Treatment of alpha and beta herpesvirus infections in solid organ transplant recipients.

INTRODUCTION: Human herpesviruses frequently cause infections in solid organ transplant (SOT) recipients. Areas covered: We provide an overview of the clinical impact of alpha and beta herpesviruses and highlight the mechanisms of action, pharmacokinetics, clinical indications, and adverse effects of antiviral drugs for the management of herpes simplex virus, varicella zoster virus and cytomegalovirus. We comprehensively evaluated key clinical trials that led to drug approval, and served as the foundation for management guidelines. We further provide an update on investigational antiviral agents for alpha and beta herpesvirus infections after SOT. Expert commentary: The therapeutic armamentarium for herpes infections is limited by the emergence of drug resistance. There have been major efforts for discovery of new drugs against these viruses, but the results of early-phase clinical trials have been less than encouraging. We believe, however, that more antiviral drug options are needed given the adverse side effects associated with current antiviral agents, and the emergence of drug-resistant virus populations in SOT recipients. Likewise, optimized use and strategies are needed for existing and novel antiviral drugs against alpha and beta-herpesviruses in SOT recipients.

Current practices for treatment of respiratory syncytial virus and other non-influenza respiratory viruses in high-risk patient populations: a survey of institutions in the Midwestern Respiratory Virus Collaborative.

BACKGROUND: The optimal treatment for respiratory syncytial virus (RSV) infection in adult immunocompromised patients is unknown. We assessed the management of RSV and other non-influenza respiratory viruses in Midwestern transplant centers. METHODS: A survey assessing strategies for RSV and other non-influenza respiratory viral infections was sent to 13 centers. RESULTS: Multiplex polymerase chain reaction assay was used for diagnosis in 11/12 centers. Eight of 12 centers used inhaled ribavirin (RBV) in some patient populations. Barriers included cost, safety, lack of evidence, and inconvenience. Six of 12 used intravenous immunoglobulin (IVIG), mostly in combination with RBV. Inhaled RBV was used more than oral, and in the post-stem cell transplant population, patients with lower respiratory tract infection (LRTI), graft-versus-host disease, and more recent transplantation were treated at higher rates. Ten centers had experience with lung transplant patients; all used either oral or inhaled RBV for LRTI, 6/10 treated upper respiratory tract infection (URTI). No center treated non-lung solid organ transplant (SOT) recipients with URTI; 7/11 would use oral or inhaled RBV in the same group with LRTI. Patients with hematologic malignancy without hematopoietic stem cell transplantation were treated with RBV at a similar frequency to non-lung SOT recipients. Three of 12 centers, in severe cases, treated parainfluenza and metapneumovirus, and 1/12 treated coronavirus. CONCLUSIONS: Treatment of RSV in immunocompromised patients varied greatly. While most centers treat LRTI, treatment of URTI was variable. No consensus was found regarding the use of oral versus inhaled RBV, or the use of IVIG. The presence of such heterogeneity demonstrates the need for further studies defining optimal treatment of RSV in immunocompromised hosts.

Cytomegalovirus disease is associated with higher all-cause mortality after lung transplantation despite extended antiviral prophylaxis.

BACKGROUND: The duration of anticytomegalovirus (CMV) prophylaxis after lung transplantation (LT) varies among transplant centers. METHODS: A retrospective review of CMV donor-seropositive/recipient-seronegative (D+/R-) and CMV recipient-seropositive (R+) LT patients between January 2005 and September 2012 was performed. Starting January 2007, valganciclovir prophylaxis was given for at least 12 months (often lifelong) for CMV D+/R- and extended from three to six months for R+ LT patients. Risks of CMV infection and CMV disease, and mortality after LT, were assessed. RESULTS: A total of 88 LT patients were studied, including 32 CMV D+/R-, and 56 R+ patients. During the follow-up period, 11 (12.5%) patients had asymptomatic CMV infection, and nine (10.3%) developed CMV disease. CMV disease (HR, 4.189; 95% CI: 1.672-10.495; p = 0.002) and CMV infection and disease (HR, 3.775; 95% CI: 1.729-8.240; p = 0.001) were significant risk factors for mortality. Overall, no significant difference was observed in rates of CMV infection or disease among LT recipients who received shorter vs. extended CMV prophylaxis. CONCLUSIONS: Despite extended prophylaxis, LT patients remain at risk of CMV infection and disease. CMV remains associated with increased mortality after transplantation.

Donor-transmitted HTLV-1-associated myelopathy in a kidney transplant recipient--case report and literature review.

Clinical disease due to human T cell lymphotropic virus type 1 (HTLV-1), a retrovirus endemic in certain regions of the world, is rarely reported after solid organ transplantation. In 2009, universal deceased donor organ screening for HTLV-1 was discontinued in the United States. We report the first case of donor-derived HTLV-1-associated myelopathy in a kidney transplant recipient from the United States. The patient, who was HTLV-1-seronegative prior to transplantation, likely acquired HTLV-1 infection from a seropositive organ donor. In this era when screening of donors and recipients for HTLV infection is not mandatory, clinicians should be vigilant in recognizing the risk and potential occurrence of this donor-derived infection in recipients with epidemiologic exposures.

Emerging cytomegalovirus management strategies after solid organ transplantation: challenges and opportunities.

Cytomegalovirus (CMV) remains as one of the most common pathogens after solid organ transplantation (SOT). During the past year, management guidelines were updated, and numerous studies were published-all collectively emphasizing the ongoing efforts to improve management of CMV after SOT. Improvement in laboratory diagnostics was aided by the WHO international calibration standard for nucleic acid testing, which allows for meaningful comparison of viral load values among laboratories. The potential translation of methods for assessing CMV-specific cellular immunity could provide tools for CMV risk assessment and management. Efforts continue to optimize antiviral strategies for CMV disease prevention and treatment. CMV vaccines continue to be tested in various stages of clinical trials. Novel anti-CMV drugs are being developed, including agents that have been used as compassionate therapy for treatment of drug-resistant CMV. In this article, the authors review recent developments on CMV and discuss their implications in CMV management after transplantation.

Rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient: report of the first transplant case and review of the literature.

Rhodococcus species are environmental organisms that predominantly cause opportunistic infections in immunocompromised hosts. Rhodococcus equi is the most common species associated with human infections, but there are uncommon but increasing number of cases of infections caused by non-equi Rhodococcus species. We report a case of Rhodococcus globerulus bacteremia in an allogeneic hematopoietic stem cell transplant recipient, who presented with subacute systemic illness accompanied by severe hepatitis. In the context of this case, we review the literature on Rhodococcus species infections in transplant recipients.

Oral ribavirin therapy for respiratory syncytial virus infections in moderately to severely immunocompromised patients.

BACKGROUND: Respiratory syncytial virus (RSV) infections may be fatal in immunocompromised patients. Aerosolized ribavirin is used for treatment, but it is very costly, teratogenic, and inconvenient. We aimed to assess the outcome of oral ribavirin treatment, with or without intravenous immunoglobulin (IVIG), for RSV infections in moderately to severely immunocompromised patients. METHODS: Medical records of RSV polymerase chain reaction (PCR)-positive patients during 2011-2013 were reviewed retrospectively. Eligible patients were moderately to severely immunocompromised and received oral ribavirin (600-800 mg twice daily) with or without IVIG (500 mg/kg q 48 h) as per protocol. RESULTS: Of 96 adults with PCR-proven RSV infection, 34 were moderately to severely immunocompromised and received oral ribavirin treatment. The mean age was 56.2 years (range: 18-90); 21 were male. Underlying conditions were hematologic malignancy with or without hematopoietic stem cell transplant (n = 25), lung transplant (n = 3), or receipt of cytotoxic chemotherapy (n = 11). The presenting symptoms were cough (94%), fever (62%), and dyspnea (59%). The most common radiographic findings were patchy and nodular infiltrates and opacities. Of 34 patients, 31 were hospitalized, with 13 admitted to the intensive care unit and 6 required mechanical ventilation. The median absolute lymphocyte count on presentation was 480 cells/mm(3) . RSV pneumonia developed in 24 patients. The median initial duration of oral ribavirin treatment was 10 days (range: 4-11); 4 patients were re-treated. Of 34 patients, 19 received a mean of 2.7 doses of IVIG. Two patients had adverse reactions to ribavirin (hemolytic anemia and lactic acidosis in 1 patient, and altered mental status in another). No patient died from RSV infection. Three patients died from complications of their underlying illness; all others recovered clinically. CONCLUSIONS: Oral ribavirin with or without IVIG is a well-tolerated treatment for RSV infection in moderately to severely immunocompromised hosts. Comparative prospective studies should ideally be performed to determine if oral ribavirin is the optimal therapy for RSV infection in this patient population.

Elizabethkingia species sepsis after lung transplantation: case report and literature review.

Elizabethkingia species are environmental bacteria that rarely cause infection in neonates and immunocompromised adults, usually as part of nosocomial outbreaks. We report an isolated fatal case of disseminated Elizabethkingia species infection in a lung transplant recipient and review the literature of this bacterial infection in transplant recipients.

A multicenter evaluation of pandemic influenza A/H1N1 in hematopoietic stem cell transplant recipients.

BACKGROUND: Hematopoietic stem cell transplant (HSCT) recipients have increased morbidity from respiratory viral infections. Pandemic influenza A - A(H1N1)/pdm09 - in 2009-2010 was associated with increased severity of illness in patients with underlying co-morbidities including HSCT, but the factors that contribute to severe disease in HSCT patients are not well characterized. METHODS: We conducted a multicenter review of microbiologically proven influenza A(H1N1)pdm09 in the HSCT population between April 2009 and April 2010 to determine factors that are associated with severe disease. RESULTS: We identified 37 adult patients (26 allogeneic and 11 autologous HSCT recipients). Median time from transplant to diagnosis was 411 days (range 4 days-14.9 years). Three cases were hospital acquired. Twenty-eight of 37 (75.7%) had confirmed A(H1N1)pdm09. Presumed viral lower respiratory tract infection was present in 12/37 (32.4%) patients. Antiviral therapy was given to 33/37 (89%) patients, primarily oseltamivir (n = 24) and oseltamivir before or after another antiviral (n = 8). Excluding those with nosocomial A(H1N1)pdm09, 18/34 (52.9%) were hospitalized and 6 (33%) required admission to an intensive care unit. Mortality within 30 and 60 days of symptom onset was 7/37 (18.9%) and 11/37 (29.7%), respectively. Factors associated with mortality included nosocomial acquisition (P = 0.023), receipt of mycophenolate mofetil (P = 0.001), or antilymphocyte antibody (P = 0.005) within the past 6 months, reduced-intensity conditioning (P = 0.027), and bacteremia (P = 0.021). CONCLUSIONS: A(H1N1)pdm09 infection was particularly severe in HSCT recipients, specifically among those receiving augmented immunosuppression for graft-versus-host disease. The high mortality of the nosocomial cases highlights the need for strict infection-control measures in hospitals during influenza outbreaks.

Human herpesviruses 6, 7 and 8 in solid organ transplant recipients.

Human herpesviruses (HHV) 6 and 7 are ubiquitous infections that reactivate commonly in transplant recipients. However, clinical diseases due to these viruses are reported only in 1% of solid organ transplant recipients. Fever, rash and bone marrow suppression are the most common manifestations, but symptoms of tissue invasive disease may be observed. Treatment of HHV-6 and HHV-7 disease includes antiviral therapy and cautious reduction in immunosuppression. HHV-8 is an oncogenic gamma-herpesvirus that causes Kaposi's sarcoma, Castleman's disease and primary effusion lymphomas in transplant recipients. Nonmalignant diseases such as bone marrow suppression and multiorgan failure have also been associated with HHV-8. Reduction in immunosuppression is the first line treatment of HHV-8 infection. Other alternatives for treatment, especially for HHV-8 diseases not responsive to immuno-minimization strategies, are surgery and chemotherapy. Sirolimus has been shown to be a beneficial component for the treatment of Kaposi's sarcoma and the role of antivirals for HHV-8 infection is being investigated.

Association between a functional polymorphism in Toll-like receptor 3 and chronic hepatitis C in liver transplant recipients.

BACKGROUND: Toll-like receptor 3 (TLR3) is implicated in the pathogenesis of viral diseases owing to its ability to recognize viral double-stranded RNA. We hypothesized that single nucleotide polymorphism (SNP) in TLR3 gene that impairs the function of the protein-receptor influences the outcome of hepatitis C virus (HCV) infection after liver transplantation. METHODS: The clinical characteristics of 611 liver recipients (HCV-infected: n = 153, non-HCV-infected: n = 458) were assessed to investigate the impact of TLR3 L412F SNP on transplant outcomes. RESULTS: TLR3 L412F is common, and it was significantly more prevalent among the HCV-infected cohort (57.5% vs. 45.2%, P = 0.008). In a multivariate analysis, TLR3 L412F was significantly associated with chronic hepatitis C (odds ratio: 1.73, 95% confidence interval [CI]: 1.13-2.65, P = 0.01). In an analysis that compared HCV-infected patients with wild-type versus TLR3 L412F, a marginally higher rate of allograft failure and mortality was observed in the TLR3 L412F group (44.3% vs. 30.8%, P = 0.09). However, in a multivariate analysis, only donor age was significantly associated with allograft failure and mortality (relative risk: 1.04, 95% CI: 1.007-1.06, P = 0.02). CONCLUSION: TLR3 L412F is significantly common in HCV-infected liver recipients, and may be associated with worse outcomes. However, larger studies are needed to determine its significant association with allograft failure and mortality after liver transplantation for chronic hepatitis C.

Outcomes of transplantation using organs from a donor infected with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae.

Transmission of pathogens from donor to recipient is a potential complication of organ transplantation. Herein, we describe the clinical course and outcomes of 4 transplant recipients who received tissues from a donor with multi-organ infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae. Recipient 1 underwent simultaneous liver and kidney transplantation for alpha-1 antitrypsin deficiency and alcohol-related cirrhosis, and acute tubular necrosis, respectively. Soon after transplantation, he developed an infected hematoma and peritonitis due to KPC-producing K. pneumoniae despite receiving tigecycline prophylaxis. He was treated with a prolonged course of tigecycline, amikacin, and meropenem, in conjunction with surgical evacuation and percutaneous drainage of the infected fluid collections. Recipient 2 underwent living-donor liver transplantation for cholangiocarcinoma and primary sclerosing cholangitis using vein graft from the donor infected with KPC-producing K. pneumoniae. Culture of the preservation fluid containing the vein graft was positive for KPC-producing K. pneumoniae. The patient received preemptive amikacin and tigecycline, and he did not develop any infection (as evidenced by negative surveillance blood cultures). The isolates from the donor and Recipients 1 and 2 were indistinguishable by pulsed-field gel electrophoresis. Recipients 3 and 4 underwent kidney and heart transplantation, respectively; both patients received perioperative tigecycline prophylaxis and did not develop infections due to KPC-producing K. pneumoniae. All transplant recipients had good short-term outcomes. These cases highlight the importance of inter-institutional communication and collaboration to ensure the successful management of recipients of organs from donors infected with multidrug-resistant organisms.

Chromosomally integrated human herpesvirus-6 in transplant recipients.

Human herpesvirus-6 (HHV-6) is unique among human herpesviruses because of its ability to integrate into chromosomes. This entity, termed chromosomally integrated HHV-6 (CIHHV-6), is often mistaken for active infection and treated unnecessarily. The clinical significance of CIHHV-6 in transplant recipients is not defined. Herein, the clinical characteristics of 7 liver transplant patients with CIHHV-6 from our recent study, together with 14 other published cases of CIHHV-6 were reviewed. Of the 21 cases, CIHHV-6B was reported most commonly among solid organ transplant recipients, while CIHHV-6A was mostly seen in allogeneic hematopoietic stem cell recipients. None of the 21 patients developed clinical symptoms related to HHV-6 after transplantation. However, antiviral therapy was administered to 5 asymptomatic patients mistaken to have HHV-6 infection because of their very high HHV-6 DNA levels, 3 who developed symptomatic cytomegalovirus disease, and 1 with graft-versus-host disease that was mistaken for HHV-6 infection. In patients who received antiviral therapy, there was no apparent decline in HHV-6 DNA load, although change in viral kinetics is difficult to discern in the setting of high baseline HHV-6 DNA load. Clinicians should be aware of this entity of CIHHV-6 so that antiviral therapy can be considered in the proper clinical context.

Prosthetic joint infection in solid organ transplant recipients: a retrospective case-control study.

BACKGROUND: The clinical features and outcome of prosthetic joint infection (PJI) among solid organ transplant (SOT) recipients have not been characterized. We performed a retrospective, matched case-control study to examine potential risk factors. METHODS: We reviewed cases of PJI among transplant recipients who were evaluated at the Mayo Clinic between 1989 and 2009. Cases were matched to non-infected controls based on transplant type, prosthetic joint type, and order of organ transplantation/joint implantation. RESULTS: Among 367 patients with both a joint prosthesis and an SOT, there were 12 cases of infection in those receiving immunosuppression. These occurred in 8 renal recipients, 3 liver recipients, and 1 heart transplant recipient. Six subjects had hip and 6 had knee arthroplasty infections. The observed time to prosthesis failure ranged from 0.5 to 148 months after implantation. Gram-positive bacteria (staphylococci and streptococci) caused the infection in 8 subjects. Two cases were caused by nontuberculous mycobacteria, whereas the remaining 2 cases were culture-negative in the setting of antimicrobial use. We did not find a statistically significant association between obesity, diabetes mellitus, or antimicrobial prophylaxis (given in the setting of immunosuppression) and development of PJI. A marginal association was seen between surgical site infection and the risk of PJI; however, this did not reach statistical significance. CONCLUSION: In our series, infection was mainly caused by gram-positive bacterial pathogens, similar to the commonly encountered organisms in the immunocompetent host, although opportunistic pathogens were also isolated.

Incidental hepatic schistosomiasis in a liver transplant recipient.

Hepatic schistosomiasis is a well recognized cause of chronic liver disease and portal hypertension. Herein, we describe a case of a 62-year-old Kuwaiti man who underwent liver transplantation for non-alcoholic steatohepatitis and, as an incidental finding in the histopathology of the explanted liver, eggs consistent with Schistosoma were found. In endemic regions, hepatic schistosomiasis is often observed as an incidental finding in explanted livers of patients who receive liver transplantation for other indications. In the context of this case, we provide a brief review of the management of schistosomiasis in transplant recipients.

Clinical and radiological features of respiratory syncytial virus in solid organ transplant recipients: a single-center experience.

BACKGROUND: Respiratory syncytial virus (RSV) infections range from upper respiratory illness to severe lower respiratory disease. There is no universally accepted treatment for RSV in solid organ transplant (SOT) recipients. METHODS: Retrospective review of adult SOT patients with RSV infections, between January 2007 and December 2009, in a single transplant center was performed. RESULTS: During the 3-year period, a total of 24 adults developed RSV infection, including 12 (50%) SOT recipients (5 kidneys, 4 livers, and 3 lungs). Most cases were seen in 2009 during the influenza H1N1 pandemic, likely as a result of increased testing. In 83% of the cases, the diagnosis was based on RSV antigen detection, which was also used to follow subsequent shedding (mean duration: 20.6 days). Most of the cases presented with lower respiratory disease and required hospitalization. All the patients were on at least two classes of immunosuppressive drugs. We observed a lower lymphocyte count in patients with lower respiratory tract infection. Computed tomography was superior to chest x-ray in demonstrating pulmonary disease, with the most common findings being pulmonary nodules and ground-glass opacities. Novel radiographic findings were small cavities and pleural effusions. No co-infections were documented, and no mortality could be attributed to RSV. Inhaled or oral ribavirin was administered in 67% of the cases, with variations in the treatment regimens. CONCLUSION: SOT recipients accounted for half of all adult cases of RSV at our institution. Type and length of treatment varied widely, and we cannot conclude that outcomes differed between treatments with oral or inhaled ribavirin. Current therapeutic management of RSV in SOT is empiric, and can be rather expensive and difficult, without clear evidence of effectiveness.