Transplant Infections -3E

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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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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

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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.



Diana Averbuch, M.D.

Department of Pediatrics

The Hebrew University HadassahMedical School

Infectious Diseases Consultant


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


Hospital of the University of

Pennsylvania

Philadelphia, Pennsylvania

Michael J. Boeckh, M.D.

Associate Professor


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


Director

Fellowship Program

Division of Geographic Medicine and

Infectious Diseases



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


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


Attending Surgeon



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


Medical Director

Cardiac Transplant Program

Cardiology/Medicine



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


University Wrzburg

Director

Department of Internal Medicine II

University Hospital Wrzburg

Wrzburg, Germany


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Dan Engelhard, M.D.

Associate Professor


The Hebrew University Hadassah Medical

School

Chief


Hadassah University HospitalJerusalem, Israel

Janet A. Englund, M.D.

Professor



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


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



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


Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania

Andreas H. Groll, M.D.Associate Professor


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


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


University of Florida

Clinical Assistant Professor


University of Florida Shands Cancer

Center


Abhinav Humar, M.D.

Professor


University of Pittsburgh

Chief of Transplant

Starzl Transplant Institute

University of Pittsburgh Medical Center


Atul Humar, M.D., M.SC., F.R.C.P. (C)

Associate Professor of MedicineTransplant Infectious Diseases


Director


University of Alberta Hospital


Contributors vii


8/798

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


Harvard Medical School

Clinical Director

Transplant Infectious Disease and

Compromised Host Program

Infectious Diseases Division

Massachusetts General Hospital


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


Deepali Kumar, M.D., M.SC.,F.R.C.P. (C)




Staff Physician


University of Alberta Hospital


Shimon Kusne, M.D.



Mayo Medical School

Chair



Mayo Clinic ArizonaPhoenix, Arizona

Roberta Lattes, M.D.

Assistant Professor Infectious Diseases


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



Senior Clinical Pharmacy Specialist

Pharmacy



Ingi Lee, M.D., M.S.C.E.

Instructor


University of Pennsylvania School of

Medicine



Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania

Ajit P. Limaye, M.D.

Associate Professor



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



Chairman


Baystate Medical Center

Springfield, Massachusetts

Mitchell R. Lunn, B.S.


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.



Johns Hopkins University

Director

Transplant and Oncology Infectious

Disease


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


9/798

Lisa M. McDevitt, PHARM.D.,B.C.P.S.

Assistant Professor



Senior Clinical Specialist

Organ Transplantation

Department of PharmacyTufts Medical Center


George B. McDonald, M.D.

Professor



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


Division of Pediatric Infectious Diseases


Childrens Hospital of Pittsburgh of

University of Pittsburgh Medical

Center


Barbara Montante, M.D.

Resident

Pediatric Hematology and Bone Marrow

Transplant Unit

San Camillo Hospital

Rome, Italy

Jose G. Montoya, M.D.


Division of Infectious Diseases and

Geographic Medicine

Stanford University School of Medicine

Attending Physician


Stanford Hospital and Clinics

Stanford, California

David C. Mulligan, M.D., F.A.C.S.

Professor


Mayo Clinic School of Medicine

Director

Transplant Center

Mayo Clinic Arizona

Phoenix, Arizona

Patricia Muoz, M.D., Ph.D.

Professor



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


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.


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.





Marcelo Radisic, M.D.

Attending Physician


Instituto De Nefrologa

Buenos Aires, Argentina

Raymund R. Razonable, M.D.



Mayo Clinic College of Medicine

Consultant Staff


Mayo Clinic


Jorge D. Reyes, M.D.

Professor



Chief

Division of Transplant Surgery


CenterSeattle, Washington

Andrew R. Rezvani, M.D.

Research Associate

Transplantation Biology Program


Acting Instructor

Medical Oncology


Center

Seattle, Washington

Jason Rhee, M.D.

Transplant Research Fellow




Stanely R. Riddell, M.D.



Seattle, Washington

Antonio Romn, M.D., Ph.D.

Senior Consultant

Pneumology Department

Vall dHebronBarcelona, Spain

Brahm H. Segal, M.D.


State University of New York at Buffalo

Head of Infectious Disease

Roswell Park Cancer Institute

Buffalo, New York

Maria Teresa Seville, M.D.

Instructor


Mayo Clinic

ChairInfection Prevention and Control

Mayo Clinic Hospital

Phoenix, Arizona

Nina Singh, M.D.




Contributors ix


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David R. Snydman, M.D., F.A.C.P.



Chief, Division of Geographic Medicine

and Infectious Diseases

Hospital Epidemiologist



Gideon Steinbach, M.D., Ph.D.

Associate Professor



Associate Member

Gastroenterology, Hospital Section


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


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


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


Center/Seattle Cancer Care Alliance

(inpatients)

Seattle, Washington

John R. Wingard, M.D.

Professor


University of Florida

Director of Bone Marrow Transplant

Program


University of Florida Shands CancerCenter


Jo-Anne H. Young, M.D.

Associate Professor


University of Minnesota

Director of the Program in Transplant

Infectious Disease


University of Minnesota Medical Center

Minneapolis, Minnesota

x Contributors


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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

xii Contents


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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.


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



19/798

(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

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