, and 13% among liver, heart, kidney,ung, and combined pancreas–kidney transplant recipients,espectively. In our study recurrence was reported in 2342.4%) cases.1 There was no relation between recurrencend viral load. The high incidence of recurrence in ourtudy may be due to the short-term treatment used for theseatients, whereas other studies have reported that 3 monthsontinued treatment with an oral agent is necessary torevent recurrence.According to our data, the patients who experience CMV

isease have poorer renal function at the time of CMViagnosis. The difference in the mean creatinine betweenefore, at the time of CMV detection, and when the patientas cured was statistically significant. Thus, CMV infectionay influence renal function as creatinine was reduced to

ts normal range after CMV treatment.CMV is also a significant underlying cause of morbidity

nd mortality in this setting. The impact of CMV on overallortality was examined in a prospective, single-center study

f almost 500 patients who did not receive inductionherapy or CMV prophylaxis. Patients were monitored byeekly CMV pp-65 antigenemia for 100 days and followed

or a median time of 66 months. Compared to those withoutMV, CMV disease was associated with a relative risk ofverall mortality of 2.5, and surprisingly, asymptomaticMV infection was associated with a relative risk of overallortality of 2.9.1 In our study, one patient died of cardiac

roblems apparently unrelated to CMV infection. It is possi-le that the diagnosis and treatment of CMV infection wasone before organ involvement.In conclusion, symptomatic CMV infection was relatively

ommon among our renal transplant population. Comingcross any post transplant patient with constitutional symp-oms or an elevated serum creatinine, clinicians must alwayshink of CMV infection. This presumption along with thefforts to develop more sensitive methods to detect earlyMV infections may be of value for surveillance strategies.ecause of the high recurrence rate in these patients, there

s a need for long-term treatment. Prophylaxis and treat-ent of CMV infection may be enhanced with the intro-

uction of newer agents such as valgancyclovir.

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EFERENCES

1. Yeung JS, Tong KL, Chan HWH: Clinical pattern, riskactors, and outcome of CMV infection in renal transplant recipi-nts: Local experience. Transplant Proc 30:3144, 1998

2. Geddes C, Church C, Collidge T, et al: Management ofytomegalovirus infection by weekly surveillance after renal trans-lant: analysis of cost, rejection and renal function. Nephrol Dial

ransplant 18:1891, 2003 c

3. Nordoy I, Muller F, Nordal K, et al: Immunologic parameterss predictive factors of cytomegalovirus disease in renal allograftecipients. J Infect dis 180:195, 1999

4. Armstrong J, Evans A, Rao N, et al: Viral infections in renalransplant recipients. Infect Immuni 14:970, 1976

5. Waiser J, Budde K, Schreiber M, et al: Effectiveness ofeferred therapy with gancyclovir in renal allograft recipients with

ytomegalovirus disease. Transplant Proc 30:2083, 1998