Organ Transplantation

Community-acquired respiratory viruses Purpose of review Community-acquired respiratory viruses (CARV) have been historically linked to upper respiratory tract infections; however, new data has emerged in recent years that has provided new insight into their role as causative pathogens for lower respiratory tract infections. We aim to discuss the importance of recognition of viruses both epidemiologically and clinically as causes of lower respiratory tract infection. Recent findings With advances of molecular testing it is now possible to identify viruses from clinical specimens which have many implications that range from therapeutics to antibiotic stewardship. Recent studies suggest that most of the cases of community-acquired pneumonia are caused by viruses, which corresponds to a paradigm shift for most clinicians. Summary As community-acquired lower respiratory infections are the most common cause of ICU admission in the USA, it is important for medical providers to be aware of the association with viruses, especially in patients with immunosuppression because of solid organ transplant and hematologic malignancies when sometimes diagnosis can be challenging and patients can be exposed to unnecessary antibiotics. Correspondence to Emily Blodget, MD, MPH, Division of Infectious Diseases, University of Southern California, Keck School of Medicine, 2020 Zonal Avenue, IRD Room 436, Los Angeles, CA 90033, USA. Tel.: +1 323 409 4444;. fax: +1 323 226 7726; e-mail: eblodget@med.usc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Innovations in kidney paired donation transplantation Purpose of review To analyze the innovations that have increased the reliability, convenience, and outcomes of kidney paired donation (KPD) that has led to thousands of living donor kidney transplants across the United States. Recent findings Over the past 10 years, KPD has grown over 200% on an annual basis. Though concerns had existed over cold ischemia time, research has shown that there is no correlation between travel time of a shipped kidney and the transplant outcome. The voucher program has started to continue to expand how to overcome obstacles to donation by solving the issue of a pair chronological incompatibility. Summary KPD is a relatively new field and the innovations it has spawned should continue to improve availability of high-quality living donor organs. The introduction of the family voucher should continue this trend. Correspondence to Thomas D’Alessandro, National Kidney Registry, 42 Fire Island Avenue, Babylon, NY 11702, USA. Tel: +1 631 560 7887; fax: +1 800 401 8919; e-mail: TDAlessandro@kidneyregistry.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Coccidioidomycosis in solid organ transplant recipients Purpose of review The purpose of the review is an update of diagnosis and treatment of coccidioidomycosis infection in solid organ transplant (SOT) patients. Endemic fungal infections continue to be a cause of serious morbidity and mortality in transplant recipients. Recent findings In transplant patients there are recommendations regarding screening in areas that are endemic for coccidioidomycosis. This screening involves serologic testing and chest imaging. In endemic areas pretransplant seropositivity varies from 1.4 to 5.6%. In immunocompromised patients with elevated complement fixation titers, evaluation of cerebrospinal fluid is recommended even in the absence of symptoms. Although coccidioidomycosis can be a self-limited disease in immunocompotent patients, all SOT patients should be treated regardless of severity. This may include intravenous amphotericin B in severe cases and fluconazole therapy in milder episodes. In those SOT recipients with evidence of prior coccidioidomycosis, lifelong secondary prophylaxis with fluconazole given risk of recurrent disease. Summary Coccidioidomycosis continues to be a cause of serious morbidity and mortality in transplant recipients but with proper screening and treatment can be successfully managed. Correspondence to Emily Blodget, MD, Division of Infectious Disease, Keck School of Medicine of University of Southern California, 2020 Zonal Avenue, Room 436, Los Angeles, CA 90033, USA. Tel: +1 323 409 4444; e-mail: eblodget@med.usc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Carbapenemase-producing organisms in solid organ transplantation Purpose of review Carbapenem-resistant enterobacteriaceae (CRE) are a critical healthcare threat. Infections caused by CRE disproportionately affect transplant patients. Retrospective case studies suggest that up to 10% of transplant recipients develop a CRE infection. The current literature is reviewed with a particular focus on transplant-specific implications. Recent findings There are specific risks inherent to transplant recipients that result in an elevated risk for CRE carriage and subsequent infection. Additionally, the manifestations of these infections are dependent on the specific transplant type. The optimal treatment of CRE infections in transplant recipients has not been defined. Summary A reduction in the regional community CRE burden can lead to a secondary reduction in their occurrence within vulnerable transplant populations. Therefore, core principles of antibiotic stewardship and infection control within all levels of the healthcare system remains the most effective strategy for addressing the current health crisis. Simultaneously, an integrated approach to risk stratification and an approach to treatment is postulated for management of CRE infection within the solid-organ transplant population. Correspondence to Darren Wong, MD, Division of Infectious Diseases, Keck School of Medicine at the University of Southern California (USC), Los Angeles, California, USA. Tel: +1 323 409 4397; e-mail: darrenww@med.usc.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Current state of organ transplant tolerance Purpose of review Immunological tolerance has long been considered the ‘holy grail’ of organ transplantation. Although tolerance has been an active area of research for 70 years, its clinical application has only been possible in the last two decades and widespread use remains an, as yet, unattained goal. Recent advances in the understanding of immune regulation have identified many new approaches to tolerance induction and several clinical trials are currently aimed at bringing this treatment to more patients. Recent findings Mixed chimerism remains the most successful approach to tolerance induction. However, many treatments, including adoptive transfer of regulatory T cells, regulatory B cells, and immune suppressive dendritic cells and myeloid derived suppressor cells have shown great promise in preclinical models. Recent clinical studies have found that both kidney and liver operational tolerance are achievable in the appropriate settings. Furthermore, combining multiple tolerance approaches has shown potential to produce durable and safer tolerance. Summary Tolerance to protect kidney and liver allografts has become a valuable therapy in the correct circumstances. Through further clinical trials and an improved understanding of immune regulatory components, tolerance is poised to have a significant impact on transplantation in the years to come. Correspondence to James F. Markmann, MD, PhD, Massachusetts General Hospital, 55 Fruit Street – White 507, Boston, MA 02114, USA. Tel: +1 617 643 4533; fax: +1 617 643 4579; e-mail: jmarkmann@partners.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Updates on antiviral drugs for cytomegalovirus prevention and treatment Purpose of review Cytomegalovirus (CMV) is the most common infection after organ transplant. In addition to causing a viral syndrome and infection, it also increases the risk for complications in the organ transplant, along with higher overall morbidity and mortality. Prevention and ideal treatment of CMV is paramount for optimal outcomes, both for individuals as well as for transplant programs. New guidelines and novel therapies are changing the way we manage disease. Recent findings Several new antiviral agents have emerged in recent times, including letermovir, maribavir, and brincidofovir, enhancing our ability to prevent and treat CMV. Recent data on novel agents will be reviewed, with an emphasis on recent guidelines and best practices. Summary Optimal treatment, influenced by recent advances in the field, including management of resistant virus, results in better outcomes with this significant and virulent virus. Correspondence to Camille N. Kotton, Transplant and Immunocompromised Host Infectious Diseases, Infectious Diseases Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Cox 5th floor, Boston, MA 02114, USA. Tel: +1 617 724 0082 (Karen Manning, Administrative Assistant); fax: +1 617 726 7653; e-mail: ckotton@partners.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The past, present, and future of costimulation blockade in organ transplantation Purpose of review Manipulating costimulatory signals has been shown to alter T cell responses and prolong graft survival in solid organ transplantation. Our understanding of and ability to target various costimulation pathways continues to evolve. Recent findings Since the approval of belatacept in kidney transplantation, many additional biologics have been developed targeting clinically relevant costimulation signaling axes including CD40-CD40L, inducible costimulator-inducible costimulator ligand (ICOS-ICOSL), and OX40-OX40L. Currently, the effects of costimulation blockade on posttransplant humoral responses, tolerance induction, and xenotransplantation are under active investigation. Here, we will discuss these pathways as well as preclinical and clinical outcomes of biologics targeting these pathways in organ transplantation. Summary Targeting costimultion is a promising approach for not only controlling T cell but also B cell responses. Consequently, costimulation blockade shows considerable potential for improving outcomes in antibody-mediated rejection and xenotransplantation. Correspondence to Stuart J. Knechtle, MD, 330 Trent Drive, DUMC Box 3512, Durham, NC 27710, USA. Tel: +1 919 613 9687; fax: +1 919 684 8716; e-mail: stuart.knechtle@dm.duke.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nontuberculous mycobacteria in solid organ transplant Purpose of review Nontuberculous mycobacteria (NTM) are emerging pathogens of concern especially in solid organ transplant candidates and recipients. This review aims to address diagnostic challenges, new and emerging treatment options, and infection prevention. Recent findings The incidence of NTM infections in transplant candidates and recipients is rising. The infection prevalence of these environmental pathogens varies geographically by species with a coastal predominance. Although existing guidelines from the American Thoracic Society, Infectious Diseases Society of America, and British Thoracic Society provide recommendations for diagnosis and management, they do not fully address the subtle nuances and challenges faced in managing infections in immunocompromised transplant recipients. Evolving data on new therapeutic agents and their use in combination therapy will help individualize treatment regimens while limiting adverse effects and improving compliance. Use of combination β-lactams, avibactam, tedizolid, clofazimine, bedaquiline, liposomal amikacin, and ciprofloxacin for commonly isolated species such as Mycobacterium abscessus and Mycobacterium avium complex have proven effective. Summary Further studies are needed to determine the incidence of NTM infection in a prospective, multicentric manner and evaluate the most promising synergistic treatment combinations in transplant recipients. Correspondence to Shweta Anjan, MD, 1120 NW 14th Street Suite 863, Miami, FL 33136, USA. Tel: +1305 243 4598; fax: +1305 243 4037; e-mail: sxa835@med.miami.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The future of HIV Organ Policy Equity Act is now: the state of HIV positive to HIV+ kidney transplantation in the United States Purpose of review We report the current state of HIV-to-HIV kidney transplantation in the United States and remaining challenges in implementing this practice nationally. Recent findings The HIV Organ Policy Equity (HOPE) Act, which was the first step in unlocking the potential of HIV+ organ donors, mandates clinical research on HIV positive to HIV+ transplantation. As of March 2019, there have been 57 HOPE donors, including both true and false-positive HOPE donors resulting in more than 120 transplants. Summary The HOPE Act, signed in 2013, reversed the federal ban on the transplantation of organs from HIV D+ into HIV R+ . Ongoing national studies are exploring the safety, feasibility, and efficacy of both kidney and liver transplantation in this population. If successfully and fully implemented, HIV positive to HIV+ transplantation could attenuate the organ shortage for everyone waiting, resulting in a far-reaching public health impact. Correspondence to Christine M. Durand, MD, Medicine and Oncology, Johns Hopkins University School of Medicine, 725 North Wolfe Street/PCTB Room 228, Baltimore, MD 21205, USA. E-mail: christinedurand@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The true risk of living kidney donation Purpose of review The safety of living donor nephrectomy is essential to the continued success, growth, and sustainability of the clinical practice of living donor kidney transplantation. This review summarizes recent advances in our understanding of the perioperative and long-term risks faced by living kidney donors. Recent findings Although adverse perioperative complications are extremely rare, donors particularly men, Black, or obese, frequently experience minor complications that result in delayed return to normal duties at home and work. Similarly, although long-term complications such as end-stage renal disease (ESRD) are rare, recent studies suggest a relative increase in risk of ESRD that is attributable to donation. Several risk calculators have been developed to help donors and their care providers quantify the baseline and postdonation risk of ESRD based on demographic and health characteristics. Thresholds of risk may help define what is an acceptable level of risk to the donor and the transplant center. Summary Individualized risk calculators now allow care providers and potential donors to objectively and transparently participate in shared decision-making about the safety of living kidney donation. Correspondence to Macey Henderson, JD, PhD, Department of Surgery, Division of Transplantation, Johns Hopkins School of Medicine, 2000 E Monument Street Baltimore, MD 21205, USA. Tel: +1 443 287 6649; fax: +1 410 630 7217; e-mail: macey@jhmi.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.