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Signs and Symptoms of Cytomegalovirus Disease in Kidney Transplant Recipients
Signs and Symptoms of Cytomegalovirus Disease in Kidney Transplant Recipients F. 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 kidney recipients who developed CMV disease between 1984 and December 2002 for demographic 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 alkaline phosphatase in 24, leukocytosis in 22, and leukopenia in 21. Tissue involvement was relatively rare, but six patients had pneumonia, two had conjunctivitis, and one had vascular dermatitis. Four percent of the patients had received intravenous ganciclovir prophylaxis, and 7% had received oral ganciclovir prophylaxis. Fever was associated with number of hospitalizations (P ⫽ .006), elevated creatinine (P ⫽ .006), nausea (P ⫽ .017), vomiting (P ⫽ .031), and previous posttransplantation infections (P ⬍ .001). All the patients with conjunctivitis, pneumonia, pulmonary symptoms, and abnormal heart sounds and most of those with arthralgia, nausea, and vomiting were febrile during their CMV disease course. Conclusion. Our findings showed that leukocytosis should be considered as much as leukopenia when CMV disease is suspected. CMV-induced pneumonia is not common in renal transplant recipients compared to other organ transplant recipients. CMV invasion to 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 most frequent type of infection in kidney transplant recipients.1,2 The prevalence of CMV infection, as signaled by detectable levels of anti-CMV immunoglobulin G antibodies in serum, increases with age in the general population, and serological findings indicate that more than two-thirds of donors and recipients have had this infection prior to transplantation.1 Association of CMV infection with graft outcome has been proven in many studies, which seems to be due to its additional immunosuppressive effects. In addition its immunocompromising effects can lead to other potential complications in recipients.3 The clinical manifestations of CMV disease in renal transplant patients often differ from those in the general population. Consequently, in kidney recipients, it can be difficult to diagnose CMV infection based on clinical features.4 Careful interpretation of presenting signs and symp-
toms of CMV infection is important in this patient group, but the literature contains little information related to this. In attempt to expand knowledge in this area, we reviewed all cases of CMV disease that occurred in kidney recipients at our center in order to evaluate the signs and symptoms of CMV disease in this patient group. MATERIALS AND METHODS From 1984 to December 2002, among 1925 patients who had undergone kidney transplant surgery, 100 were diagnosed with From the Urology and Nephrology Research Center, Shaheed Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. Address reprint requests to Farhat Farrokhi, Urology/Nephrology Research Center (UNRC), No. 44, 9th Boustan, Pasdaran, Tehran, 1666679951, Iran. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.07.051
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 37, 3056 –3058 (2005)
SIGNS AND SYMPTOMS OF CMV DISEASE
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Table 1. Laboratory Findings During CMV Clinical Course for the 100 Kidney Recipients With CMV Disease Mean ⫾ SD
White blood cells Hemoglobin Hematocrit Platelets Creatinine BUN ALT AST Alkaline phospatase
6820.4 ⫾ 3223.9/mm 10.8 ⫾ 2.4 mg/dL 31.1 ⫾ 69% 212189.7 ⫾ 88661.5/mm3 2.4 ⫾ 1.8 mg/dL 60.5 ⫾ 38.1 mg/dL 26.8 ⫾ 33.9 IU/L 23.8 ⫾ 16.1 IU/L 213.3 ⫾ 137.6 IU/L 3
Increased (%)
Decreased (%)
22 — — 11 71 67 19 15 24
21 59 54 43 — — — — —
BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransaminase.
CMV disease at some stage after transplantation. In each case, CMV disease was diagnosed according to clinical features and detection of CMV antigen (pp65 antigenemia) in serum. The 100 cases were retrospectively investigated for details related to transplantation, demographic characteristics, as well as physical examination and laboratory findings after hospitalization for CMV disease. The results were statistically analyzed with the chi-square and the Student t tests to assess differences between subgroups of patients, based on the presence of fever.
RESULTS
Of the 100 kidney recipients with CMV disease, 62 were men and 38 were women. The mean age at time of transplantation was 33.8 ⫾ 15.1 years. The median interval from transplantation to diagnosis with CMV was 3.4 months (range, 1 to 9 months). Prior to transplantation, the mean dialysis duration for the group was 14.9 ⫾ 22.9 months. Seventy-seven patients had been on hemodialysis and four had been on peritoneal dialysis. The other 19 patients had undergone preemptive transplantation. Ninetyfour of the patients had received their first transplant, five had received their second graft, and one had received a third graft. Eighty-six of the transplants were from living unrelated donors, 10 were from living related donors, and four were deceased donor grafts. Thirty-seven patients had received intensive antirejection agents after transplantation (pulse-steroid therapy in 27 cases, antilymphocyte globulin in 10 cases). The mean number of hospitalizations after transplantation was 2.5 ⫾ 2.1. More than 90% of the recipients and donors were positive for CMV immunoglobulin G at the time of transplantation. The following signs and symptoms were present during hospitalization for CMV disease: fever in 71 cases, nausea in 32, vomiting in 26, pulmonary signs and symptoms in 20, arthralgia in 10, and ocular abnormalities in four. CMV tissue invasion occurred in 16 patients, including heart involvement (new abnormal heart sounds) in seven, pneumonia in six, conjunctivitis in two, and dermal vasculitis in one. The abnormal laboratory findings were elevated creatinine (71 cases), thrombocytopenia (43), leukocytosis (22),
leukopenia (21), elevated alanine aminotransferase (19), and elevated aspartate aminotransferase (15) (Table 1). Analysis revealed associations between fever and number of hospitalizations after transplantation (P ⫽ .006), elevated creatinine (P ⫽ .006), nausea (P ⫽ .017), vomiting (P ⫽ .031), number of infection episodes after transplantation (P ⫽ .001), and pulmonary symptoms (P ⫽ .002). All of the patients with conjunctivitis, pneumonia, pulmonary symptoms, and abnormal heart sounds were febrile during hospitalization for CMV disease (Table 2). Eighty-eight of the patients had not been given CMV prophylaxis. Of the remaining 12 patients, seven had received a 12-week course of oral ganciclovir and four had received a 2-week course of intravenous ganciclovir. Two of the patients who had been given oral prophylaxis and two who had received intravenous prophylaxis had at least one episode of fever. Of the 88 patients who had not received CMV prophylaxis, 71.6% had at least one episode of fever, while none of the patients who received prophylactic treatment developed fever (P ⫽ .018) or CMV tissue invasion. No deaths occurred and all of the patients responded to treatment. Table 2. Association of Fever With Other Characteristics of Patients and CMV Disease
Age (y) Dialysis duration (months) No. of hospitalizations after transplantation History of dialysis ALG/pulse Posttransplant infections Nausea Vomiting Arthralgia Pulmonary symptoms Pneumonia Abnormal heart sounds Vasculitis Conjunctivitis
Fever
No fever
33.3 ⫾ 18.4 13.5 ⫾ 23.1
31.1 ⫾ 15.0 15.4 ⫾ 16.7
P value
.60 .71
2.9 ⫾ 2.2 79.1% 73.1% 71.6% 40.2% 32.8% 13.4% 28.3% 8.9% 10.4% 1.5% 2.9%
1.5 ⫾ 1.5 84.6% 58.4% 25.9% 14.8% 11.2% 3.7% 0% 0% 0% 0% 0%
.006 .12 .47 .001 .017 .031 .16 .002 .10 .081 .52 .38
ALG, antilymphocyte globulin. *Administration of antilymphocyte globulin or steroid-pulse therapy before CMV disease.
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DISCUSSION
In kidney recipients, CMV infection most often occurs in the first few months after transplantation.1 In the 100 cases in our study, the median interval from transplantation to diagnosis with CMV was 3.4 months, findings consistent with those reported by Abbott and colleagues.5 They found that 79% of hospitalizations for CMV infection in kidney recipients occurred in the first 6 months after transplantation. Farrugia and Schwab identified fever, malaise, myalgia, leukopenia, and elevated transaminase levels as the most common manifestations of CMV disease in kidney recipients.6 Ranked in descending order, the most common manifestations of CMV in our series were fever, elevated creatinine, thrombocytopenia, nausea, vomiting, leukocytosis, leucopenia, and pulmonary signs and symptoms. In a study conducted by Durlik et al on clinical manifestations and diagnosis of CMV infection in renal allograft recipients, the most frequent clinical manifestations of CMV disease were fever (91%), leukopenia (82%), and thrombocytopenia (27%).7 Compared with these rates, our frequency of fever was lower (71%) and our rate of leukocytosis was high (22%), which is a considerable finding. Elevated serum creatinine was a considerable finding in our series; however, not all these patients were investigated with renal biopsy to assess for CMV-induced glomerulonephritis8 or other potential renal impacts of CMV. Our data indicate that fever is associated with more severe forms of CMV disease. This is in line with findings from other studies; for instance, fever was present in all of our cases complicated with pneumonia and in 91% of pneumonia cases of the study of Uchida and coworkers study.9 Thus, when fever is present, a more serious clinical course of CMV disease should be anticipated. Tissue invasion is one of the characteristic features of CMV infection in transplant recipients and pneumonia is one of the most frequent forms of CMV organ involvement.6,9 Viral invasion of tissues in our series occurred in 16 cases, and the clinical course of these conditions was moderate to severe. pneumonia, which occurred in six
POUR-REZA-GHOLI, LABIBI, FARROKHI ET AL
patients, represented an incidence lower than rates documented in other studies. Abbott and coworkers reported pneumonia in 17% of their 422 kidney transplant patients.5 Another study on clinical manifestations of CMV in kidney recipients revealed a 9% pneumonia rate.7 Most of the signs and symptoms in kidney recipients with CMV were not specific for CMV infection, thus diagnostic testing is essential. At our hospital, we investigated all suspect CMV cases with the CMV antigenemia assay (pp65). On the other hand, Durlik and colleagues found no statistical correlation between a positive result on this test and clinical manifestations of CMV in kidney recipients (P ⫽ .98).7 This suggests that clinical findings are generally not reliable for diagnosing CMV in this patient group and more accurate laboratory investigations are needed to identify whether the nonspecific manifestations are due to CMV.
REFERENCES 1. Rubin RH: Infectious disease complications of renal transplantation. Kidney Int 44:221, 1993 2. Brennan DC: Cytomegalovirus in renal transplantation. J Am Soc Nephrol 12:848, 2001 3. Nett PC, Heisey DM, Fernandez LA, et al: Association of cytomegalovirus disease and acute rejection with graft loss in kidney transplantation. Transplantation 78:1036, 2004 4. Lautenschlager I: Cytomegalovirus and solid organ transplantation: an update. Curr Opin Transplant 8:269, 2003 5. Abbott KC, Hypolite IO, Viola R, et al: Hospitalizations for cytomegalovirus disease after renal transplantation in the United States. Ann Epidemiol 12:402,2002 6. Farrugia E, Schwab TR: Management and prevention of cytomegalovirus infection after renal transplantation. Mayo Clin Proc 67:879, 1992 7. Durlik M, Siennicka J, Litwinska B, et al: Clinical manifestations and diagnosis of cytomegalovirus infection in renal allograft recipients. Transplant Proc 33:1237, 2001 8. Onuigbo M, Haririan A, Ramos E, et al: Cytomegalovirusinduced glomerular vasculopathy in renal allografts: a report of two cases. Am J Transplant 2:684, 2002 9. Uchida K, Nakayama H, Yoshida K, et al: Opportunistic pneumonia after kidney transplantation. Nihon Kokyuki Gakkai Zasshi 39:166, 2001
C
YTOMEGALOVIRUS (CMV) disease is the most frequent type of infection in kidney transplant recipients.1,2 The prevalence of CMV infection, as signaled by detectable levels of anti-CMV immunoglobulin G antibodies in serum, increases with age in the general population, and serological findings indicate that more than two-thirds of donors and recipients have had this infection prior to transplantation.1 Association of CMV infection with graft outcome has been proven in many studies, which seems to be due to its additional immunosuppressive effects. In addition its immunocompromising effects can lead to other potential complications in recipients.3 The clinical manifestations of CMV disease in renal transplant patients often differ from those in the general population. Consequently, in kidney recipients, it can be difficult to diagnose CMV infection based on clinical features.4 Careful interpretation of presenting signs and symp-
toms of CMV infection is important in this patient group, but the literature contains little information related to this. In attempt to expand knowledge in this area, we reviewed all cases of CMV disease that occurred in kidney recipients at our center in order to evaluate the signs and symptoms of CMV disease in this patient group. MATERIALS AND METHODS From 1984 to December 2002, among 1925 patients who had undergone kidney transplant surgery, 100 were diagnosed with From the Urology and Nephrology Research Center, Shaheed Labbafinejad Medical Center, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. Address reprint requests to Farhat Farrokhi, Urology/Nephrology Research Center (UNRC), No. 44, 9th Boustan, Pasdaran, Tehran, 1666679951, Iran. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.07.051
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
3056
Transplantation Proceedings, 37, 3056 –3058 (2005)
SIGNS AND SYMPTOMS OF CMV DISEASE
3057
Table 1. Laboratory Findings During CMV Clinical Course for the 100 Kidney Recipients With CMV Disease Mean ⫾ SD
White blood cells Hemoglobin Hematocrit Platelets Creatinine BUN ALT AST Alkaline phospatase
6820.4 ⫾ 3223.9/mm 10.8 ⫾ 2.4 mg/dL 31.1 ⫾ 69% 212189.7 ⫾ 88661.5/mm3 2.4 ⫾ 1.8 mg/dL 60.5 ⫾ 38.1 mg/dL 26.8 ⫾ 33.9 IU/L 23.8 ⫾ 16.1 IU/L 213.3 ⫾ 137.6 IU/L 3
Increased (%)
Decreased (%)
22 — — 11 71 67 19 15 24
21 59 54 43 — — — — —
BUN, blood urea nitrogen; ALT, alanine aminotransferase; AST, aspartate aminotransaminase.
CMV disease at some stage after transplantation. In each case, CMV disease was diagnosed according to clinical features and detection of CMV antigen (pp65 antigenemia) in serum. The 100 cases were retrospectively investigated for details related to transplantation, demographic characteristics, as well as physical examination and laboratory findings after hospitalization for CMV disease. The results were statistically analyzed with the chi-square and the Student t tests to assess differences between subgroups of patients, based on the presence of fever.
RESULTS
Of the 100 kidney recipients with CMV disease, 62 were men and 38 were women. The mean age at time of transplantation was 33.8 ⫾ 15.1 years. The median interval from transplantation to diagnosis with CMV was 3.4 months (range, 1 to 9 months). Prior to transplantation, the mean dialysis duration for the group was 14.9 ⫾ 22.9 months. Seventy-seven patients had been on hemodialysis and four had been on peritoneal dialysis. The other 19 patients had undergone preemptive transplantation. Ninetyfour of the patients had received their first transplant, five had received their second graft, and one had received a third graft. Eighty-six of the transplants were from living unrelated donors, 10 were from living related donors, and four were deceased donor grafts. Thirty-seven patients had received intensive antirejection agents after transplantation (pulse-steroid therapy in 27 cases, antilymphocyte globulin in 10 cases). The mean number of hospitalizations after transplantation was 2.5 ⫾ 2.1. More than 90% of the recipients and donors were positive for CMV immunoglobulin G at the time of transplantation. The following signs and symptoms were present during hospitalization for CMV disease: fever in 71 cases, nausea in 32, vomiting in 26, pulmonary signs and symptoms in 20, arthralgia in 10, and ocular abnormalities in four. CMV tissue invasion occurred in 16 patients, including heart involvement (new abnormal heart sounds) in seven, pneumonia in six, conjunctivitis in two, and dermal vasculitis in one. The abnormal laboratory findings were elevated creatinine (71 cases), thrombocytopenia (43), leukocytosis (22),
leukopenia (21), elevated alanine aminotransferase (19), and elevated aspartate aminotransferase (15) (Table 1). Analysis revealed associations between fever and number of hospitalizations after transplantation (P ⫽ .006), elevated creatinine (P ⫽ .006), nausea (P ⫽ .017), vomiting (P ⫽ .031), number of infection episodes after transplantation (P ⫽ .001), and pulmonary symptoms (P ⫽ .002). All of the patients with conjunctivitis, pneumonia, pulmonary symptoms, and abnormal heart sounds were febrile during hospitalization for CMV disease (Table 2). Eighty-eight of the patients had not been given CMV prophylaxis. Of the remaining 12 patients, seven had received a 12-week course of oral ganciclovir and four had received a 2-week course of intravenous ganciclovir. Two of the patients who had been given oral prophylaxis and two who had received intravenous prophylaxis had at least one episode of fever. Of the 88 patients who had not received CMV prophylaxis, 71.6% had at least one episode of fever, while none of the patients who received prophylactic treatment developed fever (P ⫽ .018) or CMV tissue invasion. No deaths occurred and all of the patients responded to treatment. Table 2. Association of Fever With Other Characteristics of Patients and CMV Disease
Age (y) Dialysis duration (months) No. of hospitalizations after transplantation History of dialysis ALG/pulse Posttransplant infections Nausea Vomiting Arthralgia Pulmonary symptoms Pneumonia Abnormal heart sounds Vasculitis Conjunctivitis
Fever
No fever
33.3 ⫾ 18.4 13.5 ⫾ 23.1
31.1 ⫾ 15.0 15.4 ⫾ 16.7
P value
.60 .71
2.9 ⫾ 2.2 79.1% 73.1% 71.6% 40.2% 32.8% 13.4% 28.3% 8.9% 10.4% 1.5% 2.9%
1.5 ⫾ 1.5 84.6% 58.4% 25.9% 14.8% 11.2% 3.7% 0% 0% 0% 0% 0%
.006 .12 .47 .001 .017 .031 .16 .002 .10 .081 .52 .38
ALG, antilymphocyte globulin. *Administration of antilymphocyte globulin or steroid-pulse therapy before CMV disease.
3058
DISCUSSION
In kidney recipients, CMV infection most often occurs in the first few months after transplantation.1 In the 100 cases in our study, the median interval from transplantation to diagnosis with CMV was 3.4 months, findings consistent with those reported by Abbott and colleagues.5 They found that 79% of hospitalizations for CMV infection in kidney recipients occurred in the first 6 months after transplantation. Farrugia and Schwab identified fever, malaise, myalgia, leukopenia, and elevated transaminase levels as the most common manifestations of CMV disease in kidney recipients.6 Ranked in descending order, the most common manifestations of CMV in our series were fever, elevated creatinine, thrombocytopenia, nausea, vomiting, leukocytosis, leucopenia, and pulmonary signs and symptoms. In a study conducted by Durlik et al on clinical manifestations and diagnosis of CMV infection in renal allograft recipients, the most frequent clinical manifestations of CMV disease were fever (91%), leukopenia (82%), and thrombocytopenia (27%).7 Compared with these rates, our frequency of fever was lower (71%) and our rate of leukocytosis was high (22%), which is a considerable finding. Elevated serum creatinine was a considerable finding in our series; however, not all these patients were investigated with renal biopsy to assess for CMV-induced glomerulonephritis8 or other potential renal impacts of CMV. Our data indicate that fever is associated with more severe forms of CMV disease. This is in line with findings from other studies; for instance, fever was present in all of our cases complicated with pneumonia and in 91% of pneumonia cases of the study of Uchida and coworkers study.9 Thus, when fever is present, a more serious clinical course of CMV disease should be anticipated. Tissue invasion is one of the characteristic features of CMV infection in transplant recipients and pneumonia is one of the most frequent forms of CMV organ involvement.6,9 Viral invasion of tissues in our series occurred in 16 cases, and the clinical course of these conditions was moderate to severe. pneumonia, which occurred in six
POUR-REZA-GHOLI, LABIBI, FARROKHI ET AL
patients, represented an incidence lower than rates documented in other studies. Abbott and coworkers reported pneumonia in 17% of their 422 kidney transplant patients.5 Another study on clinical manifestations of CMV in kidney recipients revealed a 9% pneumonia rate.7 Most of the signs and symptoms in kidney recipients with CMV were not specific for CMV infection, thus diagnostic testing is essential. At our hospital, we investigated all suspect CMV cases with the CMV antigenemia assay (pp65). On the other hand, Durlik and colleagues found no statistical correlation between a positive result on this test and clinical manifestations of CMV in kidney recipients (P ⫽ .98).7 This suggests that clinical findings are generally not reliable for diagnosing CMV in this patient group and more accurate laboratory investigations are needed to identify whether the nonspecific manifestations are due to CMV.
REFERENCES 1. Rubin RH: Infectious disease complications of renal transplantation. Kidney Int 44:221, 1993 2. Brennan DC: Cytomegalovirus in renal transplantation. J Am Soc Nephrol 12:848, 2001 3. Nett PC, Heisey DM, Fernandez LA, et al: Association of cytomegalovirus disease and acute rejection with graft loss in kidney transplantation. Transplantation 78:1036, 2004 4. Lautenschlager I: Cytomegalovirus and solid organ transplantation: an update. Curr Opin Transplant 8:269, 2003 5. Abbott KC, Hypolite IO, Viola R, et al: Hospitalizations for cytomegalovirus disease after renal transplantation in the United States. Ann Epidemiol 12:402,2002 6. Farrugia E, Schwab TR: Management and prevention of cytomegalovirus infection after renal transplantation. Mayo Clin Proc 67:879, 1992 7. Durlik M, Siennicka J, Litwinska B, et al: Clinical manifestations and diagnosis of cytomegalovirus infection in renal allograft recipients. Transplant Proc 33:1237, 2001 8. Onuigbo M, Haririan A, Ramos E, et al: Cytomegalovirusinduced glomerular vasculopathy in renal allografts: a report of two cases. Am J Transplant 2:684, 2002 9. Uchida K, Nakayama H, Yoshida K, et al: Opportunistic pneumonia after kidney transplantation. Nihon Kokyuki Gakkai Zasshi 39:166, 2001