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      Infections Caused by Mycobacterium tuberculosis in Recipients of Hematopoietic Stem Cell Transplantation

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          Mycobacterium tuberculosis ( M. tuberculosis) infections are uncommon in recipients of hematopoietic stem cell transplantation. These infections are 10–40 times commoner in recipients of stem cell transplantation than in the general population but they are 10 times less in stem cell transplantation recipients compared to solid organ transplant recipients. The incidence of M. tuberculosis infections in recipients of allogeneic stem cell transplantation ranges between <1 and 16% and varies considerably according to the type of transplant and the geographical location. Approximately 80% of M. tuberculosis infections in stem cell transplant recipients have been reported in patients receiving allografts. Several risk factors predispose to M. tuberculosis infections in recipients of hematopoietic stem cell transplantation and these are related to the underlying medical condition and its treatment, the pre-transplant conditioning therapies in addition to the transplant procedure and its own complications. These infections can develop as early as day 11 and as late as day 3337 post-transplant. The course may become rapidly progressive and the patient may develop life-threatening complications. The diagnosis of M. tuberculosis infections in stem cell transplant recipients is usually made on clinical grounds, cultures obtained from clinical specimens, tissues biopsies in addition to serology and molecular tests. Unfortunately, a definitive diagnosis of M. tuberculosis infections in these patients may occasionally be difficult to be established. However, M. tuberculosis infections in transplant recipients usually respond well to treatment with anti-tuberculosis agents provided the diagnosis is made early. A high index of suspicion should be maintained in recipients of stem cell transplantation living in endemic areas and presenting with compatible clinical and radiological manifestations. High mortality rates are associated with infections caused by multidrug-resistant strains, miliary or disseminated infections, and delayed initiation of therapy. In recipients of hematopoietic stem cell transplantation, isoniazid prophylaxis has specific indications and bacillus Calmette-Guerin vaccination is contraindicated as it may lead to disseminated infection. The finding that M. tuberculosis may maintain long-term intracellular viability in human bone marrow-derived mesenchymal stem cells complicates the development of effective vaccines and strategies to eliminate tuberculosis. However, the introduction of linezolid, cellular immunotherapy, and immunomodulation in addition to autologous mesenchymal stem cell transplantation will ultimately have a positive impact on the overall management of infections caused by M. tuberculosis.

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          Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective

          Table of Contents Author List 1143 Preface 1145 Executive Summary 1146 Background to HCT 1147 Hematopoietic Cell Graft Safety 1153 Bacterial Infections 1156 Viral Infections 1159 Fungal Infections 1170 Regionally Limited or Rare Infections 1176 Infection Control and Prevention in Health care Facilities 1182 Safe Living after Transplantation 1195 Vaccinations 1203 References 1207 Appendices 1229 Executive Committee Marcie Tomblyn, University of Minnesota, Minneapolis, MN Tom Chiller, Centers for Disease Control and Prevention, Atlanta, GA Hermann Einsele, Universitatsklinik Wurzburg Medizinische Klinik und Poliklinik II, Wurzburg, Germany Ronald Gress, National Institutes of Health, Bethesda, MD Kent Sepkowitz, Memorial Sloan Kettering Cancer Center, New York, NY Jan Storek, University of Calgary, Calgary, Alberta, Canada John R Wingard, University of Florida, Gainesville, FL Jo-Anne H Young, University of Minnesota, Minneapolis, MN Michael A Boeckh, University of Washington Fred Hutchinson Cancer Research Center, Seattle, WA Introduction/Background Crystal Mackall, National Institutes of Health, Bethesda, MD Terry Fry, National Institutes of Health, Bethesda, MD Ronald Gress, National Institutes of Health, Bethesda, MD Karl Peggs, University College London Hospital, London, United Kingdom Jan Storek, University of Calgary, Calgary, Alberta, Canada Antoine Toubert, University Paris Diderot, Hôpital Saint-Louis, Paris, France Hematopoietic Graft Cell Safety Dennis Confer, National Marrow Donor Program, Minneapolis, MN Ronald Gress, National Institutes of Health, Bethesda, MD Marcie Tomblyn, University of Minnesota, Minneapolis, MN Gerhard Ehninger, Universitatsklinikum Dresden, Dresden, Germany Bacterial Infection Dan Engelhard, Hadassah Medical Center, Jerusalem, Israel Murat Akova, Hacettepe University School of Medicine, Ankara, Turkey Michael A Boeckh, University of Washington Fred Hutchinson Cancer Research Center, Seattle, WA Alison Freifeld, Nebraska Medical Center, Omaha, NE Kent Sepkowitz, Memorial Sloan Kettering Cancer Center, New York, NY Claudio Viscoli, Ospedale San Martino, Genoa, Italy James Wade, Medical College of Wisconsin, Milwaukee, WI Issam Raad, MD Anderson Cancer Center, Houston, TX Viral Infection John Zaia, City of Hope, Duarte, CA Lindsey Baden, Brigham and Women's Hospital, Boston, MA Michael A Boeckh, University of Washington Fred Hutchinson Cancer Research Center, Seattle, WA Suparno Chakrabarti, St. George's Hospital, London, United Kingdom Hermann Einsele, Universitatsklinik Wurzburg Medizinische Klinik und Poliklinik II, Wurzburg, Germany Per Ljungman, Karolinska University Hospital, Stockholm, Sweden George McDonald, University of Washington, Seattle, WA Hans H. Hirsch, University Hospital, Basel, Switzerland Fungal Kieren Marr, Johns Hopkins University, Baltimore MD Eric Bow, University of Manitoba, Winnipeg, Manitoba, Canada Tom Chiller, Centers for Disease Control and Prevention, Atlanta, GA Georg Maschmeyer, Center for Hematology, Oncology and Radiotherapy Klinikum Ernst von Bergmann Charlottenstr, Potsdam, Germany Patricia Ribaud, MD, Hôpital Saint-Louis, Paris, France Brahm H. Segal, Roswell Park Cancer Institute, Buffalo, NY William J. Steinbach, Duke University Medical Center, Durham, NC John R. Wingard, University of Florida, Gainesville, FL Marcio Nucci, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil Regionally Limited/Rare Infections Juan Gea-Banacloche, National Institutes of Health, Bethesda, MD Henry Masur, National Institutes of Health, Bethesda, MD Clovis Arns da Cuhna, Universidade Federal do Parana, Curitiba, Brazil Tom Chiller, Centers for Disease Control and Prevention, Atlanta, GA Louis Kirchoff, University of Iowa, Iowa City, IA Peter Shaw, Children's Hospital at Westmead, Sydney, Australia Marcie Tomblyn, University of Minnesota, Minneapolis, MN Catherine Cordonnier, Hôpital Henri Mondor, Creteil, France Infection Prevention and Control Deborah S. Yokoe, Brigham & Women's Hospital and Dana-Farber Cancer Institute, Boston, MA Corey Casper, University of Washinton Fred Hutchinson Cancer Research Center, Seattle, WA Erik R. Dubberke, Washington University School of Medicine, St. Louis, MO Grace M. Lee, Children's Hospital Boston, Boston, MA Patricia Muñoz, Hospital General Universitario Gregorio Marañón, University of Madrid, Spain Tara Palmore, National Institutes of Health, Bethesda, MD Kent Sepkowitz, Memorial Sloan Kettering Cancer Center, New York, NY Jo-Anne H Young, University of Minnesota, Minneapolis, MN J Peter Donnelly, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Safe Living After HCT Deborah S. Yokoe, Brigham & Women's Hospital and Dana-Farber Cancer Institute, Boston, MA Corey Casper, University of Washinton Fred Hutchinson Cancer Research Center, Seattle, WA Erik R. Dubberke, Washington University School of Medicine, St. Louis, MO Grace M. Lee, Children's Hospital Boston, Boston, MA Patricia Muñóz, Hospital General Universitario Gregorio Marañón, University of Madrid, Spain Tara Palmore, National Institutes of Health, Bethesda, MD Kent Sepkowitz, Memorial Sloan Kettering Cancer Center, New York, NY Jo-Anne H Young, University of Minnesota, Minneapolis, MN J Peter Donnelly, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands Vaccinations Per Ljungman, Karolinska University Hospital, Stockholm, Sweden Catherine Cordonnier, Hôpital Henri Mondor, Creteil, France Hermann Einsele, Universitatsklinik Wurzburg Medizinische Klinik und Poliklinik II, Wurzburg, Germany Janet Englund, University of Washington/Seattle Children's Hospital and Regional Medical Center, Seattle, WA Clarisse Martins Machado, Universidade de São Paulo, São Paulo, Brazil Jan Storek, University of Calgary, Calgary, Alberta Trudy Small, Memorial Sloan Kettering Cancer Center, New York, NY Preface This report, cosponsored by the Center for International Blood and Marrow Transplant Research (CIBMTR), National Marrow Donor Program (NMDP), European Blood and Marrow Transplant Group (EBMT), American Society for Blood and Marrow Transplant (ASBMT), Canadian Blood and Marrow Transplant Group (CBMTG), Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), Association of Medical Microbiology and Infectious Diseases (AMMI), the Center for Disease Control and Prevention (CDC), and the Health Resources and Services Administration, represents an update of the guidelines published in 2000 for preventing infections among hematopoietic cell transplantion (HCT) recipients [1]. An international group of experts in infectious diseases, HCT, and public health worked together to compile this document with 4 goals in mind: (1) to summarize the current available data in the field, (2) to provide evidence-based recommendations regarding prevention of infectious complications among HCT patients, (3) to serve as a reference for health care providers worldwide who care for HCT recipients, and (4) to serve as a reference for HCT recipients and their nonmedical caregivers. In updating these guidelines, the committee sought to summarize the currently available data and present them as concisely as possible in an evidence-based fashion. Significant changes in the field of HCT since the publication of the original guidelines necessitated this update. These changes include new antimicrobial agents, broader use of reduced-intensity conditioning (RIC), the increasing age of HCT recipients, and more frequent use of alternative donor stem cell sources such as haploidentical donors and umbilical cord blood. Furthermore, as with any field of medicine, published studies continue to add to the evidence regarding supportive medical care. Despite—or perhaps because of—these changes, infections still occur with increased frequency or severity among HCT recipients as a patient population. In presenting these guidelines, the committee is not intending to dictate standards of practice. Although considerable effort has gone into ensuring that the guidelines have a global perspective based on the currently available medical evidence, adherence to a particular recommendation may be inconsistent with national or regional guidelines, the availability of specific procedures or medications, or local epidemiological conditions. Individual clinicians may follow practice patterns that, although deviating from these recommendations, are nevertheless effective and sound. Using These Guidelines For the purposes of this report, HCT is defined as transplantation of any blood- or marrow-derived hematopoietic stem cells (HSCs), regardless of transplant type (ie, allogeneic or autologous) or cell source (ie, bone marrow [BM], peripheral blood [PB], or umbilical cord blood [UCB]). The definition of immune competence following transplant is loosely defined by the ability of the HCT recipient to receive live vaccine following recovery from transplant. Conventionally, this is thought to occur at approximately 24 months following HCT in patients who are not receiving immunosuppressive therapy and do not have active graft-versus-host disease (GVHD) [1]. For patients with on-going GVHD or continued use of immunosuppressive therapy, it is recommended to consider the patient as immune deficient and still at risk for significant infectious complications. Unless otherwise noted, the recommendations presented in this report address allogeneic and autologous and pediatric and adult HCT recipients. These recommendations are intended for use by the recipients, their household and other close contacts, transplant and infectious diseases specialists, HCT center personnel, and public health professionals. For most recommendations, prevention strategies are rated by the strength of the recommendation and the quality of the evidence supporting the recommendation (Table 1 ). The principles of this rating system were developed by the IDSA and the U.S. Public Health Service for use in guidelines for preventing opportunistic infections among HIV-infected persons [2]. This rating system allows assessments of the strength of recommendations. Table 1 Evidence-Based Rating System Used in the Hematopoietic Cell Transplantation (HCT) Guidelines [2] Strength of Recommendation Category Definition A Both strong evidence for efficacy and substantial clinical benefit support recommendation for use. Should always be offered. B Moderate evidence for efficacy—or strong evidence for efficacy, but only limited clinical benefit—supports recommendation for use. Should generally be offered. C Evidence for efficacy is insufficient to support a recommendation for or against use, or evidence for efficacy might not outweigh adverse consequences (eg, drug toxicity, drug interactions), or cost of the chemoprophylaxis or alternative approaches. Optional. D Moderate evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should generally not be offered. E Good evidence for lack of efficacy or for adverse outcome supports a recommendation against use. Should never be offered. Quality of Evidence Supporting the Recommendation Category Definition I Evidence from at least one well-executed randomized, controlled trial II Evidence from at least one well-designed clinical trial without randomization; cohort or case-controlled analytic studies (preferably from more than one center); multiple time-series studies; or dramatic results from uncontrolled experiments III Evidence from opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees Executive Summary In the past decade, modifications in HCT management and supportive care have resulted in changes in recommendations for the prevention of infection in HCT patients. These changes are fueled by new antimicrobial agents, increased knowledge of immune reconstitution, and expanded conditioning regimens and patient populations eligible for HCT. Despite these advances, infection is reported as the primary cause of death in 8% of autologous HCT patients and 17% to 20% of allogeneic HCT recipients [3]. The major changes in this document, including changes in recommendation ratings, are summarized here. The organization of this document is similar to the previous guidelines. Specifically, the prevention of exposure and disease among pediatric and adult autologous and allogeneic HCT recipients is discussed. The current recommendations consider myeloablative (MA) conditioning and RIC for allogeneic HCT similarly, because data on infectious complications following RIC compared to MA conditioning are sparse 4, 5, 6, 7. However, increased information regarding posttransplant immune recovery highlighting differences between MA and RIC HCT are included. The sections of the document have been rearranged in an attempt to follow the time course of potential infectious risks for patients receiving HCT. Following the background section, information on hematopoietic cell product safety is provided. The subsequent sections discuss prevention of infection by specific microorganisms. Following organism-specific information, the sections then discuss means of preventing nosocomial infections as well as “dos and don'ts” for patients following discharge posttransplant. Finally, information on vaccinations is provided. This will hopefully allow the reader to follow the prevention practices needed from the time a donor is selected until the patient regains immune competence. Several topics are new or expanded from the prior document (Table 2 ). These include information on multiple organisms that were previously not discussed, but have seemingly become more clinically relevant in HCT patients over the past decade. Data, and where possible, recommendations, are provided regarding the following organisms that were not included in the previous document: Bordetella pertussis; the polyomaviruses BK and JC; hepatitis A, B, and C viruses (HAV, HBV, HCV); human herpesviruses (HHV) 6, 7, and 8; human metapneumovirus; human immunodeficiency virus (HIV); tuberculosis; nocardiosis; malaria; and leishmaniasis. In recognition of our global society, several organisms are discussed that may be limited to certain regions of the world. Included in that section are also those infections that may be ubiquitous but occur infrequently, such as Pneumocystis jiroveci and Nocardia. Table 2 Summary of Changes Compared to the Guidelines Published in 2000 [1] Major Changes Starting Page Updated background on immune recovery following HCT including differences based on conditioning regimen and stem cell sources 7 Changes to the Bacterial Section  1) Quinolone prophylaxis is recommended for patients with neutropenia expected to last ≥7 days (BI) 14  2) Added recommendations regarding Central Line-Associated Bloodstream Infections (CLABSI) (in addition to the section in Infection Prevetion and Control) 15  3) Streptococcus pneumoniae    a) Contact precautions now an AIII (prior BIII)    b) Antimicrobial prophylaxis in patients with GVHD now an AIII (prior BIII)    c) Vaccination with PCV now a BI recommendation (prior BIII) 15 Changes to the Fungal Section  1) Micafungin is an alternative for prevention of candidiasis during preengraftment (BI) 32  2) Voriconazole and Posaconazole may be used for prevention of candidiasis postengraftment (BI) 33  3) Itraconazole oral solution as prevention of mold infections (BI—prior, no data) 34  4) Posaconazole for prevention of mold infections in patients with GVHD (BI) 34 PCR screening for Toxoplama gondii can be considered in high-risk patients when unable to tolerate prophylaxis (BII) 37 Changes in Vaccination Recommendations  1) Pneumococcal Vaccine: Use PCV vaccine and start 3-6 months post-HCT 63  2) Optional to use acellular pertussis vaccine in all patients 64  3) Varicella vaccine (Varivax) is optional. Zostavax is contraindicated 64  4) Vaccinations with inactivated vaccines may be started as early as 6 months post-HCT (and earlier for PCV and influenza) 31  5) Information regarding use of HPV vaccine 32 Sections added to the Infection Prevention and Control Section  1) Recommendations regarding multiply drug-resistant Gram-negative bacilli 49  2) Recommendations regarding adenovirus 52  3) Recommendation regarding viral gastroenteritis 52 Section added to the Safe Living after Hematopoietic Cell Transplantation Recommendations regarding household contacts who receive live-attenuated vaccines 55 Appendix 1 (Dosing) changes  1) Alternative CMV prophylaxis/treatment: Foscarnet now AI (prior CIII) and added Valganciclovir and Cidofovir 89  2) EBV prophylaxis/treatment with Rituximab 89  3) VZV: added alternatives to VZIG for exposure and new information on prophylaxis 90  4) Influenza: added dosing information for Oseltamivir and Zanamivir 91  5) RSV: Added dosing information 91  6) Split the fungal section into data for standard-risk and high-risk patients 92  7) Added dosing information for Micafungin, Posaconazole, and Voriconazole 92  8) Alternative PCP prophylaxis: Added atovaquone and changed aerosolized Pentamidine to CII (prior CIII) 92 New Organisms  Bordatella pertussis 16  Human Metapneumovirus 23  Polyomaviruses BK and JC 24  Hepatitis A 25  Hepatitis B 25  Hepatitis C 26  Human Herpes Virus 6 and 7 27  Human Herpes Virus 8 28  Human Immunodeficiency Virus 28  Mycobacterium tuberculosis 34  Nocardia 38  Leishmania 39  Malaria 39 GVHD indicates graft-versus-host disease; HCT, hematopoietic cell transplantation; CVM, cytomegalovirus; EBV, Epstein-Barr virus; VZV, varicella zoster virus; PCP, Pneumocystis jiroveci pneumonia; RSV, respiratory syncytial virus; VZIG, varicella-zoster immunoglobulin. Several other changes should be noted. For bacterial infections, these guidelines now recommend quinolone prophylaxis for patients with neutropenia expected to last as least 7 days (BI). Additionally, the recommendations for contact precautions (AIII), vaccination (BI), and prophylaxis for patients with GVHD (AIII) against Streptococcus pneumoniae have been strengthened. The subsection on central line-associated blood stream infections is now in the bacterial section. The vaccination section has been dramatically expanded. Changes include the recommendations for pneumococcal conjugate vaccine (PCV) rather than polysaccharide vaccine (PPSV-23) for pneumococcal vaccination, starting some vaccinations earlier posttransplant, and the addition of recommendations for Varivax, HPV vaccine, and (the nonuse of) Zostavax vaccine are included. Two additional appendices were added to provide information on desensitization to sulfa drugs and visitor screening questionnaires. Finally, the dosing appendix has merged both adult and pediatric dosing, and provides recommendations for several newer antimicrobial agents that were not previously available. In summary, the changes and expansion to this document reflect the growing body of literature detailing infectious complications in HCT patients. Background to HCT, Including Posttransplant Immune Recovery C. Mackall, T. Fry, R. Gress, K. Peggs, J. Storek, A. Toubert Hematopoietic cell transplantation (HCT) can be defined as the transfer of hematopoietic stem cells (HSCs) from 1 individual to another (allogeneic HCT) or the return of previously harvested cells to the same individual (autologous HCT) after manipulation of the cells and/or the recipient. The goal of HCT is lifelong engraftment of the administered cells, resulting in some or all of the recipient's lymphohematopoietic system being derived from the HCT graft. Full donor engraftment occurs when the recipient lymphohematopoietic system is fully replaced by progeny of the HCT graft. This is the ultimate goal of many HCT protocols, especially for achieving optimal graft-versus-tumor (GVT) activity in patients with malignant disease 8, 9, 10. In some clinical settings, however, a state of “mixed chimerism,” wherein elements of both the donor and recipient lymphohematopoietic system survive, may be sufficient to cure the underlying condition 11, 12. Allogeneic HCT can cure or improve outcome in a wide variety of diseases, including leukemia, lymphoma, myeloproliferative disorders, myelodysplastic syndrome (MDS), bone marrow (BM) failure syndromes, congenital immunodeficiencies, enzyme deficiencies, and hemoglobinopathies 13, 14, 15, 16, 17. However, because allogeneic HCT is associated with significant morbidity and mortality because of regimen-related toxicity (RRT) [18], infection [19], and graft versus host disease (GVHD) [20], a recommendation regarding transplantation for the individual patient requires careful risk assessment that takes into account disease status [21], comorbidities, previous therapies, other standard therapies available for the underlying disease [22], donor stem cell source [23], and histoincompatibility [24]. Autologous HCT can improve outcomes in neoplastic diseases [25] and autoimmune conditions [26], and continues to be investigated as a platform for gene therapy [27]. RRT and infections contribute to the morbidity and mortality associated with autologous HCT; however, morbidity because of GVHD generally does not occur after this procedure. Substantial progress has been made in allogeneic HCT during the past 15 years as a result of improvements in 4 distinct, but interrelated, areas. First, improvements in the supportive care of patients with severe immunosuppression and myelosuppression have diminished morbidity and mortality because of infection 19, 28, 29. Second, the critical contribution of immune-mediated GVT effects toward eradicating malignant disease and facilitating engraftment is now well established, and factors prominently in the design of individual HCT regimens [21]. Third, alternative donor (nonsibling) transplants and new stem cell sources now provide HCT options for a larger percentage of potential candidates 23, 30, 31. Fourth, newer, less toxic preparative regimens have been developed that allow reliable engraftment with a lower risk for treatment-related mortality (TRM) and long-term adverse effects 18, 32. Classically, transfer of the hematopoietic cell graft was seen as a means to rescue the recipient's lymphohematopoietic system from an otherwise lethal myeloablative (MA) preparative regimen. In this model, the preparative regimen was used as the primary tool to eradicate malignant disease, or to eradicate the recipient's immune system when HCT was used to treat benign diseases. However, careful clinical studies over the last 4 decades have revealed that the effectiveness of allogeneic HCT in eradicating malignant disease is intimately linked to the activity of immunoreactive cells in the graft, most notably T cells and, in some cases, natural killer (NK) cells 24, 33, 34. Indirect demonstration of this graft-versus-leukemia (GVL) effect comes from reports of increased leukemic relapse following syngeneic (identical twin) HCT and increased leukemia relapse following T cell-depleted HCT. Direct demonstration has been provided by the ability of donor lymphocyte infusions (DLIs) to induce remission in substantial numbers of patients with chronic myelogenous leukemia (CML) [35]. Evidence for a GVT effect also exists for other malignancies [36], but the effect appears to be less potent than that observed in CML. Furthermore, even when HCT is performed for benign diseases, the rate and degree of donor engraftment can be enhanced with the use of donor leukocyte infusions, demonstrating that immune cells also contribute to the engraftment process. Thus, HCT has evolved from a therapy designed primarily to provide lymphohematopoietic rescue after MA conditioning to a form of immunotherapy wherein mature immune cells contained within the graft and/or reconstituted from donor progenitors play an active role in eradicating the underlying neoplastic disease and in facilitating donor engraftment. Expansion of graft sources has contributed to substantial progress in allogeneic HCT. Traditionally, allogeneic HCT involved transfer of marrow grafts harvested from HLA-matched sibling donors, in which case histoincompatibility was limited to minor antigens, for which reliable typing is not routinely available. Approximately 25% to 30% of potential HCT recipients will have a matched sibling donor available. Through the efforts of the NMDP in the United States and donor registries throughout the world, approximately 12 million individuals have undergone preliminary HLA typing over the last 20 years, and as a result, 75% of Caucasian individuals will find a suitably matched unrelated donor (URD). For other racial or ethnic groups, however, the chance of finding a suitable donor using existent registries is substantially less. Recent studies have demonstrated that with proper HLA matching, outcomes following matched URD HCT approach those reported for matched sibling transplants. Umbilical cord blood (UCB) transplants have also shown promise. The benefits of UCB as a stem cell source are ready accessibility and the ability to cross HLA barriers 23, 31, 37, 38. Mismatched related and haploidentical donor grafts also continue to have a role in clinical HCT, especially for patients with congenital immunodeficiency [39] and in specialized centers where this approach continues to be optimized 40, 41. Beyond the multitude of choices regarding donor source, progress during the last 15 years has also demonstrated that granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cell (PBSC) allografts provide a reliable source for engraftment, and offer the advantage of improved myelogenous and T cell recovery 30, 42 than with traditional marrow grafts and thus fewer infections. However, G-CSF-mobilized blood grafts also appear to carry a greater risk for chronic GVHD (cGVHD) compared with marrow grafts 23, 43, 44. New approaches have been developed to minimize the likelihood of graft failure, conditioning toxicity, GVHD, and infections 45, 46, 47, 48. The addition of T cell-depleting agents (eg, antithymocyte globulin [ATG] or alemtuzumab) to conditioning regimens has been associated with a reduced incidence of GVHD and diminished graft rejection, but may delay immune recovery. Nonmyeloablative (NMA) preparative regimens that use cytotoxic drugs or low-dose total body irradiation (TBI) in conditioning regimens have been associated with reduced nonrelapse mortality (NRM), and have provided new options for HCT among the elderly and in patients with substantial comorbidities. The choice of preparative regimen and the decision regarding the relative merit of an MA versus an NMA regimen is complex and should involve a risk-adapted strategy that takes into account the underlying disease, patient age, comorbidities, stem cell source, histoincompatibility, and other relevant factors. In summary, HCT plays a central role in the treatment of a variety of benign and malignant diseases and the field continues to evolve rapidly, with new options for donor sources and preparative regimens. At the same time, standard treatments for many of the diseases wherein HCT historically provided the mainstay of therapy have also evolved, rendering the decision of whether, when, and how to proceed to HCT highly complex and requiring careful consideration of the individual case in light of evidence-based data. For patients who undergo HCT, the major causes of early morbidity and mortality are disease relapse, acute GVHD (aGVHD), infection, RRT, and graft failure. Long-term survivors of HCT are at risk for a variety of long-term adverse effects, including cGVHD, infections, hypothyroidism, sterility, growth failure and other endocrine disturbances, cataracts, avascular necrosis, disease relapse, and second malignancy. The incidence of each of those adverse effects varies greatly with differing preparative regimens, comorbidities, age at transplantation, and whether the individual experiences cGVHD [49]. Immune System Recovery following HCT Following MA conditioning, HCT recipients typically experience a period of profound pancytopenia spanning days to weeks depending upon the donor source. The rapidity of neutrophil recovery varies with the type of graft: approximate recovery time is 2 weeks with G-CSF-mobilized PBSC grafts, 3 weeks with marrow grafts, and 4 weeks with UCB grafts. Neutrophil, monocyte, and NK-cell recovery is followed by platelet and red cell recovery, which is followed by B and T cell recovery (Figure 1 ). Simultaneously, MA regimens damage mucosal surfaces and thereby provide a source for bloodstream seeding of commensal pathogens that inhabit the gastrointestinal tract. As a result, infectious complications in the immediate posttransplant period usually present as febrile neutropenia, with the severity of risk related to the depth and duration of neutropenia and the degree of mucosal damage induced. Figure 1 Approximate immune cell counts (expressed as percentage of normal counts) peri- and post-MA HCT. Nadirs are higher and occur later after NMA than MA transplantation, as recipient cells persist after NMA transplant for several weeks to months (in the presence of GVHD) or longer (in the absence of GVHD). The orange line represents the innate immune cells (eg, neutrophils, monocytes, and natural killer [NK] cells), the recovery of which is influenced by the graft type (fastest with filgrastim-mobilized blood stem cells, intermediate with marrow, and slowest with UCB). The green line represents the recovery of CD8+ T cells and B cells, the counts of which may transiently become supranormal. B cell recovery is influenced by graft type (fastest after CB transplant), and is delayed by GVHD and/or its treatment. The blue line represents the recovery of relatively radiotherapy/chemotherapy-resistant cells such as plasma cells, tissue dendritic cells (eg, Langerhans cells) and, perhaps, tissue macrophages/microglia. The nadir of these cells may be lower in patients with aGVHD because of graft-versus-host plasma cell/Langerhans cell effect. The red line represents CD4+ T cells, the recovery of which is influenced primarily by T cell content of the graft and patient age (faster in children than adults). From Storek J. Immunological reconstitution after hematopoietic cell transplantation—its relation to the contents of the graft. Expert Opin Biol Ther (Informa). 2008;8:583-597. Recipients of NMA allogeneic transplants exhibit substantial heterogeneity in the depth and duration of pancytopenia, with some regimens accomplishing reliable engraftment without clinically significant myelosuppression. In regimens with minimal myelosuppression and minimal mucosal toxicity, the risk for infection in the immediate posttransplant period is reduced. In fact, regimens based on low-dose TBI and fludarabine (Flu) can sometimes be performed in the outpatient setting, with a virtual elimination of neutropenic complications. Although the degree of myelosuppression is milder following NMA regimens, the depth and extent of lymphodepletion tends to be similar, with prolonged periods of immune incompetence observed in recipients of both MA and NMA regimens. This is because engraftment of allogeneic hematopoietic progenitor cells requires significant recipient immunosuppression to prevent graft rejection, even in the context of full HLA matching. With some regimens, essentially complete eradication of recipient lymphocytes is accomplished by the preparative regimen itself. However, with other regimens, depletion of recipient lymphocytes occurs more gradually via the use of donor leukocyte infusions following transplant. In both cases, the vast majority of HCT recipients experience near-total lymphocyte depletion, and thus must undergo lymphoid reconstitution via mature lymphocytes and lymphoid progenitors contained in the graft. Furthermore, except when T cell-depleted HCT grafts are administered, all allogeneic HCT recipients must also receive some form of immunosuppression to prevent GVHD, further limiting immune competence. Unlike recovery of other hematopoietic lineages, which typically occurs over the course of weeks following HCT, lymphocyte recovery is a prolonged process. Reestablishment of immunocompetence requires at least several months, and some patients continue to demonstrate immune deficits for several years after HCT. In general, NK cells are the first lymphocyte subset to recover, followed by CD8+  T cells, which often reach supranormal levels within 2 to 8 months after HCT. Subsequently, B cells and ultimately CD4+  T cells recover. The pace and extent of recovery of each lymphocyte subset is highly dependent upon several factors, which ultimately determine the degree, extent, and duration of immune incompetence experienced by the individual HCT recipient (Figure 1). Regeneration of lymphocytes in humans is an inefficient process, which primarily involves 2 distinct pathways. In the first pathway, lymphocytes regenerate from bone marrow (BM) lymphoid progenitors, thus recapitulating ontogeny and regenerating a naïve immune system, similar to that found in a newborn child [50]. NK cell recovery uses this pathway exclusively. Full recovery of NK cell counts is typically achieved within 1 to 2 months following HCT. B cells are also primarily regenerated from lymphoid progenitor cells, as evidenced by the appearance of primitive B cell subsets as the harbinger of B cell immune reconstitution [51]. Unlike NK cell recovery, however, B cell lymphopoiesis is highly dependent upon a specialized marrow microenvironment termed the “bursal equivalent,” which is susceptible to damage by the preparative regimen and is exquisitely sensitive to the toxic effects of GVHD and/or its treatment. Indeed, patients who experience even a limited episode of steroid-responsive GVHD show significantly diminished B cell reconstitution in the long term, compared with patients who do not experience GVHD [52]. Although recent data have demonstrated that mature B cells can also contribute to B cell reconstitution via homeostatic expansion, this pathway appears to be minor compared with the marrow-derived pathway for B cell regeneration. Restoration of full humoral immune competence following HCT requires reconstitution not only of naïve B cells, but of a memory B cell pool as well. The latter occurs as a result of environmental or vaccine-based exposure to common pathogens and also requires help from CD4+  T cells. Therefore, even HCT recipients who do not experience GVHD and who demonstrate recovery of total B cell numbers within 6 months posttransplant should not be considered to have regained full humoral immunocompetence by this time. For at least 1 year following transplantation, essentially all HCT recipients remain predisposed to infections from encapsulated bacteria and viruses, against which neutralizing antibodies provide a first line of defense. Serum IgG levels provide little insight into B cell reconstitution, because long-lived, radioresistant plasma cells survive many preparative regimens [53] and can produce substantial circulating IgG without providing humoral responses to specific pathogens. The only reliable means by which one can assess humoral immune competence following transplantation is by documenting clinically significant rises in antigen-specific antibodies following vaccination or infection. Indeed, some medical centers use a rise in antibody levels in response to administration of a killed vaccine as a prerequisite for use of live-attenuated vaccines. T cell regeneration is predominantly driven by a thymic-independent pathway, termed homeostatic peripheral expansion. Here, mature T cells contained within the graft dramatically expand in vivo in response to T cell lymphopenia. This process is driven by a combination of factors, among which are increased availability of homeostatic cytokines, including interleukin (IL)-7 and IL-15, which accumulate during lymphopenia; inflammatory cytokines associated with tissue damage induced by the preparative regimen; and exposure to viral antigens (either environmentally or via reactivation) during the period of profound lymphopenia. Peripheral homoeostatic expansion is much more efficient for CD8+  T cells than for CD4+  T cells [54], resulting in chronically reduced CD4/CD8 ratios in HCT recipients for several months following HCT. Memory T cells are the first to expand after HCT, and may be either of donor origin, in the case of non-T cell-depleted HCT, or originate from host T cells that have survived the conditioning regimen, in the case of T cell-depleted HCT [55]. Memory T cells respond quickly to previously encountered pathogens such as herpesviruses. Of all factors analyzed thus far, CD4+ counts may provide the most readily available and predictive marker of the restoration of immune competence following HCT. Although the predictive value of low CD4+ counts has not been as extensively studied in recipients of HCT as they have in HIV infection, several studies have demonstrated that CD4+ recovery is associated with diminished infectious risk and improved transplant outcomes 56, 57, 58, 59. When T cell regeneration occurs via the ontogenic or thymic-dependent pathway, there is a substantial rise in CD4+  T cell numbers, with recovery of naïve CD4+ and CD8+  T cells and diversification of the T cell repertoire [60]. However, because the microenvironment of the thymus is highly susceptible to damage from age, therapy, and GVHD, many adult HCT recipients show little or no thymic-dependent T cell regeneration for months to years following HCT 61, 62, 63. A study of adult recipients of autologous HCT for breast cancer revealed that with each advancing decade of patient age between 30 and 60 years, a decreasing percentage of patients achieved effective CD4+ immune reconstitution after 2 years of follow-up [64]. Beyond the general rule that all HCT recipients experience profound immunosuppression at some point, the degree of immunosuppression experienced by individual patients varies greatly and is influenced by several factors. First and foremost is the profound adverse effect of GVHD on the overall process. In essentially every series, GVHD severity correlates with the degree of immunosuppression and infectious complications. This correlation is because of a variety of factors that compound one another, including damage to lymphoid microenvironments, adverse effects of GVHD on homeostatic peripheral expansion, as well as the obvious impact that chronic immunosuppression has on a reconstituting immune system. Second, recipient factors such as age, comorbidities, and infectious exposure prior to transplant contribute substantially to the risk for posttransplant infectious complications. This is illustrated in studies of severe combined immunodeficiency (SCID) patients, wherein outcomes are most successful in children who undergo transplantation before experiencing severe, life-threatening infection [65]. Third, graft-associated factors also play an important role. Recent studies have suggested that PBSC graft recipients show more rapid immune reconstitution, as measured by lymphocyte subsets [42], whereas UCB transplantation in adults 66, 67 and transplantation of profoundly T cell-depleted haploidentical grafts result in poor immune reconstitution and high rates of infectious complications. CD34 dose is crucial and levels of 3 × 106 CD34+ cells/kg or more are associated with an improved hematopoietic recovery, a decreased incidence of fungal infections, and improved overall survival (OS) in recipients of unmanipulated BM transplants from HLA-identical sibling donors [68]. Models that distinguish between infectious complications occurring during different posttransplantation phases have been put forth, based largely upon an MA paradigm. Such a model is shown in Figure 2 , in which phase I is the preengraftment phase ( 100 days after HCT). During phase I, prolonged neutropenia and breaks in the mucocutaneous barrier result in substantial risk for bacteremia and fungal infections involving Candida species and, as neutropenia continues, Aspergillus species. Additionally, herpes simplex virus (HSV) reactivation occurs during this phase. During phase II, infections relate primarily to impaired cell-mediated immunity. The scope and impact of this defect is determined by the extent of GVHD and immunosuppressive therapy for it. Herpesviruses, particularly cytomegalovirus (CMV), are common infectious agents during this period. Other dominant pathogens during this phase include Pneumocystis jiroveci and Aspergillus species. During phase III, persons with cGVHD and recipients of alternate-donor allogeneic transplants remain most at risk for infection. Common pathogens include CMV, varicella-zoster virus (VZV), and infections with encapsulated bacteria (eg, Streptococcus pneumoniae). The relative risk for these infections is approximately proportional to the severity of the patient's GVHD during phases II and III. For recipients of NMA grafts, substantial differences may be observed during phase I, but the susceptibility to infections during phases II and III are largely similar, and driven primarily by the status of the underlying disease, a history of GVHD, and/or the need for ongoing immunosuppression. The risk of disease from community-acquired respiratory viruses (CRV) is elevated during all 3 phases; in phase III, however, the outpatient status of HCT recipients can complicate efforts to reduce exposure and provide timely intervention. Figure 2 Phases of opportunistic infections among allogeneic HCT recipients Abbreviations: EBV, Epstein-Barr virus; HHV6, human herpesvirus 6; PTLD, posttransplant lymphoproliferative disease. Thus, the risk of infection is primarily determined by the time from transplant and the presence or absence of GVHD. Other factors include donor/host histocompatibility, disease status, graft type, graft contents, conditioning intensity, and neutrophil engraftment (Table 3 ) 6, 7, 52, 69, 70, 71, 72, 73, 74. Unfortunately, there is currently no definitive laboratory marker of immune reconstitution that would predict infectious risk that could be used to tailor infection prophylaxis. It is likely that the degree of immune recovery measured by various assays is associated with clinical outcomes including infection rates, based on retrospective studies that included relatively small numbers of patients (Table 4 ). However, a rigorous proof of the association is lacking. Moreover, most of the published studies have focused on the association of immune assay results with outcomes that can be clearly defined and captured (eg, survival or NRM) rather than with infections. Additionally, information from the published studies is limited because of publication bias (ie, there is a tendency to publish studies that find an association rather than negative studies). Tools are now available to precisely monitor viral-specific (Epstein-Barr virus [EBV], CMV) immune responses (HLA tetramers, interferon-γ production assays), and may help in understanding this issue [75]. Large (ideally, prospective) studies are needed, first to conclusively determine what immune monitoring test has prognostic value and ultimately to determine whether outcomes would improve if such a test were used to tailor infection prophylaxis. Table 3 Factors Affecting the Risk of Infection Factor Risk of Infection Type of transplant Higher risk with allogeneic, lower risk with autologous or syngeneic, depending on graft manipulation and clinical setting, including previous therapies Time from transplant Lower risk with more time elapsed from transplant Pretransplant factors Higher risk with extensive pretransplant immunosuppressive therapy (eg, fludarabine, clofaribine), prolonged pretransplant neutropenia, or pretransplant infection GVHD Higher risk with grade III-IV acute GVHD or extensive chronic GVHD HLA match Higher risk with HLA-mismatched donors, particularly with haploidentical donors Disease (eg, leukemia) status Higher risk with more advanced disease at the time of transplant Donor type Higher risk with marrow unrelated donor than with a fully matching sibling donor Graft type Highest risk with cord blood, intermediate risk with bone marrow and lowest risk with colony stimulating factor-mobilized blood stem cells. Higher risk with T cell-depleted grafts (depending upon method used) Immunosuppression after transplant Higher with immunosuppressive drugs, in particular with corticosteroids, antithymocyte globulin, alemtuzumab Conditioning intensity Lower risk in the first 1-3 months posttransplant with low-dose chemo/radiotherapy Neutrophil engraftment Higher risk with delayed engraftment/nonengraftment GVHD indicates graft-versus-host disease. Table 4 Parameters Reported to Correlate with Clinical Outcomes after HCT Parameter (Ref.) Timing Result Outcome Multivariate Analysis Lymphocyte count 813, 814, 815 Day 15 400 mg/dL, as the half-life of IVIG among HCT recipients (generally, 1-10 days) is much shorter than the half-life among healthy adults (generally, 18-23 days) (BII) 167, 168, 169. Preventing late disease (>100 days after HCT) Prolonged antibiotic prophylaxis is recommended only for preventing infection with S. pneumoniae among allogeneic recipients with chronic (cGVHD) for as long as active cGVHD treatment is administered (AIII) [170]. Antibiotic selection should be guided by local antibiotic resistance patterns. In the absence of severe hypogammaglobulinemia (ie, IgG levels 100 days after allogeneic or autologous HCT is not recommended (DI) 171, 172 as a means of preventing bacterial infections. Recommendations for preventing late bacterial infections are the same among pediatric or adult HCT recipients. Recommendations Regarding CLABSI Catheter-associated infections are a leading cause of bloodstream infections in HCT recipients, particularly during the preengraftment phase and in patients with GVHD 173, 174. These infections often result in catheter removal and, much less commonly, in death 175, 176. In HCT recipients, all central venous catheters (CVCs), whether tunneled or nontunneled, should be inserted using maximal sterile barrier precautions (AI) [177]. The preferred approach is the CLABSI prevention bundle, which consists of hand hygiene, full barrier precautions, cleaning the insertion site with chlorhexidine, avoiding femoral sites for insertion, and removing unnecessary catheters [178]. Although the efficacy of the CLABSI prevention bundle has not been studied in HCT recipients, all 5 elements of the bundle are recommended for this patient population (AII). Other measures to decrease the risk of CLABSI have been studied. Catheters impregnated with minocycline/rifampin 179, 180, 181 have been shown to decrease CLABSI in patients requiring nontunneled subclavian central venous access, including HCT patients. In 1 retrospective study, the minocycline/rifampin impregnated catheters did not affect the susceptibility of staphylococci to tetracyclines or rifampin [181]. For HCT centers with high CLABSI rates (more than 1 per 1000 catheter days) despite effective implementation of the CLABSI bundle elements, use of additional interventions, such as minocycline/rifampin antimicrobial-impregnated catheters, to prevent CLABSIs should be considered (BIII) [182]. Additional prevention strategies (eg, catheter-site dressing regimens, antimicrobial/antiseptic ointments, and antimicrobial lock prophylaxis) have been evaluated but not extensively assessed among the HCT patient population. A review found a similar risk of infection regardless of whether catheter dressings consisted of a transparent, semipermeable polyurethane dressing, or of sterile gauze and tape [183]. Povidone-iodine ointment, mupirocin ointment, and other antimicrobial ointments applied at the catheter insertion site have failed to show a consistent advantage when compared with no antimicrobial ointment. Recently, data have shown in non-HCT patients that chlorhexadine-impregnated sponges have decreased the rates of catheter related infections 184, 185. Topical antimicrobials should be avoided because of the risk of antimicrobial resistance or increased fungal colonization in immunosuppressed HCT patients (DIII). Antimicrobial lock prophylaxis using antimicrobial solutions, including those that contain vancomycin, have been studied in patients with long-term venous access devices and who develop neutropenia. A meta-analysis of the prospective, randomized trials testing the vancomycin-lock solution reported a decreased rate of bloodstream infections with vancomycin-susceptible organisms and a delay in the onset of the first bloodstream infection. However, the use of vancomycin-containing locks is not recommended, because of the increased risk of selecting for staphylococci with reduced vancomycin susceptibility [186] (DIII). Other alternatives, including lock solutions containing minocycline/EDTA, taurolidine citrate, or ethanol, have shown success in preventing CLABSI and salvaging vascular access 187, 188, 189, 190. These approaches, though promising, cannot be recommended in routine catheter care until further investigation is completed (DIII) When adopting prevention practices such as these, HCT programs should institute prospective data collection and reporting that allows for analysis of the success of the practices. HCT teams can also make use of a systemic review that defines benchmark rates of CLABSI for a wide range of catheter types [191]. Although not all of the studies included in the meta-analysis were conducted exclusively among HCT patients, HCT teams can use the results to assess their own center's relative performance, as an aspect of quality improvement efforts. Recommendations Regarding Streptococcus pneumoniae Preventing exposure Standard precautions should be taken with hospitalized patients infected with S. pneumoniae (AIII), including patients with infection caused by drug-resistant strains [192]. Preventing disease Invasive pneumococcal infection (IPI) is a life-threatening complication that may occur months to years after HCT. The annual incidence of IPI is 8.23/1000 transplants among allogeneic HCT recipients, and higher still among those with cGVHD (20.8/1000 transplants) [193]. Although IPI occurs less frequently in autologous HCT recipients (annual incidence, 3.8/1000 transplants), the risk remains much higher than in an immunocompetent population [193]. Efforts to prevent IPI should include active immunization and prophylactic antibiotics (Table 6 and Appendix 1). Vaccination against S. pneumoniae is recommended for all HCT recipients, preferably with pneumococcal 7-valent conjugate vaccine (BI) (see HCT Recipient Vaccinations). Antibiotic prophylaxis against pneumococcal infection is indicated in patients with cGVHD and those with low IgG levels (AIII). Antibiotic prophylaxis should be administered even to patients who have received pneumococcal vaccine, because not all strains are included in the vaccines, the immunogenicity of vaccines against the vaccine strains in HCT patients is only, at most, about 80% 194, 195, and because of the theoretic concern that strains not included in the vaccine will replace vaccine strains. Oral penicillin remains the preferred choice, but antibiotic selection depends on the local pattern of pneumococcal resistance to penicillin and other antibiotics (ie, second-generation cephalosporins, macrolides, and quinolones) 196, 197, 198, 199. Early empirical antibiotic treatment is required in any HCT patient with suspected IPI, regardless of the time since transplant, the immunization status, and the use of chemoprophylaxis (AIII) [193]. Recommendations Regarding Viridans Streptococci Preventing exposure Viridans streptococci are normal commensals, primarily of the oral surfaces. Hence, preventive efforts must focus on preventing systemic infection and disease rather than preventing exposure. Preventing disease Chemotherapy-induced oral mucositis is a potential source of viridans streptococcal bacteremia and sepsis. Consequently, before the start of conditioning, dental consults should be considered for all HCT candidates to assess their state of oral health and to perform any needed dental procedures to decrease the risk for oral infections after transplant (AIII) [200]. Many experts recommend that antibiotics active against viridans streptococci be given from the time of transplantation until a minimum of day +21 afterward (CIII). However, this approach has not been systematically studied. Penicillin-, quinolone-, and vancomycin-resistant strains of viridans streptococci have been reported 201, 202. Empiric treatment of any HCT recipient with fever, severe mucositis, and neutropenia should include an agent active against viridans streptococci to prevent complications from this potentially fatal infection [203]. Recommendations Regarding Haemophilus influenzae Type b Preventing exposure Vaccination campaigns have markedly reduced the incidence of H. influenzae type b (Hib) disease. However, in the rare event of a patient being hospitalized with Hib, standard precautions are recommended, with droplet precautions added for the first 24 hours after initiation of appropriate antibiotic therapy (BIII) 144, 204. Preventing disease Vaccination against Hib is recommended for all HCT recipients, as at least one-third of HCT recipients do not have protective antibody levels of Hib capsular polysaccharide antibodies after HCT, and the Hib conjugate vaccine has excellent efficacy among HCT recipients (BII) 194, 205 (see HCT Recipient Vaccinations). All HCT recipients who are exposed to persons with Hib disease should receive prophylaxis with 4 days of rifampin [204], or with an alternative antimicrobial agent if rifampin would likely interfere with other prophylactic agents the patient is receiving (eg, extended-spectrum azoles) (BIII) (Appendix 1). Antibiotic prophylaxis is especially indicated for allogeneic HCT recipients with cGVHD, who are at increased risk for developing infections from Hib and other encapsulated organisms (see section on S. pneumoniae) [206]. Recommendations Regarding Bordetella pertussis Preventing exposure HCT recipients may be exposed to persons with pertussis, as this disease is increasingly frequent in the general community. Pertussis in an adolescent recipient of an unrelated cord blood transplant (CBT) has been reported [207]. In addition to standard precautions, droplet precautions should be used in patients hospitalized with pertussis; droplet precautions are recommended for 5 days after initiation of effective therapy or, if antibiotic treatment is not given, until 3 weeks after the onset of paroxysmal cough (BIII) [208]. Preventing disease All HCT recipients who are exposed to persons with pertussis should receive prophylaxis with azithromycin or another macrolide (trimethoprim-sulfamethoxazole [TMP-SMZ] may be an alternative antimicrobial agent) regardless of age and immunization status (BIII) [208]. Following HCT, all HCT recipients should receive vaccination with acellular pertussis (see HCT Recipient Vaccinations). Viral Disease Prevention after HCT J. Zaia, L. Baden, M.A. Boeckh, S. Chakrabarti, H. Einsele, P. Ljungman, G.B. McDonald, H. Hirsch Recommendations Regarding Cytomegalovirus Preventing exposure Hematopoietic Cell Transplantation (HCT) candidates should be tested for the presence of serum anti-cytomegalovirus (CMV) IgG antibodies before transplantation to determine their risk for primary CMV infection and reactivation after HCT (AII). CMV is shed intermittently from the oropharynx and the genitourinary tract of both immunocompetent and immunosuppressed subjects. There are no data demonstrating that avoiding these body fluids is feasible or effective in preventing acquisition of CMV in CMV-seronegative HCT recipients. Because CMV-seronegative pregnant health care workers may be at risk for contracting CMV from these and other patients, standard universal precautions should be used in these situations. With proper management, CMV-seronegative patients have a low risk for contracting CMV infection. To reduce the risk of CMV transmission, blood products from CMV-seronegative donors or leukocyte-depleted blood products should be used in CMV-seronegative allogeneic HCT recipients (AI) 209, 210, 211. The benefit of using either of these products in autologous HCT recipients to prevent CMV transmission is less clear. However, because many autologous HCT recipients have received previous T cell suppressive therapy such as fludarabine (Flu) or alemtuzumab, the use of CMV-safe blood products is recommended (BII). In many centers, and even in entire countries, leukocyte filtration of blood products is mandatory. No controlled study has examined the potential benefit of the combination of seronegative blood products and filtered blood products. Leukocyte filtration should be performed at the blood bank and the established quality standard of 30 days after HCT might be considered for persons with frequent recurrences of HSV infection (BIII) (Appendix 1). Acyclovir or valacyclovir can be used during phase I (preengraftment) for administration to HSV-seropositive autologous recipients who are likely to experience substantial mucositis from the conditioning regimen (CIII). Acyclovir prophylaxis doses should be modified for use among children (Appendix 1). Because of limited published data regarding valacyclovir safety and efficacy among children, no recommendations for the pediatric population can be made [281]. Recommendations Regarding VZV Preventing exposure HCT candidates should be tested for the presence of serum anti-varicella zoster virus (VZV) IgG antibodies (AII). However, these tests are not 100% reliable, particularly among severely immunosuppressed patients. All HCT candidates and recipients, particularly those who are VZV seronegative, should be informed of the potential seriousness of VZV disease among immunocompromised persons and advised of strategies to decrease their risk for VZV exposure (AII) [282]. Although the majority of VZV disease after HCT is caused by reactivation of endogenous VZV, HCT candidates and recipients who are VZV seronegative, or VZV seropositive and immunocompromised, should avoid exposure to persons with active VZV infections (AII) [283]. Health care workers (HCWs), family members, household contacts, and visitors who are healthy and do not have a reported history of varicella infection or who are VZV-seronegative should receive VZV vaccination before being allowed to visit or have direct contact with an HCT recipient (AIII). Ideally, VZV-susceptible family members, household contacts, and potential visitors of immunocompromised HCT recipients should be vaccinated as soon as the decision is made to perform HCT and the vaccination schedule completed ≈4-6 weeks before the HCT is performed (BIII). To date, no serious disease has been reported among immunocompromised patients from transmission of VZV vaccine virus, and the VZV vaccine strain is susceptible to acyclovir. However, HCT recipients undergoing conditioning therapy should avoid contact with any VZV vaccine recipient who experiences a rash after vaccination (BIII). Rash after vaccination can be because of the wild-type VZV (median: 8 days; range: 1-20 days) or the VZV vaccine strain (median: 21 days; range: 5-42 days) 284, 285. All HCT recipients with multidermatomal VZV disease should be placed under airborne and contact precautions (AII) [144] to prevent transmission to other HCT recipients. Dermatomal zoster requires contact precautions until all skin lesions are crusted (AII), and some researchers also recommend airborne precautions because in immunocompromised patients there is a high risk for dissemination of the zoster rash (CII). Airborne precautions should be instituted 8 days after exposure to VZV and continued until 21 days after last exposure (AII) or 28 days postexposure if the patient received varicella-zoster immunoglobulin (VZIG) (BII) [144] because a person infected with VZV can be inectious before the rash appears. The VZIG product currently available in the United States is VariZIG [286]. Preventing disease Antiviral drugs Long-term acyclovir prophylaxis to prevent recurrent VZV infection is routinely recommended for the first year after HCT for VZV-seropositive allogeneic (BI) 280, 287 and autologous (CII) HCT recipients (Appendix 1). The 1-year regimen of acyclovir is highly effective in reducing the risk of VZV disease during the year of acyclovir administration (BI) 280, 287. Acyclovir prophylaxis may be continued beyond 1 year in allogeneic HCT recipients who have cGVHD or require systemic immunosuppression (BII) 280, 288. The optimal duration of prophylaxis is poorly defined in patients with cGVHD, as there appears to be a persistent risk of VZV reactivation disease even if the acyclovir is continued until all systemic immunosuppressive drugs are discontinued and the CD4+ count exceeds 200 cells/μL [288]. Some clinicians advocate continuing acyclovir prophylaxis until 6 months after discontinuation of all systemic immunosuppressive agents (CIII). Valacyclovir is a prodrug of acyclovir, and may be used as an alternative to acyclovir at any time that oral medications are used. Valacyclovir may provide higher drug levels in severely immunosuppressed patients than acyclovir (BII). Although valacyclovir is not licensed in the United States for use in HCT recipients, a large randomized trial in HCT recipients found no safety issues with valacyclovir, even when used at very high doses [216]. No data on famciclovir in HCT recipients were found; consequently, no recommendations can be made regarding its use in place of acyclovir or valacyclovir. Resistance to acyclovir has been rarely documented to date in HCT recipients [289]; however, when clinically suspected or virologically documented acyclovir resistance occurs among patients, HCT physicians should use foscarnet for preemptive treatment of VZV disease (BIII) 289, 290. Any HCT recipient or candidate undergoing conditioning therapy who experiences a VZV-like rash (whether after exposure to a person with wild-type varicella or shingles or exposure to a VZV vaccinee with a rash) should receive preemptive intravenous acyclovir until ≈2 days after all lesions have crusted (BII). Treatment may be completed with oral valacyclovir if the patient can tolerate oral medication. Passive immunization and VZV-seronegative HCT recipients Because of the high morbidity of VZV-associated disease among severely immunocompromised HCT recipients and until further data are published, there are situation-specific indications for the administration of VZIG or VariZIG, where available, for VZV-seronegative HCT recipients. Immunocompromised HCT recipients (ie, an allogeneic patient 3 weeks after receiving VZIG or VariZIG, they should receive another dose of VZIG or VariZIG, or another course of valacyclovir if VZIG or VariZIG is not available (BIII) [282]. Passive immunization and VZV-seropositive HCT recipients VZIG or VariZIG, acyclovir, or valacyclovir can be used following VZV exposure, including exposure to a VZV vaccinee having a varicella-like rash, for HCT recipients who were VZV-seropositive before HCT and are highly immunosuppressed (ie, because of high-dose steroid therapy, or T CD) (CIII) [292]. These recommendations are made because the vaccinee might be unknowingly incubating wild-type varicella, particularly during the first 14 days after varicella vaccination, and because vaccine-strain VZV has been rarely transmitted by VZV vaccinees with postvaccination vesicular rashes [282]. Furthermore, varicella vaccination is only approximately 85% effective. Thus, vaccine recipients may still become infected with wild-type virus years after vaccination [293] and may thus be a source of transmission to immunocompromised patients. VZV Vaccines Use of VZV vaccines (Varivax and Zostavax) is discussed in the HCT Recipient Vaccination section. A vaccine-associated rash occurs in approximately 1% to 5% and 0.5% of recipients of the varicella and zoster vaccine, respectively 294, 295. This rash is a potential source of transmission of vaccine virus strain to HCT recipients. Because the risk of vaccine virus transmission is low, particularly in the absence of a vaccine-associated rash, household members should receive varicella vaccine to protect HCT recipients from potential exposure to wild-type disease (AIII). Individuals who experience a vaccine-associated rash should avoid close contact with HCT recipients in the home setting (BIII). If contact occurs, the HCT recipient should be considered for postexposure prophylaxis with valacyclovir, as outlined earlier (CIII). An inactivated VZV vaccine has been used investigationally among HCT recipients [296]. Studies are ongoing to further define its utility and no recommendation regarding its use can be made at this time. Other recommendations Recommendations for VZV prevention are the same for allogeneic or autologous recipients. Recommendations are also the same for allograft recipients with different-intensity conditioning regimens. Recommendations for preventing VZV disease among pediatric or adult HCT recipients are the same, except that appropriate dose adjustments for acyclovir derivatives and VZIG should be made for pediatric HCT recipients (AIII) (Appendix 1). Recommendations Regarding CRV Infections: Influenza, Respiratory Syncytial Virus, Human Metapneumovirus, and Parainfluenza Virus Preventing exposure Preventing CRV exposure is critical in preventing CRV disease 297, 298. Measures for preventing nosocomial CRV transmission are presented in the Infection Prevention and Control in Health care Facilities: Recommendations Regarding CRV Infections section. Use of PCR testing in donors with respiratory infections remains investigational (CIII). Viral cultures of asymptomatic HCT candidates are unlikely to be useful. Whether multiplex PCR testing can identify asymptomatic shedders before HCT is presently being studied. PCR-based routine surveillance of asymptomatic patients after HCT remains investigational. HCT recipients with symptoms of an upper respiratory infection (URI) or lower respiratory infection (LRI) should be placed under contact precautions to avoid transmitting infection to other HCT candidates and recipients, HCWs, and visitors until the etiology of the illness is identified (BIII) [144]. Optimal isolation precautions should be modified as needed after the etiology is identified (BIII). HCT recipients and candidates, their family members and visitors, and all HCWs should be informed regarding CRV infection control measures and the potential severity of CRV infections among HCT recipients (BIII) 297, 298, 299. Preventing disease HCT physicians should determine the etiology of a URI in an HCT recipient, if possible, because respiratory syncytial virus (RSV), influenza, parainfluenza, and adenovirus URIs can progress to more serious LRI, and certain CRVs can be treated (BIII). Appropriate diagnostic samples include nasopharyngeal washes, swabs or aspirates; throat swabs (in combination with nasal samples); and bronchoalveolar lavage (BAL) fluid. HCT candidates with URI symptoms at the time conditioning therapy is scheduled to start should postpone their conditioning regimen until the URIs resolve, if possible, because certain URIs might progress to LRI during immunosuppression (BIII) 298, 300, 301, 302. The clinical relevance of recently discovered viruses (eg, human bocavirus, non-SARS coronaviruses, human rhinoviruses, human metapneumovirus) that are detectable by molecular methods is currently undefined, and no recommendations can be made for routine screening for these viruses (CIII). Recommendations regarding influenza Life-long seasonal influenza vaccination with the trivalent inactivated vaccine is recommended for all HCT candidates and recipients (see Vaccination section) (AII). Additionally, influenza vaccination of family members and close or household contacts is strongly recommended during each influenza season (eg, October-May in the Northern Hemisphere), starting the season before HCT and continuing ≈24 months after HCT (AII) [303] to prevent influenza. All family members and close or household contacts of HCT recipients should continue to be vaccinated annually as long as the HCT recipient's immunocompromise persists, even if beyond 24 months after HCT (AII) [303]. Seasonal influenza vaccination is strongly recommended for all HCWs of HCT recipients (AI) [304]. If HCWs, family members, or other close contacts of HCT recipients receive influenza vaccination during an influenza outbreak, they should receive chemoprophylaxis, if feasible, for 2 weeks after influenza vaccination (BI) while the immunologic response to the vaccine develops. However, if an outbreak occurs with an influenza strain that is not contained in the available influenza vaccine, all healthy family members, close and household contacts, and HCWs of HCT recipients and candidates should receive influenza chemoprophylaxis with an active agent against the current circulating strain of influenza until the end of the outbreak (BIII) [303]. Zanamivir may be given for prevention of influenza A and B, including influenza from strains resistant to oseltamivir. The duration of prophylaxis depends on the type of exposure. Zanamivir can be administered to persons 5 years of age and older for prevention of influenza, and 7 years and older for treatment of influenza. Oseltamivir can be administered to persons ≈1 year of age and older. Patients with influenza should be placed under droplet and standard precautions (AIII) to prevent transmission of influenza to HCT recipients. HCWs with influenza should be excused from patient care until they are no longer infectious (AIII). HCT recipients 24 months after HCT and substantially immunocompromised regardless of vaccination history, because of their likely suboptimal immunologic response to influenza vaccine (BII) 305, 306. Drug resistance patterns of circulating influenza strains should guide the choice of prophylactic agent. Healthy children who receive influenza vaccination for the first time might not generate protective antibodies until 2 weeks after receipt of the second dose of influenza vaccine. Therefore, during an influenza A outbreak, pediatric recipients who are 2-3 log10, use of anti-T cell antibodies (eg, antithymocyte globulin [ATG], alemtuzumab) 331, 336. For patients at highest risk, weekly monitoring for active adenovirus infection by PCR for either the first 6 months after HCT or the duration of severe immunosuppression/lymphopenia could be considered (CII) 333, 337. Quantitative PCR testing should be strongly considered for monitoring progression of adenovirus infection and response to treatment (BII). There are no definitive data on a critical value for viral load in peripheral blood to indicate initiation of intervention; thus, no recommendation can be made. Clearance of adenovirus has been shown to be associated with recovery of adenovirus-specific T cell immunity 338, 339. When possible, rapid tapering or withdrawal of immunosuppression constitutes the best way to prevent progression of adenovirus infection (AII) 331, 332, 340, 341. However, this strategy might not always be feasible in severe GVHD or with severe lymphopenia because of use of anti-T cell antibodies or T CD of the graft. Few antiviral agents have in vivo activity against adenoviruses, and no randomized, placebo-controlled study of antiviral drug therapy for adenoviral infection has been performed. The available data suggest that cidofovir or ribavirin could be used as preemptive antiviral therapy of adenoviral disease in selected high-risk HCT patients (CII) (Appendix 1). A reduction of DNA load has been shown mainly with cidofovir 342, 343 but the evidence of its efficacy in preventing mortality in HCT patients is inconsistent [344]. Differences in responses may be because of strain-specific susceptibilities [345]. The duration of preemptive therapy is subject to tolerance and clearance of viral load. Current evidence strongly supports the role of adenovirus-specific T cells in controlling the progression of adenoviral disease [346]. However, this approach is at an early stage of development and should not be used outside the context of a clinical trial. Recommendations Regarding Polyomaviruses BK and JC Human polyomavirus type I, commonly called BK virus (BKV), and human polyomavirus type II, commonly called JC virus (JCV), infect 50% to 90% of humans worldwide before the age of 10 years, without known symptoms or signs 347, 348. Urinary shedding of BKV and/or JCV occurs in 5% to 20% of healthy immunocompetent blood donors [349]. BKV and JCV are nonenveloped virions found in urban sewage and fairly resistant to environmental inactivation [350]. Polyomavirus disease in HCT patients most often corresponds to secondary BKV replication with impaired polyomavirus-specific cellular immunity. Urinary shedding of BKV occurs in 60% to 80% of HCT recipients 347, 348, 351, 352, 353. The major disease linked to high-level polyomavirus replication is BKV-associated hemorrhagic cystitis (PVHC), which affects 5% to 15% of HCT recipients at 3 ro 6 weeks posttransplant 352, 354. PVHC occurs typically after engraftment, and must be distinguished from hemorrhagic cystitis caused by other pathogens (eg, adenovirus or CMV) and from early-onset hemorrhagic cystitis, which arises preengraftment and has been linked to urotoxic conditioning regimens with cyclophosphamide (Cy), ifosfamide, busulfan (Bu), and/or TBI 352, 354. BKV viruria reaching high viral loads of >107 genome equivalents/mL (geq/mL) is observed in 20% to 80% of HCT patients, but less than one-fifth of HCT recipients develop PVHC [354]. PVHC is diagnosed in HCT patients with postengraftment cystitis who have pain and urinary urgency together with hematuria of grade II (macrohematuria [352]) or higher, high-level BKV replication (ie, ≥107 gEq/mL), and exclusion of other pathogens. There are reports of sporadic cases of JCV-associated PVHC [355], BKV- or JCV-associated polyomavirus nephropathy (PVAN) 347, 356, 357, 358, 359, and JCV- or BKV-mediated polyomavirus multifocal leukoencephalopathy (PVML) 360, 361. Preventing exposure There is no evidence to support routine testing of HCT recipients or donors for the presence of BKV-specific or JCV-specific antibodies (DIII). There are no commercially available, standardized, or FDA-approved assays to measure BKV- or JCV-specific antibodies. The role of primary infection, of donor-recipient mismatch, and of BKV-specific antibody titers in HCT recipients is presently unknown. There is no evidence to support specific infection-control measures for HCT patients with BKV viruria (DIII). In patients with disseminated BKV replication involving the respiratory and the gastrointestinal (GI) tract, separation from other patients with significant immunodeficiency should be considered (CIII). Preventing disease and disease recurrence There is no evidence to support the use of quinolones or cidofovir as specific universal prophylaxis for PVHC or other polyomavirus-associated complications (DIII). There is insufficient evidence to support the use of quinolones for preemptive treatment of asymptomatic HCT patients who develop BKV viruria or viremia (DIII). Fluoroquinolones can inhibit BKV replication in tissue culture, and have been reported to reduce BKV loads in HCT patients, but a significant reduction of PVHC has not been demonstrated [362]. Ciprofloxacin and levofloxacin are frequently used, alone or in combination with other antibiotics, in patients undergoing HCT in antibacterial prophylaxis during neutropenia, in empiric or specific antibiotic therapy, and seemingly resistant BKV isolates have been reported 362, 363. There is no evidence to support the use of cidofovir for preemptive treatment of asymptomatic HCT patients who develop BKV viruria or viremia (DIII). Cidofovir has been administered intravenously in a low dose (ie, up to 1 mg/kg 3 times weekly, without probenecid) or a high dose (ie, 5 mg/kg per week with probenecid) to HCT patients with PVHC, but no randomized trials are available proving its clinical efficacy (CIII). Recommendations Regarding Hepatitis A virus (HAV) The seroprevalence of HAV varies widely, with higher rates in resource-limited societies. Testing of HCT candidates or donors for HAV IgG antibodies is generally not recommended, as its sole positivity in the absence of IgM indicates remote exposure and has no impact on HCT outcome (DIII). However, testing for IgM is indicated as part of the workup of patients with signs of acute hepatitis (AII). If an HCT candidate tests positive for HAV IgM, transplantation should be delayed because of an increased risk of sinusoidal obstruction syndrome (SOS) following liver-toxic myeloablative (MA) conditioning regimens (DII). If the HCT donor tests positive for HAV IgM, transplantation should be delayed because of a high risk of transmission and increased morbidity and mortality (EII). HAV vaccination recommendations for HCT recipients are provided in Table 7. Recommendations Regarding Hepatitis B virus (HBV) HBV can cause severe hepatitis following HCT. However, rates of HBV-associated cirrhosis and hepatocellular carcinoma do not appear higher in HCT patients than in non-HCT patients [364]. Severe hepatitis B has been observed in HCT recipients in the following situations: • 1. HBV-naïve HCT recipients exposed to HBV via an infected donor, infected blood products, or through sexual contact; • 2. HCT recipients with chronic hepatitis B experiencing prolonged immune suppression; • 3. HCT recipients with serologic evidence of resolved HBV infection who have reverse seroconversion following prolonged immune suppression; • 4. HCT patients—generally in countries with endemic HBV—with latent occult hepatitis B (all serologic markers negative) that activates following prolonged immune suppression [365]. Risk factors for reactivation and exacerbation of HBV replication in HCT recipients include treatment with high-dose steroids 366, 367, Flu/rituximab [368], or alemtuzumab 366, 367, 369. Clinical hepatitis may become further exacerbated during immune recovery and discontinuation of immunosuppression. Preventing exposure Testing both recipients and potential donors for evidence of active or past HBV infection is critical to preventing HBV exposure and disease in HCT recipients. The appropriate assays include HBV surface antigen (HBsAg), antibodies to HBV surface antigen (anti-HBs), and antibodies to HBV core antigen (anti-HBc) (AII). All anti-HBc positive and HbsAg-positive donors and recipients should also be tested for HBV DNA (AIII). HBV-naïve HCT candidates should not receive transplants from HBsAg-positive or HBV DNA-positive donors, if another equally suitable donor is available (AII). However, the use of a donor with active HBV replication is not absolutely contraindicated for an HBV-naïve recipient because viral transmission is not universal (BIII). The overriding concern must be HLA matching and other outcome-related issues. Vaccination of all HBV-naïve HCT candidates should be considered (AIII). An attempt should be made to provide hepatitis B immunization to HBV-seronegative HCT candidates with HBsAg-positive donors, preferably prior to chemotherapy for the initial 2 doses 3 to 4 weeks apart and a third dose 6 months later, ideally prior to HCT (BIII). If this schedule cannot be met, the third dose should be administered a few months after completion of chemotherapy. Of note, the response to vaccination is likely to be poor in patients undergoing chemotherapy. If the postvaccination anti-HBs titer is 10 years • Clinical evidence of chronic liver disease. Patients with evidence of cirrhosis or hepatic fibrosis should not be considered for conventional MA conditioning therapy that contains either Cy or TBI ≥12 Gy (DIII), because those regimens are associated with a 9.6-fold increased risk of fatal SOS in these patients [378]. Instead, regimens that do not contain either Cy or TBI, which pose a lower risk for fatal SOS, should be used [383]. For patients with cirrhosis, however, even an RIC regimen poses a mortality risk [384]. Treatment for chronic HCV should be considered in all HCV-infected HCT recipients, because limited data suggest improved outcome in those who respond to combination therapy (BIII) [385]. To qualify for antiviral treatment, the patient must be in complete remission from the original disease, be ≥2 years posttransplant without evidence of either protracted aGVHD or cGVHD, have been off immunosuppression for 6 months, and have normal blood counts and serum creatinine (BIII). Treatment should consist of full-dose peginterferon and ribavirin (BIII). Dose modifications should be made if intolerance develops (eg, development of cytopenias). In survivors whose neutrophil and platelet counts are below normal at baseline, daily interferon alpha can be substituted for peginterferon to assess hematologic toxicity before moving to peginterferon. Treatment should be continued for 24 to 48 weeks, depending on response. Human Herpesviruses 6 and 7 Preventing exposure Human herpesvirus 6 (HHV-6) is the cause of the classic childhood illness roseola, which is also known as exanthema subitum or sixth disease [386]. Clinical disease associated with human herpesvirus 7 (HHV-7) infection remains to be defined. Nearly all children are infected with HHV-6 by 2 to 3 years of age 387, 388, 389 and HHV-7 by the age of 5 years [390]. Preventing disease and disease recurrence The spectrum of HHV-6-associated complications after HCT has not been completely described. HHV-6 reactivation is common during the early allogeneic HCT transplant period, with viremia occurring in approximately 40% to 60% of patients 387, 391, 392, 393, 394. The clinical significance of detection of HHV-6 viremia is unknown, although it has been associated in the posttransplant setting with hepatitis, fever, rash, idiopathic pulmonary syndrome, and delayed platelet and monocyte engraftment. HHV-6 can also be chromosomally integrated, potentially resulting in a false-positive PCR assay result [395]. A posttransplantation acute limbic encephalitis syndrome associated with HHV-6 reactivation in the cerebral spinal fluid (CSF) has been reported [396]. This syndrome is uncommon, occurring in approximately 1% to 2% of HCT patients in some series. It typically occurs 1 to 2 months posttransplantation and appears to be more common after receipt of a UCB or HLA-mismatched graft. Manifestations include profound memory loss, seizures, hyponatremia, mild CSF pleocytosis, and significant mesial temporal lobe abnormalities on magnetic resonance imaging (MRI) 396, 397. In addition, HHV-6 may interfere with MHC class I antigen presentation and augment local immunosuppression [398]; however, the implications of this viral property are unknown. The role of HHV-7 in posttransplant complications remains to be defined. At this time, there are no data to guide preemptive monitoring or a prophylactic antiviral strategy to prevent potential HHV-6-associated disease (DIII). Ganciclovir, cidofovir, and foscarnet have variable in vitro activity against HHV-6, and may have a role in treating HHV-6-associated disease 399, 400. There are no data to support recommendations for monitoring of potential HHV-7-associated disease (DIII). Human Herpesvirus 8 Preventing exposure Human herpesvirus type 8 (HHV-8) is the cause of Kaposi's sarcoma, and is also known as KSHV. Unlike other herpesvirus infections, HHV-8 infection is not ubiquitous. There is significant geographic variability in prevalence of HHV-8 infection, with high infection rates reported in sub-Saharan Africa (50%), modest rates in the United States (about 5%), and low rates in Japan ( 180°; other meats >160°) · Canned meats (beef, pork, lamb, poultry, fish, shellfish, game, ham, bacon, sausage, hot dogs) · Eggs cooked until both white and yolk are firm · Pasteurized eggs and egg substitutes (such as Egg Beaters®), and powdered egg white (all can be used uncooked) · Commercially packaged salami, bologna, hot dogs, ham, and other luncheon meats, heated until steaming · Canned and shelf-stable∗ smoked fish (refrigerate after opening) · Pasteurized or cooked tofu† · Refrigerated smoked seafood such as salmon or trout if cooked to 160°F or contained in a cooked dish or casserole · Raw or undercooked meat, poultry, fish, game, tofu∗ · Raw or undercooked eggs and nonpasteurized egg substitutes; no eggs over easy, soft-boiled eggs, or poached eggs. · Meats and cold cuts from delicatessens · Hard cured salami in natural wrap · Uncooked refrigerated smoked seafood such as salmon or trout labeled as “nova-style,” “lox,” “kippered,” “smoked,” or “jerky” · Pickled fish · Tempe (tempeh) products Fruits and nuts · Well washed‡ raw and frozen fruit; · Foods containing well-washed raw fruits · Cooked, canned, and frozen fruit · Pasteurized juices and frozen juice concentrates · Dried fruits · Canned or bottled roasted nuts · Shelled, roasted nuts, and nuts in baked products · Commercially packaged nut butters (such as peanut butter, almond butter, soybean butter) · Unwashed raw fruits · Fresh or frozen berries · Unroasted raw nuts · Roasted nuts in the shell · Nonpasteurized fruit and vegetable juices · Fresh fruit salsa found in the grocery refrigerator case · Nonpasteurized items containing raw fruits found in the grocery refrigerator case Entrees, soups ·All cooked entrees and soups ·All miso products (such as miso soup and miso paste) Vegetables · Well washed‡ raw and frozen vegetables · All cooked fresh, frozen, or canned vegetables, including potatoes · Shelf-stable∗ bottled salsa (refrigerate after opening) · Cooked vegetable sprouts (such as mung bean sprouts) · Fresh, well-washed‡ herbs and dried herbs and spices (added to raw or cooked foods) · Unwashed raw vegetables or herbs · Fresh, nonpasteurized vegetable salsa found in the grocery refrigerator case · Nonpasteurized items containing raw vegetables found in the grocery refrigerator case · All raw vegetable sprouts (alfalfa sprouts, clover sprouts, mung bean sprouts, all others) · Salads from delicatessens Bread, grain, and cereal products · All breads, bagels, rolls, English muffins, muffins, pancakes, sweet rolls, waffles, French toast · Potato chips, corn chips, tortilla chips, pretzels, popcorn · Cooked grains and grain products, including pasta and rice · All cereals, cooked and ready-to-eat · Raw (not baked or cooked) grain products (such as raw oats) Beverages · Boiled well water§ · Tap water and ice made from tap water¶ · Commercially bottled distilled, spring, and natural waters⊥ · All canned, bottled and powdered beverages · Instant and brewed coffee and tea; cold brewed tea made with boiling water · Herbal teas brewed from commercially packaged tea bags · Commercial nutritional supplements, both liquid and powdered · Commercially sterile ready-to-feed and liquid-concentrate infant formulas (avoid powdered infant formulas if a ready-to-feed or liquid concentrate alternative is available) · Unboiled well water · Cold-brewed tea made with warm or cold water · Nonpasteurized fruit and vegetable juices · Maté tea · Wine, nonpasteurized beer (Note: all alcoholic beverages should only be consumed following physician approval.) Desserts · Refrigerated commercial and homemade cakes, pies, pastries, and pudding · Refrigerated cream-filled pastries · Cookies, both homemade and commercially prepared · Shelf-stable‡ cream-filled cupcakes (such as Twinkies®, Ding Dongs®) and fruit pies (such as Poptarts® and Hostess® fruit pies) · Canned and refrigerated puddings · Ices, popsicles, and similar products · Candy, gum ·Unrefrigerated cream-filled pastry products (not shelf-stable‡) Fats · Vegetable oils and shortening · Refrigerated lard, margarine, butter · Commercial, shelf-stable‡ mayonnaise and salad dressings including Blue Cheese and other cheese-based salad dressings (refrigerate after opening) · Cooked gravy and sauces ·Fresh salad dressings (stored in the grocer's refrigerated case) containing raw eggs or cheeses listed as “Do Not Eat” under “Dairy.” Other · Commercial pasteurized Grade A honey∗∗ · Salt, granulated sugar, brown sugar · Jam, jelly, syrups (refrigerate after opening) · Catsup, mustard, BBQ sauce, soy sauce, other condiments (refrigerate after opening) · Pickles, pickle relish, olives (refrigerate after opening) · Vinegar · Raw honey; honey in the comb · Herbal and nutrient supplement preparations · Brewers yeast, if uncooked Concern arising from the detection of potential pathogens in food has not been supported by documented evidence of such organisms as the source of opportunistic infections in immunocompromised persons. The potential benefit of food safety recommendations directed specifically toward HCT recipients must be weighed against the uncertain value of such recommendations [767] and their potential to adversely affect patients` nutritional intake and/or quality of life. ∗ Shelf-stable refers to unopened canned, bottled, or packaged food products that can be stored before opening at room temperature; container may require refrigeration after opening. † Aseptically packaged, shelf-stable tofu and pasteurized tofu do not need to be boiled. Nonpasteurized tofu must be cut into 1-inch cubes or smaller, and boiled a minimum of 5 minutes in water or broth before eating or using in recipes. ‡ Rinse under clean, running water before use, including produce that is to be cooked or peeled (such as bananas, oranges, and melon). § Bring tap water to a rolling boil and boil for 15-20 minutes. Store boiled water in the refrigerator. Discard water not used within 48 hours (2 days). ¶ Recommend using boiled or bottled water if using a water service other than city water service. Please see Water Safety Guidelines in “Food Safety Guidelines.” ⊥ See Water Safety Guidelines in “Food Safety Guidelines” for approved bottled water treatments. ∗∗ Honey products are not allowed for any child less than 1 year of age and not allowed for children with SCIDS until 9 months posttransplant. Table 6 Vaccinations Recommended for Both Autologous and Allogeneic HCT Recipients Vaccine Recommended for Use after HCT Time Post-HCT to Initiate Vaccine Number of Doses∗ Improved by Donor Vaccination (Practicable Only in Related-Donor Setting) Pneumococcal Conjugate (PCV) Yes (BI) 3-6 months 3-4† Yes; may be considered when the recipient is at high risk for chronic GVHD Tetanus, diphtheria, acellular pertussis‡ Yes Tetanus-diphtheria: (BII) Pertussis (CIII) 6-12 months 3§ Tetanus: likely Diphtheria: likely Pertussis: unknown Haemophilus influenzae conjugate Yes (BII) 6-12 months 3 Yes Meningococcal conjugate Follow country recommendations for general population (BII) 6-12 months 1 Unknown Inactivated polio Yes (BII) 6-12 months 3 Unknown Recombinant Hepatitis B Follow country recommendations for general population (BII) 6-12 months 3 Likely¶ Inactivated Influenza Yearly (AII) 4-6 months 1 -2⊥ Unknown Measles- Mumps- Rubella†† Measles: all children and seronegative adults Measles: BII Mumps: CIII Rubella: BIII 24 months 1 -2‡‡ Unknown (live) EIII ( 24 months, without active GVHD, or on immunosuppression) Human papillomavirus Follow recommendations for general population in each country No data exist regarding the time after HCT when vaccination can be expected to induce an immune response CIII Yellow fever (live) Limited data regarding safety and efficacy. The risk-benefit balance may favor use of the vaccine in patients residing in or traveling to endemic areas. EIII ( 24 months, without active GVHD, or on immunosuppression) Rabies Appropriate for use in HCT recipients with potential occupational exposures to rabies [827] Preexposure rabies vaccination should probably be delayed until 12-24 months after HCT. Postexposure administration of rabies vaccine with human rabies Ig can be administered any time after HCT as indicated∗ 827, 828 CIII Tick-borne encephalitis (TBE) According to local policy in endemic areas. No data exist regarding the time after HCT when vaccination can be expected to induce an immune response CIII Japanese B encephalitis According to local policy when residing in or traveling to endemic areas. No data exist regarding the time after HCT when vaccination can be expected to induce an immune response CIII Not Recommended Vaccine Recommendations for use Rating Bacillus Calmette-Guérin (live) Contraindicated for HCT recipients EII Oral poliovirus vaccine (live) Should not be given to HCT recipients since an effective, inactivated alternative exist EIII Intranasal influenza vaccine (live) No data regarding safety and immunogenicity. Should not be given to HCT recipients since an effective, inactivated alternative exist EIII Cholera No data were found regarding safety and immunogenicity among HCT recipients DIII Typhoid, oral (live) No data were found regarding safety and immunogenicity among HCT recipients. EIII Typhoid (intramuscular) No data were found regarding safety, immunogenicity, or efficacy among HCT recipients. DIII Rotavirus Must be given before 12 weeks of age to be safe. EIII Zoster vaccine (Zostavax) (live) No data regarding safety among HCT recipients. EIII HCT indicates hematopoietic cell transplantation; GVHD, graft-versus-host disease. ∗ Current Advisory Committee on Immunization Practices (ACIP) and American Academy of Pediatrics guidelines for postexposure human rabies immunoglobulin and vaccine administration should be followed, which include administering 5 doses of rabies vaccine administered on days 0, 3, 7, 14, and 28 postexposure. Preventing disease Growth factors (eg, granulocyte-macrophage colony-stimulating factor [GM-CSF] and G-CSF) shorten the duration of neutropenia after HCT [412]. However, a meta-analysis showed that use of growth factors did not reduce the attack rate of invasive fungal disease [165], and therefore, no recommendation can be made for the use of growth factors for prophylaxis against invasive fungal disease (CI). Topical antifungal drugs applied to the skin or mucosa (eg, nystatin or clotrimazole) might reduce colonization by yeasts and molds in the area of application. However, these agents have not been proved to prevent locally invasive or disseminated yeast or mold infections and their use for prophylaxis is unclear (CIII). Performing fungal surveillance cultures is not indicated for asymptomatic HCT recipients (DII) 413, 414. Other recommendations Patients receiving antifungal prophylaxis who develop clinical signs or symptoms of infection should be evaluated for breakthrough bloodstream or pulmonary fungal infections (AIII). Such infections may occur because the prophylactic drug has no activity against the organism; because the organism has developed resistance to the drug; or because of other factors, such as severe immunosuppression or low serum levels of the prophylactic agent [415]. Recommendations Regarding Yeast Infections Preventing exposure The risk for invasive candidiasis is significantly higher during the early posttransplant period (phase I) because of neutropenia, severe mucositis, and the presence of a central venous catheter (CVC) [416]. During phase II, the risk factors for invasive candidiasis are the presence of a CVC and severe gastrointestinal (GI) graft-versus-host disease (GVHD) [416]. Among autologous HCT recipients, the risk of invasive candidiasis is minimal once neutropenia and mucositis have resolved. Invasive candidiasis is usually caused by dissemination of endogenous Candida species that have colonized a patient's GI tract [417]. Consequently, methods of preventing exogenous yeast exposure usually do not prevent invasive yeast infections after HCT. However, because Candida species can be carried on the hands, HCWs and others in contact with HCT recipients should follow appropriate hand-washing practices to avoid exposing patients to fungal pathogens (AII). Preventing disease Fluconazole is the drug of choice for the prophylaxis of invasive candidiasis before engraftment in allogeneic HCT recipients, and may be started from the beginning or just after the end of the conditioning regimen (AI) 418, 419. Low-dose fluconazole has variable efficacy; therefore, doses lower than 200 mg are not recommended (DII). The optimal duration of fluconazole prophylaxis—specifically, whether prophylaxis confers significant benefits when continued postengraftment—is not defined. A post hoc analysis of a randomized clinical trial has shown that fluconazole given until day 75 posttransplant was associated with prolonged protection against invasive candidiasis, even beyond the period of prophylaxis [420]. Fluconazole is not effective against Candida krusei, and has variable activity against C. glabrata, which can become resistant [421]; moreover, the use of fluconazole for prophylaxis may result in the selection of azole-resistant Candida species (principally C. glabrata and C. krusei) [422]. Therefore, fluconazole is not recommended for prevention of such infections (DI). This may be a consideration in patients who are known to be colonized with fluconazole-resistant Candida species. Cros-sresistance to azoles (ie, fluconazole, voriconazole, posaconazole) may occur among Candida species, particularly C. glabrata 423, 424. Therefore, clinicians should be alert for the possibility of breakthrough infection with resistant organisms in patients receiving prophylaxis with any azole drug (CIII). Micafungin is an alternative prophylactic agent, as 1 study has shown it to be comparable to fluconazole for preventing possible or documented fungal infection (BI) [425]. Use of micafungin as a prophylactic agent is limited by the necessity of i.v. infusion and cost. There have been case reports of sporadic resistance to echinocandin antifungal agents [426]. Itraconazole oral solution has been shown to prevent invasive fungal infections, but use of this drug is limited by poor tolerability and toxicities (CI) 427, 428. If antimold activity is warranted in antifungal prophylaxis, posaconazole and voriconazole are options 429, 430. Posaconazole has not been studied in the preengraftment phase of HCT. Few HCT recipients require prophylaxis against Candida in the postengraftment period (phases II and III), but if needed (eg, because of the presence of GVHD), options include voriconazole (BI) [430] and posaconazole (BI) [429]. Oral, nonabsorbable antifungal drugs, including oral amphotericin B (500 mg suspension every 6 hours), nystatin, and clotrimazole troches, might reduce superficial colonization and control local mucosal candidiasis, but have not been demonstrated to reduce invasive candidiasis (CIII). Other recommendations HCT candidates with candidemia or invasive candidiasis can safely receive transplants [431] if (1) their infection was diagnosed early and treated immediately and aggressively with effective anti-Candida therapy; and (2) there is evidence of infection control before the transplant (BIII). Such patients should continue receiving therapeutic doses of an appropriate antifungal drug throughout phase I (BII) and until a careful review of clinical, laboratory, and serial computed tomography scans verifies resolution of candidiasis (BII). As radiographic abnormalities may persist for a long period of time among patients with hepatosplenic candidiasis, complete resolution is not necessary before transplantation, provided that the patient has received appropriate therapy and shows clinical improvement. Because autologous recipients generally have an overall lower risk for invasive fungal infection than allogeneic recipients, most autologous recipients do not require routine antiyeast prophylaxis (CIII). However, experts recommend administering antiyeast prophylaxis to a subpopulation of autologous recipients who have underlying hematologic malignancies (eg, lymphoma, leukemia, or myeloma) and who have or will have prolonged neutropenia and mucosal damage from intense conditioning regimens or graft manipulation, or have received fludarabine (Flu) or 2-CDA within the 6 months prior to HCT (BIII). Recommendations regarding the prevention of invasive yeast infections are the same among pediatric and adult HCT recipients, except that appropriate dose adjustments for prophylactic drugs should be made for pediatric recipients (Appendix 1). When considering continuation of antifungal therapy in patients with prior infection, HCT clinicians should be mindful of drug interactions, especially with calcineurin inhibitors, particularly with drugs in the azole class, which affect cytochrome P450 metabolism [432]. Results of recent studies suggest differential toxicities and effects on cyclophosphamide (Cy) metabolites with coadministration of different azole drugs 432, 433. Specifically, coadministration of fluconazole was associated with fewer early toxicities and different metabolites compared with itraconazole [433]. This was hypothesized to be because of fluconazole inhibition of cytochrome P450 2C9 providing a “protective” effect compared to itraconazole, which inhibits only P450 3A4 [432]. In general, clinicians should be careful about coadministering drugs that have an impact on any cytochrome subunits active in conditioning metabolism. Recommendations Regarding Mold Infections Preventing exposure Nosocomial mold infections among HCT recipients result primarily from respiratory exposure to and direct contact with fungal spores [434]. Measures for minimizing exposure to mold in HCT candidates and recipients are discussed in the Infection Prevention and Control in Health care Facilities section. In addition to air, water may also be a source of pathogenic fungi. Opportunistic molds (eg, Aspergillus and Fusarium species) are present in the water and on water-related surfaces of hospitals caring for cancer patients, and molecular studies have suggested potential relatedness of environmental and clinical strains among patients with aspergillosis and fusariosis 435, 436, 437. Therefore, hospital water should be considered a potential source of nosocomial invasive mold infections. Although some investigators believe it is necessary to decrease patient exposure during periods of severe immunosuppression [438], current data are insufficient to support the formulation of definitive recommendations. Cleaning of water-related structures in patients' bathrooms may be attempted 435, 436. Preventing disease Invasive mold infections have a trimodal incidence distribution among allogeneic HCT recipients 439, 440, 441. Before engraftment (ie, during phase I), the main risk factor is prolonged neutropenia, and therefore, the risk is higher with bone marrow (BM) and umbilical cord blood (UCB) transplants and lower with peripheral blood (PB) and nonmyeloablative (NMA) transplants. In addition, the risk is higher among patients with prolonged low-level neutropenia prior to transplant, such as aplastic anemia (AA) patients. In phases II and III, the main risk factor is severe cell-mediated immunodeficiency caused by GVHD and its treatment. Therefore, recipients of transplants with higher risks for severe GVHD (unrelated donor, mismatched transplant, haploidentical) are at greater risk of mold infections. Patients at high risk for mold infections should be considered for prophylaxis with mold-active drugs during periods of risk (BI). Trials assessing the efficacy of cyclodextrin oral solution and intravenous formulations of itraconazole have shown efficacy in preventing mold infections (BI), but the benefit was offset by poor tolerance and toxicity of the oral formulation, with ∼25% discontinuation for GI side effects 427, 433.One study has shown micafungin to be effective in preventing invasive fungal infections (including fever) when administered during neutropenia [425], but the incidence of invasive aspergillosis is low during the preengraftment phase, so antimold efficacy could only show a display of activity rather than efficacy (BI). Experience with other echinocandins (eg, caspofungin) demonstrates some efficacy (CII), but breakthrough mold infections during echinocandin prophylaxis have been reported [442]. Fluconazole has no activity against molds [443]. Based on the results of a study presented to date only in abstract form [430], voriconazole appears to be an alternative to fluconazole prophylaxis. Because the results of this study have not been presented in detail, the committee is not assigning a recommendation. Specific molds are resistant to certain drugs (eg, voriconazole does not have activity against Zygomycetes, and Scedosporium prolificans is resistant to all available antifungal agents). In patients with GVHD, posaconazole has been reported to prevent invasive mold infections (BI) [429]. In 1 study, patients with GVHD were randomized to receive either fluconazole (400 mg) or posaconazole (200 mg 3 times daily). Results showed a trend toward a lower incidence of invasive fungal infection, with particular differences in mold infections. The optimal duration of prophylaxis in the setting of GVHD is not defined. Aerosolized liposomal amphotericin B has been found to be effective in reducing invasive pulmonary aspergillosis in 1 randomized trial that included leukemia and HCT patients and can be considered as an alternative to mold-active azoles (BII) [444]. However, administration of the drug was interrupted by cough in many patients, and the optimal aerosol dose and delivery device have not yet been determined. Thus, further study is needed before its role can be determined. Other recommendations Patients with prior invasive aspergillosis should receive secondary prophylaxis with a mold-active drug (AII). The optimal drug has not been determined, but voriconazole has been shown to have benefit for this indication (AII) [445]. Recommendations Regarding Serum Level Monitoring Absorption of itraconazole and posaconazole is poor in patients who are not eating. Meta-analyses suggest that the efficacy of itraconazole is associated with bioavailability; blood levels of >0.5 μg/mL are associated with effective prevention of proven invasive fungal infection [446]. Posaconazole levels for therapeutic effectiveness have not been established. Median levels of posaconazole are relatively lower in patients who have aGVHD and symptomatic diarrhea [447]. Voriconazole blood levels of at least 1 μg/mL are thought to be required for efficacy. Low voriconazole levels have been reported in patients with documented breakthrough infections [415]. There is relative controversy over the utility of routine monitoring of azole drug levels, but most clinicians agree that measurement of levels should be considered in patients who have documented breakthrough infection. A change to, or addition of, an antifungal agent of a different class is advisable until the blood level has been determined. If the level is found to be low, then consideration can be given to resuming the earlier drug at a higher dose (CIII) 415, 448. Regionally Limited or Rare Infections—Prevention after HCT J. Gea-Banacloche, H. Masur, C. Arns da Cuhna, T. Chiller, L. Kirchoff, P. Shaw, M. Tomblyn, C. Cordonnier This section covers infections that are prevalent only in certain geographic areas, or that occur uncommonly among hematopoietic cell transplantation (HCT) recipients. Diseases covered are tuberculosis, Pneumocystis jiroveci Pneumonia (PCP), toxoplasmosis, strongyloidiasis, Chagas disease, leishmaniasis, malaria, and Nocardia infection. Other infections, such as babesiosis, can be transmitted in the course of transplant via blood products, in addition to the hematopoietic cell graft [449]. Guidelines for prevention of these graft-transmissible infections are found in the Hematopoietic Cell Safety Section. Recommendations Regarding Mycobacterium tuberculosis Tuberculosis (TB) is uncommon among HCT recipients. The main risk factor is undergoing transplant in a country with a high endemic rate of TB 450, 451. In countries where TB is uncommon, TB is more prevalent among patients who have come for HCT from countries or were born in countries with a higher rate of endemic TB 452, 453. Patients with household members at risk (eg, recent immigrants, correctional facility discharges) also deserve particular attention. It must always be remembered that there is no definitive test to exclude TB and a high level of clinical awareness must be maintained in all immunosuppressed patients. The rate of TB reported after HCT is 10 times less than after solid organ transplantation [454], as HCT patients do not receive life-long immunosuppression. However, patients with prolonged immunosuppression, such as those with chronic graft-versus-host disease (cGVHD), remain at risk for TB. Because control of TB is T cell mediated, restoration of T cell function over time and with cessation of immunosuppression reduces the patient's risk of TB. Most patients who develop TB after HCT have not had clearly identified risk factors 455, 456. Most had normal pretransplant chest radiographs and no direct history of contact with TB. Most had been transplanted for leukemia, had received total body irradiation (TBI)-based conditioning, and were allograft recipients. Most were receiving treatment for GVHD and were >100 days posttransplant. Although most cases of TB have occurred in allogeneic HCT recipients, 20% have occurred in autologous recipients. Despite this low rate 454, 457, diagnostic vigilance must be maintained. For example, mycobacterial infection may occur more frequently in patients who have undergone autologous HCT for chronic lymphocytic leukemia (CLL), in whom prior therapy with fludarabine (Flu) and alemtuzumab induces profound T cell deficiency, and susceptibility to a variety of opportunistic infections [458]. Preventing exposure HCT candidates and recipients should avoid exposure to persons or environments where there is a substantial risk of respiratory contact with individuals with active TB. It is prudent to advise HCT candidates and recipients that certain occupations (eg, volunteer work or employment in health care facilities, correctional institutions, or shelters for the homeless) can increase their risk for TB exposure (BIII) [459]. Preventing disease Evaluation of patients before HCT Experts recommend evaluation for latent or active TB in patients who are candidates for HCT (BII). Assessment should include a history of: • Prior active TB • Prior exposure—evaluate as high-priority contacts as per CDC guidelines [460]. • Results of previous tuberculin skin tests (TSTs) or interferon-gamma release assays (IGRA). Experts disagree about the convenience or benefit of routinely obtaining a TST or IGRA in every transplant candidate. Interpretation of the TST may also be complicated by a history of prior Bacillus Calmette-Guérin (BCG) vaccination, although tuberculin reactivity following BCG tends to wane over time [461]. The American Thoracic Society (ATS) states that a positive TST may be considered diagnostic of latent M. tuberculosis infection in BCG recipients who are at risk for recent M. tuberculosis infection or who have a medical condition that increases the risk for progression to active TB (CIII) [462]. Because of prior chemotherapy-induced immunosuppression, the TST is not as sensitive in HCT candidates as it is in the healthy population. IGRAs are specific for TB, but a negative test does not exclude latent TB infection, particularly in the immunocompromised patient. In a meta-analysis, IGRAs were found to be more sensitive than TST in immunocompromised patients suspected of having TB [463]. This was particularly the case among patients with autoimmune disease and receiving antitumor necrosis factor therapy (eg, infliximab), who are at particular risk of TB [464]. Studies specifically in HCT patients are awaited. However, Canada and the United States have made recommendations for use of IGRAs in immunocompromised patients 465, 466. Any patient with a recently positive TST or IGRA or a history of a positive test and no prior preventive therapy, should be evaluated for active TB. At a minimum, the patient should be asked about symptoms of systemic disease and respiratory symptoms such as cough and shortness of breath, and a chest radiograph should be assessed (AII) [462]. If active TB is detected, therapy and appropriate isolation should be initiated. HCT should be delayed until the active infection is deemed controlled based on clinical judgment, because no objective definition of adequate control has been formulated. If the TST or IGRA is positive, but no active TB identified, treatment for latent TB infection (Appendix 1) should be initiated but the HCT need not be delayed. Indications for treatment of latent TB infection or prophylaxis Because of high risk of reactivation or new infection, prophylaxis should be administered to immunocompromised HCT recipients or candidates who: • Have been exposed to someone with active, infectious (ie, sputum-smear positive) pulmonary or laryngeal TB, regardless of the HCT recipient's or candidate's TST or IGRA status (BIII) • Have a positive TST result—regardless of prior BCG vaccination—without previous treatment and no evidence of active TB disease (BII). A positive TST with a history of BCG vaccination is still considered by the ATS as an indication for prophylaxis in patients who “have medical conditions that increase the risk for disease” [462], which presumably include HCT (CIII) • Have a positive IGRA result, without previous treatment and no evidence of active TB (BII). A report of high frequency of reactivation of previously treated TB following transplantation, especially in some parts of the world where the endemic prevalence of TB is high, suggests such patients may be at high risk, and therefore, isoniazid (INH) prophylaxis should be considered (CIII) [467]. The value of prophylaxis in countries with a high rate of TB, or in HCT patients from such countries, should be considered at an institutional level. Because of the high prevalence of multidrug-resistant TB in some of these countries, single-agent prophylaxis may be ineffective. Consequently, maintaining a very high index of suspicion and providing early intervention may be preferable to universal prophylaxis. An HCT candidate or recipient who has been exposed to an active case of extrapulmonary, and therefore noninfectious, TB does not require preventive therapy (DIII). Prophylactic regimens INH is well tolerated post-HCT even with concurrent fluconazole use 450, 467, 468. Concurrent use with itraconazole is not recommended, and the impact of voriconazole or posaconazole is not known. INH with pyridoxine should be continued for at least 9 months and until immunosuppression dosages are substantially reduced (ie, prednisolone 1 mg/kg [309]. RSV viral shedding has been reported to last 112 days in a child with severe combined immunodeficiency [676]. HCT recipients with CRV infection should be placed on the appropriate precautions for at least the duration of illness (AII) and precautions should be continued for the duration of hospitalization or viral shedding to prevent transmission within the unit (CIII). Some HCT centers conduct routine CRV surveillance among asymptomatic HCT recipients to detect outbreaks and implement infection control measures as early as possible [677]. To date, however, data are insufficient to provide recommendations regarding routine surveillance testing of asymptomatic patients for CRV infections. During periods of widespread RSV or influenza activity in the surrounding community or suspected health care-associated CRV outbreaks, all HCT recipients and candidates with signs or symptoms of respiratory infection should be tested for RSV and influenza infection (ie, the presence of RSV and/or influenza antigen in respiratory secretions tested by enzyme-linked immunosorbent assay and viral culture). During an outbreak of health care-associated RSV infection, managers should cohort health care personnel as much as is practical (ie, restrict personnel who care for RSV-infected patients from giving care to uninfected patients) (CIII) 297, 298, 678. No recommendation can be made for cohorting of personnel during an outbreak of other health care-associated CRV infections. HCWs and close contacts of HCT recipients should receive yearly influenza vaccine at the start of the influenza season, preferably with trivalent inactivated influenza vaccine rather than live attenuated influenza vaccine to avoid concerns about transmission of vaccine virus (Table 7) (AI). Use of influenza vaccine along with prophylaxis and early antiviral therapy among at-risk healthcare workers and high-risk patients reduces the spread of influenza within healthcare facilities [534]. During an outbreak of health care-associated influenza infection, in addition to use of droplet precautions for patients with suspected or confirmed influenza and rapid influenza virus testing for symptomatic patients, HCT centers should consider rapid influenza virus testing of symptomatic HCT staff; administration of inactivated influenza vaccine to unvaccinated HCT staff and appropriate patients (see HCT Recipient Vaccinations section); and administration of influenza antiviral chemoprophylaxis to HCT staff and patients according to current recommendations (BIII) [603]. Healthcare personnel with influenza should be excluded from work for 5 days following the onset of symptoms (AIII) 303, 679. Preventing CRV exposure among HCT recipients after hospital discharge is more challenging because of high CRV prevalence. Preventive measures should be individualized in accordance with the immunologic status and tolerance of the patient. In outpatient waiting rooms, patients with CRV infections should be separated to the extent possible from other patients and should be instructed to use respiratory hygiene/cough etiquette (BIII). Recommendations Regarding Adenovirus Adenovirus can cause large outbreaks in hospital settings and chronic care facilities. Outbreaks of diarrheal illness because of adenovirus have been previously described among adult HCT recipients [680]. Transmission can occur via inhalation of aerosolized droplets; direct and indirect contact through contaminated surfaces; fecal-oral spread; exposure to infected tissue or blood; and rarely, contaminated water [330]. Sputum or oral secretions of infected adults contain 106 to 107 particles/mL. Nonimmune adults can be infected by inhaling as few as 5 viral particles [681]. Prolonged fecal shedding has been demonstrated in HIV-infected patients with and without diarrhea. Immunocompromised hosts are known to have asymptomatic shedding of adenovirus from the GI and respiratory tracts for months after initial infection. Furthermore, immunosuppressed individuals may either reactivate endogenous infection or acquire new infection. Adenovirus survives on nonporous surfaces up to 35 days 682, 683, 684. Recommendations for isolation precautions in the hospital setting depend on the type of syndrome caused by adenovirus. HCT recipients with adenoviral gastroenteritis should be placed on contact precautions for at least the duration of illness (AIII), and precautions should be continued for the duration of hospitalization or viral shedding (CIII) to prevent transmission within the unit. For cases of respiratory illness or disseminated infection associated with adenovirus, droplet and contact precautions should be maintained for at least the duration of illness (AIII) [144]. For cases of adenoviral conjunctivitis in immunosuppressed patients, contact precautions (AIII) and droplet precautions (CIII) should be instituted for at least the duration of illness (usually 5-7 days) (CIII) [144]. Hand hygiene with either an alcohol-based hand rub or soap and water has been shown to be effective against adenovirus (BIII) [685]. Environmental disinfection of surfaces with hospital-approved disinfectants (eg, chlorine-based products, ethyl alcohol, ethanol mixed with quaternary ammonium compounds) is important to limit the spread of adenoviral infection [686]. Recommendations Regarding Viral Gastroenteritis Viral gastroenteritis is most commonly spread by the fecal-oral route. Common pathogens include rotavirus, norovirus, astrovirus, and adenovirus (see the Adenovirus section for adenovirus-specific recommendations). To prevent the acquisition and spread of viral gastroenteritis among HCT recipients, HCT centers should ensure adherence to hand hygiene, appropriate isolation precautions, and environmental disinfection (AII) [531]. Appropriate precautions should be maintained for at least the duration of illness (AII). Because HCT recipients may continue to shed virus after symptoms resolve, HCT centers may choose to continue precautions for the duration of hospitalization, or the duration of viral shedding if diagnostic laboratory testing is available (CIII). Rotavirus Rotavirus is the most common cause of severe gastroenteritis in infants and young children worldwide. Virus is shed in high concentrations in the stool of infected children and is transmitted primarily by the fecal-oral route, through person-to-person contact and fomites [687]. Environmental contamination is common because rotavirus can survive on nonporous surfaces for more than 10 days 688, 689. Health care-associated transmission because of rotavirus infection has been linked to toys [594] and contaminated hands [690]. Contact precautions should be implemented for HCT recipients with suspected or confirmed rotavirus gastroenteritis to prevent transmission in the health care setting (AIII). Alcohol-based hand gel has some virucidal activity against rotavirus and is sufficient for routine hand hygiene unless hands are visibly soiled [685]. Because prolonged shedding can occur in immunocompromised patients, HCT staff should ensure consistent environmental cleaning and disinfection and removal of soiled diapers (AIII) [144]. If soiled diapers need to be weighed outside of the patient room, it is important to ensure environmental disinfection of items in contact with soiled diapers (eg, cover the scale with paper, appropriately discard soiled diapers and paper, and disinfect the scale after each use) (BIII). Norovirus Noroviruses are the most common cause of outbreaks of nonbacterial gastroenteritis. Fecal-oral transmission is most common, although environmental and fomite contaminations are also important sources of infection. Aerosolization of vomitus resulting in droplets that contaminate surfaces or are swallowed also contribute to transmission. Infected individuals are contagious up to 72 hours after recovery. The low infectious dose ( 200, none shed LAIV virus longer than 10 days. Furthermore, clinical trial data suggest that when vaccine virus is shed by vaccine recipients, none have reverted to wild type 742, 743. Because an alternative trivalent inactivated influenza vaccine (TIV) exists, household members of HCT recipients should receive TIV to avoid potential concerns for transmission of vaccine virus (AI). Health care center personnel and HCT center visitors who receive LAIV instead of TIV should avoid contact with severely immunosuppressed persons for 7 days after vaccination (CIII) [307]. • Zoster vaccine: herpes zoster vaccine is currently recommended for adults 60 years of age and older in the United States [744]. There is no evidence to date that transmission of vaccine-associated virus has occurred. However, HCT centers should exclude visitors who develop a varicella- or zoster-like rash after vaccination (AIII). If a household member develops a varicella or zoster-like rash after vaccination, close contact with the HCT recipient should be avoided and affected areas should be covered (AIII). • Varicella vaccine (AIII): In 1 small study of 37 healthy children receiving vaccine and their 30 immunocompromised siblings, there was no evidence of vaccine virus transmission [745]. In the postlicensure era, transmission from immunocompetent persons after vaccination has been documented by PCR from only 5 persons resulting in 6 secondary infections, with over 55 million doses estimated to have been given [282]. Because the risk of vaccine virus transmission is low, particularly in the absence of a vaccine-associated rash, household members should receive varicella vaccine to protect HCT recipients from potential exposure to wild-type disease (AIII). Individuals who experience a vaccine-associated rash within 1 month after varicella vaccination should be excluded from visiting the HCT center and should avoid close contact with HCT recipients in the home setting (BIII). Measures such as removal of the vaccinee or transplant recipient from the domicile have not been studied. • Measles, mumps, rubella (MMR) vaccine (AIII): Household members should receive age-appropriate MMR vaccination as recommended. However, vaccine recipients who develop a fever and/or rash postvaccination should be excluded from visiting the HCT center while symptomatic and should avoid close contact with HCT recipients in the home setting (BIII). Safe Sex Sexually active patients who are not in long-term monogamous relationships should always use latex condoms during sexual contact to reduce their risk for exposure to cytomegalovirus (CMV), herpes simplex virus (HSV), HIV, human papilloma virus (HPV), hepatitis b virus (HBV), hepatitis c virus (HCV), and other sexually transmitted infections (STIs) (AII). However, even long-time monogamous partners can be discordant for these infections. Reinfection with some STIs has been reported in seropositive recipients with long-term partners years after transplant [370]. Therefore, sexually active HCT recipients in long-term monogamous relationships should consider using latex condoms during sexual contact to reduce the risk for exposure to these STIs (CIII). Additionally, contact with oral or genital secretions has been associated with acquisition of many STIs, including those from HSV, CMV, Epstein-Barr virus (EBV), HHV-8, and HPV. Severely immunosuppressed HCT recipients should consider completely avoiding unprotected sexual activity (ie, activities that involve contact of the HCT recipient's mucous membranes with saliva, semen, or vaginal secretions) for as long as they remain severely immunodeficient (CIII). Sexually active HCT recipients should avoid sexual practices that could result in oral exposure to feces (AIII) 2, 746. Animal Safety Preventing pet-transmitted zoonotic infections HCT physicians should advise recipients and candidates undergoing conditioning therapy of the potential infection risks posed by pet ownership; however, they should not routinely advise HCT recipients to part with their pets, with limited exceptions. Immunocompromised HCT recipients and candidates should avoid adopting ill or juvenile pets (eg, cats 1 days of incubation to become infectious. If HCT recipients perform this task during the first 6 months after HCT and during subsequent periods of substantial immunocompromise (eg, during GVHD, systemic steroid use, or relapse of the underlying disease for which the transplant was performed), they should wear disposable gloves [747]. Gloves should be discarded after a single use (BIII). Soiled, dried litter should be disposed of carefully to prevent aerosolizing the T. gondii oocysts (BIII). Cat feces (but not litter) can be flushed down the toilet, although this is not recommended because T. gondii oocysts are not consistently inactivated by sewage systems (DIII). Also, persons who clean cat litter, particularly HCT recipients, should wash their hands thoroughly with soap and water afterward to reduce their risk for acquiring toxoplasmosis (BIII). HCT recipients and candidates with cats should keep their cats inside (BIII) and should not adopt or handle stray cats (DIII). Cats should be fed only canned or dried commercial food or well-cooked table food, not raw or undercooked meats, to eliminate the possibility of causing an illness that could be transmitted from the cat to the HCT recipient (BIII). Pet cats of HCT recipients do not need to be tested for toxoplasmosis (EII). Playground sandboxes should be kept covered when not in use to prevent cats from soiling them (BIII). HCT recipients and candidates undergoing conditioning therapy should avoid drinking raw goat's milk, to decrease the risk for acquiring toxoplasmosis (DIII). Toxoplasmosis may also be acquired after contact with cat feces encountered while gardening. Water and Other Beverage Safety HCT recipients should avoid walking, wading, swimming, or playing in recreational water (eg, ponds or lakes) that is likely to be contaminated with Cryptosporidium, E. coli O157:H7 749, 757, 758, 759, sewage, or animal or human waste (DII). HCT recipients should also avoid swallowing such water (eg, while swimming) 2, 757, 759, as well as any water taken directly from rivers and lakes (EIII) 2, 746. Water and other beverages may pose a risk to immunocompromised HCT candidates and recipients because of bacterial, viral, and parasitic pathogens. HCT recipients should not use well water from private wells or from public wells in communities with limited populations (DIII) because tests for microbial contamination are performed too infrequently (eg, in certain locations, tests are performed ≤1 times/month) to detect sporadic bacterial contamination. However, drinking well water from municipal wells serving highly populated areas is regarded as safe from bacterial contamination because the water is tested ≥2 times/day for bacterial contamination. If HCT recipients consume tap water, they should routinely monitor mass media (eg, radio, television, or newspapers) in their area and immediately implement any boil-water advisories that might be issued for immunocompromised persons by state or local governments (BIII). A boil-water advisory means that all tap water should be boiled for >1 minute before it is consumed [760]. Although municipal tap water is generally safe, it may not be completely free of Cryptosporidium. Although limited data exist regarding the risks for and epidemiology of Cryptosporidium disease among HCT recipients [761], HCT recipients should avoid possible exposures to Cryptosporidium (DIII) because this pathogen has been reported to cause severe, chronic diarrhea, malnutrition, and death among other immunocompromised persons 746, 762, 763. To eliminate the risk for Cryptosporidium exposure from tap water, HCT recipients can boil tap water for ≥1 minute before consuming it (CIII) [746]. Alternatively, they can use certain types of water filters or a home distiller to reduce their risk for exposure to Cryptosporidium [746] and other waterborne pathogens (CIII). If a home water filter is used, it should be capable of removing particles ≥1 μm in diameter, or should filter by reverse osmosis (for a list of filters certified under National Sanitation Foundation [NSF] Standard 053 for cyst (ie, Cryptosporidium) removal, contact the NSF International consumer line or http://www.nsf.org). However, the majority of these filters are not capable of removing smaller microbes (eg, bacteria or viruses), and therefore, should be used only on properly treated municipal water. The majority of these devices are inappropriate for use on water from an unchlorinated private well to control viral or bacterial pathogens. Bottled water can be consumed if it conforms to regional standards (eg, the FDA for the United States and Directive 80/777/EEC for the EU) and has been processed to remove Cryptosporidium by 1 of 3 processes: reverse osmosis, distillation, or 1-μm particulate absolute filtration. HCT recipients should contact the bottler directly to confirm that a specific bottled water has undergone 1 of these processes. The International Bottled Water Association can be contacted in the United States at (703) 683-5213 from 9 a.m. to 5 p.m. EST or anytime at their Internet site (http://www.bottledwater.org) to obtain contact information regarding water bottlers. Patients can take other precautions in the absence of boil-water advisories to further reduce their risk for cryptosporidiosis. These extra precautions include avoiding fountain beverages and ice made from tap water at restaurants, bars, and theaters; fruit drinks made from frozen concentrate mixed with tap water; and iced tea or coffee made with tap water [746]. Drinks that are likely to be Cryptosporidium-safe for HCT recipients include nationally distributed brands of bottled or canned carbonated soft drinks; commercially packaged noncarbonated drinks that contain fruit juice; fruit juices that do not require refrigeration until after opening (eg, those that are stored unrefrigerated on grocery shelves); canned or bottled soda, seltzer, or fruit drinks; steaming hot (>175° F [80 °C]) tea or coffee; juices labeled as pasteurized; and nationally distributed brands of frozen fruit juice concentrate that are reconstituted with water from a safe source 705, 746. HCT recipients should not drink nonpasteurized milk or fruit or vegetable juices (eg, apple cider or orange juice), to avoid infection with Brucella species, E. coli O157:H7, Salmonella species, Cryptosporidium, and other pathogens (DII) 763, 764, 765, 766. Food Safety Recommendations on food safety are based largely on observations in the general population. Concern arising from the detection of potential pathogens in food has not been supported by documented evidence of such organisms as the source of opportunistic infections in immunocompromised persons. The potential benefit of food safety recommendations directed specifically toward HCT recipients must be weighed against the uncertain value of such recommendations [767] and their potential to adversely affect patients` nutritional intake and/or quality of life. HCT candidates and persons who will prepare food for them after HCT should review general food safety practices (AIII) [768] and should be educated regarding additional food safety practices appropriate for HCT recipients. This review and education should be done before the conditioning regimen (ie, chemotherapy and radiation) begins (BIII). Adherence to these guidelines will decrease the risk for food-borne disease among HCT recipients. Food safety practices appropriate for all persons Raw poultry, meats, fish, and seafood should be handled on separate surfaces (eg, cutting board or counter top) from other food items. Persons preparing food should always use separate cutting boards or wash the board(s) with warm water and soap between cutting different food items (AIII). To prevent foodborne illnesses caused by Campylobacter jejuni and Salmonella enteritidis, which can cause severe and invasive infections among immunocompromised persons [769], uncooked meats should not come in contact with other foods (DIII). After preparing raw poultry, meats, fish, and seafood and before preparing other foods, food handlers should wash their hands thoroughly in warm, soapy water. Any cutting boards, counters, knives, and other utensils used should also be washed thoroughly in warm, soapy water (AIII). Food preparers should keep shelves, countertops, refrigerators, freezers, utensils, sponges, towels, and other kitchen items clean (AIII). All fresh produce should be washed thoroughly under running water before serving (AIII) [768]. Persons preparing food should follow published recommendations regarding safe food thawing (BIII) [770]. Persons cooking food for HCT recipients should follow established guidelines for monitoring internal cooking temperatures for meats, which is the only method for determining if meat has been adequately cooked (AII). Different kinds of meat should be cooked to varying internal temperatures, all >150°F (66 °C) (AII). Specifically, food oversight agencies such as the U.S. Department of Agriculture recommend that poultry be cooked to an internal temperature of 180°F (82 °C). Other meats and egg-containing casseroles and soufflés should be cooked to an internal temperature of >160°F (71 °C). Cold foods should be stored at 140°F (60 °C) (BIII). Food preparers should wash their hands before and after handling leftovers (AIII); use clean utensils and food-preparation surfaces (AIII); divide leftovers into small units and store in shallow containers for quick cooling (AII); refrigerate leftovers within 2 hours of cooking (AII) or discard leftovers that were kept at room temperature for >2 hours (AIII); reheat leftovers or heat partially cooked foods to >165°F (74 °C) throughout before serving (AII); bring leftover soups, sauces, and gravies to a rolling boil before serving (AIII); and follow published guidelines for cold storage of food (AII). Leftover foods placed in the refrigerator should be dated and discarded after 72 hours. Additional food safety practices appropriate for HCT recipients HCT recipients' diets should be restricted prior to engraftment to decrease the risk for exposure to food-borne infections from bacteria, yeasts, molds, viruses, and parasites. A low-microbial diet is recommended for HCT recipients prior to engraftment 771, 772, although evidence for its efficacy to prevent infection is lacking (CIII) [773]. Once HCT recipients have engrafted, they should follow a diet that balances the risk for acquiring food-borne illnesses with the importance of proper nutritional supplementation, as recommended below and outlined in Table 5. This diet should be continued for 3 months after autologous HCT, and allogeneic HCT recipients should remain on this diet until all immunosuppressive drugs are discontinued and the patient has reached the milestone of receiving live virus vaccines. However, the HCT physician should have final responsibility for determining when the diet can be discontinued safely. HCT recipients should not eat raw or undercooked meat, including beef, poultry, pork, lamb, venison or other wild game, or combination dishes containing raw or undercooked meats or sweetbreads from these animals (eg, sausages or casseroles) (EII). HCT recipients and candidates should only consume meat that is well done when they or their caretakers do not have direct control over food preparation (eg, when eating in a restaurant) (AI). Hot dogs and deli-style ready-to-eat meats should be avoided unless heated until steaming (AII). HCT recipients should not consume raw or undercooked eggs or foods that might contain them (eg, certain preparations of hollandaise sauce, Caesar and other salad dressings, homemade mayonnaise, and homemade eggnog) because of the risk for infection with Salmonella enteritidis (EII) [774]. HCT recipients should not consume raw or undercooked seafood (eg, oysters or clams), to prevent exposure to Vibrio species, viral gastroenteritis, and Cryptosporidium parvum (EII) [769]. Fruits and vegetables provide essential nutritional elements to HCT patients, but certain precautions should be taken to prevent acquisition of infection. In general, it may be helpful to remind patients of the adage “If you can't peel or wash it, don't eat it.” Most infections from agricultural products are acquired either through contamination of the item while in the field or subsequent to harvesting during processing. Washing of fruits and vegetables in tap water is advisable even for those with skin or rinds, organic foods, and prepackaged items labeled as “prewashed” (BIII). Such washing may prevent many contamination-related infections, but not all. HCT recipients should avoid fruits and vegetables that may confer higher risk of infection, including raw vegetable sprouts (E. coli and Salmonella), fresh salsa, and berries (EII). Other food items that have been associated with food-borne outbreaks in the past and, therefore, which HCT patients should avoid, include unroasted raw nuts or nuts in the shell, miso products, raw grain products, nonpasteurized milk products (milk, cheese, yogurt), cheeses containing uncooked vegetables, cheeses with molds (ie, blue, Stilton, Roquefort, and gorgonzola), soft cheeses (eg, brie and feta), smoked or pickled seafood, raw honey, and tempe products (EII). To date, no evidence exists that there is a greater risk for acquiring infection from eating at a fast food restaurant than at a conventional sit-down restaurant. Several steps can be taken to ensure the safety of food consumed at such establishments (AIII): (1) ask that food be freshly prepared (ie, avoid food that has been sitting under heat lamps); (2) ask if fruit juices are pasteurized; (3) avoid any raw fruits and vegetables when dining out; (4) ask for single-serving condiment packages (avoid use of public self-serve condiment containers); (5) avoid salad bars, delicatessens, buffets, smorgasbords, etc.; (6) set utensils on a napkin or clean tablecloth or placemat (rather than directly on the table); and (7) if planning to take the leftovers home, transfer the food directly to a box at the table. Similarly, although consumption of prepared food purchased from street vendors in industrialized countries has not been associated with infection, food preparation under stringent sanitary conditions cannot be guaranteed and therefore such food should be avoided (DIII); the same is true of food brought by others to gatherings such as potlucks or picnics. The consumption of foods with “active” or “live” yeast cultures (“probiotics”) has been promoted as an effective means of preventing infections. Studies to date have not been definitive, but there is some support in the literature for the possibility that consumption of probiotics reduces antibiotic-associated diarrhea [775] or genitourinary infections [776]. The use of probiotics has not been examined in the setting of HCT. Disseminated infection from probiotic administration has been reported in HCT patients, however [777], and HCT recipients should avoid the use of probiotics (DIII). HCT candidates undergoing conditioning therapy and HCT recipients with neutropenia (ie, ANC 200/μL by 6 to 9 months after transplant, whereas adults, particularly those with cGVHD, may require >2 years. Most of the circulating T cells in the first year after transplantation, particularly in adults, are memory/effector T cells, likely derived from the T cells infused with the graft and capable of responding to antigens encountered by the donor prior to the transplant. Naïve T cells capable of responding to new antigens start to be generated only at 6 to 12 months posttransplant, earlier in young children and later in older adults. Because HCT recipients have varying immune system recovery after HCT, it has been proposed that different vaccination schedules be recommended for recipients of different types of HCT, with the rationale that, for example, autologous HCT patients do not lose immunity as frequently or rapidly as patients after allogeneic HCT. The existing evidence suggests, however, that loss of immunity is also common after autologous HCT (particularly in patients who have received multiple courses of chemotherapy before HCT), and that responses to vaccination are similar to those that occur after allogeneic HCT 194, 790, 791, 802, 803, 804, 805. It should also be recognized that limited information regarding vaccine immunogenicity exists for patients transplanted with umbilical cord blood (UCB) or haploidentical grafts, or after reduced-intensity conditioning (RIC). For the sake of simplicity, therefore, the committee has chosen to recommend the same vaccination schedule for all HCT recipients until additional data are published. T cell response to vaccines for pathogens encountered pretransplant (eg, varicella zoster virus [VZV]) can be observed as soon as 1 to 6 months posttransplant. Antibody response to vaccines for pathogens encountered pretransplant (eg, tetanus toxoid) can be observed at 6 to 12 months after HCT. T cell or antibody response to vaccines for pathogens not encountered pretransplant (eg, hepatitis B virus [HBV] in most European and American adults) can usually be observed later (1 year or more posttransplant). HCT recipients are similar to young children in that they respond poorly to pure polysaccharide antigens such as those included in the 23-valent polysaccharide pneumococcal vaccine. Pure polysaccharide antigens elicit antibody responses later after HCT than protein antigens (eg, diphtheria toxoid) or polysaccharide-protein conjugates (eg, Hib capsular polysaccharide conjugated to a carrier protein). Graft-versus-host disease (GVHD) and/or its treatment hamper T cell and antibody responses to vaccines. Because studies have shown that patients with chronic GVHD (cGVHD) can mount responses to vaccines and clearly need protection against pneumococci, these guidelines do not recommend postponing vaccination in patients with GVHD with the exception of withholding live vaccines. However, when vaccinating patients with active GVHD, it may be prudent to measure specific antibody levels before and after vaccination, to determine their level of protection and need for booster immunizations. The committee has split the recommendations into different categories. In Table 6, the vaccines are listed for which evidence exists regarding safety and immunogenicity and that are generally recommended to be used in HCT recipients. Since the previous version of the vaccination guidelines was published, new vaccines have been introduced. In addition, clinicians at HCT centers get questions from patients, family members, and HCWs regarding vaccinations in special situations, such as after disease exposure or before travel to areas endemic for infections not previously considered in these recommendations. Therefore, comments are made regarding these vaccines and situations (Table 7), although very limited or no data exist. Finally, there are situations when vaccination of family members, household contacts, and HCWs is recommended to minimize exposure of vaccine-preventable diseases among HCT recipients (Table 8 ). Table 8 Vaccinations for Family, Close Contacts, and Healthcare Workers (HCWs) of HCT Recipients Vaccine Recommendations for Use Rating Hepatitis A [829] Routine vaccination is recommended for: • Children ≥12 months of age; and • Other persons at increased risk for hepatitis A or its adverse consequences BIII Inactivated Influenza∗, † 307, 308 NOTE: Use of intranasal influenza vaccine is contraindicated (EIII) Family and close contacts Vaccination with trivalent inactivated vaccine (TIV) is strongly recommended annually for all during each influenza season, beginning in the season before the transplant and continuing as long as there is contact with an immunocompromised HCT recipient HCWs Annual vaccination with TIV is strongly recommended during each influenza season. AII AI Polio‡ Not routinely recommended for adults but inactivated§ polio vaccine should be administered when polio vaccination is indicated AII Rotavirus Vaccination not contraindicated in contacts of HCT transplant patients. Follow recommendations for general population in each country CIII Measles-mumps-rubella (MMR) (live) Vaccination is recommended for all persons who are ≥ 12 months old and are not pregnant or immunocompromised. No evidence exists that live-attenuated vaccine-strain viruses in MMR vaccine are transmitted from person to person AIII Pertussis Vaccination with DTaP is recommended for children  4 weeks before the conditioning regimen begins or >6 weeks (42 days) before contact with the HCT recipient is planned (BIII). If a varicella vaccinee develops a postvaccination rash within 42 days of vaccination, the vaccinee should avoid contact with HCT recipients until all rash lesions are crusted or the rash has resolved 282, 304 ⊥ Children 12 months to 12 years should receive two doses 3 months apart; adolescents ≥13 years and adults should receive 2 doses 4 weeks apart. Donor vaccination Vaccination of the donor has been shown to improve the posttransplant immunity of the patient in the case of tetanus toxoid, 7-valent PCV, and Hib-conjugate vaccines. No recommendations are made regarding donor vaccination, because of practical and ethical difficulties surrounding this issue. Serological testing HCT patients are immunosuppressed to varying degrees, and it is therefore prudent to test immunity to some infections before or after vaccination. Testing before vaccination Testing for antibodies to measles is recommended in adults, with vaccination performed only if the patient is seronegative (CIII) (Table 6). If vaccination against varicella is contemplated, testing of immunity should be performed and vaccination given to seronegative patients only (CIII) (Table 6). Testing after vaccination Testing after vaccination can be indicated either to assess the response to vaccination and the need for additional doses or to check durability of response during long-term follow-up. Testing to assess the response to vaccination against pneumococcal disease is recommended at 1 month or later after the third or fourth dose of pneumococcal vaccine (BIII) (Table 6). There are different methods for assessment of pneumococcal antibody levels, each having advantages and disadvantages; thus, no specific method can be recommended. Likewise, as a widely accepted definition of adequate response to pneumococcal vaccine is lacking, guidelines for revaccination of nonresponders are not given. Testing to assess the response to HBV vaccination is also recommended. Testing should be done 1 month or later after the third vaccine dose (BIII). A second 3-dose vaccination schedule is recommended in nonresponders (CIII). The interval between the first and second series has to be determined individually because nonresponsiveness to HBV vaccine can have different causes (eg, cGVHD, in which case it may be prudent to revaccinate only after GVHD has abated). Regular testing of long-term HCT survivors for maintenance of antibody levels is recommended (BIII). Testing should be conducted approximately every 4 to 5 years to assess for immunity to HBV, measles, tetanus, diphtheria, and polio (BIII). Testing for immunity to pneumococcus might reasonably be repeated every 2 years for the first 4 years (BIII). The need for revaccination has to be assessed on an individual basis. Comments Regarding Specific Vaccines Pneumococcal vaccine There are 2 types of pneumococcal vaccine: a conjugate vaccine (PCV) and a polysaccharide vaccine (PPSV23). As with most conjugate vaccines compared with polysaccharide vaccines, PCV is more immunogenic than PPSV23. However, the spectrum of protection is narrower, as PCV7 covers only 7 strains of pneumococci whereas PPSV23 covers 23 strains. When given during the first year after transplantation, PPSV23 elicits inadequate responses. Four prospective trials demonstrate better responses with PCV in HCT recipients 195, 797, 806, 807; thus, PCV is the preferred vaccine. It is likely beneficial to use PPSV23 for the fourth dose (after 3 doses of PCV) (BII), to broaden the immune response [808]. A fourth dose of PCV might increase the response rate in patients with cGVHD, who are less likely to respond to PPSV23 (CIII). If a microbiologically documented pneumococcal infection occurs after pneumococcal vaccination, documenting the serotype of the strain is recommended (BIII), to know whether the serotype is among those included in the vaccine, which can be indicative of a nonresponse to the vaccine(s). Such patients should receive additional doses of pneumococcal vaccine, with the choice of vaccine (ie, PCV or PPSV23) depending on the documented strain (BIII). The time posttransplant to initiate routine vaccination with PCV is controversial. One trial showed similar antibody responses with vaccination started at 3 months (early) and 9 months (late) posttransplant [808]. Thus, early vaccination may be preferred as it may protect against not only late but also early pneumococcal disease. It should be noted that early vaccination may not prime for a PPSV23 boost as efficiently as the late vaccination. Also, early vaccination may result in a shorter lasting antibody response. Therefore, if vaccination is started early, it may be particularly important to determine pneumococcal antibody levels and, if these are “low,” revaccinate (BIII). Diphtheria-tetanus vaccine There are 2 general types of diphtheria and tetanus vaccines: those containing “full”-dose diphtheria toxoid in combination with tetanus toxoid (DT) and those containing reduced dose diphtheria toxoid (such as Td; the lower case “d” indicates reduced diphtheria toxoid, while the tetanus content is essentially the same in TD and Td). Use of reduced diphtheria toxoid vaccines following transplant can be associated with lack of response. Therefore, posttransplant patients should be viewed as “never vaccinated” and full toxoid vaccines should be used if possible. The DT vaccine is not approved in individuals >7 years of age in the United States because of side effects, although experience with adult HCT recipients receiving DT vaccine indicates a lower risk for side effects than in previously vaccinated healthy adults. Adult transplant recipients might have an adequate response to the diphtheria portion of Td. However, whether the response is equal to TD has not been studied. Checking diphtheria antibody level after vaccination with Td might therefore be warranted in situations where an increased risk for diphtheria might be envisaged. Pertussis vaccine For the general population, the Advisory Committee on Immunization Practices and the CDC have recommended use of acellular (rather than whole cell) pertussis vaccine in pediatric vaccination regimens since 1997. Because of the steady increase in pertussis over the last decade and the licensing of 2 vaccines containing tetanus, reduced dose diphtheria, and reduced dose pertussis (Tdap), the CDC now recommends that adolescents (10-18 years of age) and adults (19-64 years of age) receive a single dose of Tdap to replace their routine adult tetanus and diphtheria toxoids (Td) booster. For adolescents, the preferred age range is 11 to 12 years. For adults (11-64 years), a single Tdap is recommended to replace their routine Td booster if given ≥10 years earlier. The recommended interval of 10 years between Td and Tdap was because of concerns of local site reactions. However, for adults who have contact with infants 6 months old, annual seasonal influenza vaccination is recommended (BIII). Children <9 years old who are receiving influenza vaccination for the first time require 2 doses administered ≈1 month apart (AI). Varicella vaccines There are 2 main varicella vaccines, directed against preventing chickenpox (Varivax) or shingles (Zostavax). The difference between these vaccines is the number of plaque forming units of attenuated virus. The chickenpox vaccine has lower viral titers and can be used for all HCT recipients who have met the criteria for live virus vaccination. The new shingles vaccine should not be used because of the much higher viral titers. HBV vaccine Vaccination is recommended for HBsAg or HBcAb-positive patients, because vaccination can reduce the risk for reverse seroconversion (BII). For HBsAg or HBcAb-negative HCT patients, the recommendations for the general population in their country of residence should be followed. Meningococcal vaccine Both polysaccharide-based and conjugate vaccines exist. It is reasonable to assume that, as is true of vaccines against pneumococci and Hib, conjugated meningococcal vaccine will give more stable immune responses than polysaccharide-based vaccines, although no comparative study of the 2 vaccine types has been performed 811, 812.
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            The challenge of new drug discovery for tuberculosis.

            Tuberculosis (TB) is more prevalent in the world today than at any other time in human history. Mycobacterium tuberculosis, the pathogen responsible for TB, uses diverse strategies to survive in a variety of host lesions and to evade immune surveillance. A key question is how robust are our approaches to discovering new TB drugs, and what measures could be taken to reduce the long and protracted clinical development of new drugs. The emergence of multi-drug-resistant strains of M. tuberculosis makes the discovery of new molecular scaffolds a priority, and the current situation even necessitates the re-engineering and repositioning of some old drug families to achieve effective control. Whatever the strategy used, success will depend largely on our proper understanding of the complex interactions between the pathogen and its human host. In this review, we discuss innovations in TB drug discovery and evolving strategies to bring newer agents more quickly to patients.
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              Is Open Access

              Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?

              In this review we discuss recent progress in the development, testing, and clinical evaluation of new vaccines against tuberculosis (TB). Over the last 20 years, tremendous progress has been made in TB vaccine research and development: from a pipeline virtually empty of new TB candidate vaccines in the early 1990s, to an era in which a dozen novel TB vaccine candidates have been and are being evaluated in human clinical trials. In addition, innovative approaches are being pursued to further improve existing vaccines, as well as discover new ones. Thus, there is good reason for optimism in the field of TB vaccines that it will be possible to develop better vaccines than BCG, which is still the only vaccine available against TB.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/56474
                URI : http://frontiersin.org/people/u/117405
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                26 August 2014
                2014
                : 4
                Affiliations
                1Section of Adult Hematology and Oncology, Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University , Riyadh, Saudi Arabia
                2Central Regional Laboratory, Ministry of Health , Riyadh, Saudi Arabia
                Author notes

                Edited by: Partow Kebriaei, The University of Texas MD Anderson Cancer Center, USA

                Reviewed by: Partow Kebriaei, The University of Texas MD Anderson Cancer Center, USA; Amir Hamdi, The University of Texas MD Anderson Cancer Center, USA

                *Correspondence: Khalid Ahmed Al-Anazi, College of Medicine, King Khalid University Hospital, King Saud University, P.O. Box: 2925, Riyadh, Central Province, Saudi Arabia e-mail: kaa_alanazi@ 123456yahoo.com

                This article was submitted to Hematology Oncology, a section of the journal Frontiers in Oncology.

                10.3389/fonc.2014.00231
                4144006
                Copyright © 2014 Al-Anazi, Al-Jasser and Alsaleh.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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                Figures: 0, Tables: 5, Equations: 0, References: 99, Pages: 11, Words: 10380
                Categories
                Oncology
                Review Article

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