Ebook Transplant infections (3rd edition): Part 1

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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


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9 8 7 6 5 4 3 2 1
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)
1. Communicable diseases. 2. Transplantation of organs, tissues, etc.—Complications. 3. Nosocomial infections.
I. Bowden, Raleigh A. II. Ljungman, Per. III. Snydman, David R.
[DNLM: 1. Transplants—adverse effects. 2. Bacterial Infections—etiology. 3. Mycoses—etiology. 4. Virus Diseases—
etiology. WO 660 T691 2010]
RC112.T73 2010
617.9'5—dc22
2010001262
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10 9 8 7 6 5 4 3 2 1

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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 do 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


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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

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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

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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


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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


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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


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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
Marañón (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


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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


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Contents

Foreword iii
Preface v
Contributors vi

13

Risks and Epidemiology of Infections
after Liver Transplantation . . . . . . . . . . . . . . . . 162
Shimon Kusne and David C. Mulligan

14

Section I

Risks and Epidemiology of Infections after
Intestinal Transplantation . . . . . . . . . . . . . . . . . 179
Jorge D. Reyes and Michael Green

Introduction to Transplant Infections
1

Introduction to Hematopoietic Cell
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Andrew R. Rezvani and H. Joachim Deeg

2

Introduction to Solid Organ
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Section III

Specific Sites of Infection
15

Barry D. Kahan

3

Immunosuppressive Agents . . . . . . . . . . . . . . . . . 26

Catherine Cordonnier and Isabel Cunningham

16

Jason Rhee, Nora Al-Mana, Jeffery T. Cooper and Richard Freeman

4

Common Drug Interactions Encountered in
Treating Transplant-Related Infections . . . . . . . . 41

Pneumonia after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . 187
Skin Infections after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . 203
Mazen S. Daoud, Lawrence E. Gibson and W. P. Daniel Su

17

Helen W. Boucher, Kenneth R. Lawrence
and Lisa M. McDevitt

Central Nervous System Infections
after Hematopoietic Stem Cell or Solid
Organ Transplantation . . . . . . . . . . . . . . . . . . . . 214
Diana Averbuch and Dan Engelhard

18

Section II

George B. McDonald and Gideon Steinbach

Risks and Epidemiology of Infections
after Transplantation
5

Risks and Epidemiology of Infections
after Allogeneic Hematopoietic Stem
Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . 53
Juan Gea-Banacloche

6

Risks and Epidemiology of Infections
after Solid Organ Transplantation . . . . . . . . . . . . 67

Section IV

Bacterial Infections
19

Ingi Lee and Emily A. Blumberg

7

Donor-Derived Infections: Incidence,
Prevention and Management . . . . . . . . . . . . . . . . 77
Transplant Infections in Developing
Countries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90

Typical and Atypical Mycobacterium
Infections after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . 282
Jo-Anne H. Young and Daniel J. Weisdorf

21

Clarisse M. Machado

9

Gram-Positive and Gram-Negative
Infections after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . . 257
Dan Engelhard

20

Michael G. Ison

8

Gastrointestinal Infections after Solid Organ
or Hematopoietic Cell Transplantation . . . . . . . 236

Risks and Epidemiology of Infections
after Heart Transplantation . . . . . . . . . . . . . . . . 104

Other Bacterial Infections after Hematopoietic
Stem Cell or Solid Organ Transplantation . . . . . 295
J. Stephen Dummer and Tue Ngo

David DeNofrio and David R. Snydman

10

Risks and Epidemiology of Infections
after Lung or Heart–Lung Transplantation . . . . 114
Joan Gavaldà, Antonio Román and Albert Pahissa

11

Infections in Kidney Transplant Recipients . . . . 138

Section V

Viral Infections
22

Deepali Kumar and Atul Humar

12

Risks and Epidemiology of Infections
after Pancreas or Kidney–Pancreas
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Atul Humar and Abhinav Humar

Cytomegalovirus Infection after Stem
Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . 311
Morgan Hakki, Michael J. Boeckh and Per Ljungman

23

Cytomegalovirus Infection after Solid
Organ Transplantation . . . . . . . . . . . . . . . . . . . . 328
Raymund R. Razonable and Ajit P. Limaye

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Contents

Epstein–Barr Virus Infection and
Lymphoproliferative Disorders after
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 362

38

Endemic Mycoses after Hematopoietic
Stem Cell or Solid Organ Transplantation . . . . . 607
Carol A. Kauffman

Jutta K. Preiksaitis and Sandra M. Cockfield

25

Herpes Simplex and Varicella-Zoster
Virus Infection after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . 391
John W. Gnann, Jr

26

Infections with Human Herpesvirus–6, –7,
and –8 after Hematopoietic Stem Cell

or Solid Organ Transplantation . . . . . . . . . . . . . 411
Nina Singh

27

Community-Acquired Respiratory
Viruses after Hematopoietic Stem Cell
or Solid Organ Transplantation . . . . . . . . . . . . . 421

Section VII

Other Infections
39

Rodrigo Martino

40

41

29

Adenovirus Infection in Solid Organ
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 459
Michael Green, Michael G. Ison and Marian G. Michaels

30

Polyoma and Papilloma Virus Infections
after Hematopoietic Cell or Solid Organ

Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 465

Section VIII

Infection Control
42

Infection Control Issues after
Hematopoietic Stem Cell Transplantation . . . . 653
Robin K. Avery and David L. Longworth

43

Hans H. Hirsch

31

Parasites after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . 632
Roberta Lattes and Marcelo Radisic

Adenovirus Infection in Allogeneic
Stem Cell Transplantation . . . . . . . . . . . . . . . . . 447
Susanne Matthes-Martin

Toxoplasmosis after Solid Organ
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . 624
Jose G. Montoya and Mitchell R. Lunn

Janet A. Englund and Estella Whimbey

28

Toxoplasmosis Following Hematopoietic
Stem Cell Transplantation . . . . . . . . . . . . . . . . . 617

Hepatic Infections after Solid Organ
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Infection Control Issues after Solid
Organ Transplantation . . . . . . . . . . . . . . . . . . . 667
Maria Teresa Seville, Sharon Krystofiak and Shimon Kusne

Ed Gane

32

Hepatitis B and C in Hematopoietic
Stem Cell Transplant . . . . . . . . . . . . . . . . . . . . . 498
Anna Locasciulli, Barbara Montante and Maria Beatrice Pinazzi

Section IX

Immune Reconstitution Strategies for
Prevention and Treatment of Infections
44

Section VI

Per Ljungman

45

Fungal Infections
33

Yeast Infections after Hematopoietic
Stem Cell Transplantation . . . . . . . . . . . . . . . . . 507

Growth Factors and Other
Immunomodulators after Transplantation . . . . 705
Jack W. Hsu and John R. Wingard

46

Tamara Aghamolla, Brahm H. Segal and Thomas J. Walsh

34

Vaccination of Transplant Recipients . . . . . . . . 691

Yeast Infections after Solid Organ
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 525

Adoptive Immunotherapy with
Herpesvirus-specific T Cells after
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 724
Hermann Einsele, Max S. Topp, Stanley R. Riddell

Peter G. Pappas

35

Mold Infections after Hematopoietic
Stem Cell Transplantation . . . . . . . . . . . . . . . . . 537
William J. Steinbach and Kieren A. Marr

36

Aspergillus and Other Mold Infections
after Solid Organ Transplant . . . . . . . . . . . . . . . 554
Patricia Muñoz, Maddalena Giannella, Almudena Burillo
and Emilio Bouza

37

Section X

Hot Topics
47

Staci A. Fischer

48

Infections Caused by Uncommon
Fungi in Patients Undergoing
Hematopoietic Stem Cell or Solid
Organ Transplantation . . . . . . . . . . . . . . . . . . . 586
John W. Hiemenz, Andreas H. Groll and Thomas J. Walsh

Emerging and Rare Viral Infections
in Transplantation . . . . . . . . . . . . . . . . . . . . . . . 745
Travel Medicine, Vaccines and
Transplant Tourism . . . . . . . . . . . . . . . . . . . . . . . .756
Camille Nelson Kotton

Index

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I ■ Introduction to Transplant Infections
CHAPTER

Introduction to Hematopoietic
Cell Transplantation

1

ANDREW R. REZVANI, H. JOACHIM DEEG

The lymphohematopoietic system is the only organ system in
mammals that has the capacity for complete self-renewal.
Therefore, donation of lymphohematopoietic stem cells does not
result in a permanent loss for the donor. Reports on the therapeutic use of bone marrow to treat anemia associated with parasitic
infections date back a century (1,2), but not until the observations
on irradiation effects in Hiroshima and Nagasaki and the ensuing
systematic research into hematopoietic cell transplantation (HCT)
in animal models were the principles of HCT established (1,3,4).
In 1957, the first clinical transplant attempts of the modern
era were undertaken (1,5,6). As predicted from animal studies,
patients who underwent transplantation from allogeneic donors
(i.e., individuals who were not genetically identical) developed
graft-versus-host disease (GVHD) (4). Patients transplanted
from syngeneic (monozygotic twin) donors generally did not
develop GVHD, but many of them died from progressive
leukemia, apparently because of a lack of the allogeneic graftversus-leukemia (GVL) effect which had been described by Barnes
and Loutit (7) in murine models. These studies immediately established that allogeneic HCT functioned as immunotherapy.
Beginning in the late 1950s and early 1960s, Dausset et al.
characterized the first histocompatibility antigens in humans
(8). Epstein et al. were the first to show the relevance of those
histocompatibility antigens for the development of GVHD in
an outbred species (9). Initially, the only source of hematopoietic
stem cells (HSC) in clinical use was bone marrow. However,
cells harvested from peripheral blood, either after recovery
from chemotherapy or after the administration of hematopoietic growth factors such as granulocyte-colony stimulating factor (G-CSF), were shown to result in accelerated hematopoietic
recovery after autologous transplantation. These cells, as well as
cord blood cells, are now being used with increasing frequency
in allogeneic transplantation (10,11).

RATIONALE AND INDICATIONS
FOR HEMATOPOIETIC CELL
TRANSPLANTATION
Current indications for HCT are summarized in Table 1.1. The
majority of HCT is performed to treat malignant diseases.
Myelosuppression is the most frequent dose-limiting toxicity of

TABLE 1.1

Categories of Disease Treated with
Hematopoietic Cell Transplantation

Malignant
Hematologic malignancies
Acute leukemias
Chronic leukemias
Myelodysplastic syndromes
Myeloproliferative syndromes
Non-Hodgkin lymphoma
Hodgkin lymphoma
Plasma cell dyscrasia (e.g., multiple myeloma)
Selected solid tumors
Renal cell carcinoma
Ewing sarcoma
Neuroblastoma
Breast, colon, ovarian, and pancreatic cancer
(investigational)
Nonmalignant
Acquired

Aplastic anemia and red cell aplasias
Paroxysmal nocturnal hemoglobinuria
Autoimmune disorders (e.g., multiple sclerosis, lupus
erythematosus, systemic sclerosis, rheumatoid arthritis)
Congenital
Immunodeficiency syndromes (e.g., SCID)
Hemoglobinopathies
Congenital anemias (e.g., Fanconi anemia)
Storage diseases (e.g., mucopolysaccharidoses)
Bone marrow failure syndromes (e.g., dyskeratosis
congenita)
Osteopetrosis

the chemoradiotherapy used to treat malignancies. Infusion of
HSC—autologous or allogeneic—as a “rescue” procedure allows the dose escalation of cytotoxic therapy, such that toxicity
in the next most sensitive organs (intestinal tract, liver, or lungs)
becomes dose-limiting. This strategy, often referred to as highdose therapy with stem cell rescue, has been used extensively in
the past. However, progressive dose intensification, although
possibly effective in disease eradication, has resulted in minimal,
if any, improvement in survival because of an increase in
therapy-related toxicity and mortality. These observations, combined with an increasing appreciation of the central role of immunologic graft-versus-tumor (GVT) reactions in the success of
1


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Introduction to Transplant Infections

allogeneic HCT, have led to new concepts of transplant conditioning (see “Modalities for Transplant Conditioning”) (12).
“Replacement” therapy in patients with congenital or acquired disorders of marrow function, immunodeficiencies, or
storage diseases represents a second indication for HCT.
Patients with autoimmune diseases (e.g., rheumatoid arthritis
or systemic sclerosis) can also be considered part of this category (13). In contrast to the benefit from GVT alloreactivity in
the malignant setting, patients with these nonmalignant disorders are not thought to derive any benefit from alloreactivity
beyond its “graft-facilitating” effect.
Finally, HSC (or their more mature progeny) may be effective vehicles for gene therapy (14) and for immunotherapy.
Objectives of gene therapy include the replacement of defective
or missing enzymes (e.g., adenosine deaminase, glucocerebrosidase) or of the defective gene (15,16). Experience with the use of
allogeneic cells, often T lymphocytes, as immunologic bullets is
more extensive. Donor lymphocyte infusion (DLI) for reinduction of remission in patients with chronic myelogenous leukemia
(CML) who have relapsed after HCT has been remarkably successful, leading to broader application of this approach. A modification of this strategy is the use of genetically modified donor
lymphocytes expressing a “suicide gene,” which may be activated
to abrogate the adverse effects of DLI, particularly GVHD (17).
The principle of immunotherapy is also exploited in
reduced-intensity conditioning (RIC), also referred to as nonmyeloablative or “mini” transplants (both terms, however, are
misleading, as the end result is intended to be “ablation” of the
disease, and a mini-transplant is still a full transplant, albeit with
a lower-intensity conditioning regimen). In this approach, the

intensity of the conditioning regimen has been reduced with the
objective of preventing early mortality, and donor antihost reactivity has been enhanced to eliminate host cells (Fig. 1.1) (18).

FIGURE 1.1. Commonly used conditioning regimens for
hematopoietic cell transplantation, stratified by intensity, toxicity,
and relative reliance on immunological graft-versus-tumor
effects. Abbreviations: GVT, graft-versus-tumor; CY, cyclophosphamide; TBI, total body irradiation; Gy, gray; FLU, fludarabine;
BU, busulfan; ATG, antithymocyte globulin; araC, cytarabine.

SOURCES OF HEMATOPOIETIC STEM
CELLS AND DONOR SELECTION
HSC can be obtained from a variety of donors and cellular
compartments, including the bone marrow, peripheral blood,
cord blood, and the fetal liver. The choice of stem cell source is
dependent upon several factors. Although autologous marrow
or peripheral blood stem cells (PBSC) are theoretically available for every patient (feasibility has been reported even for
patients with severe aplastic anemia), these would not be useful without genetic manipulation for genetically determined
disorders, and would be suboptimal for malignant disorders,
because of the concern of contamination with malignant cells
and the lack of an allogeneic antitumor effect. An HLAhaploidentical donor (e.g., parent, sibling, child) is available
for most patients, and, while clearly investigational at this
time, early results show surprisingly low rates of GVHD and
graft rejection (19).
Generally, each sibling has a 25% chance of sharing the
HLA genotype of a patient. Phenotypically matched donors
can be identified among family members in about 1% of patients, and somewhat less than 1% of patients will have a syngeneic (identical twin) donor. The lack of an HLA-identical
related donor in more than 70% of patients has led to the development of (a) large data banks of volunteer unrelated
donors; (b) research into alternative allograft sources such as
HLA-haploidentical family members and umbilical cord
blood, as indicated earlier; and (c) techniques to “purge” autologous cells of tumor contamination.

Supported by the efforts of the National Marrow Donor
Program in the United States, the Anthony Nolan Appeal in
the United Kingdom, and other groups internationally, more
than 10 million volunteer donors have been typed for HLA-A
and HLA-B, and a rapidly increasing number also for HLA-C,
HLA-DR (DRB1), and HLA-DQ antigens (20). The probability of finding a suitably HLA-matched donor for a white
patient in North America is about 70% to 80%. This probability is lower for other ethnic groups, in part because of lower
representation in the data bank and in part because of greater
polymorphism of the HLA genes (21).
Cord blood cells, generally not matched for all HLA antigens of the patient, are being used with increasing frequency
(22), while fetal liver cells have been used only very rarely in
recent years.
Autologous marrow or PBSC can be purged of contaminating malignant cells by chemical means or by antibodies
that recognize tumor cells. However, slow engraftment and
residual tumor cells that resist the purging regimen limit
the usefulness of this approach. A complementary approach is
aimed at purifying stem cells using specific antibodies
to positively select cells bearing CD34, which is the closest
that the research community has come to characterizing
human HSC.


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Chapter 1

TRANSPLANT PROCEDURE
Transplant Conditioning
Rationale for Conditioning
1. To eradicate (ablate) the patient’s disease, or at least to reduce the number of malignant or abnormal cells to below
detectable levels (this applies to allogeneic, syngeneic, and
autologous donors).
2. To suppress the patient’s immunity and to prevent rejection
of donor cells (this applies to allogeneic, but not to autologous, HCT). Immunosuppression is also needed in preparation for some syngeneic transplants, apparently to
eliminate autoimmune reactivity which may interfere with
sustained hematopoietic reconstitution.
The notion that conditioning is necessary to “generate
space” in the transplant recipient has essentially been abandoned. Recent data show that donor cells, given in sufficient
numbers, create their own space and proceed to repopulate the
recipient’s marrow (23).
Exceptions to the conditioning requirement exist in children with severe combined immunodeficiency (SCID), because of the nature of the underlying disease, which does not
allow them to reject transplanted donor cells, and in patients
in whom even partial donor engraftment can completely correct the genetic defect (24).

■

Introduction to Hematopoietic Cell Transplantation

3

expressed on the recipient’s malignant cells; in addition, cytokines or cytokine antagonists are being investigated. AntiT-cell therapy predisposes the individual to viral infections,
in particular cytomegalovirus (CMV) and the development
of Epstein–Barr virus (EBV)-related lymphoproliferative
disorders (PTLD) after transplantation (31).

4. T-cell therapy is based on the observation that broad T lymphocyte depletion of donor marrow resulted in graft failure. This has led to protocols of selective T-cell add-back to
ensure engraftment. The observation that DLI was effective in inducing remission in a proportion of patients who
had experienced relapse after HCT renewed the interest in
exploiting T-cell therapy for the treatment of leukemia.
Other indications for T-cell therapy are viral infections
such as CMV (32) or EBV, especially with the development
of PTLD in the latter (33).
Other procedures involve plasmapheresis of the recipient’s blood to remove isoagglutinins directed against the
donor’s ABO blood group or the removal of plasma from the
donor marrow to remove the isoagglutinins directed at recipient cells. Alternatively, the donor red blood cells with which
recipient antibodies may react can be removed, thus minimizing transfusion reactions. Due to the procedure by which they
are obtained, these additional manipulations are generally not
required with PBSC.
Marrow Harvest

Modalities for Transplant Conditioning
Modalities used to prepare patients for HCT have been reviewed extensively elsewhere (25,26); commonly used regimens are listed in Figure 1.1. In principle, conditioning for
HCT may include the following approaches:
1. Irradiation is in the form of total body irradiation (TBI),
total lymphoid irradiation (27), or modifications thereof.
Many conventional TBI regimens deliver 1200 to 1400 cGy
over 3 to 6 days. In addition, bone-seeking isotopes (e.g.,
holmium) and isotopes (e.g., 131I, 92Y) conjugated to monoclonal antibodies (MAbs) directed at lymphoid or myeloid
antigens (e.g., anti-CD20, CD45) are in use (28). TBI may
also be a component of RIC regimens, usually at lower
doses of 2 Gy (29).
2. Chemotherapy (e.g., cyclophosphamide, 120 to 200 mg/kg
over 2 to 4 days) is included in many conventional regimens.
Busulfan (available in oral and intravenous formulations) at
16 mg/kg (or lower doses), targeted to predetermined plasma

levels, is often used in combination with cyclophosphamide.
Other agents, including etoposide, melphalan, thiotepa, cytarabine, and more recently treosulfan (30), may be used either alone or in combination (with or without irradiation).
3. Biologic reagents (e.g., antithymocyte globulin (ATG)) or
MAbs directed at T-cell antigens or adhesion molecules suppress recipient immunity. Others are directed at antigens

The marrow donor receives general or regional (e.g., epidural,
spinal) anesthesia, and, under sterile conditions, multiple aspirates of marrow are obtained from both posterior iliac crests
(34). Additional potential aspiration sites are the anterior iliac
crests and the sternum. Approximately 10 to 15 mL/kg of
donor weight is collected. If no ABO incompatibility exists
and if the marrow is not to be subjected to any in vitro purging
procedure, the resulting cell suspension is infused intravenously without manipulation.
Alternative Stem Cell Sources
HSC circulate at low concentrations in blood (35). Their frequency increases dramatically during the recovery phase following cytotoxic therapy, and after the administration of
recombinant hematopoietic growth factors such as G-CSF
which dislodge cells from the marrow. Peak blood concentrations of CD34ϩ cells are typically reached on day 4 to 5 after
initiating G-CSF. A single leukapheresis may be sufficient to
harvest the number of HSC required for a transplant. For autologous procedures, the goal is to collect at least 2 to 5 ϫ
106 CD34ϩ cells/kg recipient weight; for allogeneic transplants, the goal is 5 to 8 ϫ 106 CD34ϩ cells/kg, although the
optimum dose has not been determined (36).
Umbilical cord blood represents a segment of the peripheral circulation of the fetus and is easily accessible (37). Also,


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Introduction to Transplant Infections

cord blood cells are less immunocompetent than adult cells,
and might therefore carry a lower risk of inducing GVHD
than adult cells. The concentration of HSC in umbilical cord
blood is high, but the small volume that is usually available
(80–150 mL) initially limited the use of these cells to children
and smaller adults. In larger adults, approaches have included
the use of two cord blood units to ensure adequate cell dose
and engraftment (11), as well as ex vivo expansion of
hematopoietic precursors in umbilical cord blood units for infusion together with an unmanipulated cord blood unit (38).
Purging
Several rationales exist for purging collected donor cells or
fractionating them into subpopulations. In the autologous setting, the goal is to eliminate contaminating tumor cells, either
by negative selection (removal of tumor cells with antibodies
or physicochemical means) or by positive selection (purification of CD34ϩ cells from the graft). Conversely, one may want
to retain certain populations (e.g., CD4ϩ cells) with potential
for later uses such as posttransplant DLI.
Hematopoietic Stem Cell Infusion:
The Actual Transplant
Donor cells are infused intravenously via an indwelling central line, often a Hickman catheter. Directed by surface molecules which interact with receptors on endothelial cells, HSC
home to the marrow cavity. The actual infusion of stem cells is
generally uneventful, though it can occasionally cause transient mild hypotension or hypersensitivity reactions.

CARE AFTER TRANSPLANTATION

Complications of HCT, including infections, are related to several factors: the underlying disease, the preparative regimen,
and the interactions of donor cells with recipient tissue (GVHD
with immunosuppression and end-organ damage). All patients
experience at least transient pancytopenia, although this may be
mild with RIC regimens. Patients undergoing high-dose conditioning generally develop severe pancytopenia, including neutropenia, within days after completion of conditioning. This
period may last 2 to 4 weeks with marrow allografts, 10 to
12 days with mobilized PBSC grafts, or 4 to 6 weeks with
umbilical cord blood grafts. The period of neutropenia ends
with engraftment of the donor cells, clinically defined by stable
increases in the white blood cell count. Cytopenias are less
pronounced after RIC, and the pattern of engraftment may be
less apparent in the peripheral white blood cell count.
Engraftment in these patients is generally documented by
demonstrating donor chimerism by cytogenetic or molecular
means in peripheral blood leukocytes and bone marrow.
Most patients prepared with high-dose regimens require
transfusion support with platelets, red blood cells, or both.

Immune cell counts (% normal)

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Graft infusion

120

Neutrophils, monocytes,
NK cells

100

B cells, CD8 T cells
CD4 T cells

80

Plasma cells, dendritic cells

60

Upper normal limit

40

Lower normal limit

20
0

Weeks

Months

Years posttransplant

FIGURE 1.2. Approximate trends in immune cell counts after
myeloablative hematopoietic cell transplantation. With the use
of reduced-intensity conditioning, nadirs are higher and occur

later. These recovery rates may be influenced by clinical variables such as graft-versus-host disease, stem cell source, and
patient age. (Adapted from Storek J. Immunological reconstitution after hematopoietic cell transplantation—its relation to
the contents of the graft (Review). Expert Opin Biol Ther.
2008;8:583–597.)

Transfusion requirements are substantially reduced in patients
prepared with RIC regimens, because the nadir of cells often
is in a range in which no transfusions are required (39).
Erythropoietin administration after HCT accelerates reticulocyte recovery and moderately reduces red blood cell transfusion requirements in patients undergoing allogeneic (though
not autologous) HCT (34).
Quantitative and functional deficiencies of granulocytes
and T-lymphocytes for various periods after HCT are responsible for most of the infectious complications seen after HCT
(Fig. 1.2). Although all patients receive prophylactic antimicrobials, granulocyte transfusions are not routinely given.
Laminar air flow (LAF) rooms and gastrointestinal decontamination may reduce the frequency of infections and the duration of febrile episodes, but neither is used routinely because
of the high cost of LAF and the availability of effective broadspectrum antibiotics (40).
The most widely used modality of GVHD prophylaxis is
the in vivo administration of immunosuppressive agents, such
as methotrexate, cyclosporine (CSP), glucocorticoids, tacrolimus
(FK506), mycophenolate mofetil (MMF), sirolimus and others,
either alone or in combination (41). At many institutions, the
current standard is a combination of a calcineurin inhibitor
with methotrexate or MMF, but several other combinations are
used. Due to the nonselectivity of these agents, recipients are
broadly immunosuppressed and thus susceptible to infections.
In vitro T-lymphocyte depletion of donor marrow may obviate
the need for immunosuppressive treatment after HCT; however, the elimination of mature T-cells is associated with a risk
of rejection, delayed immunologic reconstitution, an increased
risk of PTLD, and, for some disorders, disease recurrence.
Both immunodeficiency and therapeutic immunosuppression
predispose the patient to infections. Whether the selective removal of naive T-cells will lead to successful transplants without GVHD remains under investigation.

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HEMATOLOGIC RECOVERY
A high-risk period for infections in patients conditioned with
high-dose regimens exists early after transplantation, when granulocytopenia develops due to the decline in endogenous marrow
function while donor cells are not yet proliferating. If the donor
marrow is T-cell depleted, the recovery may be even more protracted. If the granulocyte count at day ϩ21 after transplantation
is less than 200 cells/␮L, patients are generally given G-CSF or
granulocyte-macrophage colony-stimulating factor. After PBSC
transplants, engraftment (defined by Ͼ500 granulocytes/␮L)
occurs as early as day ϩ9 or ϩ10, thus clearly shortening the
length of granulocytopenia. Rather slower recovery (over several
weeks) may be seen with cord blood transplants (42).
One advantage of RIC regimens is the slow decline of patient cells, so that donor cells begin to recover before patient
cells reach their nadir. Consequently, several groups have reported lower rates of early infection after RIC conditioning as
compared with high-dose conditioning (43,44).

IMMUNOLOGIC RECOVERY
All components of the innate and adaptive immune systems
are deficient after HCT. Cell-mediated immunity, chemotaxis, and neutrophil function are severely impaired even after

autologous transplants. The development of GVHD substantially impairs immune reconstitution, through a combination
of direct graft-versus-host toxicity to the thymus resulting in
altered T-cell selection and use of immunosuppressive therapies to treat GVHD. Thus, optimal immune reconstitution
can only occur in the absence of GVHD (45).
Uncomplicated Recovery
Shortly after HCT, damaged epithelial barriers facilitate the
penetration of pathogenic bacterial or fungal organisms.
Mucosal surfaces begin to heal within a week or two of completion of high-dose conditioning, helped by the recovery of granulocytes and their scavenging function, even though phagocytosis
and superoxide production may still be impaired. After the
transplant, the volume and immunoglobulin content of saliva
also improve with time. Even with uncomplicated recovery,
T- and B-cell-mediated immune responses against viral, bacterial, fungal, and other organisms are broadly suppressed; natural killer (NK) cells recover more quickly. To some extent, the
pattern of immune recovery is dependent on the immunity of
the donor from whom the transplanted cells originated. The
pattern of immunocompetence is also influenced by the recipient’s prior antigen exposure, whether to the pathogen itself or in
the form of a vaccine. Much of the literature on immune reconstitution after allogeneic HCT describes patients who were
prepared with high-dose conditioning. While the use of RIC

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5

regimens has increased rapidly in recent years, there are fewer
data available on immune recovery in this setting, and the impact of RIC on immune reconstitution remains somewhat unclear. Preliminary studies suggest that the tempo of immune
recovery may be faster after RIC (46), but late immune function
may be similar to that seen after high-dose conditioning (47).
B Cells
B-cell numbers are undetectable or very low shortly after

high-dose conditioning, but may rise to supranormal levels by
1 to 2 years (48). Recovery is faster with autologous than with
allogeneic HCT; memory B cells lag behind naive cells. Early,
but not late, recovery for both populations is faster for PBSC
recipients than for marrow recipients (49). The B-cell compartment is generally replaced completely by donor-derived cells,
except in patients with TϩBϪ SCID, in whom the recipient’s
B cells tend to persist (50). Nonetheless, some antibodies of host
origin (e.g., isoagglutinins) that are derived from long-lived
plasma cells may be detectable for months or even years after
HCT. Persistently low B-cell counts after HCT may predict
a high risk of infection (51). In the era of targeted therapy,
treatment with B-cell-directed monoclonal antibodies such
as rituximab prior to HCT may also impair B-cell reconstitution, though relatively little is known about the long-term
implications (52).
During recovery, fewer B cells express CD25 and CD62L;
more express CD9c, CD38, IgM, and IgD; and the antigen
density is increased (as in neonatal B cells). CD5ϩ cells may or
may not be increased. Immunoglobulin gene usage appears to
be restricted shortly after HCT and to be skewed toward the
V-segments that are frequently used in neonatal B cells (e.g.,
VH6). Concordantly, the antibody repertoire is restricted (53).
IgG and IgA production may be abnormal for 1 to 2 years
after HCT. Serum isotype levels after grafting recover in the
same sequence as they evolve in neonates (i.e., IgM, IgG1, and
IgG3 recover early, but IgG2, IgG4, and IgA may not follow
until much later) (54). Many of the early antibodies are autoantibodies, or else have irrelevant specificities (55). Antibodies
with relevant specificities recover only if the antigen is encountered, and they recover more quickly if both patient and
donor are immune (56). At 3 months after HCT, total IgG levels in recipients of allogeneic PBSC tend to be lower than those
in marrow recipients. Antibodies to polysaccharide antigens
tend to recover later than those directed at proteins. B-cell

counts and IgM levels may recover more quickly after RIC as
compared to high-dose conditioned patients, though IgA
recovery is delayed in both groups (46). In addition to quantitative deficits in B-cell number and immunoglobulin levels,
the B-cell pool early after HCT is marked by qualitative
functional impairment. Isotype switching is deficient in the
absence of effective T-cell help. Additionally, B cells from
transplant recipients have a decreased capacity for somatic


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hypermutation independent of T-cell help, suggesting an
intrinsic or environmental defect (57). Thus, B-cell deficits
after HCT are comprised of at least three factors: low B-cell
numbers, decreased T-cell help, and intrinsic defects such as
impaired somatic hypermutation (54).

Antibody responses to vaccination are almost universally
lower than are those of normal controls, and repeated boosters
are required (58). Responses are better in younger individuals
and in those with T-cell-replete grafts; this may be related to
CD4 recovery, which is faster in younger individuals. The policy has been to delay revaccination until 1 to 2 years after HCT
to minimize the risk of potential side effects and to increase
the probability of antibody responses.

least 18 months (60,61). Even established and refractory CMV
infections can be treated effectively by the infusion of expanded CMV-specific CD8ϩ donor cells (62). The logistical
difficulty of generating CMV-specific cells for clinical use has
been a barrier to the wide application of this approach.
However, several groups have reported progress in developing
simpler and more scalable means of producing virus-specific
donor T cells for infusion (63,64).
The role of immunoregulatory CD4ϩCD25ϩ T cells
(Treg) in clinical transplantation remains to be fully established (65).

T Cells

Monocytes reach normal levels within 1 month after high-dose
conditioning, although their function may remain impaired for
a year (66). G-CSF-mobilized PBSC contain large numbers of
monocytes with altered cytokine profiles that may suppress allogeneic T-cell responses. G-CSF-mobilized monocytes appear
to settle in tissue in the early posttransplantation period.
The reconstitution of dendritic cells (DC), their maturation, and the development of DC1 and DC2 have been incompletely characterized. DC precursors in the blood recover
within 6 months, and DC reconstitution appears to be a clinically important event. Low numbers of DC at 1 month after
reduced-intensity HCT have been associated with an increased risk of mortality and disease relapse; CD16ϩ DC
counts at 3 months were also strongly prognostic (67). A separate investigation found that low numbers of plasmacytoid
DC at 3 months after HCT were associated with higher risks

of infection and death (68). Langerhans cell levels are low in
the early posttransplantation period, but return to normal by
6 months. Follicular DC are reconstituted rather slowly,
which may contribute to the delayed return to function of the
germinal centers and memory B cells (58).

CD4؉ Cells
The number of CD4ϩ cells is low for 1 to 3 months after highdose conditioning, and rises slowly toward normal over several
years. This rise is faster in children than in adults (58). The
kinetics are similar following both autologous and allogeneic
transplants. Early in the process, most cells are memory T cells;
naive T cells follow quite gradually, particularly in older
patients. This might be related to diminished thymic function,
although the thymus appears to play some role in T-cell reconstitution even in older patients (59). After PBSC transplantations,
both naive and memory CD4ϩ T cells are more abundant than
after marrow transplantations. Early after HCT, most CD4ϩ
T cells are derived from transplanted mature T cells and T-cell
precursors; later, they are stem-cell-derived, at least in pediatric
patients. CD4ϩ T-cell reconstitution may occur more rapidly
after RIC as compared to high-dose conditioning (46).
CD4ϩ T cells generally express CD11a, CD29, CD45RO,
and HLA-DR and less CD28, CD45RA, and CD62L, consistent with the prominence of memory cells (58). Responses to
polyclonal stimuli are low. Proliferative responses to frequently encountered antigens (e.g., Candida species) tend to
normalize over 1 to 5 years, whereas responses to unlikely
antigens (e.g., tetanus) remain subnormal. Responses to
neoantigens (e.g., dinitrochlorobenzene) and recall antigens
(e.g., mumps) are abnormally low for 2 to 3 years after HCT.
CD8؉ Cells
CD8ϩ T cells are low for 2 to 3 months after HCT; subsequently, they rise quickly, resulting in an inversion of the typical CD4:CD8 ratio (58). These CD8ϩ cells are largely memory
cells expressing CD11a, CD11b, CD29, CD57, HLA-DR, and

CD45RO but little CD28, CD45RA, and CD62L. The presence of a CD11bϩCD57ϩCD28Ϫ phenotype suggests anergic
or suppressive CD8 cells. CD8ϩ cells appear to be derived
from transplanted T cells and stem cells.
CMV-specific or EBV-specific CD8ϩ cells can be transferred successfully to a recipient, and they may persist for at

Antigen-Presenting Cells

Natural Killer Cells
NK cells recover rapidly after HCT. With the recognition of
the killer inhibitory receptor, renewed interest in these cells
has been seen because of their possible function in engraftment
and the prevention of relapse (69). Robust NK-cell reconstitution after allogeneic HCT has been associated with reduced
relapse and improved survival (70).

GRAFT-VERSUS-HOST DISEASE AND
GRAFT-VERSUS-LEUKEMIA EFFECT
Acute and chronic GVHD occur in 10% to 50% and 20% to
50%, respectively, of patients after HLA-identical sibling
HCT, and in 50% to 90% and 30% to 70%, respectively, of
patients who undergo transplantation from alternative donors


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(71,72). Without prophylaxis, virtually all recipients of allogeneic transplants develop GVHD (73). Acute GVHD is the
strongest risk factor for the development of chronic GVHD
(74,75). Acute GVHD may occur within days (e.g., among
HLA-nonidentical recipients) or by 3 to 5 weeks after HLAidentical transplantation following high-dose conditioning.
The main target organs are the immune system, skin, liver,
and intestinal tract. Only the skin, liver, and intestinal tract are
generally considered in GVHD grading systems (76).
Importantly, after RIC, classic manifestations of acute GVHD
may develop several months after HCT and may overlap considerably with those of chronic GVHD (77). Features of
chronic GVHD may be present as early as 50 to 60 days after
HCT. Therefore, recently developed NIH consensus criteria
distinguish acute from chronic GVHD on the basis of pathology and biology, rather than time of onset (78).
HCT is unique in that donor/host tolerance frequently
develops over time, to the point that maintenance immunosuppression can often be discontinued. In patients without
GVHD, all immunosuppressive medication is generally
stopped by 6 months to 1 year after HCT. Even chronic
GVHD is not necessarily a lifelong condition; many patients
with chronic GVHD develop tolerance and resolution of
GVHD over time, and are ultimately able to discontinue immunosuppressive treatment (79,80).
The immunopathophysiology of GVHD is complex.
The initial damage to host tissue is induced by the transplantconditioning regimen (81). The subsequent development of
acute GVHD requires antigen presentation; Shlomchik et al.
showed that host DC play a pivotal role in this process (82).
Interactions of major histocompatibility complex (MHC)
antigens (with bound peptides derived from minor histocompatibility antigens) and T-cell receptors lead to activation, clonal
expansion, and differentiation of donor T cells. Accessory T-cell
surface molecules, such as CD4 or CD8, also contribute to the
immunologic synapsis between T cells and antigen-presenting

cells. The effector phase leads to host-cell destruction via inflammatory signals, cytolytic effects, and programmed cell
death (apoptosis). Inflammatory cytokines, which are primarily
released from the gut, allow the transfer of endotoxins and
lipopolysaccharides (LPS) into the circulation, triggering
macrophage activation. The result is the further production of
cytokines, such as tumor necrosis factor ␣ (TNF␣) and interleukin 1 (IL-1) (83), leading to target cell death and the expression of costimulatory molecules, such as CD80, CD86, and
MHC class II antigens, on DC; T-cell stimulation; and the release of T helper-1 (Th1) cytokines (IL-2, interferon-␣ (IFN-␣)).
Recent experiments also emphasize the role of other cytokines, particularly TNF␣, IL-15, and IL-18 (84). In mouse
models, TNF␣ is a central mediator of GVHD that works
predominantly in the intestinal tract. Anti-TNF antibodies
prevent or ameliorate GVHD in mice (85). In humans, antiTNF therapy appears active in treating established acute

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7

GVHD (86), but ineffective as GVHD prophylaxis (87).
However, the actions of different cytokines and effector cells
(e.g., large granular lymphocytes) and regulatory cells are still
incompletely understood. The role of regulatory T cells with a
CD25ϩCD4ϩ phenotype, which is functionally reminiscent of
the classic “suppressor T cell,” is currently being defined (65),
as is the role of Th17 cells (88,89).
Elevated serum levels of soluble Fas ligand (FasL) have
been observed in some patients with GVHD (90), though
Fas-mediated apoptosis may also be involved in the control of
alloreactive T cells (91). Perforin-mediated cytotoxicity also
plays a role in both GVHD and GVL effects (92,93). However,

even T cells from mice doubly deficient in both FasL and perforin can cause GVHD after mismatched-donor HCT (94).
Stem Cell Source
The kinetics of GVHD depend upon the source of stem cells.
PBSC mobilized by means of chemotherapy or G-CSF have
been used extensively for allogeneic and autologous stem cell
rescue, and they are associated with rapid hematopoietic reconstitution (95). Furthermore, G-CSF may polarize donor cells
toward Th2 cells and promote regulatory T-cell function, favoring the development of tolerance (96). Several clinical studies suggest that the incidence of acute GVHD is comparable
between marrow and PBSC recipients; the incidence of chronic
GVHD appears to be increased with PBSC (97). However, a
meta-analysis of five randomized controlled trials and 11 cohort studies suggests that both acute and chronic GVHD are
more common with the use of PBSC as opposed to marrow
(98). However, the higher incidence of GVHD with PBSC may
not be associated with a significant increase in mortality. In
fact, the results of several trials suggest that, particularly in patients with “high-risk” disease, survival is improved in PBSC
recipients, perhaps due to a more vigorous GVT effect or to
more rapid immune reconstitution (95,99). Bone marrow allografts are often preferred in nonmalignant disease, where
GVT effects are unnecessary and minimization of GVHD is
the overriding goal.
Studies directed at the mechanisms involved in the effects
of PBSC show an increased production of IL-10, decreased
levels of TNF␣ in monocytes from G-CSF-mobilized PBSC,
and reduced expression of costimulatory molecules and MHC
class II antigens. Thus, a tolerogenic effect related to monocytes may be present, possibly juxtaposed with a countereffect
due to increased numbers of T cells.
Chronic GVHD has prominent features of autoreactivity
(100), and T lymphocytes with abnormal cytokine profiles
(e.g., secretion of IL-4 and IFN␥) may be present. Thymic
damage, inflicted by the conditioning regimen as well as by
preceding acute GVHD, leads to the failure of intrathymic selection and an escape of autoreactive cells to the periphery
(101). A similar mechanism appears to be responsible for

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syngeneic or autologous GVHD. Recently, the role of B cells
in chronic GVHD has been the subject of increased attention,
based on reports indicating that the anti-CD20 monoclonal
antibody rituximab could produce remissions of chronic
GVHD (102). Some groups have posited that autoantibodies
produced by autoreactive B-cell clones contribute directly to
chronic GVHD (103). Alternately, B cells may contribute indirectly, by influencing effector and regulatory T-cell compartments, as they do in other autoimmune diseases (104,105).
As stated previously, the immune system is a major target
organ of GVHD. Immunodeficiency is a key feature of
GVHD that is amplified by the immunosuppressive therapies
used to treat GVHD, thereby rendering patients highly susceptible to infections. The risk is further accentuated by damage to
various barrier structures, particularly the skin and intestinal

tract. All aspects of immune recovery after HCT are impaired
or delayed in patients with GVHD; in patients with chronic
GVHD, immunoincompetence may extend over years.
GVHD prophylaxis methods are summarized in Table 1.2.
Combination regimens of methotrexate and a calcineurin inhibitor are the most effective regimens after high-dose conditioning (106). The addition of prednisone to methotrexate and
CSP has been shown to increase or to decrease the incidence of
acute GVHD, depending on the timing of prednisone administration (107,108). Some trials of FK506 (tacrolimus) combined
with methotrexate have shown an incidence of GVHD lower
than that observed with CSP; however, disease-free survival
was not improved (109). Other trials have suggested that
tacrolimus may be superior to CSP only in the unrelated-donor
setting (110). Some groups have explored the use of sirolimus in
addition to or in place of methotrexate (111). Various prophylactic regimens have been employed after RIC HCT, including
combinations of MMF with CSP (29), sirolimus (112), and
T-cell depletion.
T-cell depletion of donor marrow, which is clearly effective in reducing the incidence of GVHD, has increased the
TABLE 1.2

Modalities of Graft-versus-Host
Disease Prevention

Selection of histocompatible donors
T-cell depletion
Ex vivo
Negative selection and removal of T cells
Positive selection and purification of hematopoietic
stem cells
In vivo
Anti-T-cell monoclonal antibodies (e.g. alemtuzumab)
Pharmacologic inhibition of T-cell function

Calcineurin inhibitors, antimetabolites, etc.
Cytokine blockade
Gnotobiosis
Establishment of mixed chimerism (unproven)

probability of graft failure, posttransplant infection, and relapse of leukemia (113,114). Graft failure problems have been
overcome in part by the in vivo administration of a Campath-1H
monoclonal antibody or of polyclonal ATG (115–117).
Alternatively, additional DLI may be given preemptively or
therapeutically after HCT to reduce the risk of disease recurrence and graft failure. Some preliminary studies have suggested
that depleting specific donor T-cell subsets (e.g., CD8ϩ T cells)
from the DLI product may render this approach more effective
(118,119). The use of Treg is currently being studied (120).
GVHD is an important risk factor for long-term survival
partly because it is associated with a high risk of early and
late, potentially lethal, infections. If GVHD develops despite
prophylaxis, aggressive therapy is required. Successful
GVHD therapy does not appear to interfere with the GVL
effect (121).

GRAFT FAILURE
With unmanipulated marrow grafts from HLA-identical siblings and high-dose conditioning, graft failure (either primary
or secondary) occurs in no more than 1% to 2% of patients.
Graft failure does occur, however, in allosensitized patients
conditioned with less-intensive regimens (e.g., patients with
aplastic anemia who are prepared with cyclophosphamide), in
patients given transplants from alternative (HLA-nonidentical)
donors, and in patients given T-cell-depleted grafts.
The probability of graft failure increases with increasing
degree of HLA-nonidentity, particularly for MHC class I

antigens (122). Several host-cell types, particularly CD8ϩ T
lymphocytes and NK cells, participate in the rejection of donor
cells. Donor T cells counteract this host response, thereby facilitating engraftment and preventing rejection. As a consequence,
T-cell-depleted marrow is more susceptible to rejection as described earlier. Graft failure is associated with an increased risk
of infections due to prolonged neutropenia. Patients with
graft failure after high-dose conditioning generally will not
have spontaneous autologous hematopoietic recovery, and require salvage with a second HCT if clinically feasible (123). In
contrast, RIC regimens generally allow recovery of host
hematopoiesis if the donor graft is rejected.

DELAYED COMPLICATIONS
By 2 years after HCT, about 80% of patients have returned to
pretransplant activities. However, some patients develop delayed or chronic complications (Table 1.3). These complications are related to elements of the conditioning regimen (most
importantly, irradiation), side effects of HCT (e.g., chronic
GVHD, immunodeficiency), or combinations thereof (124).
Life-threatening complications include infections, pulmonary


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TABLE 1.3

Delayed Complications of
Hematopoietic Cell Transplantation

Chronic GVHD
Infection
Airway and pulmonary disease (e.g., bronchiolitis
obliterans)
Autoimmune dysfunction
Impaired growth and development
Endocrine dysfunction
Sterility
Cataracts
Dental problems
Osteopenia or osteoporosis
Aseptic necrosis of the bone
New malignancies
Psychosocial dysfunction
Abbreviation: GVHD, graft-versus-host disease.

dysfunction, autoimmune disease, musculoskeletal problems,
and secondary malignancies.

SUMMARY
HCT offers effective and potentially curative therapy for
many life-threatening diseases. Side effects include acute toxicity to multiple organs, the development of GVHD and
immunoincompetence, and secondary effects related to immunosuppressive therapy. The result is a high susceptibility
to infections, which are a major cause of mortality after
HCT. Both GVHD and its therapy are important predisposing factors; thus, reducing the incidence and severity of
GVHD is an important component of efforts to reduce posttransplant infections. Transplant-conditioning regimens
have been modified to reduce early toxicity and to permit

transplantation of older patients. RIC may allow faster immune recovery and better infection control; however, its
availability has also expanded the availability of HCT to
higher-risk patient populations. New antibiotics and methods of cellular therapy have also enhanced the ability to
eradicate infections.

ACKNOWLEDGMENTS
This work was supported by grants number CA18105,
CA87948, and HL36444 from the National Institutes of
Health (Bethesda, Maryland). We thank Bonnie Larson and
Helen Crawford for assistance with the manuscript.

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CHAPTER

Introduction to Solid Organ
Transplantation

2

BARRY D. KAHAN

HISTORY OF TRANSPLANTATION
Mythology
For more than three millennia, organ replacement has been
the medicine of mythology. The literature of several cultures

alludes to organ transplantation both as a symbol of renewal
and as a cure for disease. An Indian legend from the
12th century BC recounts the powers of Shiva, the Hindu god
who xenotransplanted an elephant head onto his child to create
Ganesha, the god of wisdom and vanquisher of obstacles (1).
Eight centuries later, Pien Ch’iao (born 430 BC) exchanged the
hearts of two patients afflicted with an unbalanced equilibrium of energies; he administered powerful herbs after the
transplantation to promote acceptance of the hearts (2).
The classic Leggenda Aurea of Jacopo da Varagine (3) describes
the “miracle of the black leg” in which the limb of a deceased
Ethiopian gladiator was retrieved by the saints Cosmas and
Damian and was transplanted to the gangrenous leg of a
Roman sacristan. Today, after decades of laboratory experiments and clinical trials, kidney, liver, pancreas, lung, heart,
and small bowel transplantations are considered routine.
During the past millennium, transplant technology has been
successfully transferred from the realm of mythology to the
arena of fact.
Surgical Advances
The modern era of transplant surgery began in the 1900s, in
part because of the discovery of new techniques for vascular
anastomosis. In 1902, Ullmann (4) of Vienna performed the
first successful experimental transplantation in dogs, and,
within 8 years, he reported that he had performed more than
100 technically successful canine kidney transplantations.
In Lyon, Jaboulay and his assistant Carrel devised the modern
techniques of vascular suture (5). By 1933, the first human
kidney transplantation had been performed, albeit unsuccessfully, by the Ukrainian surgeon Voronoy. His five subsequent
attempts also failed (6,7); consequently, the interest in organ
transplantation diminished.
Hume performed an ex vivo human kidney transplantation that transiently functioned in 1947 (8). During the same

period, surgeons in Paris and Boston were developing surgical
techniques for kidney transplantation. In Paris, Kuss et al. (9),
Servelle et al. (10), and Dubost et al. (11) reported technically
successful transplantation of kidney allografts in patients using
heterotopic placement in the iliac fossa. In Boston, Hume et al.
(12) used femoral placement of the graft in conjunction with
the emerging practice of hemodialysis to prepare patients for
transplantation. Although the grafts in these pioneering studies
eventually failed, in 1954, Murray et al. (13,14) obtained permanent survival of identical-twin donor kidney transplants. By
the fall of 1963, approximately 30 of these syngeneic grafts had
been performed worldwide. Also in 1963, the first human liver
transplantation was performed (15). One year later, Barnard
(16) performed the first successful human heart transplantation. Shortly thereafter, techniques were developed for clinical
heart–lung (17) and pancreas (18) grafts.

Immunobiology of Alloresponsiveness
Medawar’s (19) seminal experiments on the immunologic basis
of graft rejection led to recognition of the necessity of immunosuppression for successful organ transplantation. The
three pivotal experiments were the following: first, the second
set phenomenon, namely, a repeat graft is rejected faster than
the first one. Second, the systemic nature of the response—no
matter where the second graft is placed, it is rejected faster
than the first. Third, the response is donor specific—challenge
grafts from an unrelated donor are rejected in first set fashion.
The acquired immune response toward allografts has
been shown to include two arms—T and B cells—mediating
cellular and humoral immunity, respectively. However, they
are not totally independent: the B-cell response depends upon
T-cell activation. Circulating small T lymphocytes become activated via an antigenic stimulus (signal 1) delivered either directly by interstitial donor cells bearing foreign markers or

indirectly by host antigen-presenting cells (APCs) that display
processed alloantigen fragments thereby interacting with recipient CD4ϩ T lymphocytes. This interaction is strengthened
by a series of coreceptors, including the binding of intercellular
adhesion molecule-1 to lymphocyte function antigen 1 and of
lymphocyte function antigen 3 to CD2. Signal 1 is amplified by
13