(BQ) Part 1 book Transplant infections presents the following contents: Introduction to transplant infections, risks and epidemiology of infections after transplantation, specific sites of infection, bacterial infections.
58202_fm.qxd 2/18/10 12:06 PM Page i Transplant Infections THIRD EDITION EDITORS RALEIGH A BOWDEN, MD Clinical Associate Professor of Pediatrics University of Washington School of Medicine Seattle, Washington PER LJUNGMAN, MD, PhD Professor of Hematology Karolinska University Hospital and Karolinska Institutet Stockholm, Sweden DAVID R SNYDMAN, MD, FACP Professor of Medicine Tufts University School of Medicine Chief, Division of Geographic Medicine and Infectious Diseases Tufts Medical Center Boston, Massachusetts 58202_fm.qxd 2/18/10 12:06 PM Page ii Acquisitions Editor: Julia Seto Product Manager: Leanne McMillan Development Editor: Jenny Koleth Production Manager: Bridgett Dougherty Senior Manufacturing Manager: Benjamin Rivera Marketing Manager: Kimberly Schonberger Design Coordinator: Stephen Druding Production Service: MPS Limited, A Macmillan Company Third Edition Copyright © 2010 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com Printed in China All rights reserved This book is protected by copyright No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the above-mentioned copyright Library of Congress Cataloging-in-Publication Data Transplant infections / editors, Raleigh A Bowden, Per Ljungman, David R Snydman.—3rd ed p ; cm Includes bibliographical references and index ISBN 978-1-58255-820-2 (alk paper) Communicable diseases Transplantation of organs, tissues, etc.—Complications Nosocomial infections I Bowden, Raleigh A II Ljungman, Per III Snydman, David R [DNLM: Transplants—adverse effects Bacterial Infections—etiology Mycoses—etiology Virus Diseases— etiology WO 660 T691 2010] RC112.T73 2010 617.9'5—dc22 2010001262 DISCLAIMER Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of the information in a particular situation remains the professional responsibility of the practitioner The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly important when the recommended agent is a new or infrequently employed drug Some drugs and medical devices presented in the publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320 International customers should call (301) 223-2300 Visit Lippincott Williams & Wilkins on the Internet: at LWW.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to pm, EST 10 58202_fm.qxd 2/18/10 12:06 PM Page iii Foreword Transplantation infectious disease has emerged as an important clinical subspecialty in response to a growing need for clinical expertise in the management of patients with various forms of immune compromise The field is evolving rapidly In the past, with fairly standardized immunosuppressive regimens, clinical expertise in the care of immunocompromised patients required an understanding of the common pathogens causing infection at various times after transplantation and an understanding of the common toxicities and interactions of immunosuppressive medications and antimicrobial agents Some of these concepts have now reached the level of “transplant gospel.” Thus, the equation of infectious risk after transplantation is determined by the relationship between two factors: the individual’s epidemiologic exposures and a conceptual measure of all those factors contributing to an individual’s infectious risk—“the net state of immunosuppression.” In the absence of assays that measure an individual’s absolute risk for infection, allograft rejection, or graft-vs.-host disease, any determination of the net state of immunosuppression is imprecise and is largely based on the clinician’s bedside skills and experience In practice, the lack of such assays predicts that most patients will suffer excessive or inadequate immunosuppression at some points during their posttransplant course provoking infection and/or rejection or GvHD As with most good “rules” in medicine, exceptions to the rules have become common Presentations of infection have been altered as transplantation has been applied to a broader range of clinical conditions, immunosuppressive regimens have become more diverse, and prophylactic antimicrobial regimens have been deployed How we proceed? Some components of the “risk equation” have changed little While different factors control the risk for infection in the earliest (weeks) periods following either transplant surgery (technical issues) or hematopoietic transplantation (neutropenia), the full impact of immunosuppression on adaptive immunity has not yet been achieved Thus, in both groups, colonization by nosocomial flora and mechanical or technical challenges dominate risk including postoperative fluid collections, vascular catheters and surgical drains, tissue ischemia, drug side effects, underlying immune deficits (e.g., diabetes), organ dysfunction, metabolic derangements, and antimicrobial exposures Following the earliest posttransplant time period, investigations into the pathogenesis of infection are beginning to unravel some of the underpinnings of host susceptibility via advances in microbiology, molecular biology, and immunology While the equation of risk for infection balancing epidemiology and the “net state of immune suppression” remain valuable, at the basic science level, “susceptibility” to infection is now recognized to be a function of both the “virulence” of the organism and of host defenses, including both innate and adaptive immunity The determinants of virulence of a particular organism are the genetic, biochemical, and structural characteristics that contribute to the production of disease Susceptibility can be explained with reference to the presence or absence of specific receptors for pathogens, the cells and proteins determining protective immunity, and the coordination of the host’s response to infection The relationship between the host and the pathogen is dynamic Thus, some of the alterations in susceptibility previously ascribed to “indirect effects” of the pathogen (e.g., for cytomegalovirus) can now be explained as virally mediated effects on processes including antigen presentation, cellular maturation and mobilization, and cytokine profiles Much of the impact of these infections appears to be at the interface of the innate immune system (monocytes, macrophages, dendritic cells, and NK cells) and the adaptive immune system (lymphocytes and antibodies) Other effects are the result of alterations in cell-surface (e.g., toll-like) receptors and on the milieu of other inflammatory mediators— both locally and systemically In an admittedly anthropomorphic description of these effects, the virus (and other pathogens) has altered the host to avoid detection and destruction and to promote successful parasitism and persistence As host and pathogen “respond” during the course of infection (and are modified by antimicrobial therapy or immunosuppression), each modifies the activities and functions of the other and a dynamic relationship develops The outcome of such a relationship depends on the virulence of the pathogen and the relative degree of resistance or susceptibility of the host, due largely to host defense mechanisms and to a more trivial degree, by antimicrobial therapies Investigations into immune mechanisms are beginning to provide assays that measure an individual’s pathogen-specific immune function (T-cell subsets, HLA-restricted lymphocyte sorting using tetramers, antigen-specific interferon-γ release assays) as a suggestion of pathogen-specific infectious risk This approach may be of particular relevance in the future in regard to development of vaccines for use in immunocompromised hosts and in the assessment of immune reconstitution following chemotherapy and hematopoietic stem cell transplantation The “equation of risk” has been further altered by a number of additional factors Outbreaks of epidemic infections (West Nile virus, H1N1 “swine” influenza, SARS) have disproportionately affected transplant recipients The epidemiology of infection has also been changed by the expanded population of patients undergoing immunosuppression for transplantation, notably in terms of parasitic, mycobacterial, and other endemic infections Thus, Chagas disease and leishmaniasis are routinely considered in the differential diagnosis of infection in the appropriate setting Donor-derived infections have been recognized in both hematopoietic and solid organ transplant recipients Until recently, careful medical histories coupled with serologic and culture-based screening of organ donors and recipients, and routine antimicrobial prophylaxis for surgery have successfully prevented the transmission of most infections with grafts With the emergence of antimicrobial-resistant organisms in hospitals and 58202_fm.qxd iv 2/18/10 12:06 PM Page iv Foreword in the community, routine surgical prophylaxis for transplantation surgery may fail to prevent transmission of common organisms including methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus species, and azole-resistant yeasts Highly sensitive molecular diagnostic assays have also allowed the identification of a series of uncommon viral infections (lymphocytic choriomeningitis virus [LCMV], West Nile virus, rabies virus, HIV) with allografts These infections appear to be amplified in the setting of immunosuppression Despite technological advances, deficiencies in the available screening assays are notable in that both false-positive assays (causing discarding of potentially usable organs) and false-negative assays (the inability to identify LCMV in a deceased donors transmitting LCMV to multiple recipients) have been recognized Sensitive and specific diagnostic assays remain unavailable for some pathogens of interest and those that are available require careful validation and standardization Improved molecular assays and antigen detection-based diagnostics may help to prevent graft-derived transmissions in the future Routine use of antimicrobial prophylaxis has also altered the presentation of infection following transplantation In part, this manifests as a “shift-to-the-right” (late infections) due to common pathogens such as cytomegalovirus (CMV) in solid organ recipients Increasingly, this is reflected in the emergence of antimicrobial-resistant pathogens The impact of routine prophylaxis is difficult to measure—it is uncertain that there is a clear mortality benefit of these strategies Sicker patients arrive at transplantation having survived multiple infections, organ failure, or malignancies that would have been fatal in the past These individuals may become “Petri dishes” for organisms for which effective therapies are lacking The need for new antimicrobial agents is increasing at a time when the pipeline for new agents appears to be contracting The net state of immunosuppression has also shifted The duration of neutropenia following HSCT and with nonmyeloablative transplantation is shorter than that after traditional bone marrow transplantation The duration of neutropenia has also been reduced with the introduction of chemotherapeutic agents targeting specific cellular sites (enzymes, proteasomes) rather than acting on rapidly dividing cancer cells Among solid organ transplants, the recent introduction of experimental protocols that use combinations of HSCT with renal transplantation to induce immunologic tolerance carries the promise of immunosuppression-free lifetimes for patients A series of innovations will impact future clinical practice The adoption of quantitative molecular and protein-based microbiologic assays in routine clinical practice has enhanced diagnosis and serves as a basis for the deployment of antiviral agents and modulation of exogenous immune suppression In many ways, given currently available science, these assays may be the best measure of an individual’s immune function relative to their own pathogens Potent “biologic agents” in transplantation including antibody-based therapies to deplete lymphocytes (and other cells) have the capacity to reduce both graft rejection and graft-vs.-host disease in place of commonly used agents including corticosteroids and the calcineurin inhibitors The shortterm gain in terms of infectious risk and renal dysfunction from currently available agents must be balanced against longer term susceptibly to infections with organisms including mycobacteria, fungi, and viruses Among the side effects of these therapies may be an increased risk for virally mediated malignancies (including PTLD) and BK (nephropathy) and JC polyomavirus-associated infections (i.e., progressive multifocal leukoencephalopathy, PML) The full impact of the biologic agents remains to be determined High throughput sequencing and genome-wide association studies are beginning to determine the basis of both genetic susceptibility to infection and responses to antimicrobial therapies (e.g., hepatitis C virus and interferon) These observations will allow the application of specific drugs to the populations in which they are most useful and least toxic (pharmacogenomics) The introduction of clinical xenotransplantation (i.e., pig-to-human transplantation) may introduce a series of novel pathogens into the epidemiologic equation in the near future The evolution of the immunosuppression used in organ and hematopoietic stem cell transplantation has reduced the incidence of acute graft rejection and graft-vs.-host disease while increasing the longer term risks for infection and virally mediated malignancies With introduction of each new immunosuppressive agent, a new series of effects on the presentation and epidemiology of infection have been recognized in the transplant recipient In the absence of assays that measure “infectious risk,” transplant infectious disease remains as much a clinical art form as a science In the future, improved assays for microbiologic and immunologic monitoring will allow individualization of prophylactic strategies for transplant recipients and reduce the risk of infection in this highly susceptible population As a reflection of the challenges posed by a rapidly changing field, the editors and contributors of this text have identified both the advances and the gaps in our knowledge in transplant infectious diseases The unique risk factors and epidemiology for infection have been characterized for each of the major transplant populations Important shifts in the epidemiology that have been identified include those due to donor-derived pathogens and the introduction of transplantation into geographically diverse populations The clinical utility of the text is enhanced by discussions of common and important presentations of infection including infections of the lungs, skin, central nervous system, and gastrointestinal tract Individual pathogens and therapies are addressed in detail Vaccination for the immunocompromised host and innovative therapies entering clinical practice are clearly presented and assessed, including adoptive immunotherapy In each case, clinically important management issues are identified including infection control, immunosuppressive adjustments, and prophylactic and therapeutic antimicrobials The authors have, in addition, identified important controversies and trends for each topic so as to clue the reader into areas in which change is ongoing In sum, this volume is an important addition to the currently available literature in transplantation for infectious disease and transplantation specialists, for both expert and novice alike The availability of this information in a single volume will serve one group particularly well—our patients Jay A Fishman, MD Boston, Massachusetts, USA 58202_fm.qxd 2/18/10 12:06 PM Page v Preface The success of both the first edition of Transplant Infections, published in 1998, and the second edition, published in 2003, as a reference work to bring together information directed at the management of the infectious complications occurring specifically in immunocompromised individuals undergoing transplantation has led to the creation of this third edition No other text focuses solely on exogenously immunosuppressed transplant patients, and no text combines solid organ and hematopoietic stem cell transplantation (historically referred to as bone marrow transplantation) Many texts focus on immunocompromised patients, but the field of transplant infectious diseases has evolved over the past 20 years as a field unto itself, with conferences devoted solely to this specialty, and guidelines, both national and international, being developed for the management of such patients In addition, peer reviewed journals now exist which publish information on this specialized area, and training programs devoted to the subspecialty of transplant infectious diseases within the field of infectious disease are being developed The field of transplant infectious diseases has continued to grow and expand since the second edition was published in 2003 We have expanded the third edition to include a greater emphasis on surgical complications for each type of organ transplanted In addition, there are new chapters on organ donor screening, drug interactions after transplantation, and new immunosuppressive agents Chapters differentiating differences between solid organ and hematopoietic stem cell transplantation have been expanded, as have chapters discussing fungal infections, as more data accumulate for improved diagnosis and treatment and many new antifungal agents are developed There is a new section in the cardiac transplant chapter on ventricular assist device infections, a problem the transplant infectious disease specialist must wrestle with often in patients awaiting cardiac transplantation We have also expanded some chapters on viral infections, such as the polyomaviruses and adenovirus since recognition of the importance of these pathogens has grown A chapter on rare viral infections has been updated as well Transplant tourism as a topic has also been added to a section on transplant travel medicine and vaccines A number of new authors have been added and chapters have been substantially revised or completely rewritten This edition remains a globally inclusive product of leading authors and investigators from around the world Perspectives from Argentina, Brazil, Chile, New Zealand, Western Europe (Italy, Spain, Sweden, Germany, France, and Switzerland), Austria, the United States, Canada, and Israel have been synthesized in this edition We continue to believe that much can be learned regarding an appreciation of both the similarities and the differences in the pattern of infections and the resulting morbidity and mortality in various transplant settings Our goal with this textbook is to provide background and knowledge for all practitioners who work with transplant patients, in order to improve both the care and outcomes of transplant recipients and to provide a framework for education of physicians, and transplant coordinators, and trainees in the field As success in the field continues to grow we hope that this text would provide some small incremental knowledge base that would advance the field and make transplantation safer for all who need this lifesaving intervention We thank all the contributors for their effort, and trust the reader will find this a valuable reference text as they care for transplant recipients Raleigh A Bowden Per Ljungman David R Snydman v 58202_fm.qxd 2/18/10 12:06 PM Page vi Contributors Tamara Aghamolla Helen W Boucher, M.D., F.A.C.P Isabel Cunningham, M.D Immunocompromised Host Section Pediatric Oncology Branch Clinical Research Center National Cancer Institute National Institutes of Health Bethesda, Maryland Adjunct Associate Research Scientist Hematology Oncology Columbia University College of Physicians and Surgeons New York, New York Nora Al-mana, M.B.B.S Assistant Professor of Medicine Tufts University School of Medicine Director Fellowship Program Division of Geographic Medicine and Infectious Diseases Tufts Medical Center Boston, Massachusetts Tufts Medical Center Boston, Massachusetts Emilio Bouza, M.D., Ph.D Diana Averbuch, M.D Department of Pediatrics The Hebrew University Hadassah Medical School Infectious Diseases Consultant Department of Pediatrics Hadassah University Hospital Jerusalem, Israel Robin K Avery, M.D Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Section Head Transplant Infectious Disease The Cleveland Clinic Cleveland, Ohio Emily A Blumberg, M.D Professor Department of Medicine University of Pennsylvania School of Medicine Division of Infectious Diseases Department of Medicine Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Michael J Boeckh, M.D Associate Professor Department of Medicine University of Washington Member Vaccine and Infectious Disease Institute Fred Hutchinson Cancer Research Center Seattle, Washington vi Professor Clinical Microbiology University Complutense of Madrid Chief Clinical Microbiology and Infectious Diseases Hospital General Universitario Gregorio Marañon (HGUGM) Madrid, Spain Almudena Burillo, M.D., Ph.D Physician Clinical Microbiology and Infectious Diseases Hospital de Mostoles Madrid, Spain Sandra M Cockfield, M.D Professor Department of Medicine University of Alberta Medical Director Renal Transplant Program Walter C Mackenzie Health Science Center Edmonton, Alberta, Canada Jeffrey T Cooper, M.D Assistant Professor of Surgery Tufts University School of Medicine Attending Surgeon Tufts Medical Center Boston, Massachusetts Catherine Cordonnier, M.D Professor of Hematology Hematology Oncology Université Paris 12 Head Clinical Hematology Department Henri Mondor University Hospital Créteil, France Mazen S Daoud, M.D Director Dermatopathology Laboratory Associates in Dermatology Fort Myers, Florida H Joachim Deeg, M.D Professor of Medicine Medical Oncology University of Washington Medical Center Member Transplantation Biology Fred Hutchinson Cancer Research Center Seattle, Washington David DeNofrio, M.D Associate Professor of Medicine Cardiology/Medicine Tufts University School of Medicine Medical Director Cardiac Transplant Program Cardiology/Medicine Tufts Medical Center Boston, Massachusetts J Stephen Dummer, M.D Professor Departments of Medicine and Surgery Vanderbilt University School of Medicine Chief Transplant Infectious Diseases Vanderbilt University Hospital Nashville, Tennessee Hermann Einsele Professor Department of Medicine University Würzburg Director Department of Internal Medicine II University Hospital Würzburg Würzburg, Germany 58202_fm.qxd 2/18/10 12:06 PM Page vii Contributors Dan Engelhard, M.D Juan Gea-Banacloche, M.D Morgan Hakki, M.D Associate Professor Department of Pediatrics The Hebrew University Hadassah Medical School Chief Department of Pediatrics Hadassah University Hospital Jerusalem, Israel Infectious Diseases Section Experimental Transplantation and Immunology Branch National Cancer Institute, National Institutes of Health Chief Infectious Diseases Consultation Service National Institutes of Health Clinical Research Center Bethesda, Maryland Assistant Professor Division of Infectious Diseases Oregon Health and Science University Portland, Oregon Janet A Englund, M.D Professor Department of Pediatrics University of Washington Professor Pediatric Infectious Diseases Seattle Children’s Hospital Seattle, Washington Staci A Fischer, M.D Associate Professor Department of Medicine The Warren Alpert Medical School of Brown University Director Transplant Infectious Diseases Rhode Island Hospital Providence, Rhode Island Maddalena Giannella, M.D PhD Course Clinical Microbiology University Complutense of Madrid Research Fellow Clinical Microbiology and Infectious Diseases Hospital General Universitario Gregorio Marañon (HGUGM) Madrid, Spain Lawrence E Gibson, M.D Professor of Dermatology Director of Dermatopathology Mayo Clinic Rochester, Minnesota Richard Freeman, M.D John W Gnann, Jr., M.D Professor and Chair Department of Surgery Dartmouth Medical School Hanover, New Hampshire Chair Department of Surgery Dartmouth-Hitchcock Medical Center Lebanon, New Hampshire Professor of Medicine, Pediatrics, and Microbiology Department of Medicine, Division of Infectious Diseases University of Alabama at Birmingham and Birmingham Veterans Administration Medical Center Birmingham, Alabama Ed Gane, M.D., F.R.A.C.P Michael Green, M.D., M.D.H Associate Professor Faculty of Medicine University of Auckland Consultant Hepatologist Liver Unit Auckland City Hospital Auckland, New Zealand Professor Pediatrics and Surgery University of Pittsburgh School of Medicine Attending Physician Division of Infectious Diseases Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania Joan Gavaldà, M.D., Ph.D Andreas H Groll, M.D Senior Consultant Servei Malalties Infeccioses Vall d’Hebron Barcelona, Spain Associate Professor Department of Pediatrics Wilhelms University Head Infectious Disease Research Program Center for Bone Marrow Transplantation and Department of Pediatric Hematology/Oncology Children’s University Hospital Muenster, Germany vii John W Hiemenz, M.D Professor of Medicine Division of Hematology/Oncology University of Florida College of Medicine Attending Physician Bone Marrow Transplant/Leukemia Program Shands at the University of Florida Gainesville, Florida Hans H Hirsch, M.D., M.S Professor Institute for Medical Microbiology Department of Biomedicine University of Basel Senior Physician Infectious Diseases & Hospital Epidemiology Department of Internal Medicine University Hospital Basel Petersplatz, Basel, Switzerland Jack W Hsu, M.D Assistant Professor Department of Medicine University of Florida Clinical Assistant Professor Department of Medicine University of Florida Shands Cancer Center Gainesville, Florida Abhinav Humar, M.D Professor Department of Surgery University of Pittsburgh Chief of Transplant Starzl Transplant Institute University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Atul Humar, M.D., M.SC., F.R.C.P (C) Associate Professor of Medicine Transplant Infectious Diseases University of Alberta Director Transplant Infectious Diseases University of Alberta Hospital Edmonton, Alberta, Canada 58202_fm.qxd viii 2/18/10 12:06 PM Page viii Contributors Michael G Ison, M.D., M.S Shimon Kusne, M.D Anna Locasciulli, M.D Assistant Professor Divisions of Infectious Diseases & Organ Transplantation Northwestern University Feinberg School of Medicine Medical Director Transplant & Immunocompromised Host Infectious Diseases Service Northwestern Memorial Hospital Chicago, Illinois Professor of Medicine Department of Medicine Mayo Medical School Chair Division of Infectious Diseases Department of Medicine Mayo Clinic Arizona Phoenix, Arizona Associated Professor Pediatric Hematology University of Medicine Director Pediatric Hematology San Camillo Hospital Rome, Italy Roberta Lattes, M.D Professor of Medicine and Deputy Chairman Department of Medicine Tufts University School of Medicine Chairman Department of Medicine Baystate Medical Center Springfield, Massachusetts Barry D Kahan, M.D., Ph.D Professor Emeritus The University of Texas Medical School at Houston Houston, Texas Carol A Kauffman, M.D Professor Department of Internal Medicine University of Michigan Medical School Chief Infectious Diseases Section Veterans Affairs Ann Arbor Healthcare System Ann Arbor, Michigan Camille Nelson Kotton, M.D Assistant Professor Department of Medicine Harvard Medical School Clinical Director Transplant Infectious Disease and Compromised Host Program Infectious Diseases Division Massachusetts General Hospital Boston, Massachusetts Sharon Krystofiak, M.S., M.T (A.S.C.P.), C.I.C Infection Preventionist Infection Control and Hospital Epidemiology University of Pittsburgh Medical Center Presbyterian Pittsburgh, Pennsylvania Deepali Kumar, M.D., M.SC., F.R.C.P (C) Assistant Professor of Medicine Transplant Infectious Diseases University of Alberta Staff Physician Transplant Infectious Diseases University of Alberta Hospital Edmonton, Alberta, Canada Assistant Professor Infectious Diseases Department of Medicine University of Buenos Aires – School of Medicine Chief Departement of Transplantation Transplant Infectious Disease Instituto de Nefrología Buenos Aires, Argentina Kenneth R Lawrence, B.S., PHARM.D Assistant Professor Department of Medicine Tufts University School of Medicine Senior Clinical Pharmacy Specialist Pharmacy Tufts Medical Center Boston, Massachusetts Ingi Lee, M.D., M.S.C.E David L Longworth, M.D Mitchell R Lunn, B.S Department of Medicine Stanford University School of Medicine Stanford, California Clarisse M Machado, M.D Virology Laboratory São Paulo Institute of Tropical Medicine University of São Paulo São Paulo, Brazil Kieren A Marr, M.D Instructor Department of Medicine University of Pennsylvania School of Medicine Division of Infectious Diseases Department of Medicine Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Professor of Medicine Department of Medicine Johns Hopkins University Director Transplant and Oncology Infectious Disease Department of Medicine Johns Hopkins University Baltimore, Maryland Ajit P Limaye, M.D Rodrigo Martino, M.D., Ph.D Associate Professor Department of Medicine University of Washington Director Solid-Organ Transplant Infectious Disease University of Washington Medical Center Seattle, Washington Attending Senior Physician Hematology Hospital de la Santa Creu i Sant Pau Barcelona, Catalonia, Spain Per Ljungman, M.D., Ph.D Professor of Hematology Karolinska Institutet Director Department of Hematology Karolinska University Hospital Stockholm Stockholm, Sweden Susanne Matthes-Martin, M.D Associate Professor Head of Unit St Anna Children’s Hospital Stem Cell Transplant Unit Children´s Cancer Research Institute Vienna, Austria 58202_fm.qxd 2/18/10 12:06 PM Page ix Contributors Lisa M McDevitt, PHARM.D., B.C.P.S Patricia Muñoz, M.D., Ph.D Jorge D Reyes, M.D Assistant Professor Department of Surgery Tufts University School of Medicine Senior Clinical Specialist Organ Transplantation Department of Pharmacy Tufts Medical Center Boston, Massachusetts Professor Clinical Microbiology University Complutense of Madrid Clinical Section Chief Clinical Microbiology and Infectious Diseases Hospital General Universitario Gregorio Marón (HGUGM) Madrid, Spain Professor Department of Surgery University of Washington Chief Division of Transplant Surgery University of Washington Medical Center Seattle, Washington George B McDonald, M.D Tue Ngo, M.D., M.D.H Professor Department of Medicine University of Washington Head and Member Gastroenterology, Hospital Section Fred Hutchinson Cancer Research Center Seattle, Washington Infectious Diseases Fellow Division of Infectious Diseases Vanderbilt University School of Medicine Nashville, Tennessee Marian G Michaels, M.D., M.D.H Professor Department of Pediatrics and Surgery University of Pittsburgh Division of Pediatric Infectious Diseases Department of Pediatrics Children’s Hospital of Pittsburgh of University of Pittsburgh Medical Center Pittsburgh, Pennsylvania Barbara Montante, M.D Resident Pediatric Hematology and Bone Marrow Transplant Unit San Camillo Hospital Rome, Italy Jose G Montoya, M.D Associate Professor of Medicine Division of Infectious Diseases and Geographic Medicine Stanford University School of Medicine Attending Physician Department of Medicine Stanford Hospital and Clinics Stanford, California David C Mulligan, M.D., F.A.C.S Professor Department of Surgery Mayo Clinic School of Medicine Director Transplant Center Mayo Clinic Arizona Phoenix, Arizona Albert Pahissa, M.D., Ph.D Chair Professor Infectious Diseases Medicine Universitat Autònoma de Barcelona Chief Servei Malalties Infeccioses Vall d’Hebron Bellaterra, Barcelona, Spain Peter G Pappas, M.D., F.A.C.P Professor of Medicine Medicine and Infectious Diseases University of Alabama at Birmingham Birmingham, Alabama Andrew R Rezvani, M.D Research Associate Transplantation Biology Program Fred Hutchinson Cancer Research Center Acting Instructor Medical Oncology University of Washington Medical Center Seattle, Washington Jason Rhee, M.D Transplant Research Fellow Department of Surgery Tufts Medical Center Boston, Massachusetts Stanely R Riddell, M.D Professor of Medicine Fred Hutchinson Cancer Research Center Seattle, Washington Maria Beatrice Pinazzi, M.D Antonio Román, M.D., Ph.D Full-time Assistant Pediatric Hematology and Bone Marrow Transplant Unit San Camillo Hospital Rome, Italy Senior Consultant Pneumology Department Vall d’Hebron Barcelona, Spain Jutta K Preiksaitis, M.D Professor of Medicine Department of Medicine University of Alberta Edmonton, Alberta, Canada Assistant Professor of Medicine State University of New York at Buffalo Head of Infectious Disease Roswell Park Cancer Institute Buffalo, New York Marcelo Radisic, M.D Maria Teresa Seville, M.D Attending Physician Transplant Infectious Diseases Instituto De Nefrología Buenos Aires, Argentina Instructor Division of Infectious Diseases Mayo Clinic Chair Infection Prevention and Control Mayo Clinic Hospital Phoenix, Arizona Raymund R Razonable, M.D Associate Professor of Medicine Department of Medicine Mayo Clinic College of Medicine Consultant Staff Division of Infectious Diseases Mayo Clinic Rochester, Minnesota ix Brahm H Segal, M.D Nina Singh, M.D Associate Professor of Medicine University of Pittsburgh Pittsburgh, Pennsylvania 58202_fm.qxd x 2/18/10 12:06 PM Page x Contributors David R Snydman, M.D., F.A.C.P Professor of Medicine Tufts University School of Medicine Chief, Division of Geographic Medicine and Infectious Diseases Hospital Epidemiologist Tufts Medical Center Boston, Massachusetts Gideon Steinbach, M.D., Ph.D Associate Professor Department of Medicine University of Washington Associate Member Gastroenterology, Hospital Section Fred Hutchinson Cancer Research Center Seattle, Washington William J Steinbach, M.D Associate Professor Departments of Pediatrics and Molecular Genetics & Microbiology Duke University Durham, North Carolina W P Daniel Su, M.D Professor of Dermatology Mayo Clinic Rochester, Minnesota Max S Topp, M.D Director Internal Medicine II University Medical Center II Würzburg, Germany Thomas J Walsh, M.D., F.A.C.P., F.I.D.S.A., F.A.A.M Adjunct Professor of Pathology The Johns Hopkins University School of Medicine Adjunct Professor of Medicine University of Maryland School of Medicine Senior Investigator Chief, Immunocompromised Host Section National Cancer Institute Baltimore, Maryland Daniel J Weisdorf, M.D Professor & Director Adult Blood and Marrow Transplant Program Department of Medicine University of Minnesota Minneapolis, Minnesota Estella Whimbey, M.D Associate Professor of Medicine University of Washington Associate Medical Director Employee Health Center University of Washington Medical Center Medical Director Healthcare Epidemiology and Infection Control University of Washington Medical Center/Seattle Cancer Care Alliance (inpatients) Seattle, Washington John R Wingard, M.D Professor Department of Medicine University of Florida Director of Bone Marrow Transplant Program Department of Medicine University of Florida Shands Cancer Center Gainesville, Florida Jo-Anne H Young, M.D Associate Professor Department of Medicine University of Minnesota Director of the Program in Transplant Infectious Disease Department of Medicine University of Minnesota Medical Center Minneapolis, Minnesota 58202_ch21.qxd 296 2/18/10 Section IV 12:11 PM ■ Page 296 Bacterial Infections An examination of the cerebrospinal fluid (CSF) usually reveals a pleocytosis of less than 1000 leukocytes per milliliter with a mixture of neutrophils and lymphocytes (4) Common findings include an elevated CSF protein level and decreased CSF glucose levels, although these parameters may also be normal, particularly early in the illness L monocytogenes has been cultured from completely normal CSF The organism is only occasionally visualized on a Gram stain of CSF, but centrifugation of the sample may increase the yield Clinical isolates of L monocytogenes may be misidentified as either diphtheroids or streptococcal species In a compatible clinical situation, such reports should heighten the suspicion of listerial infection and prompt empirical therapy while awaiting definitive identification L monocytogenes has a tropism for brain tissue, and in addition to meningitis can cause several forms of parenchymal CNS infection, including cerebritis, encephalitis, and brain abscess An unusual form of listerial encephalitis involving the brainstem (rhomboencephalitis) presents with movement disorders, facial nerve palsies, cerebellar signs and hemiparesis or hemisensory deficits (4) Direct invasion of the CNS in the form of cerebritis or brain abscess is more common among transplant recipients than in normal hosts (3) Listerial brain abscesses differ from brain abscesses due to other bacteria by their tendency to involve the brainstem, the presence of meningitis in 25% of patients, a high frequency of subcortical location and the almost universal presence of bacteremia (4) The mortality rate of isolated bacteremia with L monocytogenes is only 3%, but may be as high as 30% in patients with CNS involvement (3,4,21) Several forms of localized listerial infection have also been reported in transplant recipients, including peritonitis (17), hepatitis (16), arthritis (22), endophthalmitis (23), and endocarditis (24) No controlled studies have evaluated the treatment of listeriosis in any patient population Recommendations are based on the in vitro activity of antibiotics, animal studies, and clinical observation The therapy of choice is high-dose penicillin or ampicillin with or without an aminoglycoside (4,6,25) Data from in vitro and animal experiments show a synergistic activity of ampicillin and aminoglycosides against L monocytogenes; this combination is often recommended in severe infection and in compromised hosts, but in transplant recipients the potential benefits should be carefully weighed against the risk of nephrotoxity (26) The use of intrathecal gentamicin is not recommended because listerial infection of the CNS typically involves the ventricles and the brain parenchyma Trimethoprimsulfamethoxazole (TMP-SMX) has excellent activity and is the drug of choice in penicillin allergic patients (6,25) Listeria infection may be effectively prevented by TMP-SMX prophylaxis (27) Imipenem and meropenem have been successfully used to treat Listeria infections, but they are generally somewhat less active than ampicillin and may lower the seizure threshold (28,29) Vancomycin has good in vitro activity against Listeria, but its poor penetration into the CNS undermines its worth in treating this infection Clinical data on the use of the quinolones and tetracyclines are limited, and these agents cannot be recommended for routine use (6) Cephalosporins should be avoided because they have no activity against Listeria Chloramphenicol, which has good in vitro activity, has been associated with an unacceptable rate of failure and relapse Among newer agents, linezolid is the most attractive option It has good in vitro activity, penetrates the CNS well, and has proved effective in a few clinical cases (30) Transplant recipients have a higher risk of recurrence or reinfection than other patients (13,31); they should therefore receive weeks of therapy for bacteremia or meningitis and longer courses in the case of brain abscess Guidelines for preventing listerial infection have been issued by the Centers for Disease Control and Prevention (4) Although these guidelines specifically target listeriosis, they should also help to prevent other enteric infections They include standard items of kitchen hygiene, such as thorough cooking of raw meat, thorough washing of fresh fruits and vegetables, and physical separation of uncooked meat during the preparation process from other foods, cooked or uncooked, that are ready to be ingested The guidelines also suggest that persons at risk of listeriosis should avoid particular foods that may harbor Listeria These include raw or unpasteurized milk and soft cheeses, such as feta, Brie, Camembert, blue-veined cheeses, and unprocessed Mexican-style cheeses Nocardia Nocardia is an aerobic, gram-positive rod with a typical appearance on clinical microscopy of filamentous, branching chains The organism has been isolated from soil and decaying organic material throughout the world, and most human infection results from the inhalation of airborne bacilli Infection caused by Nocardia species was first described in transplant recipients in the 1960s (32) In 1976, Beaman et al (33) estimated that transplant recipients accounted for 13% of the cases of nocardiosis occurring in the United States Two decades later, their estimate of the proportion of cases occurring in transplant recipients had increased to 22% (34) Much of this increase appeared to be due to the growth in the pool of susceptible persons due to the rapid expansion of heart and liver transplantation after 1980 In 1989, Wilson et al reviewed available clinical and epidemiological data on nocardiosis after solid organ transplantation Almost all of this data came from published series before the introduction of cyclosporine (32) The frequency of Nocardia in different centers varied from 0% to 20%, with a mean of 2.8% Most larger series had an incidence between 1% and 4% (32) By contrast, the frequency of Nocardia infection in five reports from three cardiac transplant centers was 10.3% suggesting a greater susceptibility of these patients (32) The combined 58202_ch21.qxd 2/18/10 12:11 PM Page 297 Chapter 21 ■ Other Bacterial Infections after Hematopoietic Stem Cell or Solid Organ Transplantation frequency of nocardiosis from two early liver transplant series was 1.7%, but the number of studied patients was small (32) It should be noted that frequencies cited in these studies cannot be translated into incidence rates as the length of follow-up was variable between series and often not given Most infections caused by Nocardia are sporadic and they are generally acquired in the outpatient setting However, some small nosocomial outbreaks have been reported (32,35) The incidence of nocardial infection in transplant recipients appears to have decreased since the introduction of cyclosporine Hofflin et al (12) reported a reduction in the incidence of nocardial infection at Stanford University from 13% to 4.2% after the introduction of cyclosporine; similarly, the incidence of nocardiosis in the renal transplant population at the University of Texas in Houston declined from 2.6% to 0.7% after the introduction of cyclosporine (36) In the latter study, the investigators were not able to correlate this decrease in Nocardia infection with the introduction of routine sulfonamide prophylaxis for Pneumocystis jiroveciii infection Large single center series in lung, heart–lung, and liver transplant recipients since 1990 have reported rates of nocardiosis between 1.9% and 3.7% (37–39) The most recent comparative data on the frequency of nocardiosis comes from the University of Pittsburgh where a population of 5126 patients transplanted between 1995 and 2005 was investigated In this study there were striking differences in frequency of nocardiosis in the different transplant groups with the highest rate in lung recipients (3.6%) followed by heart (2.5%), intestinal (1.3%), renal (0.2%), and liver recipients (0.1%) An embedded case-control study, in which the cases were matched with controls for type of transplant and time posttransplant, showed that receipt of high-dose prednisone in the preceding months, the presence of cytomegalovirus disease, and highmedian calcineurin inhibitor levels in the preceding 30 days were significant risk factors for infection The use of low-dose TMP-SMX prophylaxis was not protective against nocardial infection as 69% of the patients had received prophylaxis with this agent (40) The frequency of nocardial infection occurring after bone marrow and stem cell transplantation has been low A 0.3% rate of nocardiosis was reported by van Burik et al (41) in more than 6000 bone marrow transplant recipients at three large marrow transplantation centers Cases occurred only in allogeneic bone marrow recipients, who made up approximately 80% of the study population In a separate study at Vanderbilt University, 1.7% of 302 allogeneic bone marrow recipients developed nocardial infection versus only 0.2% of 542 autologous bone marrow transplant recipients (42) In both series, some patients developed nocardial infection despite taking low-dose, intermittent TMP-SMX as prophylaxis for Pneumocystis infection The timing of nocardial infection after solid organ and bone marrow transplantation is similar Wilson et al (32) noted 297 that cases of nocardiosis were uncommon in the first weeks after transplantation The frequency of cases peaked between and months after transplantation, and cases then occurred sporadically at lower rates thereafter Cases of nocardiosis after bone marrow transplantation rarely occur before engraftment The preponderance of cases occurs in the early postengraftment period (41,42) The clinical presentation of nocardiosis is similar in solid organ and bone marrow transplant recipients (32,41–43) Eighty percent to 90% of patients present with chest symptoms Usually, these chest symptoms have been present for week or more Typical symptoms are fever, productive cough, pleuritic chest pain, dyspnea, weight loss, and hemoptysis Approximately one third of patients have disseminated infection at presentation The most common sites of dissemination are the CNS (15% to 20%), skin and soft tissues (15% to 20%), and bone or joints (2% to 5%) Occasionally, patients have disseminated disease at presentation without an identifiable pulmonary focus Rarely patients have isolated soft-tissue infection arising from a traumatic wound contaminated with soil The soft-tissue lesions associated with disseminated disease usually present as deep abscesses that are palpable and tender but may not be erythematous Biopsy or aspiration detects the organism Nocardia infection of the CNS usually causes brain abscess The symptoms are the same as those of any space-occupying lesion—focal neurologic defects, headache, and seizures (32) Meningitis due to Nocardia also occurs, but is considerably less common than brain abscess The clinical findings are similar to other bacterial meningitides, although the course may be subacute The appearance of nocardiosis on chest radiographs is quite variable Nodules and nodular infiltrates are the most common findings, but alveolar infiltrates are also seen Cavitation of nodules occurs in 20% to 25% of cases, and may take on a multiloculated appearance Pleural effusions are seen in approximately 25% of patients (32,42–44) The prognosis of nocardiosis is strongly determined by the presence or absence of CNS disease As brain abscesses may be clinically silent, it may be prudent to perform imaging studies of the brain, even in patients who have no neurologic symptoms Obtaining spinal fluid by lumbar puncture is not usually necessary if meningeal signs are absent Making a diagnosis of Nocardia infection is usually straightforward However, the isolation of the organism takes a minimum of to days and occasional isolates may require or more weeks to grow (34) Nocardia species grow readily on media designed for the isolation of fungi and mycobacteria; thus, obtaining these cultures is a valuable backup and may increase the yield Nocardia are easily visualized on Gram stain as delicate beaded and branching gram-positive rods; thus standard microscopy often allows for a presumptive early diagnosis Most strains of Nocardia are also weakly acid fast, a feature that may help to identify the organism on smears and differentiate it from Actinomyces species 58202_ch21.qxd 298 2/18/10 Section IV 12:11 PM ■ Page 298 Bacterial Infections Sulfonamides have been the drugs of choice for the treatment of nocardiosis Many clinicians prefer to use TMP-SMX, but excellent results have been achieved with other sulfonamides (32,42,44) The starting dose of sulfonamides should be in the range of to g daily, depending on body weight, with the aim of achieving serum levels of 100 to 150 mg/L Many transplant recipients will require dose reductions for renal dysfunction Other antimicrobials that have good activity against most nocardial strains are minocycline, amikacin, imipenem, cefotaxime, and ceftriaxone (34,45) Selected strains are sensitive to ampicillin, ampicillin-clavulanate, ciprofloxacin, and erythromycin or other macrolides, but the use of these is not advised unless in vitro testing provides evidence of susceptibility Linezolid is active in vitro against all Nocardia species (45) About a dozen cases of linezolid treatment for invasive Nocardia infection have been reported and have demonstrated its therapeutic potential (45,46) Unfortunately, the long-term use of linezolid may be limited by adverse effects such as myelosuppression and nausea A recent in vitro study showed good activity of tigecycline and moxifloxacin against the majority of 51 clinical strains of Nocardia By contrast, ertapenem was 16-fold less active than imipenem and should probably not be viewed as a useful agent for nocardiosis (47) Although the results of susceptibility testing of Nocardia species have not been correlated with clinical outcomes, they provide some objective data about the relative susceptibility of isolates to different therapies, and they may be helpful if therapy must be changed because of toxicity or inadequate response Several recently described strains of Nocardia, such as Nocardia farcinica or Nocardia transvalensis, are resistant to many antimicrobials in vitro, and these may present special treatment problems (34,45,47,48) For these strains, susceptibility testing aids speciation and can guide initial management In animal models of nocardial infection, antimicrobial agents, such as imipenem, cefotaxime, or amikacin, have killed Nocardia organisms more quickly than sulfonamides (49,50) These agents may be excellent alternatives to sulfonamides, or they may be used as part of a multidrug regimen in patients who are critically ill with disseminated nocardiosis until the patients are stabilized and susceptibility studies are available Ultimately, most patients who have an initial response will be switched to and managed on oral monotherapy The duration of therapy is generally months or more Treatment for as long as 12 months is preferred in patients who have disseminated or CNS disease Patients who have a significant exposure to soil or dust (e.g., jobs involving daily farming or construction work) may benefit from daily prophylaxis with sulfonamides to prevent reinfection (42) Anaerobic Actinomycetes Unlike infection with aerobic actinomycetes, such as Nocardia species, clinical infections with anaerobic actinomycetes not occur at an increased rate in immunocompromised patients A few cases of actinomycosis, however, have been reported in transplant recipients (51) Penicillin is the drug of choice in the treatment of actinomycosis Tetracyclines, clindamycin, and other macrolides are the drugs that are most commonly used in patients allergic to penicillin Other antimicrobials active against anaerobes are also likely to be effective, with the important and notable exception of metronidazole, which does not have activity against anaerobic actinomycetes Lactobacilli Lactobacilli are nonspore-forming, generally strict or facultatively anaerobic, gram-positive rods that are ubiquitous inhabitants of the human oral cavity, vagina, and gastrointestinal tract Previously, they were considered innocuous organisms or nonpathogenic contaminants However, occasional serious infections have been recognized in transplant recipients and other patient populations Bacteremia may follow disturbances of any site along the gastrointestinal tract or vagina In normal hosts, lactobacilli may cause endocarditis, but only one case of this form of infection has been reported in a transplant recipient (52) Although bacteremia may be the only demonstrable site of infection (53), invasive visceral infections and abscesses have been reported Patel et al (54) described lactobacillemia in eight patients who had received liver transplants within the previous months In all but one patient, the infections were polymicrobial and associated with other enteric flora Most patients had cholangitis or intrahepatic or perihepatic abscesses Other serious infections include pneumonia, which was thought to be transmitted in a transplanted lung (55), and a splenic abscess in a renal transplant recipient with concomitant human immunodeficiency virus infection (56) Unlike many other gram-positive organisms, Lactobacillus does not appear to be a frequent cause of intravenous catheter infection (57) Identified risk factors for infections due to Lactobacillus are the manipulation of the gastrointestinal tract or dental procedures, the use of a Roux-en-Y choledochojejunostomy, the administration of selective bowel decontamination, and the routine use of intravenous or oral vancomycin, an antibiotic to which lactobacilli are uniformly resistant The diagnosis is made by the isolation and identification of the organism from blood or tissue sites Microbiologic data, however, must always be augmented by clinical data to assess the significance of the isolate Definitive therapy should be guided by direct antimicrobial sensitivity testing, when possible, but most isolates are sensitive to penicillin Based on studies of bactericidal synergy, some investigators have suggested that an aminoglycoside should be added for the treatment of deep-seated infections (58) 58202_ch21.qxd 2/18/10 12:11 PM Page 299 Chapter 21 ■ Other Bacterial Infections after Hematopoietic Stem Cell or Solid Organ Transplantation Other antibiotics with good activity are clindamycin, erythromycin, and imipenem (57) Rhodococcus Equi R equi is a gram-positive coccobacillus of the order Actinomycetales that is related to Nocardia species and corynebacteria It is a veterinary pathogen that causes chronic suppurative pneumonia in foals and submaxillary lymphadenitis in swine (59) Herbivores, such as horses and cattle, are colonized in the gut, and the organism inhabits soil contaminated by their manure Approximately one third of individuals with Rhodococcus infection have regular contact with farms or livestock (59) Sporadic R equi infections occur in humans, most of whom have defects in cell-mediated immunity because of acquired immunodeficiency syndrome, organ transplantation, cancer, or corticosteroid use (60–65) Approximately 10% of R equi infections occur in transplant recipients (66) At least two cases have been reported after bone marrow transplantation (67) Patients with Rhodococcus infection generally present with fever, dyspnea, and nonproductive cough (59,61,68) Other common symptoms are pleuritic chest pain and hemoptysis Chest radiographs show infiltrates or nodules, which are usually located in the upper lung fields Lung nodules frequently cavitate and develop air fluid levels Pleural effusions are common and are often infected In most patients, the infection is confined to the chest cavity, but more than 80% of infected patients have positive blood cultures, and dissemination to the skin, bone, brain, and other organs has been described (59,65,66,68) About one half of transplant patients have spread of infection outside the lung (69) The diagnosis is established by isolating the organism from a sterile body site or from pulmonary secretions in the presence of a compatible clinical presentation Early growth of R equi may be seen on agar plates within 24 to 48 h, but the characteristic, mucoid, salmon-colored appearance of the colonies is not evident until a few days later (59,68) The organism is easily missed in cultures of non-sterile specimens such as sputum; therefore, the clinician should alert the laboratory whenever R equi infection is being considered Many antibiotics are active against Rhodococcus The most potent agents in vitro are vancomycin, imipenem, rifampin, erythromycin, clarithromycin and ciprofloxacin (59,68–71) Linezolid is also active in vitro (66) Clinical experience with linezolid is limited, but Munoz et al reported a case of multiresistant, relapsing Rhodococcus pulmonary infection in a heart transplant recipient that was successfully treated with longterm linezolid (72) Therapy with penicillins and cephalosporins has been unreliable and these antibiotics should be avoided A regimen of erythromycin and rifampin has had excellent success in treating horses and foals (59) The initial treatment for immunocompromised hosts should be by 299 intravenous route and should include two or three antibiotics to which the organism is likely to be susceptible (66) After the patient stabilizes and susceptibility results are available, treatment may be switched to an oral regimen which should be continued for several months with careful follow-up to monitor the clinical response Immunosuppressed patients with disseminated infection usually require at least months of treatment (66) Even with prolonged treatment relapses may occur; adjunctive surgical therapy may be useful in selected patients Clostridium Difficile C difficile is a spore-forming, gram-positive, obligate, anaerobic bacillus that is part of the normal intestinal flora in approximately 3% of healthy adults Transmission may occur in the nosocomial setting The organism has been isolated from the hands of hospital personnel caring for colonized patients The spores of C difficile can persist on fomites and surfaces for long periods of time (73) Colitis caused by C difficile is a common complication in hematopoietic stem cell and solid organ transplant populations The frequency of C difficile colitis appears to be related to the intensity of antbiotic exposure C difficile colitis has been a common cause of diarrhea after stem cell transplantation with reported rates in three reports of 13% to 18% based on toxin detection (74–76) A study by Cox et al., however, detected only cases of C difficile disease in 296 patients (77) In one study of allogeneic stem cell recipients, the diagnosis of C difficile colitis was strongly associated with the occurrence of grades II to IV graft-versus-host disease It was unclear whether the graft-versus-host disease predisposed individuals to C difficile colitis or vice versa (76) C difficile colitis has been reported in 3% to 8% of liver recipients (78,79), 3.5% to 4.5% of kidney recipients (80,81), 15.5% of kidney–pancreas recipients (80), 7.7% to 14.9% of heart recipients (82,83), and 7.4% of lung recipients (84) The most likely factor explaining the variability in the rates of infection in these studies is the intensity of antibiotic use and specific infection control practices at the different centers However, other modifiable factors could play a role For instance, in one intriguing study of heart transplant recipients, the incidence of C difficile colitis decreased from 20.6% to 6.4% after a program of prospective identification and treatment of hypogammaglobulinemia was instituted (83) A case-control study at a large transplant center did not show a difference in the severity of C difficile colitis between solid organ transplant recipients and nontransplant patients However, exposure to corticosteroids, irrespective of transplant status, was associated with an increased risk of relapse (85) Interestingly, few—if indeed any— transplant recipients develop C difficile disease while taking TMP-SMX for Pneumocystis prophylaxis Presumably, the lack of anaerobic activity of this drug combination causes relatively little perturbation of the bowel flora 58202_ch21.qxd 300 2/18/10 Section IV 12:11 PM ■ Page 300 Bacterial Infections Most transplant recipients with C difficile colitis present with watery diarrhea and abdominal pain after a course of antibiotics Fever and leukocytosis are seen in a sizeable minority of patients and associated with more severe illness (86) In symptomatic patients, the detection of C difficile cytotoxin in the stool is an adequate reason for making a presumptive diagnosis and initiating treatment Available ELISA assays for C difficile toxin are not as sensitive as cell cytoxicity assays and not absolutely exclude the diagnosis (86) Performing cultures for C difficile on selective media increases the sensitivity of detection even beyond cytoxicity assays, but a laboratory skilled in anaerobic bacteriology is required Cultures also detect carriers and nontoxigenic strains of bacteria and are therefore less specific than toxin detection A case of fatal pseudomembranous colitis caused by a strain of C difficile with a deletion of the toxin A gene has been described Because of the deletion, the infection could not be detected by repeated enzyme-linked immunosorbent assays for this protein (87) Such strains are thought to be rare, but their exact frequency is not known Outbreaks of severe C difficile colitis caused by an epidemic strain of C difficile designated as B1/NAPI and toxin type III were reported throughout the United States and in Quebec, Canada in the early 2000s This virulent strain produces more A and B toxins and has resistance in vitro to fluoroquinolones and cephalosporins (88) So far, there have not been any reports of outbreaks of infection with this strain of C difficile in transplant populations The usual treatment for C difficile colitis consists of stopping the offending antibiotic and administering 500 to 750 mg of oral metronidazole three times per day or 125 to 250 mg of oral vancomycin four times per day Many patients will be cured within to 10 days of therapy, but longer courses may be necessary in patients who are slow to respond or who have relapses Metronidazole is often the preferred initial treatment because of its lower cost, but there has been increasing use of vancomycin regimens in the last years, especially for sicker patients (89) If oral therapy is impossible, intravenous metronidazole can be given with administration of vancomycin by nasogastric tube or enema if feasible (89) Novel approaches, such as repopulating the bowel with “nonpathogenic” organisms (e.g., lactobacilli), have had anecdotal success, but they have not been rigorously studied Because commensal organisms in normal hosts may become pathogens in compromised hosts, this approach should be attempted only as a last resort in transplant recipients (54) GRAM-NEGATIVE ORGANISMS Legionella Legionella are fastidious, aerobic, gram-negative rods that are ubiquitous in nature and have been found in soil and freshwater lakes and streams (90) Over 50 species of Legionella have been described and 20 species have been isolated from infected humans The predominant species is Legionella pneumophila, which causes 95% or more of human illness in Europe and the United States (90) Serogroup makes up 80% to 90% of infectious isolates of L pneumophila Other species known to cause clinical infection in transplant patients include Legionella micdadei, Legionella bozemanii, and Legionella dumoffii (91–93) Legionella infection is common among transplant recipients; it can be either nosocomial or community acquired The exact mode of transmission is unclear, but person-to-person transmission does not occur, and most outbreaks of legionellosis are related to exposure to contaminated water (94) or soil (95) Legionella have a major, clinically relevant reservoir in institutional plumbing systems They enter these systems via contaminated cold water intakes and subsequently colonize hot water heaters From hot water tanks, they are dispersed throughout the water system to contaminate the biofilm in plumbing fixtures and pipes (94,96,97) Outbreaks of Legionella pneumonia have been epidemiologically linked to several sources of water, including potable tap water, cooling towers, evaporative condensers, humidifiers, and whirlpools (90,94,98–101) Health care facilities that experience more than a few cases of nosocomial legionellosis should investigate sources of Legionella bacteria in the institutional environment The defect in cellular immunity caused by immunosuppressive therapy makes transplant recipients particularly susceptible to legionellosis Infection has been frequently reported in recipients of renal (91,92,102,103), cardiac (104–106), liver (107), and bone marrow or stem cell (108,109) transplants Infection can occur at any time after transplantation, but it is seen with greatest frequency within a few months of transplantation or whenever immunosuppressive therapy has been augmented to treat rejection The clinical presentation can vary widely Although no findings are pathognomonic, some features may suggest legionellosis Patients often experience a flu-like prodrome of high fever, chills, myalgias, and malaise, but antecedent upper respiratory symptoms are usually absent The infection then progresses to include dyspnea and a mildly productive cough, which is often associated with pleuritic chest pain Approximately one half of patients develop watery diarrhea Mild CNS symptoms, such as headache and confusion, are often present On physical examination, the patients frequently appear quite ill, and some investigators have noted the presence of a pulse–temperature disassociation with a relative bradycardia (110) The most common physical findings are those commonly associated with any pneumonia: tachypnea; pulmonary rales; and occasionally pleural friction rub or signs of an effusion Extrapulmonary infection occurs occasionally with or without primary pneumonia These complications may result from the bacteremic spread of the organism as in the case of 58202_ch21.qxd 2/18/10 12:11 PM Page 301 Chapter 21 ■ Other Bacterial Infections after Hematopoietic Stem Cell or Solid Organ Transplantation pericardial effusion (111) or peritonitis (112) or from direct contamination as in the case of sternal wound infection (113) The mortality of untreated legionellosis in immunocompromised patients has been 80% (110); even with effective therapy, mortality ranges from 24% to 54% (110,114) The most common appearance of Legionella pneumonia on radiographs is alveolar infiltrates, which are frequently multilobar (115) One third of patients develop pleural effusions (116), and cavitation occurs in approximately 20% (103,115,117) The appearance of rapidly expanding pulmonary nodules suggestive of septic emboli is another radiographic pattern that has been noted in transplant recipients The diagnosis of legionellosis is often difficult, and it depends on the available level of laboratory expertise Legionella organisms have the ultrastructural properties of gram-negative bacilli, but they are usually not visualized on Gram stain of clinical specimens because they are small and take up stain poorly The definitive method of diagnosing Legionella infection is culture Legionella organisms are fastidious and their isolation requires the use of enriched culture media (buffered charcoal and yeast extract agar) and an environment enriched in CO2 An average of to days of incubation is necessary for colonies to appear on agar plates Overgrowth by other less fastidious organisms can mask the presence of the organism, even when media containing inhibitory antibiotics are used Cultured organisms are more readily visualized by Gram stain than are organisms in clinical specimens Several useful indirect diagnostic methods for legionellosis are available Direct fluorescent antibody (DFA) staining of sputum or tissue specimens is a rapid technique, but it has a sensitivity of only about 50%, and the reagents are available for only the most common species and serogroups (118,119) The interpretation of the assay is subjective, and it therefore requires an experienced technician; false-positive results can occur because of cross-reactivity with other organisms Demonstrating the development of a serologic response is another indirect diagnostic method that has been used with success, but is primarily useful for epidemiologic studies (119) In addition, serology relies on an adequate antibody response, which may be diminished in immunocompromised patients The detection of urinary antigen is a well-established assay that has been demonstrated to have a sensitivity of greater than 85% for infections caused by L pneumophila serogroup In the current era, the majority of diagnoses of legionellosis are made by urinary antigen testing (90,120) However, other serogroups of L pneumophila and other species of Legionella will not be detected by this technique (121,122) No controlled studies have evaluated treatment for legionellosis and recommendations are based on in vitro testing, animal studies, and clinical observation The agents that are known to be the most active include erythromycin, newer macrolides, such as azithromycin, rifampin, tetracyclines, TMP-SMX, and the fluoroquinolones All beta-lactam antibiotics, the aminoglycosides, 301 chloramphenicol, vancomycin, and clindamycin are ineffective (110,123) In the past, erythromycin was the most commonly used antibiotic, but doses as high as g/day were required Patients who did not respond to this regimen often received adjunctive treatment with rifampin (124) The use of these two antibiotics was problematic in transplant populations due to drug interactions with the metabolism of cyclosporine (125,126) Azithromycin has now replaced erythromycin as the macrolide of choice in treating legionnaires disease Its advantages are its greater intrinsic activity, less interference with the metabolism of calcineurin inhibitors, and the smaller volumes needed for the infusion of the intravenous formulation (127) Other active agents, such as TMP-SMX, tetracycline, and the fluoroquinolones, are possible alternatives The fluoroquinolones are the most active of these agents and share equal status with azithromycin as first line agents Prophylaxis with TMP-SMX, erythromycin, azithromycin, or fluoroquinolones may be a useful strategy to prevent Legionella pneumonia in transplant recipients, particularly in outbreak situations (128–130) Outbreaks of legionnaires disease have been linked to exposure to aerosolized water, such as that occurs in whirlpool spas Warning transplant recipients about the dangers of prolonged exposure to such aerosols and obtaining histories of exposure to such aerosols in patients with acute pneumonia are advisable (101) Helicobacter H pylori is a curved, gram-negative bacillus that infects the stomach in 25% to 50% of adults in developed countries, causing chronic gastritis (131) Infection with this organism has been strongly linked to the occurrence of peptic ulcer disease, and it is also a risk factor for the development of gastric cancer The presence of immunoglobulin G antibodies to H pylori in serum correlates extremely well with the presence of chronic infection with H pylori in the stomach as determined by endoscopic biopsy and culture Several studies have investigated H pylori infection in transplant recipients A seroepidemiologic study of 202 renal recipients showed a 29% rate of infection, which was similar to the rates of infection in healthy blood donors and patients on hemodialysis (132) Seropositive transplant recipients were more likely to have dyspeptic symptoms than were seronegative transplant recipients In another study, 33 renal recipients underwent upper endoscopy between and months after transplantation Forty-eight percent had H pylori identified either by histology or by testing for the urease elaborated by the organism; the patients who were infected with Helicobacter were more likely to have gastritis, peptic ulcers, or dyspeptic symptoms (133) Somewhat disparate results were seen in a study of 100 heart transplant recipients (131) Thirty-five percent of the patients were seropositive before transplantation, and only of the 65 seronegative patients seroconverted over a mean follow-up of 3.5 years Seropositive patients did not have more documented episodes 58202_ch21.qxd 302 2/18/10 Section IV 12:11 PM ■ Page 302 Bacterial Infections of ulcer disease, gastritis or gastrointestinal bleeding than did seronegative patients In long-term follow-up, 40% of Helicobacter seropositive patients became seronegative, a finding that correlated with a more intense use of antibiotics The patients appeared to have been inadvertently cured of their Helicobacter infections while receiving antibiotics for other infections Similar reversions to seronegative status have been reported from liver transplant recipients in Germany (134) and kidney transplant recipients in Finland (135) Information on Helicobacter infection in patients undergoing bone marrow transplantation is limited One study of 276 bone marrow recipients who underwent endoscopy either before or after transplantation disclosed only one case of H pylori infection (136) This rate of infection is surprisingly low However, the result could be explained if H pylori had been inadvertently eradicated by antibiotic therapy Castagnola et al diagnosed 13 cases of H pylori infection using a stool antigen assay in 478 children with hematologic malignancy including children who were being followed after stem cell transplantation (137) All patients presented with abdominal pain and improved with treatment of the Helicobacter infection, but no direct evidence was obtained that Helicobacter infection had caused the patients’ symptoms Despite the limited scope of the studies, they show that solid organ and stem cell transplant recipients are not more likely and in some cases they are less likely to be chronically infected with H pylori than are persons in the general population The studies are not large or comprehensive enough to resolve the issue of whether transplant recipients with Helicobacter infection are more or less likely than normal hosts to develop gastritis and ulcer disease A particularly intriguing manifestation of H pylori infection in transplant recipients is the occurrence of mucosaassociated lymphoid tissue (MALT) lymphomas These are low-grade, B-cell lymphomas When they occur in the stomach, these lymphomas are associated with H pylori infection They also frequently respond to and may even be cured by treatment with the antibiotics and proton pump inhibitors used to treat Helicobacter infection, thus obviating the need for more toxic cancer chemotherapies Four cases of gastric MALT lymphoma were described in a population of 1850 liver transplant recipients; the calculated rate in this group of patients was 0.2%, which is from 10 to 100 times more common than its occurrence in the general population (138), but less common than the occurrence of lymphoproliferative disease related to Epstein–Barr virus infection MALT lymphomas have also been described in cardiac and renal transplant recipients (139) The mortality of MALT lymphoma appears low compared to most other transplant tumors A report from the Israel Penn Transplant Tumor Registry documented only deaths from malignancy among 16 cases (139) One of the deaths was from persistent MALT lymphoma and the other from gastric adenocarcinoma No reports of treatment trials of Helicobacter infection in transplant recipients have been published Until these are available, the treatment regimens devised for immunocompetent hosts should be used Many such regimens have been described The older regimens combined bismuth salts with one or more antibiotics, such as metronidazole, amoxicillin, and tetracycline, usually for 14 to 21 days (140) The new regimens use antisecretory agents, such as omeprazole and ranitidine, with these antibiotics or clarithromycin (141) Eradication rates greater than 80% have been achieved with some of these regimens Patients can be monitored for cure with endoscopy, H pylori serology, a urea breath test, or stool antigen assays SPIROCHETES Treponema Pallidum T pallidum, the causative organism of syphilis, is a motile, slender, tightly coiled, helical organism that cannot be cultivated in vitro Transmission from an infected individual is by sexual or intimate contact, passage through the placenta, transfusion of fresh blood, or accidental direct inoculation Infection after organ transplantation is rare Although transmission from contaminated blood products is a theoretical possibility, the risk is thought to be negligible (142) because the organism cannot survive for longer than 24 to 48 h under the conditions of blood bank storage Indeed, this form of transmission has never been reported in a transplant recipient The potential risk of transmission from an infected organ is also a concern Gibel et al (143) reported the successful and safe transplantation of kidneys obtained from donors known to have had syphilis by using penicillin prophylaxis in the organ recipients Cortes et al., however, have reported that two kidney recipients developed serological (but not clinical) evidence of syphilitic infection after receiving organs from a donor who was seropositive for syphilis (144) In this case, the seroconversions likely occurred because the recipients were given a single dose of short-acting benzyl penicillin instead of long-acting benzathine penicillin after transplantation No cases of syphilis have been reported in bone marrow transplant recipients A handful of reports of symptomatic syphilis in renal and liver transplant recipients have been published (145,146) One of the liver recipients had luetic hepatitis, a somewhat unusual manifestation of secondary syphilis, and another had CSF pleocytosis and was treated with intravenous penicillin because of the possibility of syphilitic meningitis All patients responded well to treatment The diagnosis of syphilis has usually been based on initial serologic testing for nontreponemal antibodies (VDRL test, rapid plasma reagin) followed by specific treponemal antibody tests (fluorescent treponemal antibody [FTA], microhemagglutination-T pallidum test [MHA-TP]) Some have suggested that false-negative nontreponemal tests due 58202_ch21.qxd 2/18/10 12:11 PM Page 303 Chapter 21 ■ Other Bacterial Infections after Hematopoietic Stem Cell or Solid Organ Transplantation to the prozone phenomena may be more common in patients receiving immunosuppressive medication because of dysregulation of the B-cell response (147) The treatment of choice is parenteral penicillin, but doxycycline or erythromycin may be used if penicillin is contraindicated Leptospira Two cases of leptospirosis have been reported in kidney transplant recipients (148,149) Both patients had typical clinical manifestations of leptospirosis including fever, conjunctivitis, hyperbilirubinemia, thrombocytopenia, and renal dysfunction Both patients recovered fully after receiving antibiotics and supportive care Borrelia Lyme disease is a tickborne infection caused by Borrelia burgdorferi, a cultivable spirochete The animal reservoirs are small mammals (rodents), but large animals, such as deer and cattle, are important in the life cycle of the tick vector Ixodes species Ten cases of lyme disease have been reported in solid organ transplant recipients in the United States and Europe (150,151) Most reported cases had erythema migrans, but one patient had carditis in his transplanted heart and two patients had neurological involvement of brain or nerve roots All 10 patients had satisfactory responses to antibiotic therapy CHLAMYDIA Chlamydia species are gram-negative, obligate intracellular parasites of eukaryotic cells Transmission of Chlamydia pneumoniae (TWAR) occurs by the inhalation of aerosolized organisms The mode of transmission of Chlamydia trachomatis is by sexual contact or from mother to child during delivery Pneumonia caused by C trachomatis occurs rarely in immunocompetent adults, and the mode of transmission is not known C trachomatis is an occasional cause of pneumonia in transplant recipients It was reported in patients (6%) in a series of 72 marrow transplant recipients with interstitial pneumonitis (152) Several case reports of C trachomatis pneumonia after renal transplantation have been published (153,154) Other pathogens, most frequently cytomegalovirus, are also frequently implicated in these reports, and therefore determining whether C trachomatis was the primary pathogen is difficult Although isolation of the organism from lung tissue or pulmonary secretions is the preferred method of diagnosis, the only evidence of infection is often the demonstration of serologic conversion with or without compatible histologic findings Caution should be exercised when diagnosing C trachomatis infection based on serologic conversion alone 303 because some patients may demonstrate a fourfold increase in immunoglobulin G without clinical disease (155) Polymerase chain reaction (PCR) is a useful adjunct to the existing diagnostic tools (156) Case reports have been published of infections with C pneumoniae (TWAR) (92) and feline keratoconjunctivitis agent (157) in renal transplant recipients Both diagnoses were based on serologic conversion A case of C pneumoniae respiratory infection was also reported in an allogeneic stem cell transplant recipient (158) The organism was cultured in shell vial culture from a lung biopsy of a pleura-based nodular lesion C pneumoniae (TWAR) infection is a common cause of community-acquired pulmonary infections, and it is likely that this infection is more common in transplant recipients than is usually appreciated The therapy of choice for chlamydial infection is either tetracycline or doxycycline, with erythromycin or azithromycin as alternatives MYCOPLASMA The mycoplasmas differ from true bacteria because they lack a cell wall The mode of transmission varies with each organism Respiratory droplets spread Mycoplasma pneumoniae; M hominis, and Ureaplasma organisms are spread during vaginal delivery and sexual contact Infections caused by M pneumoniae are common in the general population They are rarely reported in transplant recipients, possibly because of the failure to perform diagnostic tests or the insensitivity of serology in this population (159) An unusual case of disseminated M pneumoniae infection in a renal transplant recipient was diagnosed by PCR of samples from multiple infected sites including an axillo-femoral bypass graft, the knee joint, and a psoas abscess (160) A M pneumoniae infection was also diagnosed by serology in a hematopoietic stem cell transplantation recipient who developed Stevens–Johnson syndrome (161) In contrast, to the paucity of reported cases of M pneumoniae infection there are numerous descriptions of infections caused by M hominis in transplant recipients (162–165) M hominis is a common commensal of the urinary tract in sexually active men and women (166,167) It is a frequent cause of self-limited postpartum fever, but occasionally it also causes invasive disease, such as septic arthritis, in new mothers (168) Immunosuppressed patients are predisposed to M hominis infection In a review of invasive M hominis infection occurring outside the genitourinary tract, 76% of patients had immunosuppressing disorders or were receiving immunosuppressive medication (163) M hominis infection has occurred in all types of solid organ transplantation (163,165,169) The transmission of M hominis from a lung donor to the recipients of both the right and left lung was reported (170) Superficial or deep 58202_ch21.qxd 304 2/18/10 Section IV 12:11 PM ■ Page 304 Bacterial Infections wound infections are a manifestation of M hominis infection in heart and heart–lung recipients and usually occur within a few weeks of transplantation These patients typically present with fever, together with erythema, tenderness, and drainage of purulent secretions along the sternal incision (164) Microscopic examination of Gram-stained wound drainage shows many leukocytes but few or no organisms This organism can have destructive effect on the sternal bone, and extensive surgical debridement of the sternal bone may be required Single lung recipients usually develop pleural space infection Renal and liver recipients present with local or diffuse peritoneal infection (171,172) Other well-documented sites of infections are joints, the CNS, and the bloodstream (162,163, 172,173) M hominis has occasionally been isolated from the respiratory tract in patients with pneumonia, but its role as a respiratory pathogen is still incompletely defined (163,165) The most convincing reports of pneumonia caused by M hominis are those in lung transplant recipients, including one case that appeared to have been acquired from the lung donor (174) The only bone marrow recipient reported to have M hominis infection had diffuse alveolar hemorrhage that was associated with the isolation of this organism (165) M hominis infection should be included in the differential diagnosis when the cultures from pyogenic infection are negative or grow a small amount of normal flora The organism grows best on specific Mycoplasma media On routine blood agar it grows as tiny translucent colonies after to days These are likely to be missed by the laboratory technologist because the organism does not take up Gram stain Because of these diagnostic difficulties, clinicians should alert the microbiologist if M hominis infection is suspected (163) Most M hominis isolates are sensitive to clindamycin, rifampin, fluoroquinolones, and tetracycline (163) The organism is resistant to aminoglycosides, sulfonamides, erythromycin, beta-lactam antibiotics, and other cell wall–active agents The treatment duration should be at least weeks A longer duration is indicated when severe, deep-seated infection is present Bone infection and endocarditis should be treated for a minimum of weeks Coinfection with Ureaplasma urealyticum has been described in a few patients (169,173) Because Ureaplasma organisms are resistant to clindamycin, avoiding the use of clindamycin or initiating therapy with more than one active drug pending the results of microbiologic studies is a sensible tactic RICKETTSIOSIS Bartonella Bartonella are fastidious, gram-negative bacilli that have been identified as the etiologic agent of a wide spectrum of clinical illnesses, including cat-scratch disease in normal hosts and bacillary angiomatosis, bacillary peliosis, and persistent bacteremia with fever in patients infected with human immunodeficiency virus Domestic cats serve as a natural reservoir for Bartonella henselae–associated disease in humans A common epidemiologic feature of this infection is recent contact with young cats, usually involving a scratch or bite (175) Unlike for B henselae, humans are the only known reservoir of Bartonella quintana, the etiologic agent of trench fever This infection is transmitted by Pediculus humanus, the human body louse (176) B quintana infection is frequently reported in homeless individuals, but it has not been reported after transplantation B henselae infection has been reported in kidney (177–179), liver (180,181), and heart (182) transplant recipients as early as 11 months and as late as 14 years after transplantation The clinical manifestations of Bartonella infection in transplant recipients can vary greatly Patients may present with the typical features of cat-scratch disease, regional lymphadenopathy, and fever, but this will often progress to a more severe, systemic illness if not treated promptly (177,180) Other patients not develop peripheral lymphadenopathy and instead progress to visceral involvement (179,181,182) Most transplant recipients with B henselae infection have involvement of the liver, spleen, or visceral lymph nodes that is initially detected by radiography and is then confirmed by biopsy and bacteriologic studies The liver and spleen are often studded with small nodules on gross examination, and they have multiple hypodense lesions (peliosis) on either computed tomography scan or ultrasonographic examination On histology, the lymph nodes have necrotizing granulomas with microabscesses, whereas visceral organs, such as the liver, usually demonstrate either necrotizing granulomas or epithelioid hemangiomatous lesions Rarely, other organs, such as the lungs, may also be involved (179) Transplant recipients have also been reported to develop bacillary angiomatosis, the form of Bartonella infection that is commonly seen in individuals infected with human immunodeficiency virus (183) Patients with bacillary angiomatosis present with fever and highly vascular, friable, red skin tumors They may also develop unusual lytic bone lesions that can be detected on plain radiographs An unusual form of bacillary angiomatosis involving the oral cavity has been reported following bone marrow transplantation Vegetating, pedunculated lesions up to cm were found on the tongue or buccal mucosa of the patients, most of whom were children The pathology showed granulation tissue with neoangiogenesis Gram-negative bacilli were seen invading endothelial cells in the lesions and the diagnosis was confirmed by PCR (184) Because Bartonella organisms are not routinely isolated from blood, establishing the diagnosis can be difficult, and it frequently requires the biopsy of involved tissues Culture of tissue specimens, such as those from the lymph node, skin, liver, and spleen, can confirm infection with the use of either blood or chocolate agar, but these cultures may require an incubation 58202_ch21.qxd 2/18/10 12:11 PM Page 305 Chapter 21 ■ Other Bacterial Infections after Hematopoietic Stem Cell or Solid Organ Transplantation period of as long as 30 days For this reason, performing PCR for the 16S RNA on tissue specimens may be preferable The diagnosis is also suggested by the appearance of typical coccobacillary organisms on a Warthin–Starry stain of the involved tissue or by demonstrating a positive serologic response Cat-scratch disease generally resolves without therapy in normal hosts and information regarding the relative effectiveness of antibiotics is limited One small randomized, controlled trial showed a greater decrease in lymph node volume over 30 days in patents treated with azithromycin as compared with placebo (185) Based on reports of successful treatment for bacillary angiomatosis, erythromycin or doxycycline should be active (186) Clarithromycin and azithromycin have in vitro activity that is superior to that of erythromycin, and they likely will prove to be clinically superior as well (175) Other evidence suggests that rifampin and aminoglycosides may also be useful (186) Coxiella Burnetti C burnetti, the etiologic agent of Q fever, is a pleomorphic coccobacillus with a gram-negative cell wall Infection is usually associated with exposure to infected livestock or unpasteurized milk The two most common clinical manifestations of disease are an acute febrile illness associated with pneumonia or hepatitis and a chronic febrile illness associated with endocarditis Infection has been reported in patients with a variety of immunocompromised conditions, such as leukemia and Hodgkin disease (187), but there are only a few reports of Q fever occurring in transplant recipients One patient developed fever and cough months after bone marrow transplantation for acute myeloid leukemia (188) Her symptoms resolved within days without specific therapy, but she was treated with doxycycline for weeks after the serologic diagnosis was made A similar presentation was reported in a young girl who developed acute lymphocytic leukemia years after a fetal liver and thymic transplant (189) The diagnosis was established retrospectively (6 weeks later) by serology, but no treatment was rendered because she was asymptomatic Nine months later, the patient developed a febrile illness, associated with seizures and hemiparesis, that was thought to be caused by recurrent C burnetti infection based on the rapid resolution of symptoms after treatment with tetracycline Based on these reports, treating patients when a positive serologic response is detected may be prudent to prevent recurrent or chronic infection The only reported case of Q fever after solid organ transplantation occurred in a 58-year-old renal transplant recipient from Arkansas who had pet goats and developed a multisystem disease with fever, diarrhea, hepatitis, diffuse pneumonitis, delirium, anemia, and thrombocytopenia He responded to an empiric 17-day course of doxycyline, which was continued for another weeks after the diagnosis was made by finding an elevated phase II IgM antibody (190) 305 Other Rickettsial Organisms Other rickettsial organisms that have been reported in transplant recipients include Rocky Mountain spotted fever and the agents of human ehrlichiosis The etiologic agents are fastidious, obligate, intracellular bacteria that have gram-negative cell walls and that are transmitted by tick vectors One patient has been reported with a typical presentation of Rocky Mountain spotted fever after heart transplantation (191) The patient’s course was relatively benign, with a response to weeks of treatment with doxycycline Although the diagnosis was initially made by immunofluorescent staining of a petechial skin lesion, the patient had an extremely delayed antibody response and only demonstrated seroconversion months after the infection The various forms of human ehrlichiosis have similar clinical manifestations but differ in their geographic distribution, the tick vector and the specific blood cells—either monocytes or granulocytes—that support infection An interesting characteristic of ehrlichiosis is that infection can sometimes be diagnosed by finding typical intracellular inclusions, called “morula,” in these blood cells Human monocytic ehrlichiosis caused by Ehrlichia chafeensis and transmitted by the lone star tick (Amblyomma americanum) was first reported in a liver transplant recipient from Kentucky in 1995 (192) This patient developed fever, pancytopenia, elevated transaminases, and shortness of breath weeks after a tick bite He recovered completely on empiric doxycycline therapy and the diagnosis was made later by serology Human granulocytic ehrlichiosis caused by Anaplasma phagocytophilum and transmitted by Ixodes scapularis was reported years later in a renal transplant recipient who developed fever, myalgia, diarrhea, and pancytopenia a week after being exposed to ticks while vacationing in a cabin in Minnesota (193) Ehrlichia ewingii is the agent that causes granulocytic ehrlichiosis in dogs It was first reported in humans in 1999 (194) Infection of humans with E ewingii appears to be less common and produces a milder illness than the other agents of ehrlichiosis Most reported cases have been in immunocompromised hosts, including transplant recipients (194,195) Thomas et al compared clinical characteristics of cases of ehrlichiosis, primarily diagnosed by PCR, in 15 transplant patients and 43 immunocompetent patients (195) On presentation, transplant recipients had less rash and lower hepatic enzyme elevations, but more leukopenia and renal dysfunction than the immunocompetent patients All transplant patients responded rapidly to doxycycline therapy and their mean hospital stay was only days These good outcomes in transplant patients differ somewhat from earlier reports (196,197) and may be 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