Clinical Manifestation, Laboratory Findings, and the Response of


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Clinical Manifestation, Laboratory Findings, and the Response of

  1. 1. Clinical Manifestation, Laboratory Findings, and the Response of Treatment in Kidney Transplant Recipients With CMV Infection E. Razeghi, A. Hadadi, M. Mansor-Kiaei, M. Molavi, P. Khashayar, and G. Pourmand ABSTRACT Objectives. To report clinical manifestations, laboratory findings, and treatment outcomes of in kidney transplant recipients who had cytomegalovirus (CMV) infections. Methods. This retrospective study evaluated the records of kidney transplant recipients followed regularly from 2001 to 2006. In some patients information was also gathered through a telephone call or physical examination. The CMV infection diagnosis was also made by detecting PP.65 antigen per 50,000 peripheral blood leukocytes. Results. Of the 200 kidney transplant recipients, 66 were infected with CMV including 42 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-months after transplantation. All except 22 patients (33%) had constitutional complaints. Fever was present in 65% of patients, abdominal pain in 21%, diarrhea in 20%, and vomiting in 15%. 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 before infection, but it was 2 in just 26% at the time CMV was diagnosed and 60% after treatment. Antiviral therapy included intravenous gancyclovir in 80% of patients and gancyclovir plus oral acyclovir in 20%. Corticosteroid pulse therapy was also administered in 78% of patients. No statistically significant correlation was observed between CMV antigen load and the severity of clinical manifestations or the time of response to treatment or 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 who has a rise in creatinine even if symptom-free. Despite the results of other studies, we found no prognostic value for the viral antigen load. C YTOMEGALOVIRUS (CMV) infection continues to be a major clinical problem after solid organ trans- plantation with significant morbidity and mortality. It CMV disease usually is manifested within 2 to 6 months after renal transplantation. The clinical manifestation in- clude signs and symptoms: fatigue, aching joints, headaches, causes symptomatic disease in 35% and death in 2% of renal transplant recipients.1 In the general population, exposure to the virus, as From the Department of Nephrology, (E.R.), the Department of Infection (A.H.) the Kidney Transplantation Research Center (M.M-K., indicated by the presence of detectable IgG anti-CMV M.M.), the Research Center, Tehran University of Medical Sciences, antibodies in the plasma, increases with age. It is present in Sina Hospital; Research Center (P.K.), Sina Hospital, Medical Sci- more than two thirds of donors and recipients before ences, University of Tehran; and the Department of Urology (G.P.), transplantation. Thus, transplants between donors who are Sina Hospital, Medical Sciences, University of Tehran, Tehran, Iran. seropositive for CMV and recipients who are seronegative Address reprint requests to E. Razeghi, Department of (D /R ) have the highest incidence (60% to 80%) of Nephrology, Sina Hospital, Imam Khomeini St, 11367-46911, subsequent CMV infections.5 Tehran, Iran. E-mail: © 2007 by Elsevier Inc. All rights reserved. 0041-1345/07/$–see front matter 360 Park Avenue South, New York, NY 10010-1710 doi:10.1016/j.transproceed.2007.02.014 Transplantation Proceedings, 39, 993–996 (2007) 993
  2. 2. 994 RAZEGHI, HADADI, MANSOR-KIAEI ET AL high temperature, leukopenia, anemia, thrombocytopenia, Table 1. Clinical and Laboratory Manifestation of CMV in atypical lymphocytosis, and deranged liver function tests.1 This Study CMV infection can be identified by several methods, Frequency (%) including pp-65 antigen detection on leukocytes, polymer- Constitutional complaints 44 (67) ase chain reaction (PCR) to detect CMV DNA in plasma Hematologic abnormalities indicating active viral replication, viral culture, seroconver- Anemia 42 (64) sion with the appearance of anti-CMV IgM antibodies; a Leukopenia 14 (21) fourfold increase in preexisting anti-CMV IgG titers for Thrombocytopenia 31 (47) qualitative detection of CMV.3 Fever 43 (65) The clinical presentation, laboratory findings, and treat- GI effects ment outcomes in kidney transplant recipients with CMV Abdominal pain 14 (21) infection in our center have not been studied extensively. Diarrhea 13 (20) Vomiting 10 (15) We therefore conducted a retrospective analysis to examine Pneumonitis the incidence, clinical pattern of symptomatic CMV infec- Cough 21 (32) tion, and factors affecting its presentation and treatment Sputum 9 (14) outcomes in our renal patients. Dyspnea 15 (23) Abnormal liver tests 14 (21) METHODS Asymptomatic 13 (20) We retrospectively reviewed the records of all renal transplant pa- tients in our center from 2001 to 2006. Criteria for the diagnosis of load and days needed for the patient to be cured was not symptomatic CMV infection included the presence of symptoms and significant (P .082). signs or laboratory abnormalities plus detectable pp-65 antigen– positive cells per 50,000 peripheral blood leukocytes. Although PCR Patients were treated with intravenous gancyclovir: oral methods are emerging as the most clinically useful diagnostic method acyclovir was added in 12 (18%) patients. Pulse therapy was with high sensitivity and specificity combined with rapid availability of done in 50(76%). results. We used the pp-65 antigen to detect this disease because PCR Twenty-eight cases of recurrence and one death were was not yet standardized in all laboratories in Iran and the pp-65 reported during this study. The estimated mean creatinine antigen test is less expensive and more accessible. value was higher among the patients who experienced infec- Depending on the organs or systems involved, the presentations tions (3.3) compared with the value estimated before diagnosis were divided into (1) fever ( 38°C); (2) hematologic involvement (2.1) and after treatment (2.4). The difference in the mean with either leukopenia (WBC 4300/L) or thrombocytopenia creatinine before, at the time of CMV detection, and upon (platelets 100,000/L) or anemia (significant decrease in hemoglo- cure was statistically significant (P .001). Seventy- eight bin); (3) a 25% rise in serum creatinine; (4) liver function derangement (ALT or AST 40 IU/L); (4) pneumonitis; (5) percent of patients had a creatinine 2 mg/dL before the gastrointestinal tract involvement; or (6) others. Patients fulfilling infection; creatinine remained 2 in only 26% when CMV criteria for diagnosis of symptomatic CMV infection were enrolled was diagnosed, and in 60% after the treatment. in this study. For statistical analysis, the 2 test was used to compare differ- DISCUSSION ences in proportions, and student’s t test was used to compare It is well known that CMV infections are common among in mean values. renal transplant recipients.4 Symptomatic CMV infections include a heterogeneous group of clinical features and RESULTS laboratory findings, ranging from mild infection to severe There was evidence of CMV disease in 66 of 200 (33%) disease. The incidence of symptomatic CMV disease in our patients, which was diagnosed at a median time of 9.7 center was 33%. The median time to diagnosis was 9.7 months (just after transplant to 10 years) posttransplanta- months posttransplant, 79% displayed symptomatic CMV tion; 52 (79%) diagnoses were made within 6 months infections within the first 6 months. This period represents posttransplantation. There were 42 males and 24 female the maximal immunosuppression for prevention and treat- affected of overall mean age of 40 13 years (range, 14 to ment of acute rejection. 67 years). Recently, attention has been focused on the role of the It is interesting to note that all donors and recipients quantitative CMV viral load as an accurate diagnostic test enrolled in our study had previous exposure to CMV. After for CMV. Although in general, CMV viral load correlates the diagnosis of CMV, the mean duration of pp65 antigen- with viral disease, CMV disease can occur in the setting of emia was 13.8 days (range, 1 to 10 weeks). The clinical and a low viral load. In many studies, viral load was reported as laboratory manifestations are shown in Table 1. All 27 an optimal parameter for monitoring responses to antiviral patients who were referred due to symptoms related to therapy, whereas in our study there was no correlation pneumonia had normal chest x-rays. between viral load and days needed for cure.3 A history of antilymphocyte globulin therapy was present CMV disease most commonly presents as a febrile illness, in 29 (44%) of the patients. The correlation between viral but can present with only blood abnormalities (leukopenia,
  3. 3. KIDNEY RECIPIENTS WITH CMV INFECTION 995 thrombocytopenia, anemia, elevated liver enzymes) or with of CMV infection after treatment with gancyclovir is more symptoms of solid organ involvement (pneumonia, retinitis, likely to occur if gancyclovir is discontinued while viral colitis).2 The clinical presentation in this study was similar replication is ongoing. Therefore, it has been recommended to other studies. Constitutional complaints were the most to continue gancyclovir until viral replication is no longer common presentation, followed by leukopenia, anemia, evident.2 thrombocytopenia, fever, gastrointestinal tract involvement, As a result of the widespread use of antiviral prophylaxis pneumonia, and abnormal liver function. However, pneu- and preemptive therapy, the incidence and severity of CMV monitis, a severe complication, was rarely reported in other disease and its indirect effects are significantly reduced. studies.1 Some of the clinical manifestations could be the However, there is the increasing recognition of gancyclovir- result of CMV infection and the side effect of the drugs, but resistant CMV infection. The overall incidence of gancyclovir- as in our study they disappeared after the cure, suggesting resistant CMV infection is 2.1%, which varies widely among CMV infection to be the main cause. transplant groups, with the highest incidence among recip- Although mycophenolate mofetil has been shown in ients of lung and combined kidney- pancreas transplants. many studies to be the agent responsible for increasing the incidence CMV infection,5 our study reported that the Gancyclovir-resistant CMV infection has been observed in combination of mycophenolate mofetil, cyclosporine Ne- 0%, 0.3%, 1%, 9%, and 13% among liver, heart, kidney, oral, and prednisolone used after the transplant in our lung, and combined pancreas– kidney transplant recipients, center, has made the manifestation of CMV disease milder; respectively. In our study recurrence was reported in 23 in other words organ involvement seemed to occur less (42.4%) cases.1 There was no relation between recurrence frequently after using this combination (data not shown). and viral load. The high incidence of recurrence in our Prophylactic, deferred treatment, and preemptive treat- study may be due to the short-term treatment used for these ment strategies have been described in renal transplanta- patients, whereas other studies have reported that 3 months tion but not compared adequately to determine the best continued treatment with an oral agent is necessary to strategy.5 In our center, prophylactic treatment included 2 prevent recurrence. weeks of gancyclovir in patients who needed ALG or ATG According to our data, the patients who experience CMV to prevent rejection or as induction therapy. disease have poorer renal function at the time of CMV In the literature, patients were treated for CMV disease diagnosis. The difference in the mean creatinine between at the discretion of the attending clinician with intravenous before, at the time of CMV detection, and when the patient gancyclovir for a course of 10 to 14 days followed by 3 was cured was statistically significant. Thus, CMV infection months of oral acyclovir with a temporary reduction in may influence renal function as creatinine was reduced to immunosuppression. Oral valgancyclovir was also indicated its normal range after CMV treatment. for a 3-month course in patients with less severe symptoms.5 CMV is also a significant underlying cause of morbidity Our patients were treated with intravenous gancyclovir and mortality in this setting. The impact of CMV on overall until a week after disappearance of CMV antigen. A small mortality was examined in a prospective, single-center study proportion of patients (12%) required treatment using oral of almost 500 patients who did not receive induction acyclovir (400 to 800 mg four times a day) plus gancyclovir therapy or CMV prophylaxis. Patients were monitored by depending on the patient’s compliance and the severity of weekly CMV pp-65 antigenemia for 100 days and followed the disease. The reason for giving the additive drug was to prevent recurrence. Valgancyclovir was not prescribed in for a median time of 66 months. Compared to those without any patient because it is too expensive and not available for CMV, CMV disease was associated with a relative risk of all. In addition, there was no relation between the type of overall mortality of 2.5, and surprisingly, asymptomatic drug and the duration of treatment. CMV infection was associated with a relative risk of overall Although a history of receiving antilymphocyte globulin mortality of 2.9.1 In our study, one patient died of cardiac was present in 29 (43.9%) of the patients; there wasn’t a problems apparently unrelated to CMV infection. It is possi- significant relation between receiving antilymphocyte glob- ble that the diagnosis and treatment of CMV infection was ulin and viral load in these patients. In a study performed in done before organ involvement. England, the difference in incidence of acute rejection In conclusion, symptomatic CMV infection was relatively between patients experiencing no infection (7.1%) and common among our renal transplant population. Coming those experiencing disease (35%) was clinically but not across any post transplant patient with constitutional symp- statistically significant due to the small number of patients toms or an elevated serum creatinine, clinicians must always in each group. One can speculate that the increased inci- think of CMV infection. This presumption along with the dence of acute rejection among patients experiencing CMV efforts to develop more sensitive methods to detect early disease is the cause of worse renal function at the first year CMV infections may be of value for surveillance strategies. following transplantation. In our study, 50 of 66 patients Because of the high recurrence rate in these patients, there needed pulse therapy due to evidence of possible rejection is a need for long-term treatment. Prophylaxis and treat- by a raised creatinine in the remaining group, there was no ment of CMV infection may be enhanced with the intro- evidence of rejection. Various studies have reported relapse duction of newer agents such as valgancyclovir.
  4. 4. 996 RAZEGHI, HADADI, MANSOR-KIAEI ET AL REFERENCES 3. Nordoy I, Muller F, Nordal K, et al: Immunologic parameters as predictive factors of cytomegalovirus disease in renal allograft 1. Yeung JS, Tong KL, Chan HWH: Clinical pattern, risk recipients. J Infect dis 180:195, 1999 factors, and outcome of CMV infection in renal transplant recipi- ents: Local experience. Transplant Proc 30:3144, 1998 4. Armstrong J, Evans A, Rao N, et al: Viral infections in renal 2. Geddes C, Church C, Collidge T, et al: Management of transplant recipients. Infect Immuni 14:970, 1976 cytomegalovirus infection by weekly surveillance after renal trans- 5. Waiser J, Budde K, Schreiber M, et al: Effectiveness of plant: analysis of cost, rejection and renal function. Nephrol Dial deferred therapy with gancyclovir in renal allograft recipients with Transplant 18:1891, 2003 cytomegalovirus disease. Transplant Proc 30:2083, 1998