Michael G. Ison

Adenovirus infections in transplant recipients.

Adenoviruses are increasingly recognized as contributors to morbidity and mortality among stem cell and solid-organ transplant recipients. Clinical presentations range from asymptomatic viremia to respiratory and gastrointestinal disease, hemorrhagic cystitis, and severe disseminated illness. The limited clinical data available support the use of cidofovir for many of these illnesses. Prospective studies are needed to better understand the pathogenesis of and therapeutic options for adenoviral infections in this patient population.

Recovery of Drug-Resistant Influenza Virus from Immunocompromised Patients: A Case Series

Influenza virus with resistance to antiviral drugs emerges with increased frequency in immunocompromised patients and can limit the benefit of M2 and neuraminidase (NA) inhibitors. We document 3 cases of influenza in severely immunocompromised patients from whom virus variants with molecular markers of resistance to anti-influenza drugs were recovered. Virus variants recovered from 2 patients had mutations in the M2, NA (with a previously recognized Glu119Val NA substitution), and hemagglutinin genes. We describe a novel Asp198Asn NA mutation in an influenza B virus and its decreased susceptibility to both oseltamivir and zanamivir.

Donor‐Derived Disease Transmission Events in the United States: Data Reviewed by the OPTN/UNOS Disease Transmission Advisory Committee

Donor‐derived disease transmission is increasingly recognized as a source of morbidity and mortality among transplant recipients. Policy 4.7 of the Organ Procurement and Transplantation Network (OPTN) currently requires reporting of donor‐derived events. All potential donor‐derived transmission events (PDDTE) reported to OPTN/UNOS were reviewed by the Disease Transmission Advisory Committee (DTAC). Summary data from January 1, 2005–December 31, 2007, were prepared for presentation. Reports of PDDTE have increased from 7 in 2005, the first full year data were collected, to 60 in 2006 and to 97 in 2007. More detailed information is available for 2007; a classification system for determining likelihood of donor‐derived transmission was utilized. In 2007, there were four proven and one possible donor‐derived malignancy transmissions and four proven, two probable and six possible donor‐derived infectious diseases transmissions. There were nine reported recipient deaths attributable to proven donor transmissions events arising from eight donors during 2007. Although recognized transmission events resulted in significant morbidity and mortality, transmission was reported in only 0.96% of deceased donor donations overall. Improved reporting, through enhanced recognition and communication, will be critical to better estimate the transmission risk of infection and malignancy through organ transplantation.

Viral infections in immunocompromised patients: what's new with respiratory viruses?

Purpose of review The leading cause of death in solid organ and hematopoietic stem cell transplant recipients is infection. The respiratory viruses, particularly respiratory syncytial virus, influenza, parainfluenza, adenovirus, and picornaviruses, are increasingly recognized as significant pathogens in these populations. Recent findings Respiratory syncytial virus has again been found to be the most common of the respiratory viruses causing severe infections in transplant recipients. Advances in prevention, particularly with regard to infection control practices, and to lesser extent treatment have had a substantial impact on the frequency and outcomes of this infection. New studies have clarified the impact of influenza in the hematopoietic stem cell transplant recipients and have provided evidence to support the use of M2 and neuraminidase inhibitors for early treatment. The epidemiology of parainfluenza and adenovirus in transplant recipients has been clarified, although therapeutic modalities are still limited and understudied. New antiviral medications may bring improved outcomes of picornavirus infections in this population. Finally, a new virus, the human metapneumovirus, has recently been described and may be a significant respiratory pathogen in immunocompromised transplant recipients. Summary Studies published over the past year have documented a new respiratory pathogen. They have also resulted in improved understanding of the epidemiology of all of the respiratory virus pathogens, and have contributed to improve management of respiratory syncytial virus and influenza infection in hematopoietic stem cell transplant and solid organ transplant recipients.

Assessment of Cytomegalovirus-Specific Cell-Mediated Immunity for the Prediction of Cytomegalovirus Disease in High-Risk Solid-Organ Transplant Recipients: A Multicenter Cohort Study

BACKGROUND Cytomegalovirus (CMV) disease remains an important problem in solid-organ transplant recipients, with the greatest risk among donor CMV-seropositive, recipient-seronegative (D(+)/R(-)) patients. CMV-specific cell-mediated immunity may be able to predict which patients will develop CMV disease. METHODS We prospectively included D(+)/R(-) patients who received antiviral prophylaxis. We used the Quantiferon-CMV assay to measure interferon-γ levels following in vitro stimulation with CMV antigens. The test was performed at the end of prophylaxis and 1 and 2 months later. The primary outcome was the incidence of CMV disease at 12 months after transplant. We calculated positive and negative predictive values of the assay for protection from CMV disease. RESULTS Overall, 28 of 127 (22%) patients developed CMV disease. Of 124 evaluable patients, 31 (25%) had a positive result, 81 (65.3%) had a negative result, and 12 (9.7%) had an indeterminate result (negative mitogen and CMV antigen) with the Quantiferon-CMV assay. At 12 months, patients with a positive result had a subsequent lower incidence of CMV disease than patients with a negative and an indeterminate result (6.4% vs 22.2% vs 58.3%, respectively; P < .001). Positive and negative predictive values of the assay for protection from CMV disease were 0.90 (95% confidence interval [CI], .74-.98) and 0.27 (95% CI, .18-.37), respectively. CONCLUSIONS This assay may be useful to predict if patients are at low, intermediate, or high risk for the development of subsequent CMV disease after prophylaxis. CLINICAL TRIALS REGISTRATION NCT00817908.

An Update on Donor-Derived Disease Transmission in Organ Transplantation

Several recent donor‐to‐recipient disease transmissions have highlighted the importance of this rare complication of solid organ transplantation. The epidemiology of donor‐derived disease transmissions in the United States has been described through reports to the Organ Procurement and Transplant Network (OPTN); these reports are reviewed and categorized by the ad hoc Disease Transmission Advisory Committee (DTAC); additional data comes through the published literature. From these reports, it is possible to estimate that donor‐derived disease transmission complicates less than 1% of all transplant procedures but when a transmission occurs, significant morbidity and mortality can result. Only through continued presentation of the available data can continuous quality improvements be made. As the epidemiology of donor‐derived disease transmission has become better understood, several groups have been working on methods to further mitigate this risk.

Guidance on novel influenza A/H1N1 in solid organ transplant recipients.

Novel influenza A/H1N1 virus has caused significant illness worldwide. In response to this global crisis, the American Society of Transplantation (AST) Infectious Diseases Community of Practice and the Transplant Infectious Diseases section of The Transplantation Society (TTS) developed a guidance document for novel H1N1. In this paper, we discuss current guidance for H1N1 as it relates to solid organ transplantation. We include discussion around clinical presentation, diagnosis, therapy and prevention specifically addressing areas such as chemoprophylaxis, immunization and donor‐derived infection. Although this document addresses conditions specific to novel H1N1, many principles could be applied to future pandemics. As new information emerges about novel H1N1, updates will be made to the electronic version of the document posted on the websites of the AST and TTS.

Rhinovirus infections in hematopoietic stem cell transplant recipients with pneumonia

Abstract Little is known about the impact of human rhinovirus (HRV) and coronavirus infections in hematopoietic stem cell transplant (HSCT) recipients. We tested bronchoalveolar lavage (BAL) samples obtained from HSCT recipients with acute pulmonary infiltrates for HRV (n = 122) and coronavirus (n = 46) by reverse-transcriptase polymerase chain reaction. HRV RNA was detected in 6 (8%) of 77 patients, and coronavirus RNA was detected in 0 of 46 of BAL samples from HSCT recipients. The fatality rate in HRV-infected patients was high (83%), but all patients had significant coinfections, and the overall mortality rate was not different from that of patients who were negative for HRV in BAL samples. These results suggest that HRV may be a cause of lower respiratory tract infections in HSCT recipients and that its detection in BAL samples is associated with frequent copathogens. Whether the poor prognosis is due to HRV or the copathogen is not clear.

Influenza Vaccination in the Organ Transplant Recipient: Review and Summary Recommendations

Influenza virus causes a spectrum of illness in transplant recipients with a high rate of lower respiratory disease. Seasonal influenza vaccination is an important public health measure recommended for transplant recipients and their close contacts. Vaccine has been shown to be safe and generally well tolerated in both adult and pediatric transplant recipients. However, responses to vaccine are variable and are dependent on various factors including time from transplantation and specific immunosuppressive medication. Seasonal influenza vaccine has demonstrated safety and no conclusive evidence exists for a link between vaccination and allograft dysfunction. Annually updated trivalent inactivated influenza vaccines have been available and routinely used for several decades, although newer influenza vaccination formulations including high‐dose vaccine, adjuvanted vaccine, quadrivalent inactivated vaccine and vaccine by intradermal delivery system are now available or will be available in the near future. Safety and immunogenicity data of these new formulations in transplant recipients requires investigation. In this document, we review the current state of knowledge on influenza vaccines in transplant recipients and make recommendations on the use of vaccine in both adult and pediatric organ transplant recipients.

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-&ggr; based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.