Table Of ContentRecent Results 132
in Cancer Research
Managing Editors
Ch. Herfarth, Heidelberg· H. -J. Senn, St. Gallen
Associate Editors
M. Baum, London· V. Diehl, Koln
F. Gutzwiller, Zurich· M. F. Rajewsky, Essen
M. Wannenmacher, Heidelberg
Founding Editor
P. Rentchnick, Geneva
s.c. Schimpff J. Klastersky (Eds.)
Infectious Complications
in Bone Marrow
Transplantation
With 30 Figures and 51 Tables
Springer-Verlag
Berlin Heidelberg New York
London Paris Tokyo
Hong Kong Barcelona
Budapest
Prof. Stephen C. Schimpff, M.D.
University of Maryland Medical System
Baltimore, MD 21201, USA
Prof. Jean Klastersky, M.D.
Institut Jule·s Bordet
Centre des Tumeurs de l'Universite
Libre de Bruxelles
Brussels, Belgium
ISBN-13:978-3-642-84901-5 e-ISBN-13:978-3-642-84899-5
DOl: 10.1007/978-3-642-84899-5
Library of Congress Cataloging-in-Publication Data.
Infectious complications in bone marrow transplantation / Stephen C. Schimpff,
Jean Klastersky (eds.). p. cm.-(Recent results in cancer research: 132) Includes
bibliographical references and index.
ISBN -13:978-3-642-84901-5
1. Bone marrow-Transplantation-Complications-Congresses. 2. Infection-Con
gresses. I. Schimpff, Stephen c., 1941- . II. Klastersky, J. (Jean) III. Series.
[DNLM: 1. Bone Marrow Transplantation- adverse effects-congresses. 2. Infec
tion-etiology-congresses. WI REI06P v. 132 1992 / WH 380 143 1992]
RC261.R35 no. 132 [RD123.5] 616.99'4 s-dc20 [617.4'4] DNLMIDLC
92-48504
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To our wives, Carol and Daisy,
and our daughters,
Elizabeth, Catherine and Sophie
Preface
As the demographics of the population shift toward an
increasingly aged society, the number of individuals with
cancer increases and with it the need to give the most
comprehensive possible health care delivery. Although
much has been written about the specific therapy best suited
for the various types of cancer and about the basic and
clinical research which has dramatically improved treat
ment, overall patient care requires attention to supportive
care, which includes such items as pain management, the
use of blood products, nutrition, and psychosocial needs.
Yet infection remains the leading cause of death in cancer
patients and is a major cause of morbidity and hospitaliza
tion, making it a major aspect of the supportive care of
cancer patients. It therefore deserves a full exposition.
Bone marrow transplantation is increasingly being
utilized as part of a therapeutic modality in the treatment
of cancer patients. Transplantation patients are at such
a particularly high risk of developing a wide variety of
different types of infection, that they inevitably can serve as
an excellent framework for discussion of all the types of
infections that occur during the treatment of cancer. The
patient undergoing allogeneic bone marrow transplantation
is at particularly high risk of infection due to the major
perturbations of host defenses, which include granulo
cytopenia, cellular immune dysfunction, humoral immune
dysfunction, blood product transfusions, and vascular access
devices. Each of these perturbations results in a different
set of infectious disease problems. The patient with
granulocytopenia tends to develop bacteremia with Gram
negative bacilli, staphylococci, and streptococci and, after
\TIll Preface
receiving broad-spectrum antibiotics, is at risk for infections
with Candida and Aspergillus. The patient who has dys
function of his/her cellular immune system is at risk for viral
infections, such as herpes simplex, varicella zoster, and
cytomegalovirus; bacterial infections, such as reactivation of
latent Mycobacterium tuberculosis; or infections caused by
Listeria, Salmonella, or other mycobacteria, by protozoa,
such as Pneumocystis carinii and Toxoplasma gondii, by the
helminth, Strongyloides stercoralis, and by fungi, which
include Cryptococcus neoformans; and the reactivation of
latent histoplasmosis or coccidioidomycosis. The patient
with humoral immune dysfunction is at risk for a totally
different group of infections, most notably the encapsulated
pyogenic coccus, Streptococcus pneumoniae and, to a lesser
degree, Haemophilus inJluenzae and Neisseria meningitidis.
Patients who have had a splenectomy or have hypoplastic
splenic function are at risk for this same group of organisms
causing overwhelming septicemia. Blood product trans
fusions have their own risk of related infection, including
cytomegalovirus carried via white blood cells, hepatitis B or
C, and occasionally other viruses and bacteria. Finally, the
patient who has a vascular access device is at risk for an
infection in connection with that device. One final set of
infections are those which relate to partial obstruction of a
natural passage, such as a postobstructive pneumonia and
urinary tract infection, where the tumor itself creates the
obstructing phenomenon.
Having now conducted three international symposia
dealing with the supportive care complications of cancer
and its treatment, we organized, in the summer of 1991, a
workshop to look specifically at the issues of infectious
disease complications and utilized as our model a patient
who received an allogeneic bone marrow transplantation
for acute nonlymphocytic leukemia. We invited 23 inter
nationally recognized experts to deal with the issues, both
to name areas of controversy and, concurrently, to seek
consensus. This workshop, graciously funded by an educa
tional grant from Merck Sharp & Dohme, brought forth
sufficient valuable information that we felt, along with
Dr. H. J. Senn, our cochairman and, likewise, organizer of
supportive care symposia, that it would be useful to make
this information available to a broader audience through
the publication of this text. Thus, we present for your
review a summary of these topics, as noted above, plus
discussions of new pathogens, drug delivery systems, and,
Preface IX
finally, some thoughts on clinical trials and clinical trial
methodology.
Baltimore, MD, USA Stephen C. Schimpff
Brussels, Belgium Jean Klastersky
Acknowledgment
The symposium-workshop which served as the basis for this
text was funded by an educational grant from Merck Sharp
& Dohme. We wish to acknowledge the corporation's
generosity and, equally importantly, acknowledge the
personal efforts of Mr. Lawrence C. Rappaport, Executive
Coordinator, Health Science Services, Infectious Diseases.
In addition to the presenter/authors, the success of the
symposium was due to the organizational efforts of Paula
Rosen with on sight assistance from her husband, Marc.
Mrs. Rosen was also responsible for all of the organiza
tional work required to ensure the successful completion of
this text. Finally, we wish to thank Professor Hans-Jorg
Senn, Editor of this series and our co-chairman of the
symposium-workshop, for assuring timely editing and
publishing.
Contents
I. Introduction . . . 1
D. D. Hurd
Bone Marrow Transplantation for Cancer:
An Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
S. C. Schimpff
Infection in Bone Marrow Transplantation:
A Model for Examining Predisposing Factors
to Infection in Cancer Patients . . . . . . . . . . . . . . .. 15
II. Case Presentation . . . . . . . . . . . . . . . . . . . . .. 35
S. C. Schimpjf
Introduction to Case Presentation. . . . . 35
III. Infection and Granulocytopenia 45
C. I. Bustamante
Initial Empiric Therapy for Fever in Neutropenia. . .. 45
P. A. Pizzo
Approach to the Patient with Prolonged
Granulocytopenia . . . . . . . . . . . . . . . . . . . . . . .. 57
J. L. Shenep
Simplification of Empiric Therapy for the Febrile
Neutropenic Oncology Patient. . . . . . . . . . . . . . .. 67
XII Contents
N. 1. Vogelzang and 1. P. Flaherty
Fever and Granulocytopenia: A Viewpoint from an
Academic Setting ... . . . . . . . . . . . . . . . . . . . .. 79
1. G. Gallagher
Empiric Antimicrobial Therapy in the Community
Hospital Setting for the Cancer Patient with Fever and
Neutropenia: The Need for Vigilance and Attention
to Detail . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 89
W. P. Peters
Observations on the Effects of Hematopoietic Colony
Stimulating Factors on the Clinical Course of Bone
Marrow Transplantation . . . . . . . . . . . . . . . . . . .. 97
K. Vollmer and G. L. Mandell
Effect of Colony-Stimulating Factors on
Granulocyte Function. . . . . . . . . . . . . . . . . . . . .. 103
R. D. Diamond
Invasive Aspergillosis: Host Defenses . . . . . . . . . .. 109
V. T. Andriole
Invasive Aspergillosis: Serologic Diagnosis. . . . . . .. 117
M. Aoun, P. Van der Auwera, 1. Gerain, and
1. Klastersky
Aspergillosis in the Immunocompromised: Focus
on Treatment . . . . . . . . . . . . . . . . . . . . . . . . . .. 127
E. Anaissie and H. Pinczowski
Invasive Candidiasis During Granulocytopenia 137
IV. Infections and Cellular Immune Dysfunction 147
1. Klastersky
Infections in Cancer Patients with Suppressed
Cellular Immunity. . . . . . . . . . . . . . . . . . . . . . .. 147
R. Saral
Herpes Simplex Infections. . . . . . . . . . . . . . . . . .. 155
G. M. Schmidt
Treatment and Prophylaxis of Cytomegalovirus
Infection After Bone Marrow Transplantation. . . . .. 161
Contents XIII
S. Feldman
Varicella Zoster Infections in Bone Marrow
Transplants . . . . . . . . . . . . . . . . . . . . . . . . . . .. 175
A. J. Barrett
Graft-Versus-Host Disease: Basic Considerations. . .. 185
P. J. Tutschka
Graft-Versus-Host Disease: Implications . . . . . . . .. 197
V. Infections Related to Humoral Immune Deficiency /
Vascular AccesslTransfusions. . . . . . . . . . . . . . . .. 205
P. J. Tutschka
Late Bacterial Infections in Humoral Immune
Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 205
G. L. Davis
Hepatitis Band C: Influence of Immunosuppression.. 213
J. E. Karp and J. D. Dick
Emergence of Gram-Positive Infections: Relationship
to Indwelling Catheters and Management During
Chemotherapy-Induced Aplasia. . . . . . . . . . . . . .. 221
VI. New Pathogens/Resistance/Drug Delivery . . . . .. 231
S. H. Zinner
New Pathogens in the Immunocompromised Host. .. 231
G. A. Jacoby
Resistant Bacterial Infections. . . . . . . . . . . . . . . .. 241
VII. Clinical Trials: Perspectives ... . . . . . . . . . .. 249
R. Feld
Organization of Clinical Trials: Problems,
Controversies, Definitions, and Methodology Related
to Infections in Neutropenic Patients. . . . . . . . . . .. 249
R. L. Comis
Organization of Clinical Trials: Problems,
Controversies, Definitions, Methodology . . . . . . . .. 257
