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TransplantInfectionsTransplantInfections
E D I T O R S
RALEIGH A. BOWDEN, MDClinical Associate Professor of Pediatrics
University of Washington School of Medicine
Seattle, Washington
PER LJUNGMAN, MD, PhDProfessor of Hematology
Karolinska University Hospital and
Karolinska Institutet
Stockholm, Sweden
DAVID R. SNYDMAN, MD, FACPProfessor of Medicine
Tufts University School of Medicine
Chief, Division of Geographic Medicine and
Infectious Diseases
Tufts Medical Center
Boston, Massachusetts
T H I R D E D I T I O N
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Third Edition
Copyright 2010 by LIPPINCOTT WILLIAMS & WILKINS, a WOLTERS KLUWER business
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All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form by any
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by the above-mentioned copyright.
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. Transplantsadverse effects. 2. Bacterial Infectionsetiology. 3. Mycosesetiology. 4. Virus Diseases
etiology. WO 660 T691 2010]RC112.T73 2010
617.9'5dc22
2010001262
DISCLAIMER
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cepted practices. However, the authors, editors, and publisher are not responsible for errors or omissions or for any
consequences from application of the information in this book and make no warranty, expressed or implied, with re-
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Transplantation infectious disease has emerged as an important
clinical subspecialty in response to a growing need for clinical ex-
pertise in the management of patients with various forms of im-
mune 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 med-
ications 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 rela-
tionship between two factors: the individuals epidemiologic ex-
posures and a conceptual measure of all those factors contribut-ing to an individuals infectious riskthe net state of
immunosuppression. In the absence of assays that measure an
individuals absolute risk for infection, allograft rejection, or
graft-vs.-host disease, any determination of the net state of im-
munosuppression is imprecise and is largely based on the clini-
cians bedside skills and experience. In practice, the lack of such
assays predicts that most patients will suffer excessive or inade-
quate immunosuppression at some points during their posttrans-
plant 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 regimenshave 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 noso-
comial 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 dysfunc-tion, metabolic derangements, and antimicrobial exposures.
Following the earliest posttransplant time period, investiga-
tions 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 de-
fenses, including both innate and adaptive immunity. The deter-
minants 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 refer-
ence to the presence or absence of specific receptors for
pathogens, the cells and proteins determining protective immu-
nity, and the coordination of the hosts 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 in-
cluding antigen presentation, cellular maturation and mobiliza-
tion, and cytokine profiles. Much of the impact of these infec-
tions 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 pro-
mote 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 vir-
ulence 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 toprovide assays that measure an individuals pathogen-specific
immune function (T-cell subsets, HLA-restricted lymphocyte
sorting using tetramers, antigen-specific interferon-release as-
says) 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 num-
ber of additional factors. Outbreaks of epidemic infections (West
Nile virus, H1N1 swine influenza, SARS) have disproportion-
ately affected transplant recipients. The epidemiology of infec-tion has also been changed by the expanded population of pa-
tients 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 appro-
priate 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 rou-
tine antimicrobial prophylaxis for surgery have successfully pre-
vented the transmission of most infections with grafts. With the
emergence of antimicrobial-resistant organisms in hospitals and
ForewordForeword
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in the community, routine surgical prophylaxis for transplanta-
tion surgery may fail to prevent transmission of common organ-
isms including methicillin-resistant Staphylococcus aureus, van-
comycin-resistantEnterococcus species, and azole-resistant yeasts.
Highly sensitive molecular diagnostic assays have also allowed
the identification of a series of uncommon viral infections (lym-
phocytic choriomeningitis virus [LCMV], West Nile virus, rabies
virus, HIV) with allografts. These infections appear to be ampli-fied 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 re-
cipients) have been recognized. Sensitive and specific diagnostic
assays remain unavailable for some pathogens of interest and
those that are available require careful validation and standardi-
zation. 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 alteredthe 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 measureit is uncertain
that there is a clear mortality benefit of these strategies. Sicker
patients arrive at transplantation having survived multiple in-
fections, 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 nonmye-
loablative transplantation is shorter than that after traditional
bone marrow transplantation. The duration of neutropenia
has also been reduced with the introduction of chemothera-
peutic agents targeting specific cellular sites (enzymes, protea-
somes) rather than acting on rapidly dividing cancer cells.
Among solid organ transplants, the recent introduction of ex-
perimental 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 mi-
crobiologic assays in routine clinical practice has enhanced diag-
nosis 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 individuals immune function relative to their
own pathogens. Potent biologic agents in transplantation in-
cluding 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 includ-
ing corticosteroids and the calcineurin inhibitors. The short-
term 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 de-
termined. High throughput sequencing and genome-wide asso-ciation studies are beginning to determine the basis of both ge-
netic susceptibility to infection and responses to antimicrobial
therapies (e.g., hepatitis C virus and interferon). These observa-
tions will allow the application of specific drugs to the popula-
tions in which they are most useful and least toxic (pharmacoge-
nomics). 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 in-
cidence of acute graft rejection and graft-vs.-host disease while
increasing the longer term risks for infection and virally medi-ated malignancies. With introduction of each new immunosup-
pressive agent, a new series of effects on the presentation and
epidemiology of infection have been recognized in the trans-
plant 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 microbio-
logic 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 infec-
tious diseases. The unique risk factors and epidemiology for in-fection 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 pop-
ulations. 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 gas-
trointestinal tract. Individual pathogens and therapies are ad-
dressed 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 identifiedincluding 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 dis-
ease and transplantation specialists, for both expert and novice
alike. The availability of this information in a single volume will
serve one group particularly wellour patients.
Jay A. Fishman, MD
Boston, Massachusetts, USA
iv Foreword
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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 im-
munocompromised patients, but the field of transplant infec-
tious 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 developedfor the management of such patients. In addition, peer re-
viewed journals now exist which publish information on this
specialized area, and training programs devoted to the subspe-
cialty of transplant infectious diseases within the field of infec-
tious 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 trans-
planted. In addition, there are new chapters on organ donor
screening, drug interactions after transplantation, and new im-
munosuppressive agents. Chapters differentiating differences
between solid organ and hematopoietic stem cell transplanta-tion have been expanded, as have chapters discussing fungal in-
fections, 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 in-
fectious 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 vac-
cines. 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 lead-
ing 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 regard-
ing 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 pro-
vide some small incremental knowledge base that would ad-
vance the field and make transplantation safer for all who
need this lifesaving intervention. We thank all the contribu-tors for their effort, and trust the reader will find this a valu-
able reference text as they care for transplant recipients.
Raleigh A. Bowden
Per Ljungman
David R. Snydman
v
PrefacePreface
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vi
ContributorsContributors
Tamara Aghamolla
Immunocompromised Host Section
Pediatric Oncology Branch
Clinical Research Center
National Cancer Institute
National Institutes of Health
Bethesda, Maryland
Nora Al-mana, M.B.B.S.
Tufts Medical Center
Boston, Massachusetts
Diana Averbuch, M.D.
Department of Pediatrics
The Hebrew University HadassahMedical 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
Helen W. Boucher, M.D., F.A.C.P.
Assistant Professor of Medicine
Tufts University School of Medicine
Director
Fellowship Program
Division of Geographic Medicine and
Infectious Diseases
Tufts Medical Center
Boston, Massachusetts
Emilio Bouza, M.D., Ph.D.
Professor
Clinical Microbiology
University Complutense of Madrid
ChiefClinical Microbiology and Infectious Diseases
Hospital General Universitario Gregorio
Maraon (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
Universit Paris 12
Head
Clinical Hematology Department
Henri Mondor University Hospital
Crteil, France
Isabel Cunningham, M.D.
Adjunct Associate Research Scientist
Hematology Oncology
Columbia University College of Physicians
and Surgeons
New York, New York
Mazen S. Daoud, M.D.
Director
Dermatopathology Laboratory
Associates in Dermatology
Fort Myers, Florida
H. Joachim Deeg, M.D.
Professor of MedicineMedical 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 HospitalNashville, Tennessee
Hermann Einsele
Professor
Department of Medicine
University Wrzburg
Director
Department of Internal Medicine II
University Hospital Wrzburg
Wrzburg, Germany
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Dan Engelhard, M.D.
Associate Professor
Department of Pediatrics
The Hebrew University Hadassah Medical
School
Chief
Department of Pediatrics
Hadassah University HospitalJerusalem, Israel
Janet A. Englund, M.D.
Professor
Department of Pediatrics
University of Washington
Professor
Pediatric Infectious Diseases
Seattle Childrens Hospital
Seattle, Washington
Staci A. Fischer, M.D.
Associate Professor
Department of MedicineThe Warren Alpert Medical School of
Brown University
Director
Transplant Infectious Diseases
Rhode Island Hospital
Providence, Rhode Island
Richard Freeman, M.D.
Professor and Chair
Department of Surgery
Dartmouth Medical School
Hanover, New Hampshire
ChairDepartment of Surgery
Dartmouth-Hitchcock Medical Center
Lebanon, New Hampshire
Ed Gane, M.D., F.R.A.C.P.
Associate Professor
Faculty of Medicine
University of Auckland
Consultant Hepatologist
Liver Unit
Auckland City Hospital
Auckland, New Zealand
Joan Gavald, M.D., Ph.D.Senior Consultant
Servei Malalties Infeccioses
Vall dHebron
Barcelona, Spain
Juan Gea-Banacloche, M.D.
Infectious Diseases Section
Experimental Transplantation and
Immunology Branch
National Cancer Institute, National
Institutes of Health
Chief
Infectious Diseases Consultation ServiceNational Institutes of Health Clinical
Research Center
Bethesda, Maryland
Maddalena Giannella, M.D.
PhD Course
Clinical Microbiology
University Complutense of Madrid
Research Fellow
Clinical Microbiology and Infectious
Diseases
Hospital General Universitario Gregorio
Maraon (HGUGM)
Madrid, Spain
Lawrence E. Gibson, M.D.
Professor of Dermatology
Director of Dermatopathology
Mayo Clinic
Rochester, Minnesota
John W. Gnann, Jr., M.D.
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
Michael Green, M.D., M.D.H.
Professor
Pediatrics and Surgery
University of Pittsburgh School of Medicine
Attending Physician
Division of Infectious Diseases
Childrens Hospital of Pittsburgh
Pittsburgh, Pennsylvania
Andreas H. Groll, M.D.Associate Professor
Department of Pediatrics
Wilhelms University
Head
Infectious Disease Research Program
Center for Bone Marrow Transplantation
and Department of Pediatric
Hematology/Oncology
Childrens University Hospital
Muenster, Germany
Morgan Hakki, M.D.
Assistant Professor
Division of Infectious Diseases
Oregon Health and Science University
Portland, Oregon
John W. Hiemenz, M.D.
Professor of MedicineDivision 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 PhysicianInfectious 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 MedicineTransplant Infectious Diseases
University of Alberta
Director
Transplant Infectious Diseases
University of Alberta Hospital
Edmonton, Alberta, Canada
Contributors vii
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Michael G. Ison, M.D., M.S.
Assistant Professor
Divisions of Infectious Diseases & Organ
Transplantation
Northwestern University Feinberg School
of Medicine
Medical Director
Transplant & Immunocompromised HostInfectious Diseases Service
Northwestern Memorial Hospital
Chicago, Illinois
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 SchoolChief
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
Shimon Kusne, M.D.
Professor of Medicine
Department of Medicine
Mayo Medical School
Chair
Division of Infectious Diseases
Department of Medicine
Mayo Clinic ArizonaPhoenix, Arizona
Roberta Lattes, M.D.
Assistant Professor Infectious Diseases
Department of Medicine
University of Buenos Aires School of
Medicine
Chief
Departement of Transplantation
Transplant Infectious Disease
Instituto de Nefrologa
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.
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
Ajit P. Limaye, M.D.
Associate Professor
Department of Medicine
University of Washington
Director
Solid-Organ Transplant Infectious Disease
University of Washington Medical Center
Seattle, Washington
Per Ljungman, M.D., Ph.D.
Professor of Hematology
Karolinska Institutet
Director
Department of Hematology
Karolinska University Hospital Stockholm
Stockholm, Sweden
Anna Locasciulli, M.D.
Associated Professor
Pediatric Hematology
University of Medicine
Director
Pediatric Hematology
San Camillo Hospital
Rome, Italy
David L. Longworth, 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
Mitchell R. Lunn, B.S.
Department of Medicine
Stanford University School of MedicineStanford, California
Clarisse M. Machado, M.D.
Virology Laboratory
So Paulo Institute of Tropical Medicine
University of So Paulo
So Paulo, Brazil
Kieren A. Marr, M.D.
Professor of Medicine
Department of Medicine
Johns Hopkins University
Director
Transplant and Oncology Infectious
Disease
Department of Medicine
Johns Hopkins University
Baltimore, Maryland
Rodrigo Martino, M.D., Ph.D.
Attending Senior Physician
Hematology
Hospital de la Santa Creu i Sant Pau
Barcelona, Catalonia, Spain
Susanne Matthes-Martin, M.D.
Associate ProfessorHead of Unit
St. Anna Childrens Hospital
Stem Cell Transplant Unit
Childrens Cancer Research Institute
Vienna, Austria
viii Contributors
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Lisa M. McDevitt, PHARM.D.,B.C.P.S.
Assistant Professor
Department of Surgery
Tufts University School of Medicine
Senior Clinical Specialist
Organ Transplantation
Department of PharmacyTufts Medical Center
Boston, Massachusetts
George B. McDonald, M.D.
Professor
Department of Medicine
University of Washington
Head and Member
Gastroenterology, Hospital Section
Fred Hutchinson Cancer Research
Center
Seattle, Washington
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
Childrens 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
Patricia Muoz, M.D., Ph.D.
Professor
Clinical Microbiology
University Complutense of Madrid
Clinical Section
Chief
Clinical Microbiology and Infectious Diseases
Hospital General Universitario GregorioMaran (HGUGM)
Madrid, Spain
Tue Ngo, M.D., M.D.H.
Infectious Diseases Fellow
Division of Infectious Diseases
Vanderbilt University School of Medicine
Nashville, Tennessee
Albert Pahissa, M.D., Ph.D.
Chair Professor
Infectious Diseases Medicine
Universitat Autnoma de Barcelona
ChiefServei Malalties Infeccioses
Vall dHebron
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
Maria Beatrice Pinazzi, M.D.
Full-time Assistant
Pediatric Hematology and Bone Marrow
Transplant UnitSan Camillo Hospital
Rome, Italy
Jutta K. Preiksaitis, M.D.
Professor of Medicine
Department of Medicine
University of Alberta
Edmonton, Alberta, Canada
Marcelo Radisic, M.D.
Attending Physician
Transplant Infectious Diseases
Instituto De Nefrologa
Buenos Aires, Argentina
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
Jorge D. Reyes, M.D.
Professor
Department of Surgery
University of Washington
Chief
Division of Transplant Surgery
University of Washington Medical
CenterSeattle, Washington
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
Antonio Romn, M.D., Ph.D.
Senior Consultant
Pneumology Department
Vall dHebronBarcelona, Spain
Brahm H. Segal, M.D.
Assistant Professor of Medicine
State University of New York at Buffalo
Head of Infectious Disease
Roswell Park Cancer Institute
Buffalo, New York
Maria Teresa Seville, M.D.
Instructor
Division of Infectious Diseases
Mayo Clinic
ChairInfection Prevention and Control
Mayo Clinic Hospital
Phoenix, Arizona
Nina Singh, M.D.
Associate Professor of Medicine
University of Pittsburgh
Pittsburgh, Pennsylvania
Contributors ix
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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
Wrzburg, 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 InvestigatorChief, 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 MedicineUniversity 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 CancerCenter
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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Foreword iii
Preface v
Contributors vi
Section I
Introduction to Transplant Infections1 Introduction to Hematopoietic Cell
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1Andrew R. Rezvani and H. Joachim Deeg
2 Introduction to Solid OrganTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Barry D. Kahan
3 Immunosuppressive Agents . . . . . . . . . . . . . . . . . 26Jason Rhee, Nora Al-Mana, Jeffery T. Cooper and Richard Freeman
4 Common Drug Interactions Encountered inTreating Transplant-Related Infections . . . . . . . . 41Helen W. Boucher, Kenneth R. Lawrence
and Lisa M. McDevitt
Section II
Risks and Epidemiology of Infectionsafter Transplantation5 Risks and Epidemiology of Infections
after Allogeneic Hematopoietic StemCell Transplantation . . . . . . . . . . . . . . . . . . . . . . . 53Juan Gea-Banacloche
6 Risks and Epidemiology of Infectionsafter Solid Organ Transplantation . . . . . . . . . . . . 67Ingi Lee and Emily A. Blumberg
7 Donor-Derived Infections: Incidence,Prevention and Management . . . . . . . . . . . . . . . . 77Michael G. Ison
8 Transplant Infections in DevelopingCountries . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90Clarisse M. Machado
9 Risks and Epidemiology of Infectionsafter Heart Transplantation . . . . . . . . . . . . . . . . 104David DeNofrio and David R. Snydman
10 Risks and Epidemiology of Infectionsafter Lung or HeartLung Transplantation . . . . 114Joan Gavald, Antonio Romn and Albert Pahissa
11 Infections in Kidney Transplant Recipients . . . . 138Deepali Kumar and Atul Humar
12 Risks and Epidemiology of Infectionsafter Pancreas or KidneyPancreasTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 150Atul Humar and Abhinav Humar
13 Risks and Epidemiology of Infections
after Liver Transplantation . . . . . . . . . . . . . . . . 162Shimon Kusne and David C. Mulligan
14 Risks and Epidemiology of Infections afterIntestinal Transplantation . . . . . . . . . . . . . . . . . 179Jorge D. Reyes and Michael Green
Section III
Specific Sites of Infection15 Pneumonia after Hematopoietic Stem
Cell or Solid Organ Transplantation . . . . . . . . . 187Catherine Cordonnier and Isabel Cunningham
16 Skin Infections after Hematopoietic StemCell or Solid Organ Transplantation . . . . . . . . . 203Mazen S. Daoud, Lawrence E. Gibson and W. P. Daniel Su
17 Central Nervous System Infectionsafter Hematopoietic Stem Cell or SolidOrgan Transplantation . . . . . . . . . . . . . . . . . . . . 214Diana Averbuch and Dan Engelhard
18 Gastrointestinal Infections after Solid Organor Hematopoietic Cell Transplantation . . . . . . . 236George B. McDonald and Gideon Steinbach
Section IV
Bacterial Infections19 Gram-Positive and Gram-Negative
Infections after Hematopoietic StemCell or Solid Organ Transplantation . . . . . . . . . . 257Dan Engelhard
20 Typical and Atypical MycobacteriumInfections after Hematopoietic StemCell or Solid Organ Transplantation . . . . . . . . . 282Jo-Anne H. Young and Daniel J. Weisdorf
21 Other Bacterial Infections after HematopoieticStem Cell or Solid Organ Transplantation . . . . . 295
J. Stephen Dummer and Tue Ngo
Section V
Viral Infections22 Cytomegalovirus Infection after Stem
Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . 311Morgan Hakki, Michael J. Boeckh and Per Ljungman
23 Cytomegalovirus Infection after SolidOrgan Transplantation . . . . . . . . . . . . . . . . . . . . 328Raymund R. Razonable and Ajit P. Limaye
ContentsContents
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24 EpsteinBarr Virus Infection andLymphoproliferative Disorders afterTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 362Jutta K. Preiksaitis and Sandra M. Cockfield
25 Herpes Simplex and Varicella-ZosterVirus Infection after Hematopoietic StemCell or Solid Organ Transplantation . . . . . . . . . 391
John W. Gnann, Jr
26 Infections with Human Herpesvirus6, 7,and 8 after Hematopoietic Stem Cellor Solid Organ Transplantation . . . . . . . . . . . . . 411Nina Singh
27 Community-Acquired RespiratoryViruses after Hematopoietic Stem Cellor Solid Organ Transplantation . . . . . . . . . . . . . 421Janet A. Englund and Estella Whimbey
28 Adenovirus Infection in AllogeneicStem Cell Transplantation . . . . . . . . . . . . . . . . . 447Susanne Matthes-Martin
29 Adenovirus Infection in Solid Organ
Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 459Michael Green, Michael G. Ison and Marian G. Michaels
30 Polyoma and Papilloma Virus Infectionsafter Hematopoietic Cell or Solid OrganTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 465Hans H. Hirsch
31 Hepatic Infections after Solid OrganTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 483Ed Gane
32 Hepatitis B and C in HematopoieticStem Cell Transplant . . . . . . . . . . . . . . . . . . . . . 498Anna Locasciulli, Barbara Montante and Maria Beatrice Pinazzi
Section VI
Fungal Infections33 Yeast Infections after Hematopoietic
Stem Cell Transplantation . . . . . . . . . . . . . . . . . 507Tamara Aghamolla, Brahm H. Segal and Thomas J. Walsh
34 Yeast Infections after Solid OrganTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 525Peter G. Pappas
35 Mold Infections after HematopoieticStem Cell Transplantation . . . . . . . . . . . . . . . . . 537
William J. Steinbach and Kieren A. Marr36 Aspergillus and Other Mold Infections
after Solid Organ Transplant . . . . . . . . . . . . . . . 554Patricia Muoz, Maddalena Giannella, Almudena Burillo
and Emilio Bouza
37 Infections Caused by UncommonFungi in Patients UndergoingHematopoietic Stem Cell or SolidOrgan Transplantation . . . . . . . . . . . . . . . . . . . 586John W. Hiemenz, Andreas H. Groll and Thomas J. Walsh
38 Endemic Mycoses after HematopoieticStem Cell or Solid Organ Transplantation . . . . . 607Carol A. Kauffman
Section VII
Other Infections39 Toxoplasmosis Following Hematopoietic
Stem Cell Transplantation . . . . . . . . . . . . . . . . . 617Rodrigo Martino
40 Toxoplasmosis after Solid OrganTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . 624Jose G. Montoya and Mitchell R. Lunn
41 Parasites after Hematopoietic StemCell or Solid Organ Transplantation . . . . . . . . . 632Roberta Lattes and Marcelo Radisic
Section VIII
Infection Control42 Infection Control Issues after
Hematopoietic Stem Cell Transplantation . . . . 653Robin K. Avery and David L. Longworth
43 Infection Control Issues after SolidOrgan Transplantation . . . . . . . . . . . . . . . . . . . 667Maria Teresa Seville, Sharon Krystofiak and Shimon Kusne
Section IX
Immune Reconstitution Strategies forPrevention and Treatment of Infections44 Vaccination of Transplant Recipients . . . . . . . . 691
Per Ljungman
45 Growth Factors and OtherImmunomodulators after Transplantation . . . . 705Jack W. Hsu and John R. Wingard
46 Adoptive Immunotherapy withHerpesvirus-specific T Cells afterTransplantation . . . . . . . . . . . . . . . . . . . . . . . . . . 724Hermann Einsele, Max S. Topp, Stanley R. Riddell
Section X
Hot Topics47 Emerging and Rare Viral Infections
in Transplantation . . . . . . . . . . . . . . . . . . . . . . . 745Staci A. Fischer
48 Travel Medicine, Vaccines andTransplant Tourism . . . . . . . . . . . . . . . . . . . . . . . .756Camille Nelson Kotton
Index 768
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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 therapeu-
tic 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 ensuingsystematic 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 graft-
versus-leukemia (GVL) effect which had been described by Barnes
and Loutit (7) in murine models. These studies immediately estab-
lished 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 hematopoi-
etic growth factors such as granulocyte-colony stimulating fac-
tor (G-CSF), were shown to result in accelerated hematopoieticrecovery 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 INDICATIONSFOR HEMATOPOIETIC CELLTRANSPLANTATION
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
the chemoradiotherapy used to treat malignancies. Infusion ofHSCautologous or allogeneicas a rescue procedure al-
lows 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 high-
dose 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, com-
bined with an increasing appreciation of the central role of im-
munologic graft-versus-tumor (GVT) reactions in the success of
SECTION I Introduction to Transplant Infections
Introduction to HematopoieticCell Transplantation
ANDREW R. REZVANI, H. JOACHIM DEEG
1
CHAPTER
1
TABLE 1.1 Categories of Disease Treated withHematopoietic Cell Transplantation
Malignant
Hematologic malignanciesAcute leukemiasChronic leukemias
Myelodysplastic syndromesMyeloproliferative syndromesNon-Hodgkin lymphomaHodgkin lymphoma
Plasma cell dyscrasia (e.g., multiple myeloma)
Selected solid tumorsRenal cell carcinomaEwing sarcoma
NeuroblastomaBreast, colon, ovarian, and pancreatic cancer
(investigational)
Nonmalignant
Acquired
Aplastic anemia and red cell aplasiasParoxysmal nocturnal hemoglobinuria
Autoimmune disorders (e.g., multiple sclerosis, lupuserythematosus, systemic sclerosis, rheumatoid arthritis)
CongenitalImmunodeficiency syndromes (e.g., SCID)
HemoglobinopathiesCongenital anemias (e.g., Fanconi anemia)Storage diseases (e.g., mucopolysaccharidoses)Bone marrow failure syndromes (e.g., dyskeratosis
congenita)Osteopetrosis
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allogeneic HCT, have led to new concepts of transplant condi-
tioning (see Modalities for Transplant Conditioning) (12).
Replacement therapy in patients with congenital or ac-
quired 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 cate-gory (13). In contrast to the benefit from GVT alloreactivity in
the malignant setting, patients with these nonmalignant disor-
ders are not thought to derive any benefit from alloreactivity
beyond its graft-facilitating effect.
Finally, HSC (or their more mature progeny) may be effec-
tive vehicles for gene therapy (14) and for immunotherapy.
Objectives of gene therapy include the replacement of defective
or missing enzymes (e.g., adenosine deaminase, glucocerebrosi-
dase) 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 reinduc-
tion of remission in patients with chronic myelogenous leukemia(CML) who have relapsed after HCT has been remarkably suc-
cessful, leading to broader application of this approach. A modi-
fication 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 non-
myeloablative 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 reac-
tivity has been enhanced to eliminate host cells (Fig. 1.1) (18).
SOURCES OF HEMATOPOIETIC STEMCELLS 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 marrowor peripheral blood stem cells (PBSC) are theoretically avail-
able for every patient (feasibility has been reported even for
patients with severe aplastic anemia), these would not be use-
ful 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 HLA-
haploidentical 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 pa-
tients, and somewhat less than 1% of patients will have a syn-
geneic (identical twin) donor. The lack of an HLA-identical
related donor in more than 70% of patients has led to the de-
velopment 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 autol-
ogous cells of tumor contamination.
Supported by the efforts of the National Marrow DonorProgram 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 proba-
bility of finding a suitably HLA-matched donor for a white
patient in North America is about 70% to 80%. This probabil-
ity 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 anti-
gens 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 contami-
nating 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.
2 Section I Introduction to Transplant Infections
FIGURE 1.1. Commonly used conditioning regimens forhematopoietic cell transplantation, stratified by intensity, toxicity,and relative reliance on immunological graft-versus-tumoreffects. Abbreviations: GVT, graft-versus-tumor; CY, cyclophos-
phamide; TBI, total body irradiation; Gy, gray; FLU, fludarabine;BU, busulfan; ATG, antithymocyte globulin; araC, cytarabine.
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TRANSPLANT PROCEDURE
Transplant Conditioning
Rationale for Conditioning
1. To eradicate (ablate) the patients disease, or at least to re-
duce the number of malignant or abnormal cells to below
detectable levels (this applies to allogeneic, syngeneic, and
autologous donors).
2. To suppress the patients immunity and to prevent rejection
of donor cells (this applies to allogeneic, but not to auto-
logous, HCT). Immunosuppression is also needed in pre-
paration 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 aban-
doned. Recent data show that donor cells, given in sufficient
numbers, create their own space and proceed to repopulate the
recipients marrow (23).
Exceptions to the conditioning requirement exist in chil-
dren with severe combined immunodeficiency (SCID), be-
cause 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 cor-
rect the genetic defect (24).
Modalities for Transplant Conditioning
Modalities used to prepare patients for HCT have been re-
viewed extensively elsewhere (25,26); commonly used regi-mens 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 mono-
clonal 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, cy-
tarabine, and more recently treosulfan (30), may be used ei-
ther 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 sup-
press recipient immunity. Others are directed at antigens
expressed on the recipients malignant cells; in addition, cy-
tokines or cytokine antagonists are being investigated. Anti-
T-cell therapy predisposes the individual to viral infections,
in particular cytomegalovirus (CMV) and the development
of EpsteinBarr virus (EBV)-related lymphoproliferative
disorders (PTLD) after transplantation (31).
4. T-cell therapy is based on the observation that broad T lym-phocyte depletion of donor marrow resulted in graft fail-
ure. This has led to protocols of selective T-cell add-back to
ensure engraftment. The observation that DLI was effec-
tive 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 recipi-
ents blood to remove isoagglutinins directed against thedonors ABO blood group or the removal of plasma from the
donor marrow to remove the isoagglutinins directed at recipi-
ent cells. Alternatively, the donor red blood cells with which
recipient antibodies may react can be removed, thus minimiz-
ing transfusion reactions. Due to the procedure by which they
are obtained, these additional manipulations are generally not
required with PBSC.
Marrow Harvest
The marrow donor receives general or regional (e.g., epidural,
spinal) anesthesia, and, under sterile conditions, multiple aspi-
rates 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 intra-
venously without manipulation.
Alternative Stem Cell Sources
HSC circulate at low concentrations in blood (35). Their fre-
quency increases dramatically during the recovery phase fol-
lowing cytotoxic therapy, and after the administration ofrecombinant hematopoietic growth factors such as G-CSF
which dislodge cells from the marrow. Peak blood concentra-
tions of CD34 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 au-
tologous procedures, the goal is to collect at least 2 to 5
106 CD34 cells/kg recipient weight; for allogeneic trans-
plants, the goal is 5 to 8 106 CD34 cells/kg, although the
optimum dose has not been determined (36).
Umbilical cord blood represents a segment of the periph-
eral circulation of the fetus and is easily accessible (37). Also,
Chapter 1 Introduction to Hematopoietic Cel l Transplantation 3
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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
(80150 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 doseand engraftment (11), as well as ex vivo expansion of
hematopoietic precursors in umbilical cord blood units for in-
fusion 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 set-
ting, 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 (purifica-
tion of CD34 cells from the graft). Conversely, one may want
to retain certain populations (e.g., CD4 cells) with potentialfor later uses such as posttransplant DLI.
Hematopoietic Stem Cell Infusion:
The Actual Transplant
Donor cells are infused intravenously via an indwelling cen-
tral line, often a Hickman catheter. Directed by surface mole-
cules 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 tran-
sient mild hypotension or hypersensitivity reactions.
CARE AFTER TRANSPLANTATION
Complications of HCT, including infections, are related to sev-
eral 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 condi-
tioning generally develop severe pancytopenia, including neu-
tropenia, within days after completion of conditioning. This
period may last 2 to 4 weeks with marrow allografts, 10 to12 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.
Transfusion requirements are substantially reduced in patientsprepared 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 reticulo-
cyte recovery and moderately reduces red blood cell transfu-
sion 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 respon-
sible for most of the infectious complications seen after HCT
(Fig. 1.2). Although all patients receive prophylactic antimi-
crobials, granulocyte transfusions are not routinely given.Laminar air flow (LAF) rooms and gastrointestinal deconta-
mination may reduce the frequency of infections and the du-
ration of febrile episodes, but neither is used routinely because
of the high cost of LAF and the availability of effective broad-
spectrum 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 areused. 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; how-
ever, 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 re-
moval of naive T-cells will lead to successful transplants with-
out GVHD remains under investigation.
4 Section I Introduction to Transplant Infections
0Weeks Months
Neutrophils, monocytes,NK cells
B cells, CD8 T cells
CD4 T cells
Plasma cells, dendritic cells
Upper normal limit
Lower normal limit
Years posttransplantImm
unecellcounts(%n
ormal)
20
40
60
80
100
120
140 Graft infusion
FIGURE 1.2. Approximate trends in immune cell counts aftermyeloablative hematopoietic cell transplantation. With the useof reduced-intensity conditioning, nadirs are higher and occurlater. These recovery rates may be influenced by clinical vari-ables such as graft-versus-host disease, stem cell source, and
patient age. (Adapted from Storek J. Immunological reconsti-tution after hematopoietic cell transplantationits relation tothe contents of the graft (Review). Expert Opin Biol Ther.2008;8:583597.)
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HEMATOLOGIC RECOVERY
A high-risk period for infections in patients conditioned with
high-dose regimens exists early after transplantation, when gran-
ulocytopenia 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 pro-tracted. If the granulocyte count at day21 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 500 granulocytes/L)
occurs as early as day 9 or 10, 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 pa-
tient cells, so that donor cells begin to recover before patient
cells reach their nadir. Consequently, several groups have re-
ported 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, chemo-
taxis, and neutrophil function are severely impaired even after
autologous transplants. The development of GVHD substan-
tially 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 thera-
pies 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 comple-
tion of high-dose conditioning, helped by the recovery of granu-
locytes and their scavenging function, even though phagocytosis
and superoxide production may still be impaired. After the
transplant, the volume and immunoglobulin content of salivaalso improve with time. Even with uncomplicated recovery,
T- and B-cell-mediated immune responses against viral, bac-
terial, fungal, and other organisms are broadly suppressed; nat-
ural 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 recipi-
ents prior antigen exposure, whether to the pathogen itself or in
the form of a vaccine. Much of the literature on immune recon-
stitution after allogeneic HCT describes patients who were
prepared with high-dose conditioning. While the use of RIC
regimens has increased rapidly in recent years, there are fewer
data available on immune recovery in this setting, and the im-
pact of RIC on immune reconstitution remains somewhat un-
clear. 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 compart-
ment is generally replaced completely by donor-derived cells,
except in patients with TB SCID, in whom the recipients
B cells tend to persist (50). Nonetheless, some antibodies of host
origin (e.g., isoagglutinins) that are derived from long-livedplasma 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 reconstitu-
tion, 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). CD5 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 autoan-
tibodies, or else have irrelevant specificities (55). Antibodies
with relevant specificities recover only if the antigen is en-
countered, and they recover more quickly if both patient and
donor are immune (56). At 3 months after HCT, total IgG lev-els 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 quanti-
tative 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
Chapter 1 Introduction to Hematopoietic Cel l Transplantation 5
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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 boostersare 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 pol-
icy 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.
T Cells
CD4 Cells
The number of CD4 cells is low for 1 to 3 months after high-
dose 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 reconsti-
tution even in older patients (59). After PBSC transplantations,
both naive and memory CD4 T cells are more abundant than
after marrow transplantations. Early after HCT, most CD4
T cells are derived from transplanted mature T cells and T-cell
precursors; later, they are stem-cell-derived, at least in pediatricpatients. CD4 T-cell reconstitution may occur more rapidly
after RIC as compared to high-dose conditioning (46).
CD4 T cells generally express CD11a, CD29, CD45RO,
and HLA-DR and less CD28, CD45RA, and CD62L, consis-
tent with the prominence of memory cells (58). Responses to
polyclonal stimuli are low. Proliferative responses to fre-
quently 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
CD8 T cells are low for 2 to 3 months after HCT; subse-
quently, they rise quickly, resulting in an inversion of the typi-
cal CD4:CD8 ratio (58). These CD8 cells are largely memory
cells expressing CD11a, CD11b, CD29, CD57, HLA-DR, and
CD45RO but little CD28, CD45RA, and CD62L. The pres-
ence of a CD11bCD57CD28 phenotype suggests anergic
or suppressive CD8 cells. CD8 cells appear to be derived
from transplanted T cells and stem cells.
CMV-specific or EBV-specific CD8 cells can be trans-
ferred successfully to a recipient, and they may persist for at
least 18 months (60,61). Even established and refractory CMV
infections can be treated effectively by the infusion of ex-
panded CMV-specific CD8 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-specificdonor T cells for infusion (63,64).
The role of immunoregulatory CD4CD25 T cells
(Treg) in clinical transplantation remains to be fully estab-
lished (65).
Antigen-Presenting 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 al-
logeneic T-cell responses. G-CSF-mobilized monocytes appearto settle in tissue in the early posttransplantation period.
The reconstitution of dendritic cells (DC), their matura-
tion, and the development of DC1 and DC2 have been incom-
pletely characterized. DC precursors in the blood recover
within 6 months, and DC reconstitution appears to be a clini-
cally important event. Low numbers of DC at 1 month after
reduced-intensity HCT have been associated with an in-
creased risk of mortality and disease relapse; CD16 DC
counts at 3 months were also strongly prognostic (67). A sepa-
rate 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).
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 reconstitu-tion after allogeneic HCT has been associated with reduced
relapse and improved survival (70).
GRAFT-VERSUS-HOST DISEASE ANDGRAFT-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 allo-
geneic 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 HLA-
identical 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 con-
siderably 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 pathol-
ogy 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 immuno-
suppression can often be discontinued. In patients withoutGVHD, 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 im-
munosuppressive treatment (79,80).
The immunopathophysiology of GVHD is complex.
The initial damage to host tissue is induced by the transplant-
conditioning 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 histocom-
patibility 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 in-
flammatory 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 ofcytokines, such as tumor necrosis factor (TNF) and inter-
leukin 1 (IL-1) (83), leading to target cell death and the expres-
sion of costimulatory molecules, such as CD80, CD86, and
MHC class II antigens, on DC; T-cell stimulation; and the re-
lease of T helper-1 (Th1) cytokines (IL-2, interferon- (IFN-)).
Recent experiments also emphasize the role of other cy-
tokines, particularly TNF, IL-15, and IL-18 (84). In mouse
mod