Albert J. Eid

Delayed-Onset Primary Cytomegalovirus Disease and the Risk of Allograft Failure and Mortality after Kidney Transplantation

BACKGROUND During the contemporary era of antiviral prophylaxis, the impact of delayed-onset primary cytomegalovirus (CMV) disease on the outcome of kidney transplantation is not known. We evaluated the incidence, clinical features, risk factors, and outcomes of CMV disease among high-risk kidney transplant recipients. METHODS The medical records of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors were reviewed. Cox proportional hazards regression was used to identify factors associated with CMV disease and to assess its impact on allograft loss and mortality. RESULTS None of the 176 CMV-seronegative recipients of kidney transplants from CMV-seropositive donors developed breakthrough CMV disease during a median of 92 days (interquartile range, 90-92 days) of oral ganciclovir or valganciclovir prophylaxis. Thereafter, 51 patients (29%) developed CMV disease at a median of 61 days (interquartile range, 40-143 days) after stopping antiviral prophylaxis. Early-onset bacterial and fungal infection (hazard ratio, 3.61; 95% confidence interval, 1.78-7.33; p < .001) and a Charlson comorbidity index > or =3 (hazard ratio, 2.21; 95% confidence interval, 1.15-4.22; p = .011) were associated with a higher risk of delayed-onset primary CMV disease, and postrejection antiviral prophylaxis (hazard ratio, 0.29; 95% confidence interval, 0.09-0.94; P = .039) was associated with a lower risk of such CMV disease. A time-dependent Cox regression analysis revealed a statistically significant association between tissue-invasive CMV disease and allograft loss or mortality (hazard ratio, 2.85; 95% confidence interval, 1.22-6.67; P = .016). CONCLUSION This study of a large cohort of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors illustrates the ongoing challenge of delayed-onset primary CMV disease and its impact on transplantation outcomes despite antiviral prophylaxis. Better strategies for CMV disease prevention after kidney transplantation are warranted.

Emergence of drug‐resistant cytomegalovirus in the era of valganciclovir prophylaxis: therapeutic implications and outcomes

Abstract:  Background:  Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir‐resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug‐resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis.

Parvovirus B19 Infection after Transplantation: A Review of 98 Cases

BACKGROUND Infections with parvovirus B19 (PVB19) can cause significant morbidity in transplant recipients. METHODS To characterize the epidemiology and clinical spectrum of posttransplant PVB19 infection, we reviewed all cases at our institution during a 16-year period, summarized the data from 91 cases published in the medical literature, and performed longitudinal molecular surveillance for PVB19 DNAemia among 47 solid organ and hematopoietic stem cell transplant recipients. RESULTS The median time to onset of PVB19 disease was 7 weeks after transplantation. Anemia, leukopenia, and thrombocytopenia were present in 98.8%, 37.5%, and 21.0% of patients, respectively. Hepatitis, myocarditis, and pneumonitis were also reported in association with PVB19 disease. Allograft tissue loss or dysfunction was observed at the time of PVB19 disease in 10% of cases. At the onset of disease, PVB19 IgM serological test results were negative in 29% of cases. Almost all patients (96%) with anti-PVB19 IgM had a positive PVB19 polymerase chain reaction assay result. Intravenous immunoglobulin was the most commonly used treatment modality. Three of 98 patients died of myocarditis and cardiogenic shock associated with PVB19 disease. Molecular surveillance throughout the first year after transplantation did not reveal PVB19 DNAemia in 47 anemic solid organ and hematopoietic stem cell transplant patients. CONCLUSIONS PVB19 is a rare but clinically significant infection that manifests as refractory anemia during the posttransplantation period. The use of polymerase chain reaction for diagnosis is particularly helpful in immunosuppressed transplant patients who may fail to mount antibodies against PVB19 during active infection.

Polyomavirus polymerase chain reaction as a surrogate marker of polyomavirus-associated nephropathy

Background. Polyomavirus-associated nephropathy (PVAN) is a significant cause of allograft loss after renal transplantation. A noninvasive assay that can guide the evaluation of PVAN would be of clinical value. We compared the utility of BK virus (BKV) polymerase chain reaction (PCR) and urine cytology in screening for concurrent PVAN. Methods. We used PCR to test urine and plasma samples from renal recipients simultaneously for BKV DNA. Additionally, we tested urine samples for decoy cells. Sample results were correlated with biopsy-proven PVAN. Receiver-operator characteristic curves were used to determine viral load thresholds associated with concurrent PVAN. Results. In this cross-sectional study, BKV viruria, viremia, and urinary decoy cells were detected in 24%, 9%, and 13% of renal recipients, respectively. Among 114 patients who had renal allograft biopsy, four (3.5%) were diagnosed with PVAN. Using pathology as gold standard for the diagnosis of PVAN, BKV viremia threshold of >1.6E+04 copies/mL had 100% sensitivity, 96% specificity, 50% positive predictive value, and 100% negative predictive value. A BKV viruria threshold of >2.5E+07 copies/mL had 100% sensitivity, 92% specificity, 31% positive predictive value, and 100% negative predictive value. In contrast, urine decoy cells had 25% sensitivity, 84% specificity, 5% positive predictive value, and 97% negative predictive value for the diagnosis of concurrent PVAN. Conclusion. BKV PCR may be a clinically useful noninvasive test to identify renal recipients with concurrent PVAN. BKV DNA >1.6E+04 copies/mL of plasma and >2.5E+07 copies/mL of urine were highly associated with concurrent PVAN whereas a negative PCR test makes the diagnosis of PVAN highly unlikely.

Delayed-onset primary cytomegalovirus disease after liver transplantation

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor‐positive/recipient‐negative (D+/R−) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R− liver transplant recipients who received antiviral prophylaxis. Sixty‐seven CMV D+/R− liver transplant recipients (mean age ± standard deviation: 49.5 ± 11.4 years; 75% male) received oral ganciclovir [n = 9 (13%)] or valganciclovir [n = 58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91‐100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed‐onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P = 0.01) and younger age at transplant (P = 0.03) were associated with an increased risk, whereas diabetes mellitus (P < 0.001) was significantly associated with a lower risk of delayed‐onset primary CMV disease. Allograft loss or mortality occurred in 8 (12%) patients during the median follow‐up period of 3.31 (range: 0.8‐5.9) years. No significant association was observed between CMV disease and patient and allograft survival. In conclusion, CMV disease remains a common complication in CMV D+/R− liver transplant patients during the contemporary era of antiviral prophylaxis. Female patients and younger patients are at increased risk of delayed‐onset primary CMV disease. Liver Transpl 13: 1703–1709, 2007.

Prosthetic Joint Infection Due to Rapidly Growing Mycobacteria: Report of 8 Cases and Review of the Literature

BACKGROUND Prosthetic joint infection (PJI) due to rapidly growing mycobacteria (RGM) is only occasionally encountered in clinical practice. Therefore, the optimal clinical management for this condition is unknown. METHODS The medical records of patients who had PJI due to RGM during 1969-2006 were reviewed to summarize its clinical characteristics, treatment, and outcome. RESULTS Eight patients developed 9 episodes of PJI (7 episodes involving the knee and 1 each involving the hip or elbow) due to RGM at a median of 312 weeks (range, 1-170 weeks) after prosthesis implantation. Patients presented with joint pain (7 patients), joint swelling (7 patients), and fever (3 patients), accompanied by an elevated erythrocyte sedimentation rate (median, 70.5 mm/h) and C-reactive protein level (median, 6 mg/dL). Mycobacterium chelonae (n=3), Mycobacterium abscessus (n=2), Mycobacterium fortuitum (n=3), and Mycobacterium smegmatis (n=1) were isolated from the 9 infected joints. Seven of 9 prostheses were resected, whereas 2 were retained after surgical debridement. Six of 8 patients received > or = 1 active antimicrobial agent for at least 6 months. During a median follow-up period of 33 weeks (range, 2.6-326 weeks) after surgical intervention, no clinical or microbiological relapses were observed. Reimplantation was performed successfully for 2 of 6 patients who underwent resection arthroplasty. The 2 patients with retained prosthesis continued to receive prolonged courses of suppressive antimicrobial therapy. CONCLUSIONS RGM is a rare cause of PJI that should be suspected in patients with negative results of routine bacterial cultures. The combination of resection arthroplasty and antimicrobial therapy is the preferred approach. However, in cases involving retained prosthetic components, RGM infection may be suppressed with lifelong courses of effective antibiotic therapy.

Clinical features and outcomes of cytomegalovirus retinitis after transplantation

Abstract: Cytomegalovirus (CMV) infection of the retina is a rarely encountered end‐organ disease after transplantation. In order to describe the clinical characteristics and outcomes of CMV retinitis after hematopoietic stem cell and solid organ transplantation, we performed a retrospective review of all cases of CMV retinitis at the Mayo Clinic (Rochester, Minnesota) during 1990–2004. During this 15‐year period, CMV retinitis was diagnosed in 14 eyes of 9 patients who had received kidney (n=5), liver (n=2), heart (n=1), and autologous hematopoietic stem cell transplant (n=1). The mean age of the patients was 58 (standard deviation±11) years; 6 were male. The median time to diagnosis of CMV retinitis was 9 months (range, 4 months to 13 years) after transplantation. Four (44%) patients had concomitant pneumonitis or hepatitis. Five (55%) patients had bilateral retinitis. Retinal involvement was ≤10% in 8 eyes, >10% but ≤50% in 4 eyes, and >50% in 2 eyes. All patients received induction therapy with intravenous ganciclovir (n=8) or foscarnet (n=1) for a median of 43 days (range, 14–100 days) followed by maintenance therapy with intravenous or oral ganciclovir for a median of 88 days (range, 36–943 days) in 6 (67%) patients. One patient developed bilateral immune recovery uveitis during treatment, and later on progressed to develop rhegmatogenous retinal detachment. During the mean follow‐up period of 20 months, visual acuity improved in 4 (28.5%), was stable in 4 (28.5%), and worsened in 6 (43%) eyes. CMV retinitis recurred in 2 patients. In conclusion, CMV retinitis is a rare, progressive, and highly morbid infectious complication of transplantation. The severity of clinical disease at the time of diagnosis may predict poor outcome. Hence, early intervention may be crucial to prevent its progression to irreversible visual loss.

Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus.

Background. Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. Methods. A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. Results. The mean patient age was 49±9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65–13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. Conclusion. Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.

Phaeohyphomycosis due to Alternaria species in transplant recipients.

R.D. Boyce, P.J. Deziel, C.C. Otley, M.P. Wilhelm, A.J. Eid, N.L. Wengenack, R.R. Razonable. Phaeohyphomycosis due to Alternaria species in transplant recipients.
Transpl Infect Dis 2010: 12: 242–250. All rights reserved

A prospective longitudinal analysis of cytomegalovirus (CMV)-specific CD4+ and CD8+ T cells in kidney allograft recipients at risk of CMV infection.

Cytomegalovirus (CMV)‐specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV‐specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine‐flow cytometry, we enumerated interferon‐γ producing CMV‐specific CD4+ and CD8+ T cells at serial time points among CMV‐mismatched (D+/R−) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (±SD) time of 151 (±33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue‐invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R−) status (HR: 13, 95% CI: 1.6–106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1–27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change‐over‐time in CMV‐specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE‐1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV‐specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV‐specific T cell assays will need to be assessed in a larger cohort of CMV D+/R− kidney recipients who remain at high‐risk of delayed‐onset CMV disease.