Healthcare-associated hepatitis C virus transmission among patients in an abdominal organ transplant center.

BACKGROUND: De novo hepatitis C virus (HCV) infection among transplant patients is rarely recognized but can have severe consequences. We investigated the scope, source, and mode of HCV transmission within a transplant center after incident HCV infection was identified in 2 patients who had liver transplantation in late 2006. METHODS: Patients were interviewed, and transplant logs, medical records, and staff practices were reviewed to identify opportunities for HCV transmission. Infection via receipt of blood or organs was evaluated. Molecular epidemiology was used to determine the relatedness between persons with incident and chronic HCV infection. RESULTS: HCV from infected blood or organ donors was ruled out. Among the 308 patients who underwent transplant in 2006, no additional incident HCV infections were identified. Eighty-five (28%) had pre-transplant chronic HCV infection; 13 were considered possible HCV source patients based upon shared days on the inpatient unit, nursing assignment, or invasive procedures in common with incident HCV case-patients. Viral isolates from 1 HCV source patient and 1 incident case-patient were found to be highly related by quasispecies analysis, confirming patient-to-patient HCV transmission. Possible modes of transmission identified were the improper use of multidose vials, sharing of blood-contaminated glucometers, and touch contamination. CONCLUSION: Sporadic transmission or endemic levels of HCV transmission might be overlooked in a setting with high HCV prevalence, such as liver transplant units, where multiple, repeated opportunities for patient-to-patient HCV transmission can occur. Surveillance through pre- and post-transplant screening is necessary to identify incident HCV infection in this setting. Constant, meticulous attention must be paid to maintaining aseptic technique and good infection control practices to eliminate HCV transmission opportunities.

Outcome of penicillin-susceptible streptococcal prosthetic joint infection treated with debridement and retention of the prosthesis.

Debridement with retention of the prosthesis was the initial treatment modality for 19 cases of penicillin-susceptible streptococcal prosthetic joint infection that occurred in 18 patients who presented to the Mayo Clinic (Rochester, Minnesota) during 1969-1998. All of the cases of prosthetic joint infection occurred >30 days after implantation of the prosthesis, which was well fixed at the time of debridement. The median duration of symptoms before debridement was 4 days (range, 1-10 days). Treatment failure (defined as relapse of infection with the original microorganism) occurred in 2 cases (10.5%) during a median follow-up period of 3.9 years (range, 0.3-21.7 years). The 1-year cumulative risk of relapse was 11% (95% confidence interval, 0%-26%). Relapse of prosthetic joint infection due to penicillin-susceptible streptococci after debridement and retention of the prosthesis is uncommon. For patients who present with a well-fixed prosthesis and a short duration of symptoms, debridement with retention appears to be an effective treatment modality.

Valaciclovir prophylaxis of cytomegalovirus infection and disease in renal transplantation: an economic evaluation.

BACKGROUND: Cytomegalovirus (CMV) disease is a major cause of morbidity and mortality in solid organ transplant patients and is associated with large additional healthcare expenditures. An economic evaluation of valaciclovir CMV prophylaxis in a renal transplant population is reported. METHODS: Medical resource use data were collected alongside a multicenter multinational randomized, placebo-controlled, double-blind trial of valaciclovir CMV prophylaxis in renal transplantation. Patients were stratified into donor seropositive/recipient sero-negative (D+R-) and recipient seropositive (R+) groups. Patients were followed-up 6 months posttransplant. A cost-effectiveness analysis from the perspective of the French health care system was performed using the number of cases of CMV disease avoided at 6 months as the clinical endpoint. RESULTS: Resource use was significantly increased among patients who developed CMV disease compared to those who did not develop disease. In the high risk D+R- group, valaciclovir prophylaxis was associated with an average of 5.5 fewer inpatient hospital days (P < OR =0.05) and with significantly lower use of other healthcare resources. In the R+ group, valaciclovir prophylaxis prevented cases of CMV disease at a marginally greater mean cost per patient compared with placebo. For D+R- patients valaciclovir prophylaxis was therefore an economically superior strategy, resulting in fewer cases of CMV disease and lower total mean healthcare expenditures. CONCLUSIONS: Valaciclovir CMV prophylaxis in renal transplantation is a more cost-effective therapy compared with placebo, in the high-risk D+R- patient population. For the R+ group, the incremental cost per case of CMV disease was modest.

Risk factors of invasive Candida and non-Candida fungal infections after liver transplantation.

Fungal infections are associated with a high mortality rate after liver transplantation. To describe risk factors for fungal infections, 405 consecutive liver transplant recipients were analyzed. Forty-five patients (11%) developed invasive fungal infection. Median posttransplantation time to the first episode was 60 days. Pathogens were Candida species (spp) (n=24, 53%), Cryptococcus neoformans (n=10, 22%), Aspergillus spp (n=6, 13%), Rhizopus spp (n=l), and others (n=4). Presentations of infection included disseminated (n=9), intra-abdominal (n=9), esophageal (n=9), lung (n=8), blood (n=6), and central nervous system infections (n=3), and sinusitis with esophagitis (n=1). Eighteen patients (40%) with invasive fungal infection died, and 13 (72%) of these deaths were attributable to fungi. Mortality in the nonfungal infection group was 12%. Univariate analysis identified separate risk factors for Candida (intra-abdominal bleeding), Aspergillus (fulminant hepatitis), and cryptococcal (symptomatic cytomegalovirus infection) infections. In both univariate and multivariate analyses, a high intratransplant transfusion requirement and posttransplant bacterial infection were identified as significant risk factors for all types of fungal infection. The risk factor analysis reported here suggests that different pathogenic processes lead to Candida and non-Candida infection in liver transplant recipients. Their identification should prompt specific prophylactic measures to reduce morbidity and mortality in this population.

The economic impact of cytomegalovirus infection after liver transplantation.

BACKGROUND: We studied the economic impact of cytomegalovirus (CMV) disease and its effective reduction with antiviral prophylaxis in liver transplant recipients. METHOD: Analysis of institutional charge data accumulated during a prospective, randomized, controlled trial comparing oral acyclovir 800 mg four times daily for 120 days (ACV) and intravenous ganciclovir 5 mg/kg every 12 h for 14 days followed by ACV for 106 days (GCV) was performed. RESULTS: Liver transplant recipients who developed CMV disease had significantly higher charges (median: $148,300) than those who developed asymptomatic CMV infection ($119,600) or experienced no CMV infection ($114,100) (P<0.01). A multiple linear regression analysis indicated that CMV disease is associated with a 49% increase in charges, independent of other factors influencing increased hospitalization charges. In CMV-seronegative patients who received a CMV-seropositive donor organ, GCV prophylaxis was associated with a significant reduction in charges, as compared to ACV prophylaxis ($113,900 vs. $153,300, respectively; P=0.02). CONCLUSIONS: CMV disease is an independent risk factor for increased resource utilization associated with liver transplantation. The use of an effective prophylactic antiviral regimen provides savings in health care resources, particularly in patients at high risk for developing CMV disease.

Prophylaxis of cytomegalovirus infection in liver transplantation: a randomized trial comparing a combination of ganciclovir and acyclovir to acyclovir. NIDDK Liver Transplantation Database.

BACKGROUND: The optimal prophylactic regimen to prevent cytomegalovirus (CMV) infection and disease in orthotopic liver-transplant patients remains to be established. We tested whether a combination of intravenous ganciclovir (GCV) followed by high dosages of oral acyclovir (ACV) for 4 months provided a higher degree of protection from CMV than oral ACV alone. METHODS: One hundred sixty-seven liver-transplant recipients were randomized to receive 120 days of antiviral treatment starting at the time of transplantation consisting of either ACV 800 mg orally four times daily (n=84) or 14 days of GCV 5 mg/kg intravenously every 12 hr followed by oral ACV 800 mg four times daily (n=83). Prospective laboratory and clinical surveillance was performed to determine primary endpoints (onset of CMV infection and CMV disease) and secondary endpoints (rates of fungal and bacterial infection, allograft rejection, and survival after transplantation). One-year event rates are presented as cumulative percentages. RESULTS: During the first year after transplantation, CMV infection developed in 57% of patients treated with ACV and in 37% of patients treated with GCV + ACV (P=0.001). CMV disease developed in 23% of patients treated with ACV and in 11% of patients treated with GCV + ACV (P=0.03). In seronegative recipients of allografts from CMV-seropositive donors (D+/R-), CMV disease developed in 58% of patients treated with ACV and in 25% of patients treated with GCV + ACV (P=0.04). In the D+/R- group, 54% of patients treated with ACV and 17% of patients treated with GCV + ACV developed infection with Candida albicans (P=0.05). CONCLUSIONS: Prophylaxis of CMV infection in liver-transplant patients with 14 days of intravenous GCV followed by high-dosage oral ACV is more effective than high-dosage oral ACV alone at reducing CMV infection and disease, even for patients in the D+/R- CMV serological group.

Antiviral agents.

In recent years, the antiviral armamentarium has expanded considerably. Currently available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome (AIDS) and is effective in the management of organ-specific cytomegalovirus infection in other immunocompromised patients. Chronic hepatitis C and condyloma acuminatum due to human papillomavirus respond to therapy with interferon alfa-2b. Patients with human immunodeficiency virus infection and CD4 lymphocyte counts of less than 500 cells/mm3 should be treated with zidovudine. Amantadine is useful in a therapeutic and prophylactic role in the management of influenza A virus infection. With the expanded use of and indications for antiviral therapy, clinically significant resistance to these agents has been encountered with increasing frequency.

Antiviral agents for non-human immunodeficiency virus infections.

Several new agents for treating viral infections have been developed in recent years. All available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome and is effective in the treatment and prevention of cytomegalovirus infection in other immunocompromised patients. Famciclovir and valacyclovir are effective in the management of herpes simplex and varicella-zoster infection. Amantadine and rimantadine are useful therapeutically and prophylactically in the management of influenza A virus infection. Chronic hepatitis B infection can respond to lamivudine therapy, and the optimal treatment of hepatitis C is the combination of interferon alfa and ribavirin. Despite pronounced toxic effects, foscarnet and cidofovir are effective antiviral agents in specific settings.

Strategies for prevention of infection after cardiac transplantation.

Infection remains a major cause of morbidity and mortality after cardiac transplantation. Most infections occur during the first few months after transplantation. Although late infection does occur, the risk of infection during maintenance immunosuppression is low in the absence of recurrent rejection that necessitates augmentation of suppression of the immune response. Before cardiac transplantation, the risk factors for infectious disease in potential candidates should be assessed. A detailed history of past infections should be elicited, and patients should be screened for the presence of active indolent infection. In addition, potential donors must be thoroughly assessed for organ-transmittable infection. Many common infections that may occur after cardiac transplantation can be prevented with the use of appropriate prophylactic regimens directed toward cytomegalovirus, Toxoplasma gondii, Pneumocystis carinii, and herpes simplex virus. Periodic surveillance serologic tests and cultures after cardiac transplantation facilitate early diagnosis and prompt institution of appropriate therapy.

Xanthomonas maltophilia: an emerging nosocomial pathogen.

Xanthomonas maltophilia is a potentially pathogenic organism with a broad clinical spectrum. Nosocomial colonization and infection are the most common manifestations. The incidence of clinical isolation of X. maltophilia is on the rise, possibly in part because of the selective pressure from the new antimicrobial agents to which it is resistant. The organism is usually resistant to commonly used antimicrobial agents, including most cephalosporins, aztreonam, antipseudomonal penicillins, imipenem, and the quinolones.

Pancreas transplantation at Mayo: III. Multidisciplinary management.

Although pancreas transplantation is a complicated procedure, a good level of success has been achieved because of the introduction of cyclosporine for immunosuppression, improved methods for diagnosing rejection, and a multidisciplinary approach to management. Our immunosuppressive regimen was quadruple therapy with induction by using Minnesota antilymphoblastic globulin. A biopsy technique was instituted in which the pancreas specimens were obtained under cystoscopic direction during episodes of hypoamylasuria. The criteria for rejection episodes were not only biochemical abnormalities but also histologic confirmation and a follow-up to exclude other causes of graft dysfunction. Infectious disease management included use of oral selective bowel decontamination for 3 weeks after transplantation. At the Mayo Clinic between October 1987 and December 1988, 16 patients received pancreaticoduodenal allografts (both kidney and pancreas in 13 and pancreas only in 3 after a prior successful kidney transplantation). In two pancreas and one kidney allograft, function was lost. One patient died of multiorgan failure. The cystoscopically directed biopsy technique was performed 23 times with minimal complications and a 93% success rate. The metabolic results have been excellent; the glycosylated hemoglobulin level was normal 3 to 6 months after transplantation. The quality of life was significantly improved in almost all patients. Nutritional assessment revealed little deterioration after transplantation. With a multidisciplinary approach, the needed answers about the effect of pancreas transplantation on the degenerative complications of diabetes should be forthcoming.

Transmission of invasive aspergillosis from a subclinically infected donor to three different organ transplant recipients.

OBJECTIVE: To describe a cluster of donor-transmitted cases of invasive aspergillosis. DESIGN: Case series of epidemiologically linked cases of invasive aspergillosis. SETTING: Two tertiary care centers with solid-organ transplant programs. PATIENTS: Two kidney recipients, one heart recipient, and the single donor. MEASUREMENTS: Routine clinical, microbiological, and pathologic investigation as dictated for patient care. Epidemiologic analysis to establish linkage among cases. RESULTS: Three allografts (two kidneys and a heart) from a single donor transmitted invasive aspergillosis to the recipients. Three weeks after transplantation, the two kidney recipients had fever and urine cultures positive for Aspergillus fumigatus. The infected kidneys had multiple Aspergillus abscesses and had to be removed to cure the patients. The heart recipient had a negative workup when a diagnosis of aspergillosis was made for the kidney recipients but presented three months later with aspergillus endocarditis with hematogenous spread to the eyes and to the skin. Treatment included eye surgery, aortic valve replacement, and antifungal therapy; control of infection ensued. The donor was intensely immunosuppressed (17 days post-liver transplantation with death from intracerebral bleeding) but had no clinical or autopsy evidence of aspergillosis. Donor tracheal secretions obtained at the time of organ harvest later grew A fumigatus. CONCLUSION: Expanded criteria for organ donation have to be balanced against infectious risk to organ recipients. A fumigatus can be transmitted from a subclinically infected donor to solid-organ transplant recipients.

Evolving strategies in lung transplantation for emphysema.

Evolving strategies of pulmonary preservation, bronchial revascularization, immunosuppression, and infectious disease management were used in 15 initial consecutive patients undergoing lung transplantation for emphysema. There were 10 women and 5 men with a mean age of 49 years (range, 36 to 60 years). All patients required supplemental oxygen therapy. One bilateral, 9 left, and 5 right transplantations were performed. Mean preoperative forced expiratory volume in 1 second and total lung capacity were 16% and 146%, respectively, of predicted. Quadruple drug immunosuppression was used. Actuarial 1-year survival in this initial series is 93.3% +/- 6.4% (Kaplan-Meier) with one early cardiac death at day 71. Mean forced expiratory volume in 1 second and diffusing capacity for carbon monoxide at discharge were 43% and 62%, respectively, of predicted. Rehabilitation has been excellent, and all survivors are active and free of supplemental oxygen. During the study, the following treatment strategies have evolved: (1) University of Wisconsin solution has replaced Euro-Collins' solution for pulmonary preservation; (2) direct bronchial revascularization with the internal thoracic artery now is used; (3) an algorithm-based variable dose OKT3 induction regimen has resulted in a major reduction in dosage; and (4) infectious disease management focuses on the prophylaxis of cytomegalovirus and fungal infection using prolonged ganciclovir and early itraconazole therapy as well as the avoidance of Epstein-Barr virus mismatches. Single-lung transplantation for emphysema has excellent early results with continuing evolving management strategies.

Antibiotics may predispose to lactobacillemia in liver transplant patients.

Lactobacilli are ubiquitous inhabitants of the human oral cavity, vagina, and gastrointestinal tract, that are generally considered non-pathogenic. We retrospectively reviewed all positive blood cultures for Lactobacillus species (sp.) from liver transplant recipients at our institution. Eight cases of lactobacillus bacteremia were identified. Selective bowel decontamination with non-absorbable oral antibiotics was administered to all patients. Additionally, all patients received intravenous vancomycin; most isolates exhibited either in vitro or in vivo vancomycin resistance. The biliary anastomosis in each patient was a Roux-Y choledochojejunostomy. The underlying clinical conditions included perihepatic abscesses in two patients, biliary strictures with either hepatic abscesses or infected bile in four, and heaptic infarctions with necrosis and infection of the liver in two. The use of selective bowel deontamination, intravenous vancomycin and Roux-Y choledochojejunostomy in liver transplantation patients may predispose to lactobacillemia.

Bacteremia due to Enterococcus avium.

Enterococcus avium, formerly "group Q streptococcus," has rarely been reported as a pathogen in humans. To determine the clinical significance of this organism, we reviewed the records of all patients whose blood cultures were positive for E. avium who were seen at our institution from 1986 through 1991 and identified nine cases of bacteremia due to E. avium. All isolates were believed to be clinically significant. Five of nine cases developed in patients with significant gastrointestinal illnesses. The remaining clinical scenarios included intravenous catheter sepsis and factitious disorders. E. avium bacteremias were polymicrobial in seven cases; in six cases, the coisolates were gastrointestinal organisms. These observations suggest that E. avium bacteremia most often originated from a gastrointestinal tract source. We conclude that, though rare, E. avium can be pathogenic in humans and that E. avium bacteremia is associated with gastrointestinal abnormalities.

Lack of extracellular slime effect on treatment outcome of Staphylococcus epidermidis experimental endocarditis.

We studied the response of two slime negative Staphylococcus epidermidis strains (NS1 and NS2) and one slime producing strain (S1) to treatment with vancomycin in the rabbit catheter-induced endocarditis model. All micro-organisms had vancomycin minimal inhibitory concentration and minimal bactericidal concentration of 4 mg/l. Three days after infection, treatment with vancomycin 25 mg/kg every 12 h was begun and continued for 4 days. Cardiac valve vegetations were harvested 12 h after the last dose of vancomycin and cultured quantitatively. In treated animals the mean +/- S.D. log10 colony forming units per g of cardiac valve vegetation were 1.6 +/- 0.1 for NS1, 4.4 +/- 1.9 for NS2, and 2.3 +/- 1.2 for S1. Slime production did not influence the results of vancomycin therapy of S. epidermidis experimental endocarditis. Other factors may cause strain-dependent variability in response to antimicrobial treatment in this model.

Infections due to nontuberculous mycobacteria in kidney, heart, and liver transplant recipients.

Infections due to nontuberculous mycobacteria (NTM) in solid-organ transplant recipients are infrequent but may be a major cause of morbidity. We describe four cases of NTM infection in solid-organ transplant recipients. The manifestations included a nodule secondary to Mycobacterium kansasii infection in a heart transplant recipient, a cutaneous lesion and a pulmonary nodule secondary to M. kansasii infection in a renal transplant recipient, tenosynovitis secondary to Mycobacterium chelonae infection in a renal transplant recipient, and cutaneous lesions secondary to M. chelonae infection in a liver transplant recipient. We also summarize previously reported cases of NTM infections in solid-organ transplant recipients; common manifestations of NTM infections in solid-organ transplant recipients include cutaneous lesions of the extremities, tenosynovitis, and joint infection. Histopathologic examination of aspirates or biopsy specimens from involved areas and staining and culture for mycobacteria are essential for diagnosis. Treatment of NTM infection most commonly involves surgery, reduction in doses of immunosuppressive medications, and/or therapy with antimycobacterial medications; these treatments are often associated with a good outcome.

A case of Aspergillus fumigatus peritonitis complicating liver transplantation.

A 55-year-old male underwent orthotopic liver transplantation for sub-fulminant hepatitis B/delta infection superimposed on probable genetic hemochromatosis with early cirrhosis. Pre-operatively, he demonstrated serologic evidence of cytomegalovirus reactivation and developed cytomegalovirus viremia when ganciclovir was discontinued post-operatively. His post-operative course was complicated by chronic ductopenic rejection, biliary anastomotic leak, and persistent confusion and malaise. At the time of laparotomy for repair of the bile leak, nodular peritoneal lesions were noted, with biopsy and culture showing angioinvasive Aspergillus fumigatus. Despite administration of amphotericin B, the patient continued to have culture-confirmed evidence of infection at follow-up peritoneoscopy. Oral itraconazole was begun, but the patient died of liver failure secondary to progressive ductolpenic rejection. At autopsy, Aspergillus organisms were seen in histologic sections taken from the small bowel; there was no evidence of disseminated disease.

Epstein-Barr virus and persistent graft dysfunction after liver transplantation.

Epstein-Barr virus infection has been associated with a broad spectrum of clinical manifestations, depending on the immune status of the host. In this report, we describe two liver transplant patients who received hepatic allografts from donors serologically positive for Epstein-Barr virus and who experienced primary infection with Epstein-Barr virus associated with prolonged liver graft dysfunction. In both patients, Epstein-Barr serologies converted within 3 mo of liver transplantation, and hepatic histological study revealed mononuclear infiltration of the sinusoids evolving to pronounced immunoblastic features suggestive of evolving lymphoma. In both cases, in situ hybridization studies confirmed the presence of Epstein-Barr virus genome in the liver. Furthermore, polymerase chain reaction analysis suggested that high levels of Epstein-Barr virus DNA were present in biopsy specimens obtained during the episode of acute hepatitis that followed Epstein-Barr virus seroconversion. The degree of Epstein-Barr virus DNA estimated by polymerase chain reaction appeared to increase in parallel with the progression of parenchymal lymphocytic infiltrates. In one patient, a biopsy sample from a cervical node also revealed high levels of Epstein-Barr virus DNA estimated using the polymerase chain reaction technique. Furthermore, in these patients, Epstein-Barr virus DNA levels appeared to decrease dramatically after discontinuing azathioprine administration and beginning treatment with acyclovir. These two cases illustrate the dynamics of Epstein-Barr virus immune regulation and confirm chronic hepatic allograft dysfunction related to Epstein-Barr viral infection.