Stephen Dummer

Posttransplant Lymphoproliferative Disease in Primary Epstein-Barr Virus Infection after Liver Transplantation: The Role of Cytomegalovirus Disease

Epstein-Barr virus (EBV) plays a major role in the pathogenesis of posttransplant lymphoproliferative disease (PTLD). Patients who undergo primary EBV infection after transplantation are at greater risk of developing PTLD. In this retrospective study, the incidence of EBV infection and associated PTLD in 40 consecutive adult recipients who were seronegative for EBV at the time of liver transplantation were investigated, and risk factors for PTLD were analyzed. Of 37 patients with available timely posttransplant serum samples, 35 (95%) developed primary EBV infection. Of the 40 patients, 13 (33%) developed PTLD a median of 126 days (range, 48-776) after liver transplantation. The factor significantly associated with the development of PTLD was cytomegalovirus disease (relative risk, 7.3; 95% confidence interval, 2.36-22.6; P = .0006). Cytomegalovirus disease is a predictor for the development of PTLD in primary EBV infection after liver transplantation, and it may be a target for prophylactic intervention.

Clinical features and outcomes of paramyxoviral infection in lung transplant recipients treated with ribavirin

BACKGROUND Paramyxoviral infections are reported in 6% to 21% of lung transplant recipients. Aerosolized ribavirin is used to treat paramyoxviral infections, but data on outcomes of this treatment in lung transplant patients are limited. METHODS Lung recipients treated with aerosolized ribavirin from 1992 through 2000 for pulmonary respiratory syncytial virus (RSV) or parainfluenza virus (PIV) infection were assessed for the following variables: age; gender; underlying diagnosis; time from transplantation; duration of illness; clinical symptoms; and change from baseline FEV(1) (forced expiratory volume in 1 second). Outcomes included FEV(1) values at 30 and 90 days, need for intubation, development of acute rejection or obliterative bronchiolitis (OB) in the year after treatment; and 90-day and overall mortality. RESULTS Fifteen patients received ribavirin for a median of 5 days (range 3 to 7) for 17 episodes of RSV (n = 12) or PIV (n = 5) infection. The clinical presentations of RSV and PIV infection were similar. Infection occurred a median of 520 days (range 7 to 1700) after transplantation. Three episodes required intubation; 2 episodes were fatal accounting for a 90-day mortality per episode of 12%. The FEV(1) at presentation declined by 25% (range 4% to 44%) from baseline. In 3 patients the FEV(1) did not return to baseline by 90 days or thereafter. All 3 patients had underlying pulmonary fibrosis (IPF) vs no IPF in 0 of 9 evaluable patients who recovered (p = 0.009). There was no correlation between response to ribavirin and subsequent development of OB. CONCLUSIONS About 33% of lung transplant patients with lower respiratory tract paramyxoviral infections who were treated with inhaled ribavirin died or did not return to baseline FEV(1). This effect was acute and not associated with later complications, including OB. Underlying IPF may be a risk factor for failure to return to baseline. Larger, prospective, multicenter studies are required to confirm these findings.

High-dose weekly intravenous immunoglobulin to prevent infections in patients undergoing autologous bone marrow transplantation or severe myelosuppressive therapy: A study of the American bone marrow transplant group

Treatment with intense myelosuppressive therapy (including bone marrow transplantation) has improved survival in patients with various malignant neoplasms [1, 2]. Unfortunately, this treatment increases the incidence of infectious complications, primarily during the period of myelosuppression [3]. Various methods have been used to limit infection during myelosuppression [4-7]. Despite these precautions, bacteremia and fungemia continue to occur in at least one third of patients with sustained neutropenia. Intravenous immunoglobulin (IVIG) therapy prevents infections in patients with inborn B-cell deficiencies and hypogammaglobulinemia secondary to hematologic disorders such as chronic lymphocytic leukemia [8-10]. Intravenous immunoglobulin has also been used successfully to treat immune thrombocytopenic purpura, alloimmunity to platelets, and other immune-mediated disorders by a mechanism of immune system modulation [11]. After allogeneic bone marrow transplantation, IVIG is commonly used to prevent graft-versus-host disease [12]. During these bone marrow transplant trials, a reduction in bacterial infection was also observed in patients who were not necessarily hypogammaglobulinemic. This finding was initially reported in small anecdotal series but was later confirmed by large prospective studies [12-17]. This effect of IVIG was observed during the pre-engraftment (neutropenic) and myelosuppression recovery phases. Most patients in these studies were undergoing allogeneic bone marrow transplantation, for which graft-versus-host disease and its treatment contribute to the rate of infection [18]. Intravenous immunoglobulin is not routinely used during autologous bone marrow transplantation or severely myelosuppressive therapy because prevention of graft-versus-host disease is unnecessary. Because IVIG prevents infection after allogeneic bone marrow transplantation, it might also do so in other patients undergoing intense myelosuppression and thus may serve as a general prophylactic agent for infections. Intravenous immunoglobulin is expensive and thus should not be used indiscriminately. We designed a prospective study that randomized patients who were expected to develop severe and sustained myelosuppression to receive IVIG or no treatment. We specifically wished to determine whether IVIG could reduce the incidence of severe infections in patients with neutropenia but without allogeneic cofactors such as graft-versus-host disease. We therefore sought to determine whether the benefits of IVIG after allogeneic bone marrow transplantation occur as a direct effect of the drug or as an indirect result of a reduced incidence of graft-versus-host disease. Methods Study Design We conducted a stratified, randomized comparison of patients who either underwent autologous bone marrow transplantation or received substantial myelosuppressive therapy for acute leukemia or other malignant conditions. The protocol and consent forms were approved by the Institutional Review Boards of the three participating institutions: Baylor University Medical Center, Dallas, Texas; The University of Louisville, Louisville, Kentucky; and Vanderbilt University, Nashville, Tennessee. Patients were stratified for treatment (autologous bone marrow transplantation or myelosuppressive therapy) and were randomized at each study center by a computer-generated scheme to receive IVIG or no treatment. Neither tumor-specific cytoreductive therapy nor state of disease were used as strata. Patients with an ongoing infection, those younger than 17 years, and those with a previous intolerance to IVIG were ineligible for the study. The main end points were the development of proven clinical infection, positive blood cultures for bacteria or fungi, and survival until hospital discharge. Other analyses included the number of platelet transfusions and the development of clinical alloimmunity to platelet transfusion. Patients Between February 1990 and December 1991, 170 patients entered the study. All patients were evaluable for efficacy and were included in the analysis. The distribution of study patients is shown in (Table 1). The duration of neutropenia, the most important determinant for infection, was similar between the two groups (P > 0.2). Patients in the treatment arm and those in the control arm had statistically similar distributions of overall cytotoxic regimens and disease diagnoses (data not shown). Table 1. Patient Characteristics Treatment Protocol The IVIG used (Sandoglobulin, Sandoz Pharmaceuticals, East Hanover, New Jersey) was commercially purchased, reconstituted as a 5% solution, and administered intravenously at an initial rate of 0.02 mL/kg per minute for 30 minutes and, if tolerated, was increased every 30 minutes to a maximum rate of 0.08 mL/kg per minute. Administration of IVIG was not blinded, and controls received no placebo. Immunoglobulin was given at a weekly dose of 500 mg/kg beginning at the start of cytotoxic treatment. It was discontinued when severe side-effects occurred or when neutropenia resolved (as defined by a neutrophil count of more than 500 109/L [500/L] for 1 day). Supportive Care The patients were hospitalized in HEPA-filtered single rooms, observed strict hand-washing rules, and received low-bacterial diets. Prophylactic oral antibacterial agents were allowed, but prophylactic parenteral antibacterial drugs were not. Patients who were seropositive for Herpes simplex virus received prophylactic acyclovir. All administered blood products were leukofiltered, and patients undergoing autologous bone marrow transplantation also received irradiated blood products. During periods of neutropenia, patients with fever greater than 38 C had two blood cultures taken and received empiric broad-spectrum antibacterial therapy as determined by the study center. Patients whose fever persisted were recultured. If fever persisted for 3 days and no bacterial cause was found, amphotericin B was administered at a dose of 0.5 mg/kg per day. Definitions and Evaluation of Infection The duration of neutropenia was defined as the interval from the first day the absolute neutrophil count decreased below 500 109/L (500/L) until the first day the count exceeded 500 109/L (500/L). In patients with neutropenia, the interval was measured from the first day of cytotoxic therapy until recovery from neutropenia. Each platelet transfusion, whether with single-donor platelets or random-donor pooled platelets, was denoted as one episode. Clinical alloimmunity was diagnosed when platelet counts measured 1 hour after transfusion increased by less than 5000 109/L (< 5000/L) per unit of random- or single-donor platelets transfused on two consecutive occasions. The diagnosis of bacteremia and fungemia required one or more positive blood cultures in patients with suspected infection. The diagnosis of clinical infection required evidence of a localized tissue infection with supporting features such as fever, chills, pain, or erythema with or without isolation of a pathogen. Fever without localized evidence of infection or without positive blood cultures was not considered to represent clinical infection. Statistical Analysis Assuming an infection rate of 40%, the study was designed to detect an anticipated decrease to 20% with a power of 0.80 and an -error of 0.05. Results were analyzed according to the intention to treat. For comparisons of patient groups, the Pearson chi-square test or the Mann-Whitney rank-sum test were used. The Pearson chi-square test with confirmation by the confidence interval method of Simon was used to evaluate study end points [19]. Confidence intervals of 95% were used. Binary logistic regression was used to evaluate the influence of various clinical and laboratory parameters on the end points of bacteremia or fungemia. These parameters included age, diagnosis, study center, duration of neutropenia, baseline IgG value, use of prophylactic oral antibacterials, and use of IVIG. To evaluate hypogammaglobulinemia, 5 g/L (500 mg/dL) was chosen as the lower limit of normal. To evaluate the duration of neutropenia, a threshold of 7 days was chosen. The trial ended with the resolution of neutropenia because this patient population rarely experiences serious infections after leukocyte recovery and because survival after hematopoietic recovery is largely determined by the underlying disease. Survival was reported using actual proportions. Results Infections Proven clinical infections were frequent, as shown in Table 2. Of all study patients, 43.5% had documented clinical infections. Bacteremia and fungemia occurred in 35% and 7.6% of patients, respectively. The incidences of proven clinical infection, bacteremia, and fungemia were 43%, 35%, and 6% in the IVIG group and 44%, 34%, and 9% in the control group, respectively. These differences were not statistically significant (P > 0.2). Analysis of bacteremia by organism (gram positive, gram negative, and mixed) showed no statistical difference. The most common infection in the study was bacteremia due to coagulase-negative Staphylococci. This organism was isolated in 58% of all cases of bacteremia and was the sole organism in 38% of all cases of bacteremia. Twenty-eight percent of the documented bloodstream infections were polymicrobial. Table 2. Treatment Results Only 8% of patients in this study had hypogammaglobulinemia. The distribution of these patients was similar in the IVIG (9%) and control (8%) groups. In multiple regression analysis, the pretreatment value of IgG (< 5 g/L [500 mg/dL] compared with > 5 g/L) did not predict the development of bacteremia or fungemia. Bloodstream infections were frequent, but most were controlled by broad-spectrum antibiotics. Death from infection occurred in 3.5% of study patients (4.9% in the IVIG group compared with 2.3% in the control group), yielding a difference of 2.6% (95% CI, 3.0% to 8.2%; P > 0.2). Platelet Transfusion Patients in the IVIG and

Polyomavirus simian virus 40 infection associated with nephropathy in a lung-transplant recipient.

Background. Between 1955 and 1963, millions of individuals worldwide received vaccines contaminated with polyomavirus simian virus (SV)40. Recent data suggest that some individuals may develop renal dysfunction related to SV40 infection, including individuals too young to have received contaminated vaccines. Case Report and Results. Three years after bilateral lung transplantation, a 32-year-old man with cystic fibrosis developed nephrotic syndrome and progressed to end-stage renal failure over 1.5 years. He was shown to have nephropathy caused by SV40. The diagnosis was documented by detecting and confirming sequences of SV40 (but not BK or JC virus) in his kidney biopsy and urine by polymerase chain reaction, Southern blot, and DNA sequencing. Positive immunohistochemistry for SV40 was found in his kidney, and neutralizing antibodies for SV40 were detected in his serum, before and after the onset of renal dysfunction. A source for the virus was not determined. His household contacts did not have serologic or molecular evidence of SV40 infection. No serum or tissue samples were available from his 27-year-old donor. Discussion. This report shows that SV40 is circulating in the community and can cause nephropathy in transplant patients.

A prospective longitudinal study of polyomavirus shedding in lung-transplant recipients.

BACKGROUND Polyomavirus infection causes renal dysfunction after kidney transplantation, but it has not been thoroughly investigated in nonrenal solid-organ transplantation. METHODS Fifty lung-transplant recipients provided prospective urine and blood samples over the course of 17 months. Samples were analyzed for BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) using conventional polymerase chain reaction (PCR), sequence analysis, and quantitative real-time PCR. RESULTS Thirty-one (62%) of 50 patients had polyomavirus detected in at least 1 urine specimen, including 16 (32%) for BKV, 12 (24%) for JCV, and 6 (12%) for SV40. Mean BKV loads (5.0 log(10) copies/mL) did not differ from those of JCV (5.7 log(10) copies/mL; P=.38), but SV40 loads (2.5 log(10) copies/mL) were lower than those of BKV (P=.006) and JCV (P=.002). Blood samples were negative. Infection with individual polyomaviruses or polyomavirus infection in aggregate was not associated with reduced creatinine clearance. Patients not shedding polyomavirus had better survival than patients shedding polyomavirus (P=.049). CONCLUSIONS Polyomaviruses BKV and JCV were commonly detected in urine from lung-transplant recipients. SV40 was found in 12% of patients but was shed at a lower frequency and with lower viral loads than the other viruses. Polyomavirus infection was not associated with renal dysfunction.

Human ehrlichiosis in transplant recipients.

To characterize the impact of immunosuppression on human ehrlichiosis, we reviewed cases of ehrlichiosis occurring in transplant recipients and immunocompetent patients at three hospitals in Nashville, Tennessee. Between 1998 and 2006, 15 transplant patients were identified as having ehrlichiosis, diagnosed either by whole blood polymerase chain reaction (PCR) (n = 14) or serology (n = 1). They were compared with 43 immunocompetent patients diagnosed by whole blood PCR. We retrospectively collected demographic and clinical information. The species of Ehrlichia (E. ewingii or E. chaffeensis) was determined for patients diagnosed by PCR. The 15 transplant recipients with ehrlichiosis included 7 kidney recipients, 6 heart recipients, 1 liver recipient and 1 lung recipient. Transplant recipients had more infections with E. ewingii than immunocompetent patients (23% vs. 5%, p = 0.08). Transplant recipients experienced less rash (0% vs. 36%, p = 0.006) and presented with significantly lower hepatic enzymes, but more leukopenia and renal dysfunction than immunocompetent patients. Doxycycline therapy was started within 48 h of presentation in 73% of transplant recipients and 78% of immunocompetent patients (p = 0.7). No patient died in either group. Ehrlichia infections can occur in transplant recipients who live in an endemic area. With prompt treatment, the infected transplant recipients in our study had similar, favorable outcomes compared to immunocompetent patients.

Other Bacterial Infections After Hematopoietic Stem Cell or Solid Organ Transplantation

This chapter describes the epidemiology, clinical presentation, diagnosis, and management of infections caused by a diverse group of bacterial pathogens. These include classic opportunistic infections, such as listeriosis or nocardiosis, and also infections that are common in immunocompetent patients but particularly prevalent or morbid in transplant populations, such as Legionella pneumonia and Clostridium difficile infection. Some uncommon bacterial pathogens that have a predilection for patients with impaired immunity such as Mycoplasma hominis and Rhodococcus equi are also discussed. Finally, the chapter touches on some miscellaneous bacterial infections that are important because they may be unanticipated in transplant recipients or present diagnostic or therapeutic challenges.

Fluffy Periostitis Induced by Voriconazole

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Antifungal management after lung transplantation (TX): a survey of 37 transplant centers

Purpose: To provide data on antifungal management after lung TX, focusing on surveillance, prophylaxis.and pre-emptive therapy. Methods: All lung TX centers in the US were asked to participate. Participating centers filled out a survey document. Results: Thirty-seven of 69 active lung TX centers, accounting for 66% of all US lung transplants, responded, The median number of transplants performed per year was 14 (range1-52). and median age of the TX center was 9 years (range2-15 yrs). Pre-TX fungal surveillance was performed by 81% of centers with 67% surveying all patients and the rest just subsets. 72% of centers started antifungal treatment if Aspergillus was isolated before TX. Itraconazole was the preferred agent (86%). After TX, 76% of centers gave antifungal prophylaxis, although 24% did so only in selected patients. Prophylactic agents in order of preference were inhaled ampho B (61%), itraconazole (46%), parenteral ampho B (25%), and fluconazole (21%); many centers used more than one agent. Prophylaxis was started within 1 day in 71% of centers and by 7 days in all centers. Median duration was 3 mos. (range 1 mo. to life). All 37 centers gave antifungal therapy (median of 4.5 mos.) to patients colonized with Aspergillus and itraconazole was the preferred agent. Only 59% of centers treated patients colonized with Candida. Centers with larger volumes were less likely to treat pre-TX colonization with Candida and more likely to use itraconazole for post-TX colonization with Aspergillus (p 0.02). Only 14% of centers engaged in antifungal research at the time of the study. Conclusions: The majority of surveyed lung transplant programs actively manage fungal infection with prophylactic and/or pre-emptive strategies. Data from this survey may provide an impetus and basis for designing prospective studies.(supported by a grant from The Liposome Company).