Escolar Documentos
Profissional Documentos
Cultura Documentos
THE MANAGEMENT
OF SICKLE
CELL DISEASE
N A T I O N A L I N S T I T U T E S O F H E A L T H
N A T I O N A L H E A R T, L U N G , A N D B L O O D I N S T I T U T E
THE MANAGEMENT
OF SICKLE
CELL DISEASE
N ATIONAL I NSTITUTES
OF H EALTH
National Heart, Lung,
and Blood Institute
Division of Blood Diseases
and Resources
NIH P UBLICATION
N O . 02-2117
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
HEALTH MAINTENANCE
5. Child Health Care Maintenance. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
6. Adolescent Health Care and Transitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
7. Adult Health Care Maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
8. Coordination of Care: Role of Mid-Level Practitioners . . . . . . . . . . . . . . . . . 47
9. Psychosocial Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
III
18. Splenic Sequestration. . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . 119
19. Renal Abnormalities in Sickle Cell Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 123
20. Priapism . . . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . 129
21. Bones and Joints . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . 133
22. Leg Ulcers. . . . . . . . . . . . . . . . . . . ....... . . . . . . . . . . . . . . . . . . . . . . . . . 139
SPECIAL TOPICS
23. Contraception and Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
24. Anesthesia and Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
25. Transfusion, Iron Overload, and Chelation . . . . . . . . . . . . . . . . . . . . . . . . . 153
26. Fetal Hemoglobin Induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
27. Hematopoietic Cell Transplantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
28. Genetic Modulation of Phenotype by Epistatic Genes . . . . . . . . . . . . . . . . 173
29. Highlights from Federally Funded Studies. . . . . . . . . . . . . . . . . . . . . . . . . . 181
IV
P REFACE
Enclosed is the fourth edition of a book that iduals with sickle cell disease and provides
is dedicated to the medical and social issues of relevant online resources at the end of the
individuals with sickle cell disease. This publi- chapters, is to serve as an adjunct to recent
cation, which was developed by physicians, textbooks that delve more deeply into all
nurses, psychologists, and social workers who aspects of the disorder.
specialize in the care of children and adults
with sickle cell disease, describes the current The authors hope that this book will be used
approach to counseling and also to manage- by medical students, house staff, general practi-
ment of many of the medical complications tioners, specialists, nurses, social workers, psy-
of sickle cell disease. chologists, and other professionals as well as
the families and patients who are coping with
Each chapter was prepared by one or more the complexities of sickle cell disease on a daily
experts and then reviewed by several others basis. The book, any part of which can be
in the field. Additional experts reviewed the copied freely, will be placed on the National
entire volume. This book is not the result of a Heart, Lung, and Blood Institute (NHLBI)
formalized consensus process but rather repre- Web site and will be updated as needed.
sents the efforts of those who have dedicated
their professional careers to the care of indi- Research is essential to provide the knowledge
viduals with sickle cell disease. The names of required to improve the care of individuals
the authors, their affiliations, and their e-mail with sickle cell disease, but it is the physicians
addresses are listed in the front of the book. and other health care personnel who must
ensure that the very best care is actually
Multiple new therapies are now available for delivered to each child and adult who has
children and adults with sickle cell disease, this disorder. We hope that this book will
and often the options to be chosen present help to achieve this goal.
a dilemma for both patients and physicians.
This book does not provide answers to many
of these newer questions but rather explains
the choices available. The book, which focuses Claude Lenfant, M.D.
primarily on the basic management of indiv- Director, NHLBI
V
VI
C ONTRIBUTORS
VII
Oswaldo Castro, M.D. Joseph DeSimone, Ph.D.
Professor of Medicine/Pediatrics Geneticist
Howard University School of Medicine VA West Side Medical Center
Comprehensive Sickle Cell Center Hematology Research (151C)
2121 Georgia Avenue, NW 820 South Damen Avenue
Washington DC 20059 Chicago, IL 60612
Tel: (202) 806-7930 Tel: (312) 666-6500 x2683
Fax: (202) 806-4517 Fax: (312) 455-5877
E-mail: olcastro@aol.com E-mail: Jdesimon@UIC.edu
VIII
Cage Johnson, M.D. Peter Lane, M.D.
Professor of Medicine Director, Colorado Sickle Cell Treatment
University of Southern California and Research Center
2025 Zonal Avenue Campus Box C-222
Los Angeles, CA 90033 University of Colorado Health Sciences Center
Tel: (323) 442-1259 4200 East Ninth Avenue
Fax: (323) 442-1255 Denver, CO 80262
E-mail: cagejohn@hsc.usc.edu Tel: (303) 372-9070
Fax: (303) 372-9161
Adrena Johnson-Telfair, P.A.C. E-mail: Peter.Lane@uchsc.edu
Associate Director for Clinical Services
University of Alabama at Birmingham Dimitris Loukopoulos, M.D., D.Sci.
Comprehensive Sickle Cell Center First Department of Medicine
1900 University Boulevard University of Athens School of Medicine
513 Tinsley Harrison Laikon Hospital
Birmingham, AL 35294-0006 Athens 11527 GREECE
Tel: (205) 975-2281 Tel: +30 1 7771 161
Fax: (205) 975-5264 Fax: +30 1 7295 065
E-mail: ajtelfair@hotmail.com E-mail: dloukop@otenet.gr
IX
Marie Mann, M.D., M.P.H. Orah Platt, M.D.
Deputy Chief, Genetic Services Branch Director, Department of Laboratory Medicine
Maternal and Child Health Bureau Enders Research Building, Room 761
Health Resources and Services Administration Children’s Hospital Medical Center
5600 Fishers Lane 320 Longwood Avenue
Rockville, MD 20857 Boston, MA 02146
Tel: (301) 443-4925 Tel: (617) 355-6347
Fax: (301) 443-8604 Fax: (617) 713-4347
E-mail: Mmann@hrsa.gov E-mail: platt@tch.harvard.edu
X
Martin Steinberg, M.D. Tim Townes, Ph.D.
Director, Center for Excellence in Sickle Cell Disease Professor, Department of Biochemistry
Boston Medical Center and Molecular Genetics
88 East Newton Street Schools of Medicine and Dentistry
Boston, MA 02118 University of Alabama at Birmingham
Tel: (617) 414-1020 BBRB 260
Fax: (617) 414-1021 1530 3rd Avenue South
E-mail: msteinberg@medicine.bu.edu Birmingham, AL 35294-0022
Tel: (205) 934-5294
Marie Stuart, M.D. Fax: (205) 934-2889
Professor of Pediatrics E-mail: ttownes@bmg.bhs.uab.edu
Division of Pediatric Hematology
Thomas Jefferson University Marsha Treadwell, Ph.D.
1025 Walnut Street, Suite 727 Hematology Behavioral Services Coordinator
Philadelphia, PA 19107 Children’s Hospital Oakland
Tel: (215) 955-9820 747 52nd Street
Fax: (215) 955-8011 Oakland, CA 94609-1809
E-mail: Marie.Stuart@mail.tju.edu Tel: (510) 428-3356
Fax: (510) 428-3973
Paul Swerdlow, M.D. E-mail: MTreadwell@mail.cho.org
Director of Red Cell Disorders
Associate Professor, Wayne State University Elliott Vichinsky, M.D.
Harper Hospital, 4 Brush South Division Head, Hematology/Oncology
Barbara Ann Karmanos Cancer Institute Director, Comprehensive Sickle Cell Center
3990 John R St. Children’s Hospital of Oakland
Detroit, MI 48201 747 52nd Street
Tel: (313) 745-9669 Oakland, CA 94609-1809
Fax: (313) 993-0307 Tel: (510) 420-3651
E-mail: swerdlow@Karmanos.org Fax: (510) 450-5647
E-mail: evichinsky@mail.cho.org
Joseph Telfair, Dr.P.H., M.S.W., M.P.H.
Department of Maternal and Child Health Mark Walters, M.D.
School of Public Health Fred Hutchinson Cancer Research Center
University of Alabama at Birmingham 100 Fairview Avenue North, C1-169
320 Royals Building P.O. Box 10924
1665 University Boulevard Seattle, WA 98109-1024
Birmingham, AL 35294-0022 Tel: (206) 667-4103
Tel: (205) 934-1371 Fax: (206) 667-6084
Fax: (205) 934-8248 E-mail: mwalters@mail.cho.org
E-mail: jtelfair@uab.edu
Winfred Wang, M.D.
Department of Hematology/Oncology
St. Jude’s Children’s Research Center
P.O. Box 318
32 North Lauderdale
Memphis, TN 38101
Tel: (901) 495-3497
Fax: (901) 521-9005
E-mail: winfred.wang@stjude.org
XI
Russell Ware, M.D., Ph.D. Robert Yamashita, Ph.D.
Professor of Pediatrics Interdisciplinary Studies in Science and Society
Duke University Medical Center Liberal Studies Department
Box 2916 DUMC California State University
R-133 MSRB, Research Drive San Marcos, CA 92096-0001
Durham, NC 27710 Tel: (760) 750-4204
Tel: (919) 684-5665 E-mail: yamashta@csusm.edu
Fax: (919) 684-5752
E-mail: ware0005@mc.duke.edu
NATIONAL INSTITUTES OF HEALTH
Doris Wethers, M.D. Barbara Alving, M.D.
1201 Cabrini Boulevard Deputy Director
Apartment #57 National Heart, Lung, and Blood Institute
New York, NY 10033 Building 31, Room 5A47, MSC 2490
Tel: (212) 928-2600 31 Center Drive
E-mail: dlwethers@earthlink.net Bethesda, MD 20892-2490
Tel: (301) 594-5171
Charles Whitten, M.D. Fax: (301) 402-0818
President Emeritus, Sickle Cell Disease Association E-mail: alvingb@nih.gov
of America
Distinguished Professor of Pediatrics and Associate Dean Griffin Rodgers, M.D.
Wayne State University School of Medicine Deputy Director
Scott Hall, Room 1201 National Institute of Diabetes and Digestive
540 East Canfield Street Kidney Diseases
Detroit, MI 48201 Building 31, Room 9A52, MSC 1822
Tel: (313) 577-1546 31 Center Drive
Fax: (313) 577-1330 Bethesda, MD 20892-1822
E-mail: cwhitten@med.wayne.edu Tel: (301) 496-5741
Fax: (301) 402-2125
Wanda Whitten-Shurney, M.D. E-mail: rodgersg@extra.niddk.nih.gov
Attending Pediatrician
Children’s Hospital of Michigan Henry Chang, M.D.
3901 Beaubien Boulevard Health Scientist Administrator
Detroit, MI 48201 Division of Blood Diseases and Resources
Tel: (313) 745-5613 National Heart, Lung, and Blood Institute
Fax: (313) 745-5237 6701 Rockledge Drive, MSC 7950
E-mail: wshurney@dmc.org Bethesda, MD 20892-7950
Tel: (301) 435-0065
Nevada Winrow, Ph.D. Fax (301) 480-0867
Postdoctoral Fellow E-mail: changh@nih.gov
9624 Devedente Drive
Owings Mills, MD 21117 Charles Peterson, M.D.
Tel: (240) 601-8683 Director, Division of Blood Diseases and Resources
Fax: (410) 902-3457 National Heart, Lung, and Blood Institute
E-mail: nwinrow@jhmi.edu 6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Tel: (301) 435-0080
Fax: (301) 480-0867
E-mail: petersoc@nih.gov
XII
Duane Bonds, M.D. Petronella Barrow
Health Scientist Administrator Office Manager
Sickle Cell Disease Scientific Research Group Division of Blood Diseases and Resources
Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute
National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7950
6701 Rockledge Drive, MSC 7950 Bethesda, MD 20892-7950
Bethesda, MD 20892-7950 Tel: (301) 435-0080
Tel: (301) 435-0055 Fax: (301) 480-0867
Fax: (301) 480-0868 E-mail: barrowp@nih.gov
E-mail: bondsd@nih.gov
Kathy Brasier
Greg Evans, Ph.D. Secretary
Health Scientist Administrator National Heart, Lung, and Blood Institute
Division of Blood Diseases and Resources Building 31, Room 5A47, MSC 2490
National Heart, Lung, and Blood Institute Bethesda, MD 20892-2490
6701 Rockledge Drive, MSC 7950 Tel: (301) 496-1078
Bethesda, MD 20892-7950 Fax: (301) 402-0818
Tel: (301) 435-0055 E-mail: brasierk@nih.gov
Fax: (301) 480-0868
E-mail: evansg@nih.gov
XIII
XIV
I NTRODUCTION
This edition of The Management of Sickle pneumococcal vaccine developed after the
Cell Disease (SCD) is organized into four trial, which has not been tested formally in
parts: Diagnosis and Counseling, Health a sickle cell population. Earlier trial results
Maintenance, Treatment of Acute and Chronic may be accepted, based on the assumption
Complications, and Special Topics. The origi- that the change is small.
nal intent was to incorporate evidence-based
medicine into each chapter, but there was In some cases, RCTs cannot be done satisfac-
variation among evidence-level scales, and torily (e.g., for ethical reasons, an insufficient
some authors felt recommendations could number of patients, or a lack of objective
be made, based on accepted practice, without measures for sickle cell “crises”). Thus the
formal trials in this rare disorder. bulk of clinical experience in SCD still
remains in the moderately strong and weaker
The best evidence still is represented by ran- categories of evidence.
domized, controlled trials (RCTs), but varia-
tions exist in their design, conduct, endpoints, Not everyone has an efficacious outcome in
and analyses. It should be emphasized that a clinical trial, and the frequency of adverse
selected people enter a trial, and results should events, such as with long-term transfusion
apply in practice specifically to populations programs or hematopoietic transplants, might
with the same characteristics as those in not be considered. Thus, an assessment of
the trial. Randomization is used to reduce benefit-to-risk ratio should enter into transla-
imbalances between groups, but unexpected tion of evidence levels into practice recommen-
factors sometimes may confound analysis or dations. A final issue is that there may be two
interpretation. In addition, a trial may last alternative approaches that are competitive
only a short period of time, but long-term (e.g., transfusions and hydroxyurea). In this
clinical implications may exist. Another issue case the pros and cons of each course of treat-
is treatment variation, for example, a new ment should be discussed with the patient.
1
Introduction
The following nomenclature, derived from the Council of Regional Networks for Genetic Services
(CORN) guidelines for the U.S. newborn screening system [Pass KA, Lane PA, Fernhoff PM, et al.
U.S. newborn screening system guidelines II: Follow-up of children, diagnosis, management, and
evaluation. Statement of the Council of Regional Networks for Genetic Services (CORN). J Pediatr
2000;(4 Suppl):S1-46], is used throughout this book:
2
DIAGNOSIS AND COUNSELING
3
4
W ORLD W IDE W EB R ESOURCES 1
5
Chapter 1: World Wide Web Resources
6
N EONATAL S CREENING 2
The demonstration in 1986 that prophylactic The sensitivity and specificity of current
penicillin markedly reduces the incidence of screening methodology are excellent (11), but
pneumococcal sepsis (1) provided a powerful neonatal screening systems are not foolproof.
incentive for the widespread implementation A few infants, even in states with universal
of neonatal screening for sickle cell disease screening, may not be screened. Other infants
(SCD) (2). Neonatal screening, when linked with SCD may go undiscovered because of
to timely diagnostic testing, parental educa- extreme prematurity, blood transfusion prior
tion, and comprehensive care, markedly to screening, mislabeled specimens, clerical
reduces morbidity and mortality from errors in the laboratory, or the inability to
SCD in infancy and early childhood (2-11). locate affected infants after discharge from
Approximately 2,000 infants with SCD are the nursery (5,14,16-20). It is imperative that
identified annually by U.S. neonatal screen- all infants, including those born at home, be
ing programs (12,13). Screening also identi- screened and that the initial screening test
fies infants with other hemoglobinopathies, always be obtained prior to any blood transfu-
hemoglobinopathy carriers, and in some sion, regardless of gestational or postnatal age.
states, infants with α-thalassemia syndromes. Information requested on screening forms
should be recorded accurately and completely
METHODS to facilitate the followup of positive screening
tests and interpretation of results. In states
Forty-four states, the District of Columbia, that have not yet implemented universal
Puerto Rico, and the Virgin Islands currently screening, neonatal screening for SCD should
provide universal screening for SCD. be requested for all high-risk infants (those
Screening is available by request in the other of African, Mediterranean, Middle Eastern,
six states. The majority of screening programs Indian, Caribbean, and South and Central
use isoelectric focusing (IEF) of an eluate from American ancestry). Any high-risk infant
the dried blood spots that also are used to not screened at birth, or for whom neonatal
screen for hypothyroidism, phenylketonuria, screening results cannot be documented,
and other disorders (13-15). A few programs should be screened for hemoglobinopathies
use high-performance liquid chromatography prior to 2 months of age.
(HPLC) or cellulose acetate electrophoresis as
the initial screening method. Most programs Hemoglobins (Hb) identified by neonatal
retest abnormal screening specimens using screening are generally reported in order of
a second, complementary electrophoretic quantity. Because more fetal hemoglobin (Hb
technique, HPLC, immunologic tests, or F) than normal adult hemoglobin (Hb A) is
DNA-based assays (13-15). present at birth, most normal infants show
Hb FA. Infants with hemoglobinopathies also
7
Chapter 2: Neonatal Screening
show a predominance of Hb F at birth. Those Hemolytic anemia and clinical signs and
with SCD show Hb S in absence of Hb A symptoms of SCD are rare before 2 months
(FS), Hb S with another hemoglobin variant of age and develop variably thereafter as Hb F
(e.g., FSC, FSDPunjab), or a quantity of Hb S levels decline (table 1). Thus for infants with
greater then Hb A (FSA). Hundreds of other an FS phenotype, serial complete blood counts
Hb variants may also be identified. Most of (CBCs) and reticulocyte counts may not clari-
these variants are associated with few or no fy the diagnosis during early infancy, and test-
clinical consequences, but some are associated ing of parents or DNA analysis may be helpful
with significant anemia or other problems. in selected cases (14). In all cases, infants with
Many screening programs also detect and Hb FS should be started on prophylactic peni-
report Hb Bart’s, indicative of α-thalassemia. cillin by 2 months of age, and parents should
be educated about the importance of urgent
SICKLE CELL DISEASE medical evaluation and treatment for febrile
illness and for signs and symptoms indicative
As shown in table 1, a number of different of splenic sequestration (11,14).
neonatal screening results may be indicative
of sickle cell disease (14,21). Hb FS in infancy Achieving an optimal outcome for each
is associated with a variety of genotypes with affected infant is a significant public health
a wide range of clinical severity. Most infants challenge. State public health agencies should
with screening results that show Hb FS have have a responsibility to ensure the availability,
SCD-SS, but other possible conditions include quality, and integration of all five components
sickle βo-thalassemia, sickle δβ-thalassemia, of the neonatal screening system: screening,
and sickle HPFH. Some infants with sickle follow-up, diagnostic testing, disease manage-
β+-thalassemia also show FS screening results ment and treatment, and evaluation of the
when the quantity of Hb A at birth is insuffi- entire system (12-15). To be beneficial,
cient for detection (22). The coinheritance of screening, follow-up, and diagnosis of sickle
α-thalassemia may complicate differentiation cell disease must be followed by prompt refer-
of genotypes in some infants (23). For infants ral to knowledgeable providers of comprehen-
with positive screening tests, confirmatory sive care (2,11). Comprehensive care includes
testing of a second blood sample should be ongoing patient and family education about
accomplished by 2 months of age so that disease complications and treatment, disease-
parental education, prophylactic penicillin, specific health maintenance services including
and comprehensive care can be promptly pneumococcal immunizations and prophylac-
implemented (11,14). In many states, confir- tic penicillin, access to timely and appropriate
matory testing is provided by the screening treatment of acute illness, nondirective genet-
program using hemoglobin electrophoresis ic counseling, and psychosocial support (14).
(cellulose acetate and citrate agar), IEF, The extent to which these services are provid-
HPLC, and/or DNA-based methods. ed directly by public health agencies or by
Solubility tests to detect Hb S are inappropri- other clinics and providers will vary among
ate screening or confirmatory tests, in part states and communities. However, all states
because high levels of fetal hemoglobin (i.e., should have the responsibility to ensure
low concentrations of Hb S) give false-nega- that each infant and family with SCD
tive results in infants with SCD. receive appropriate services and to conduct
8
Table 1. Sickle Hemoglobinopathies: Neonatal Screening and Diagnostic Test Results
MCV2 Hb A23 Hb F Hb F
(%) (%) distribution
SCD-SS 65 FS FS Hemolysis and anemia N or ↑4 <3.64 <25 Heterocellular βs
by 6-12 months
SCD-SC 25 FSC FSC Mild or no anemia N or ↓ NA5 <15 Not applicable6 βs βc
by 2 years
SCD-S 8 FSA or FS7 FSA Mild or no anemia N or ↓ >3.6 <25 Not applicable6 βA βs
β+ thal by 2 years
SCD-S 2 FS FS Hemolysis and anemia ↓ >3.6 <25 Heterocellular βA βs
βo thal by 6-12 months
SCD-S <1 FS FS Mild anemia by ↓ <2.5 <25 Heterocellular βs
δβ thal 2 years
S HPFH <1 FS FS No hemolysis N or ↓ <2.5 <25 Pancellular βs
or anemia
Hb = hemoglobin, MCV = mean cell volume, thal = thalassemia, N = normal, ↑ = increased, ↓ = decreased, HPFH = hereditary persistance of Hb F.
Table shows typical results—exceptions occur. Some rare genotypes (eg. SDPunjab, SO Arab, SC Harlem, S Lepore, SE) not included.
1. Hemoglobins reported in order of quantity (e.g. FSA = F>S>A).
2. Normal MCV: >70 at 6-12 months, >72 at 1-2 years.
3. Hb A2 results vary somewhat depending on laboratory methodology.
4. Hb SS with co-existent α-thalassemia may show ↓MCV and Hb A2 >3.6 percent; however, neonatal screening results from such infants usually show Hb Bart’s.
5. Quantity of Hb A2 can not be measured by hemoglobin electrophoresis or column chromatography in presence of Hb C.
6. Test not indicated.
7. Quantity of Hb A at birth sometimes insufficient for detection.
9
Chapter 2: Neonatal Screening
a continuing program of long-term followup Newborns with more than 10 percent hemo-
(12,14,15). Providers may be asked to supply globin Bart’s by IEF or more than 30 percent
public health agencies with the followup data hemoglobin Bart’s by HPLC or those who
needed for tracking and outcomes evaluation. develop more severe anemia need extensive
diagnostic testing and consultation with a
OTHER HEMOGLOBINOPATHIES pediatric hematologist to accurately diagnose
and appropriately treat more serious forms
As shown in table 2, neonatal screening identi- of α-thalassemia such as Hb H disease or Hb
fies some infants with non-sickle hemoglo- H Constant Spring disease (33). The identifi-
binopathies (14,25-30). Infants with Hb F cation of Hb Bart’s in Asian infants may have
only may be normal infants who do not yet important genetic implications because subse-
show Hb A because of prematurity or may quent family testing may identify couples at
have β-thalassemia major or another tha- risk for pregnancies complicated by hydrops
lassemia syndrome. Infants without Hb A fetalis (14,25,34).
need repeat testing to identify those with SCD
and other hemoglobinopathies. Homozygous
β-thalassemia may cause severe transfusion- CARRIERS OF
dependent anemia. Infants with FE [Hb F + HEMOGLOBIN VARIANTS
hemoglobin E (Hb E)] require family studies, Approximately fifty infants who are carriers
DNA analysis, or repeated hematologic evalua- of hemoglobin variants (i.e., hemoglobin traits)
tion during the first 1 to 2 years of life to dif- are identified for every one with SCD (14).
ferentiate homozygous Hb E, which is asymp- The screening laboratory can usually confirm
tomatic, from Hb E βo-thalassemia, which the carrier state by using a complementary
is variably severe (26-29). It is important methodology. Some programs recommend
to note that most infants with β-thalassemia confirmation of carriers by testing a second
syndromes (i.e., β-thalassemia minor and β- specimen from the infant.
thalassemia intermediate) are not identified
by neonatal screening. Carriers are generally asymptomatic (table 4),
and thus identification is of no immediate
ALPHA-THALASSEMIA benefit to the infant. However, parents are
entitled to the information and can benefit
SYNDROMES from knowing the child’s carrier status, in part
The red cells of newborns with α-thalassemia because the information may influence their
contain Hb Bart’s, a tetramer of γ-globin. reproductive decision-making. Therefore, par-
Many, but not all, neonatal screening programs ents of infants who are detected to be carriers
detect and report Hb Bart’s (14,25,31,32). through neonatal screening should be offered
As shown in table 3, infants with Hb Bart’s education and testing for themselves and their
at birth may be silent carriers or have α-tha- extended family (2,11,14). Such testing may
lassemia minor, Hb H disease, or Hb H raise concerns about mistaken paternity and
Constant Spring disease. Silent carriers, the should not be performed without prior discus-
largest group with Hb Bart’s at birth, have sion with the mother. Testing of potential car-
a normal CBC. Persons with α-thalassemia riers requires a CBC and hemoglobin separa-
minor generally show a decreased mean cell tion by hemoglobin electrophoresis, IEF, or
volume (MCV) with mild or no anemia. HPLC. To identify those with β-thalassemia,
10
Table 2. Non-Sickle Hemoglobinopathies Identified by Neonatal Screening*
11
Chapter 2: Neonatal Screening
12
may be reassuring for parents of infants with 8. Davis H, Schoendorf KC, Gergen PJ, et al.
hemoglobin variants that persist (α- or β-glo- National trends in the mortality of children with
sickle cell disease, 1968 through 1992. Am J Public
bin variants). For some families, it may be Health 1997;87:1317-22.
appropriate to offer hemoglobin electrophoresis, 9. Mortality among children with sickle cell disease
IEF, or HPLC and/or CBC, blood smear, and identified by newborn screening during 1990-94
reticulocyte counts on parents. Infants with —California, Illinois, and New York. MMWR
clinical or laboratory evidence of hemolysis 1998;47:169-72.
10. Eckman JR, Dent D, Bender D, et al. Follow-up of
or abnormal oxygen affinity and those without infants detected by newborn screening in Georgia,
Hb A, especially compound heterozygotes Louisiana, and Mississippi (abstr). Proceedings of
with Hb S, require definitive hemoglobin the 14th National Neonatal Screening Symposium.
identification (21,36,37). This may require Association of Public Health Laboratories,
protein sequencing, DNA analysis, or HPLC Washington DC, 1999.
11. Sickle Cell Disease Guideline Panel. Sickle Cell
combined with electrospray mass spectrometry Disease: Screening, Diagnosis, Management, and
in a specialized reference laboratory (38). Counseling in Newborns and Infants. Clinical
Identification of the hemoglobin variant to Practice Guideline No. 6. AHCRP Pub. No 93-0562.
clarify genetic risks should also be considered Rockville, MD: Agency for Health Care Policy and
Research, Public Health Service, U.S. Department
for families in which another hemoglobin
of Health and Human Services. April 1993.
variant (e.g., Hb S) is present. 12. AAP Newborn Screening Taskforce. Serving the
family from birth to the medical home. Newborn
REFERENCES screening: a blueprint for the future. Pediatrics
2000;106(Suppl):383-427.
1. Gaston MH, Verter JI, Woods G, et al. 13. The Council of Regional Networks for Genetics
Prophylaxis with oral penicillin in children with Services (CORN). National Newborn Screening
sickle cell anemia. A randomized trial. N Engl J Report—1992, CORN, Atlanta, December 1995.
Med 1986;314:1593-9. 14. Pass KA, Lane PA, Fernhoff PM, et al. U.S. new-
2. Consensus Development Panel, National born screening system guidelines II: follow-up of
Institutes of Health. Newborn screening for children, diagnosis, management, and evaluation.
sickle cell disease and other hemoglobinopathies. Statement of the Council of Regional Networks for
JAMA 1987;258:1205-9. Genetic Services. J Pediatr 2000;137(Suppl):S1-46.
3. Powars D, Overturf G, Weiss J, et al. 15. Eckman JR. Neonatal screening. In: Embury SH,
Pneumococcal septicemia in children with Hebbel RP, Mohandas N, et al., eds. Sickle Cell
sickle cell anemia. Changing trend of survival. Disease: Basic Principles and Clinical Practice. New
JAMA 1981;245:1839-42. York: Raven Press, 1994:509-15.
4. Vichinsky E, Hurst D, Earles A, et al. Newborn 16. Papadea C, Eckman JR, Kuehner RS, et al.
screening for sickle cell disease: effect on mortality. Comparison of liquid cord blood and filter
Pediatrics 1988;81:749-55. paper spots for newborn hemoglobin screening:
5. Githens JH, Lane PA, McCurdy RS, et al. laboratory and programmatic issues. Pediatrics
Newborn screening for hemoglobinopathies in 1994;93:427-32.
Colorado. The first 10 years. Am J Dis Child 17. Lobel JS, Cameron BF, Johnson E, et al. Value of
1990;144:466-70. screening umbilical cord blood for hemoglobinopa-
6. Wong WY, Powars DR, Chan L, et al. thy. Pediatrics 1989;83:823-6.
Polysaccharide encapsulated bacterial infection 18. Pass KA, Gauvreau AC, Schedlbauer L, et al.
in sickle cell anemia: a thirty-year epidemiologic Newborn screening for sickle cell disease in
experience. Am J Hematol 1992;39:176-82. New York State: the first decade. In: Carter TP,
7. Lee A, Thomas P, Cupidore L, et al. Improved sur- Willey AM, eds. Genetic Disease: Screening and
vival in homozygous sickle cell disease: lessons Management. New York: Alan R. Liss, 1986:359-72.
from a cohort study. Br Med J 1995;311:1600-2.
13
Chapter 2: Neonatal Screening
19. Miller ST, Stilerman TV, Rao SP, et al. Newborn 29. Weatherall DJ. Hemoglobin E β-thalassemia:
screening for sickle cell disease. When is an increasingly common disease wih some
an infant “lost to follow-up?” Am J Dis Child diagnostic pit falls. J Pediatr 1998;132:765-7.
1990;144:1343-5. 30. Olson JF, Ware RE, Schultz WH, et al.
20. Reed W, Lane PA, Lorey F, et al. Sickle-cell Hemoglobin C disease in infancy and
disease not identified by newborn screening childhood. J Pediatr 1994;125:745-7.
because of prior transfusion. J Pediatr 31. Zwerdling T, Powell CD, Rucknagel D.
2000;136:248-50. Correlation of α-thalassemia haplotype with
21. Shafer FE, Lorey F, Cunningham GC, et al. detection of hemoglobin Bart’s in cord blood
Newborn screening for sickle cell disease: 4 by cellulose acetate or isoelectric focusing.
years of experience from California’s newborn Screening 1994;3:131-9.
screening program. J Pediatr Hematol Oncol 32. Miller ST, Desai N, Pass KA, et al. A fast hemoglo-
1996;18:36-41. bin variant in newborn screening is associated with
22. Strickland DK, Ware RE, Kinney TR. Pitfalls α-thalassemia trait. Clin Pediatr 1997;36:75-8.
in newborn hemoglobinopathy screening: 33. Styles LA, Foote DH, Kleman KM, et al.
failure to detect β+-thalassemia. J Pediatr Hemoglobin H-Constant Spring Disease: an
1995;127:304-8. under recognized, severe form of α-thalassemia.
23. Adams JG. Clinical laboratory diagnosis. Internat J Pediatr Hematol/Oncol 1997;4:69-74.
In: Embury SH, Hebbel RP, Mohandas N, 34. Chui DHK, Waye JS. Hydrops fetalis caused by
et al., eds. Sickle Cell Disease: Basic Principles α-thalassemia: an emerging health care problem.
and Clinical Practice. New York: Raven Press, Blood 1998;91:2213-22.
1994:457-68. 35. Council of Regional Networks for Genetic
24. Update: Newborn screening for sickle cell disease Services, (CORN). Unknown hemoglobin variants
—California, Illinois, and New York, 1998. identified by newborn screening: CORN state-
MMWR 2000;49:729-31. ment. CORN, Atlanta, 1999.
25. Dumars KW, Boehm C, Eckman JR, et al. 36. Lane PA, Witkowska HE, Falick AM, et al.
Practical guide to the diagnosis of thalassemia. Hemoglobin D Ibadan-βo thalassemia: detection
Am J Med Genet 1996;62:29-37. by neonatal screening and confirmation by electro-
26. Lorey F. California newborn screening and the spray-ionization mass spectrometry. Am J Hemotol
impact of Asian immigration on thalassemia. 1993;44:153-61.
J Pediatr Hematol Oncol 1997;4:11-6. 37. Witkowska HE, Lubin BH, Beuzard Y, et al. Sickle
27. Johnson JP, Vichinsky E, Hurst D, et al. cell disease in a patient with sickle cell trait and
Differentiation of homozygous hemoglobin compound heterozygosity for hemoglobin S and
E from compound heterozygous hemoglobin hemoglobin Quebec-Chori. N Engl J Med 1991;
Eβo-thalassemia by hemoglobin E mutation 325:1150-4.
analysis. J Pediatr 1992;120:775-9. 38. Witkowska HE, Bitsch F, Shackleton CH.
28. Krishnamurti L, Chui DHK, Dallaire M, et al. Expediting rare variant hemoglobin characteriza-
Coinheritance of α-thalassemia-1 and hemoglobin tion by combined HPLC/electrospray mass spec-
E/βo-thalassemia: practical implications for neona- trometry. Hemoglobin 1993;17:227-42.
tal screening and genetic conseling. J Pediatr 1998;
132:863-5.
14
S ICKLE C ELL T RAIT 3
Individuals who have sickle cell trait (SCT) deprivation or intranasal DDAVP may be
do not have vaso-occlusive symptoms under as low as 400 to 500 mOsm/kg. Coexistent
physiologic conditions and have a normal life α-thalassemia provides partial protection
expectancy. The inheritance of SCT should against this urine-concentrating defect (2).
have no impact on career choices or lifestyle.
SCT is found in 8 percent of African H EMATURIA
Americans and is also prevalent in persons ( ALSO SEE CHAPTER 19, R ENAL A BNORMALITIES
of Mediterranean, Middle Eastern, Indian, IN S ICKLE C ELL D ISEASE )
Caribbean, and Central and South American Necrosis of the renal papillae can result in
descent. Neonatal screening (chapter 2) will hematuria, which is usually microscopic. Gross
provide early detection of SCT. This chapter hematuria is occasionally provoked by heavy
will discuss clinical syndromes associated with exercise or occurs spontaneously. Individuals
SCT, some of which occur only under condi- with hematuria should be evaluated by a urolo-
tions of extreme physiologic stress. gist, who will perform imaging studies as
needed to exclude neoplasms (3-5) or renal
EYE stones or any related problems with flow of
urine from the calyces to the urethra.
T RAUMATIC HYPHEMA
Individuals with acute episodes of gross hema-
The presence of SCT significantly alters the
turia are cautioned to avoid exercise but are
management of traumatic hyphema, which is
encouraged to continue to perform sedentary
discussed more fully in chapter 14, Sickle Cell
work. They are encouraged to take fluids
Eye Disease.
(equivalent to half-normal saline) and may
also receive sodium bicarbonate 650 to 1,200
RENAL AND mg per day. If bleeding persists, an antifibri-
GENITOURINARY TRACT nolytic agent such as epsilon aminocaproic
acid (EACA) can be prescribed (6). In a con-
H YPOSTHENURIA trolled trial of individuals with SCT who had
Individuals with SCT can develop microscopic hematuria, administration of EACA at an oral
infarction of the renal medulla, resulting in loss dose of 6 to 8 grams daily in four to six divid-
of maximal urine concentrating ability; this ed doses caused resolution of hematuria at a
condition is present in most adults with SCT mean of 2.2±0.3 days, compared with 4.5±1.9
(1). Maximum urine osmolality following fluid days for those individuals not receiving the
15
Chapter 3: Sickle Cell Trait
16
of splenic infarction with SCT usually resolves EDUCATION AND
in 10 to 21 days and rarely requires surgical GENETIC COUNSELING
intervention. Splenic infarction associated with
SCT may occur with hypoxemia from systemic All persons with SCT should be educated
disease or from exercise at sea level or at high about the inheritance of SCD and about the
altitude (1). Splenic infarction is associated availability of partner testing, genetic counsel-
with flights in unpressurized aircraft at 15,000 ing, and prenatal diagnosis (see chapter 4).
feet or more but may occur rarely at mountain
altitudes higher than 6,000 feet above sea level. REFERENCES
The frequency seems to be disproportionately
greater in phenotypically non-African American 1. Kark JA, Ward FT. Exercise and hemoglobin S.
Semin Hematol 1994;31:181-225.
individuals (16), an observation that may be 2. Gupta AK, Kirshner KA, Nicholson R, et al.
due to reporting bias. Nevertheless, numerous Effects of alpha-thalassemia and sickle
individuals with SCT have participated polymerization tendency on the urine-
successfully in long-distance races in the concentrating defect of individuals with SCT.
Cameroon and in high-altitude sports, includ- J Clin Invest 1991;88:1963-8.
3. Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal
ing the Olympics in Mexico City. Thus, the medullary carcinoma. The seventh sickle
majority of people with SCT can travel safely cell nephropathy. Am J Surg Pathol 1995;19:1-11.
to mountain altitudes for recreational activities; 4. Avery RA, Harris JE, Davis CJ Jr, et al. Renal
however, rare individuals who have had splenic medullary carcinoma: clinical and
therapeutic aspects of a newly described tumor.
complications may risk recurrence.
Cancer 1996;78:128-32.
5. Baron BW, Mick R, Baron JM. Hematuria in
SURGERY AND OTHER sickle cell anemia—not always benign: evidence
for excess frequency of sickle cell anemia in
MEDICAL CONDITIONS African Americans with renal cell carcinoma.
Surgery is not likely to be complicated by Acta Haematol 1994;92:119-22.
the fact that an individual has SCT (17). 6. Black WD, Hatch FE, Acchiardo S. Aminocaproic
acid in prolonged hematuria of patients with sick-
Individuals with SCT are not at increased lemia. Arch Intern Med 1976;136:678-81.
risk for an adverse outcome from anesthesia, 7. McInnes BK III. The management of hematuria
and they are not limited in their choice of associated with sickle hemoglobinopathies. J Urol
anesthetic agents. There is no convincing 1980;124:171-4.
8. Pastore LM, Savitz DA, Thorp JM Jr. Predictors
evidence that SCT is associated with increased
of urinary tract infection at the first prenatal visit.
frequency or severity of diabetic retinopathy, Epidemiology 1999;10:282-7.
stroke, myocardial infarction, leg ulcers, avas- 9. Heller P, Best WR, Nelson RB, et al. Clinical
cular necrosis and arthritis, or the bends due implications of sickle-cell trait and glucose-
to diving. Some case reports of possible associ- 6-phosphate dehydrogenase deficiency in
hospitalized black male patients. N Engl J Med
ations of SCT with increased medical morbid-
1979;300:1001-5.
ity may represent situations in which other 10. Yium J, Gabow P, Johnson A, et al. Autosomal
variants of β- or α-globin chains produced dominant polycystic kidney disease in
undiagnosed SCD (18). Rare cases may be blacks: clinical course and effects of sickle-cell
due to increased 2,3-DPG or altered oxygen hemoglobin. J Am Soc Nephrol 1994;4:1670-4.
11. Kark JA, Burr PQ, Wenger CB, et al. Exertional
affinity, which might increase polymerization heat illness in Marine Corps recruit training.
of Hb S sufficiently to cause a phenotype of Aviat Space Environ Med 1996;67:354-60.
SCT to behave like SCD (18,19).
17
Chapter 3: Sickle Cell Trait
18
G ENETIC C OUNSELING 4
19
Chapter 4: Genetic Counseling
20
randomly selecting tapes for review and cri- ■ Both parents must have the trait for
tique (4). Other procedures are to conduct the child to have SCD.
postsession interviews with counseled individ-
■ The 25 percent chance that each pregnan-
uals, or to periodically schedule sessions with
cy will result in a child with SCD if both
a trained, knowledgeable, simulated counselee
parents have the trait.
(preferably without the counselor’s awareness).
■ Some of the reasons couples might decide
Ideally, individuals who are trained to provide to have or not have children if both have
services for the first group should be titled the trait.
“sickle cell educators” rather than “sickle
cell counselors” because the term counseling SCT COUNSELOR
implies assisting individuals to make deci- TRAINING PROGRAMS
sions, which is not their role. The individuals
who are trained to provide services for the University of South Alabama
second group are indeed counselors. The use 1433 Springhill Avenue
of the title counselors for the first group is Mobile, Alabama 36604
so traditional that changing the title will not Contact Person: Linda Jones
occur, but the distinction is worth noting. (334) 432-0301
The second group should be counseled only Texas Department of Health
by individuals specifically trained to assist 1100 West 49th
individuals to make psychosocial decisions. Austin, Texas 78756
This includes geneticists, master’s degree Contact Person: Mae Wilborn
genetic counselors, social workers, and psy- (512) 458-7111 x2071
chologists. The latter two, of course, would
have to be “sickle cell educated.” Cincinnati Comprehensive Sickle Cell Center
3333 Burnet Avenue
MINIMAL ACCEPTABLE Cincinnati, Ohio 45229
ACHIEVEMENTS Contact Person: Lisa McDonald
(513) 636-4541
For the first group, the interest in being coun-
seled and the information of personal value is Genetic Disease Branch
so highly variable it is desirable to have a min- State Department of Health Services Branch
imal acceptable achievement level in a basic Berkeley, California 94704
counseling session. For example, the counselee Contact Person: Kathleen Valesquez
should understand: (510) 540-3035
■ The family planning options open Sickle Cell Disease Association of America,
to persons with SCT. Michigan Chapter
18516 James Couzens Highway
■ SCT is not an illness, so no restrictions
Detroit, Michigan 48235
need to be placed on his or her activities.
Contact Person: Jetohn Thomas
■ The variability in severity of SCD. (313) 864-4406
21
Chapter 4: Genetic Counseling
REFERENCES
1. Headings V, Fielding J. Guidelines for counseling
young adults with SCT. Am J Pub Health
1975;63:819-27.
2. Day SW, Brunson GE, Wang WC. Successful
newborn SCT counseling using health department
nurses. Pediatr Nurs 1977;23:557-61.
3. St. Clair L, Rosner F, James G. The effectiveness
of sickle cell counseling. Am Fam Phys
1978;17:127-30.
4. Whitten CF, Thomas JF, Nishiuria EN. SCT
counseling—evaluation of counselors and
counselees. Am J Hum Genet 1981;33:802-16.
5. Grossman L, Holtzman N, Charney E, et al.
Neonatal screening and genetic counseling
for SCT. Am J Dis Child 1985;139:241-4.
6. Rowley PT, Loader S, Sutera CJ, et al. Prenatal
screening for hemoglobinopathies III. Applicability
of the health belief model. Am J Hum Genet
1991;48:452-9.
7. Sickle Cell Disease Guideline Panel. Sickle Cell
Disease: Screening, Diagnosis, Management and
Counseling in Newborns and Infants. Clinical Practice
Guideline No. 6. AHCPR Pub. No. 93 0562.
Rockville, MD: Agency for Health Care Policy and
Research, Public Health Service, U. S. Department
of Health and Human Services. April 1993.
8. Yang YM, Andrews S, Peterson R, Shah A. Prenatal
sickle cell screening education effect on the follow-
up rates of infants with SCT. Patient Educa Couns
2000;39:185-9.
22
HEALTH MAINTENANCE
24
C HILD H EALTH C ARE M AINTENANCE 5
For decades, complications of sickle cell dis- useful because they give negative results when
ease (SCD) produced the highest mortality the fetal hemoglobin (Hb F) level is high, and
rate in the first 3 years of life (1). However, do not distinguish between sickle trait (Hb
public health programs and comprehensive AS) and different forms of SCD. Tests on
care for children who have SCD reduced early the parents may help to confirm the hemo-
childhood mortality in countries such as the globin (Hb) genotype of the baby but can
United States, United Kingdom, France, be incorrect in cases of single parenthood
Jamaica, and Saudi Arabia. Unfortunately, or nonpaternity. “Deductive” methods based
childhood mortality is high in other parts of on blood counts, red cell indices, and relative
the world, especially sub-Saharan Africa where levels of Hb F and A2 cannot distinguish
SCD is prevalent but organized SCD programs between conditions such as SCD-SS with
are rare. These guidelines are directed to α-thalassemia and SCD-S βo-thalassemia,
health care workers mainly in the United nor are they useful in children younger than
States, but the approaches may be modified 6 months of age where the relative levels of
as other conditions and situations permit. hemoglobins have not stabilized (3). These
problems are avoided if DNA-based methods
PATHOLOGIC MECHANISMS are applied to detect specific mutations. The
determinations of βs haplotypes and α-tha-
Sickle cells can obstruct blood flow to the lassemia contribute to the definitive diagnosis
spleen, which results in functional asplenia of SCD but play a minor role clinically.
within the first few years of life. In addition
to a filtration function, the spleen has B-cells Once a definitive diagnosis is made, the par-
for antibody production, and when the organ ents should start an educational program with
suffers infarcts and shrinks, this capacity is practical information about the specific type
lost. Asplenia causes susceptibility to bacterial of SCD that affects their child (4-6). The ini-
infections, particularly with pneumococcus. tial counseling session sets the tone for how
the parents regard their child’s condition and
CLINICAL FINDINGS the new health care team. Parents often ask
about the expected course and capabilities of
N EONATAL D IAGNOSIS the child with SCD. A person experienced in
Newborn screening may be performed on the care of children with SCD should be avail-
blood from the umbilical cord or a heel-prick. able to answer these questions without med-
Abnormal results should be confirmed with ical jargon and should allow time for other
a second sample, using a different method (2). questions. It is important to tell parents not
Sickling and solubility tests generally are not to raise children with SCD as sick children,
since they are not ill most of their lives.
25
Chapter 5: Child Health Care Maintenance
Parental education about SCD cannot be and parents should be made aware of it.
accomplished in one counseling session. Organomegaly leads many children with SCD
Providers who do not have the resources to have a protuberant abdomen, often with an
to provide this important service should umbilical hernia. Almost all SCD patients
refer the family to an appropriate facility. with moderate-to-severe anemia have a cardiac
Future sessions should be planned to provide systolic flow murmur that does not require
information appropriate for the child’s age, further evaluation. Parents should be reassured
diagnosis, and clinical course. about the murmur so that they will not be
alarmed when other doctors and nurses notice
S PECIAL E VALUATIONS it. Bone marrow expansion often causes maxil-
lary hypertrophy with overbite; orthodontics
Specific physical, laboratory, and other
are recommended to prevent or correct this
evaluations are needed to monitor children
problem. Growth and development should be
with SCD (7).
followed closely in children with SCD, and
Physical Examination nutrition should be optimized. Children and
SCD in young children has a variable presen- parents should be counseled about potential
tation. The earliest physical sign may be jaun- social problems related to short stature and
dice in the first few weeks of life. If hemolysis delayed sexual development, which greatly
is not significant clinically, parents and other affects adolescents.
family members should be reassured about
Laboratory Evaluation
eye color changes so that they do not become
overly anxious. Hepatomegaly is a common It is useful to collect a series of baseline values
finding in children with SCD; the cause is on each patient to compare with those at times
unknown, but it does not signify liver dys- of acute illness. Table 1 shows a typical sched-
function. Spleen size should be measured, ule of routine clinical laboratory evaluations.
Percent Hb F 6 mo – 24 mo every 6 mo
>24 mo annually*
26
Special Studies MANAGEMENT
The brain and lungs are among the organs
susceptible to serious damage in SCD. Early The major complications of SCD are dis-
detection of dysfunction may allow interven- cussed in other chapters, so only topics of
tion to reduce risk of further damage. special relevance to children and parents are
mentioned below.
Brain. Transcranial Doppler ultrasonography
(TCD), magnetic resonance imaging (MRI) PARENT E DUCATION
with or without angiography, and neuropsycho-
Home caregivers have a crucial role in the
metric (NPM) studies have been used exten-
successful management of children with SCD,
sively to evaluate children with SCD. An
and this should be emphasized at each counsel-
abnormally high blood flow velocity by TCD
ing session. Parents should be taught physical
in the middle cerebral or internal carotid arter-
assessment skills (e.g., palpation of spleen), how
ies is associated with an increased risk of stroke;
to avoid vaso-occlusive complications and treat
however, blood flow results should be interpret-
pain, and when to administer prophylactic
ed cautiously because they are dependent on
antibiotics. Educational materials and methods
the technique employed. TCD screening of
should be matched to the literacy level of the
children with SCD-SS is recommended to start
caregiver. Instruction should be provided on
at 2 years of age and continue annually if TCD
how to navigate the medical system. Informa-
is normal and every 4 months if TCD is mar-
tion about physical findings, laboratory values,
ginal. Children who have abnormal results
and medications should be retained by the
should be retested within 2 to 4 weeks. The
caregiver in case it is needed in an emergency.
STOP trial (Stroke Prevention Trial in Sickle
Cell Anemia) in 1997 showed that a transfu-
sion program reduces the risk of strokes in F EVER
patients with abnormal TCDs (see chapter 13, The constant danger of overwhelming infec-
Stroke and Central Nervous System Disease). tion is one of the most difficult concepts to
impart to caregivers (8). Fever is one of the
Children with SCD who have “silent” cerebral most common signs of illness in children,
infarcts detected by MRI have a higher rate and most parents are unaware that their child
of abnormal NPM studies and a higher risk could die from infection. Pneumococcal vacci-
for overt strokes. Stroke prevention strategies nation and penicillin prophylaxis have reduced
based on abnormal MRI results have not been the risk of mortality for SCD children, and
tested, but children with abnormal MRI or because of vigilance of parents and health care
NPM studies could be evaluated more fre- providers, death from pneumococcal infection
quently and carefully and considered for is rare at major sickle cell centers in the United
therapeutic measures. States. Current recommendations for vaccinat-
Lungs. Children with SCD frequently have ing children, providing prophylactic therapies,
abnormal pulmonary function tests (PFT). and educating parents about the signs and
PFT should be done regularly in those with dangers of infection should not be relaxed.
history of recurrent acute chest episodes or Parents should be discouraged from giving
low oxygen saturation. Lung function declines antipyretics at home at the first sign of fever.
with age, so it is important to identify those Advice that the febrile child deserves further
who need close monitoring and treatment. evaluation only after recurrence or persistence
27
Chapter 5: Child Health Care Maintenance
28
C LINICAL S EVERITY RECOMMENDATIONS
A report from the Cooperative Study of
Sickle Cell Disease (CSSCD) identified early G ENERAL H EALTH M AINTENANCE
predictors of clinical severity such as dactylitis F OR C HILDREN
before 12 months of age, average Hb level Frequent Visits
of less than 7 g/dL in the second year of life, Children with SCD should receive the same
and elevated leukocyte count (>13,700/µL) general health care as children without the dis-
before 10 years of age (10). Further studies ease. Well-child visits for growth monitoring,
will be required to identify those at high immunizations, and counseling on preventive
risk in order to consider therapies such health measures should be supplemented with
as hydroxyurea, chronic transfusions, or specific information about SCD. The schedule
bone marrow transplants. of visits in the first 2 years of life should be
every 2 to 3 months, planned to coincide with
C OMPREHENSIVE M ANAGEMENT the immunization schedule. After the age of
Comprehensive management of SCD often 2, the frequency of visits depends on patient/
requires a team that comprises doctors, nurses, family needs and access to medical consulta-
health educators, and medical social workers. tion, but it should be at least every 6 months.
Often emergency room physicians, radiolo- Immunizations
gists, anesthesiologists, surgeons, and critical In addition to routine immunizations against
care specialists also become involved. Facilities hepatitis B, polio, diphtheria, pertussis,
generally should have medical consultants, tetanus, Haemophilus influenzae type b,
hematology and microbiology laboratories, measles, mumps, and rubella, children with
a radiology service, and blood bank available SCD require additional immunizations. The
24 hours a day. On occasion, patients may recent introduction of the pneumococcal-
need TCD, computerized axial tomography, conjugated vaccine (PCV) for children in
MRI, and MRI with angiography, which are the United States is important for those with
available at major medical centers. SCD. Prevnar (Wyeth-Lederle), the 7-valent
After the diagnosis of SCD, the comprehen- PCV (PCV7) licensed in the United States,
sive care team must initiate and coordinate covers pneumococcal serotypes 4, 9V, 14,
medical and psychosocial care for the child 19F, 23F, 18C, and 6B, and has possible
and family. These activities should include cross-reactivity with serotypes 6A, 9A, 9L,
education, genetic counseling, and preparation 18B, and 18F. Together these serotypes
for independent living. account for 87 percent of bacteremia and 83
percent of meningitis due to pneumococcus
in the United States. The American Academy
SUMMARY of Pediatrics (AAP) recommends Prevnar for
Survival of children with SCD has been children with SCD up to 59 months of age.
improved largely through prevention of over- However, there is no reason why older SCD
whelming bacterial infections. Preventive patients should not receive the vaccine. The
measures include newborn screening, protective 23-valent pneumococcal polysaccharide vac-
vaccinations, teaching caregivers to recognize cine (PPV23, also known as 23PS), previously
early signs of illness, and prompt treatment recommended at 2 years of age with a booster
of suspected infections. at age 5, still should be used in addition to the
29
Chapter 5: Child Health Care Maintenance
30
Table 2. Recommended Schedule of Pneumococcal Immunization in
Previously Unvaccinated Children with Sickle Cell Disease
Current U.S. Food and Drug Administration indications are for administration of PCV7 only to children younger than 24 months of age.
31
Chapter 5: Child Health Care Maintenance
32
stops should be taken. Patients are encouraged The change from a pediatric to an adult
to consult their physicians before travel, and care setting is often difficult, and adolescents
they are advised to carry with them specific should be given help to access adult care
medical information about their diagnosis, facilities. In some centers, this transition is
baseline hematologic values, a list of current eased by concurrent pediatric/adolescent/adult
medications, and the name and telephone sickle cell clinic sessions. Chapter 6 provides
number of their physicians. Providers should more information about how to facilitate
give patients the names of physicians or health the patient’s transfer from pediatric to adult
care facilities to contact in case of emergencies. health care specialists.
33
Chapter 5: Child Health Care Maintenance
34
A DOLESCENT H EALTH C ARE AND T RANSITIONS 6
Adolescents with sickle cell disease (SCD) Moreover, the current health care environment
face the same challenges as their healthy coun- tends to neglect the needs of patients with
terparts. They desire acceptance by their peers chronic disorders. Insurers seek groups of
but, at the same time, wish to become more young and healthy people to reduce costs.
independent. Additional help is needed to Patients with chronic illnesses such as SCD
transition to new health care providers and frequently lose medical coverage when they
facilities (1). In a prospective study of over become legally independent of their parents.
3,500 patients (2), the course of SCD varied To reduce expensive hospitalizations, integrat-
as patients matured, but the frequency of ed transition programs can provide age-appro-
pain episodes correlated with disease severity. priate treatment and continuity of care from
Patients older than age 20 with frequent pediatric to adult facilities.
painful events had the greatest risk of early
death, indicating that continuity of care is CLINICAL FINDINGS
important to minimize morbidity and mortali-
ty. Communication with the patient, family, Studies from the Duke Comprehensive Sickle
and multiple providers is needed, but coordi- Cell Center show that a patient’s coping style
nation may be difficult between different significantly predicts the extent of health care
departments, such as pediatric and adult clinics. contact, activity, and psychological distress
(3). Patients with active coping styles (use of
multiple cognitive and behavioral strategies)
ISSUES had fewer emergency room visits. Those
Several factors conspire to make transition using passive adherence coping styles (reliance
difficult. Young people with SCD become on concrete, passive approaches to pain, such
familiar with the pediatric environment and as resting, without resourcefulness when
providers to whom they may literally owe their initial efforts fail) had more emergency room
lives. Adolescent bravado may result in a ten- visits and participated in fewer activities at
dency to deny illness and a reluctance to go home and in school. Another study found
to a strange adult care facility. Adolescents that negative thinking (expression of fear
desire independence as adults but may not be and anger) correlates with psychological
ready to face new responsibilities for appoint- distress (4). Nine months after the initial
ments and medications. For example, although assessment, these studies showed that the
young patients with SCD feel healthy, they coping strategies of younger children and
must have routine ophthalmology exams to adults are relatively stable, but those of adoles-
forestall blindness. They also need support to cents are in flux. For individuals who rely
deal with issues such as contraception, sexually on less adaptive strategies (passive adherence
transmitted diseases, and family planning. or negative thinking), adolescence may be
35
Chapter 6: Adolescent Health Care and Transitions
a period when these maladaptive styles pre- pediatric and adult teams are organized differ-
dominate. This stress complicates transition. ently, which creates problems with transition.
General pediatricians often are the focus of
The unpredictability and stress of SCD pain care for children with SCD, and hematologists
episodes affects the entire family, but the are usually consultants. This structure was
extent of the psychological impact varies established because all children need to see
among studies. Some show little psychological pediatricians for development checks and
variation between adjustment in siblings and routine immunizations. Since many children
patients, and little difference from population with SCD have few other problems, general
norms (5), while others show significant stress pediatricians are the main contacts, and pedi-
on siblings (6). Parents’ coping styles also atric hematologists advise about additional
affect children’s activity levels, distress, and interventions such as pneumococcal vaccina-
coping strategies. Kramer (7) found 49 per- tion and penicillin prophylaxis.
cent of the parents of SCD patients in their
sample to be clinically depressed according By contrast, most adolescents and young
to the Center for Epidemiological Studies adults ages 18–30 are healthy, so few see
Depression scale (CES-D). Programs exist to health care providers for preventive measures.
improve the education and coping of family The result is that hematologists become the
members, reduce daily strain, and teach stress primary providers for young people with
management techniques (8,9). SCD. Because patients must take the initiative
for health maintenance, their readiness to
IMPLEMENTATION accept this responsibility should be assessed.
OF TRANSITION A patient’s chronologic age should not auto-
matically trigger transition. Some 18-year-old
A SSESSMENT youths are not ready to go from pediatric to
The members of a transition team include adult care, so developmental age is a more
physicians, mid-level practitioners (e.g., nurses appropriate guide. For instance, delayed neu-
or physician assistants), and social service rocognitive development from cerebrovascular
workers—from both pediatric and adult facili- injury may hamper a patient’s ability to adjust
ties. Each of these providers views patients to adult health care until age 20 or 21.
from a different perspective, so they must meet Similarly, a patient who has just experienced
together often to assess readiness of patients a serious complication, such as acute chest
and their families for transition. Written med- syndrome, is unprepared psychologically for
ical records may not contain enough details transition to new providers.
of a patient’s history, so verbal discussion of
“group” knowledge helps. New providers can Social service workers play a major role in
miss problems when presented with just a dis- assessment, since they have more contact with
charge summary and list of medications. The patients and parents than any other members of
meetings also give providers who treat adults the team and can judge how families deal with
a chance to ask questions and to assure pedia- psychosocial problems of chronic illness, such
tricians that patient needs will be met. as anxiety and depression. If they concur that
the patient and family are ready for transition,
Physicians and nurses are the primary health the subject should be broached to the parents
care providers for most people with SCD, but and child well ahead of time to prepare them.
36
P REPARATION AND S UPPORT personnel allocated by the administration.
All parties—patients, providers, and facilities— A single provider without nursing or social
must agree beforehand on a plan for transition, service support cannot deliver care or transi-
which is an orderly movement of the patient’s tion patients adequately. Some pediatric facili-
medical care from one set of places and ties have an upper age limit for inpatient care,
providers to another. This is a process that and transition may be suboptimal if patients
occurs gradually, in contrast to an abrupt trans- with delayed development are transferred to
fer of locale. The idea of transition is men- adult facilities just because of age.
tioned a year or so before the process begins,
to prepare families mentally; reading material T RANSFER P ROCESS
can reinforce the concept between clinic visits. The pediatric providers should introduce the
Patients and providers should make plans adult team to the patient and parents in the
together to ensure they are clear to all. Providers pediatric setting first, if possible. In this famil-
can gauge success at each point, and patients iar environment, the family will have a chance
may ask questions and voice concerns. to clarify details of the transition before a last
pediatric visit. Pediatric providers should not
For parents, transition to adulthood entails
simply give patients the phone number and
loss of responsibility for, and control over,
instruct them to call. At the last pediatric visit,
their child’s medical care. They often have
providers should schedule the next appoint-
difficulty relinquishing the central role, and
ment as they normally do, but it will be with
this can produce resistance to the transition
the adult team. The first transferred clinic
effort. Reassurance that the pediatric and adult
appointment is a crucial test of transition.
providers will remain in contact is important
A member of the adult team should escort the
to alleviate the fear that the pediatricians are
family to the new facility, and introduce them
abandoning them. Patients, parents, and
to the staff there. Patients with SCD may find
providers should view transition as a positive
it hard to locate a new clinic, especially if they
milestone. Together, they have achieved a
are symptomatic. For example, a pain episode
significant step and should be congratulated.
is not the best time to meet new providers in
Adult providers then become positive addi-
a strange place.
tions to an already successful team.
If the patient misses the next appointment,
One of the most effective ways to dispel fears
a pediatric team member (e.g., social worker)
of transition is to make contact with people
should call and work with the patient, parents,
who have gone through the process. Support
and adult providers to resolve any issues.
groups with older adolescents and young
A “no show” at the adult facility may be an
adults are particularly helpful. Community
indirect way to ask for more help with the
events, such as picnics or holiday celebrations,
transition process. Often, patients are reluc-
often work better than meetings because they
tant because the adult clinic is unfamiliar,
focus on activity rather than disability, and
yet they will not return to the pediatric clinic,
discussion is easier without health providers.
which they perceive to have discharged them.
Institutional administrators are also important Continuity is lost, and patients may suffer
to support transition programs, which require a medical catastrophe.
37
Chapter 6: Adolescent Health Care and Transitions
Young adults with mild SCD tend to skip patients can dispel such misconceptions. In
followup with specialists who can prevent fact, institutional commitment to transition
complications of SCD. For example, asymp- programs should be bolstered by data indicat-
tomatic retinal blood vessel proliferation may ing that a well-organized adult care program
result in ocular hemorrhage unless treated by for SCD is financially beneficial (10). Both
an ophthalmologist before visual loss occurs. professional and lay patient advocates should
Prevention is a key step in the management make this point known.
of SCD, but young people may be lost during
the transition from pediatric to adult care and If no local adult care program exists, pediatri-
suffer unnecessarily. Intervention, coaching, cians may hold on to their patients and treat
and continued support can avert this poten- problems outside their area of expertise (e.g.,
tial disaster. ischemic heart disease). Nevertheless, they also
should empower the patients to deal with an
Other obstacles may exist, due to the infra- unfamiliar system. They should give parents a
structure of the medical system. The best situa- summary of the child’s medical course for use
tion is where good programs for children and in emergencies. This should include copies of
adults with SCD coexist, and efforts are coor- basic records, such as immunizations, blood
dinated easily. However, when health care type, complications, and current medications,
delivery is unbalanced (e.g., a strong pediatric especially those that work during an acute
program but a weak adult one), transition is pain episode.
more difficult.
Most children with SCD are the offspring of
SUMMARY
heterozygous parents who have health insur- Transition programs prepare an adolescent
ance. They have fewer chronic complications to assume responsibility for his or her health
than adults, and hospitalizations occur mainly care. The primary charge lies with the pedi-
for self-limited painful events. In contrast, atric providers, whose first step is to assess the
adults with SCD have difficulty keeping steady readiness of the patient and family. The transi-
jobs because their organ damage progresses. tion process encourages the gradual matura-
Thus they often require government assistance, tion of relationships with adult providers via
but these programs lack full coverage, such as steps that are designed individually, due to
for transition programs. The combination of differences among institutions, providers, and
chronic illness and poor reimbursement deters patients. Such development does not occur
some adult providers from the care of patients automatically, and a comprehensive transition
with SCD. Adult providers sometimes feel program is not always possible. Nevertheless,
they are given only problem patients, while adult providers and administrators should be
pediatricians keep those who are easiest to enlisted to deliver continuous care, which can
treat. Frequent transition team meetings where avert medical disasters.
adult and pediatric providers discuss the
38
REFERENCES
1. Telfair J, Myers J, Drezner S. Transfer as a compo-
nent of the transition of adolescents with sickle cell
disease to adult care: adolescent, adult, and parent
perspectives. J Adolesc Health 1994;15:558-65.
2. Platt OS, Thorington BD, Brambilla DJ, et al.
Pain in sickle cell disease. Rates and risk factors.
N Engl J Med 1991;325:11-6.
3. Gil KM, Williams DA, Thompson RK Jr, Kinney
TR. Sickle cell disease in children and adolescents:
the relation of child and parent pain coping strate-
gies to adjustment. J Psychol 1991;16:643-63.
4. Gil KM, Thompson RK Jr, Keith BR, et al. Sickle
cell disease pain in children and adolescents:
change in pain frequency and coping strategies
over time. J Pediatr Psychol 1993;18:621-37.
5. Gold J, Treadwell M, Barnes M, et al.
Psychological and social effects of sickle cell disease
on live-in siblings. Annual Meeting of the National
Sickle Cell Disease Program, Boston, MA, 1995.
6. Treiber F, Mabe A, et al. Psychological adjustment
of sickle cell children and their siblings. Child
Heath Care 1987;16:82-8.
7. Kramer K, Nash K. The prevalence of depression
among a sample of parents of children with sickle
cell disease. Annual Meeting of the National Sickle
Cell Disease Program, Boston, MA, 1995.
8. Kaslow N, Rowland S, Dreelin B, et al.
Psychosocial interventions for children and adoles-
cents with sickle cell syndromes. Annual Meeting,
National Sickle Cell Disease Program, Boston,
MA, 1995.
9. Shearer J. Reducing hospital admissions for
uncomplicated pain episodes through intensive
case management and family therapy techniques.
Annual Meeting, National Sickle Cell Disease
Program, Boston, MA, 1995.
10. Benjamin LJ, Swinson GI, Nagel RL. Sickle
cell anemia day hospital: an approach for the
management of uncomplicated painful crises.
Blood 95;2000:1130-6.
39
40
A DULT H EALTH C ARE M AINTENANCE 7
There have been significant improvements episodes increases in early adulthood (3).
in the outlook for adults with sickle cell Hydroxyurea provides the first pharmacologic
disease (SCD). The Cooperative Study of intervention that reduces the frequency of
Sickle Cell Disease (CSSCD) and other obser- pain episodes in adults (4). Proliferative
vational studies have helped to define the retinopathy is a life-long risk that increases
prognosis and common complications that in prevalence with age (5). Vision may be
occur as the patients age. Improved manage- compromised by these vascular changes that
ment of infections and central nervous system predispose to retinal hemorrhages, retinal
(CNS) complications in childhood, active detachments, and increased intraocular pres-
health maintenance for adults, new interven- sure (5). Renal glomerular disease is prevalent
tions, and improved psychosocial support have in adults and may cause increasing anemia,
all contributed to a reduction in morbidity renal failure, and premature death (6-8).
and mortality. Prevalence of chronic pulmonary disease and
pulmonary hypertension also increases as
The prognosis in SCD has dramatically patients age, and may contribute to morbidity
improved over the past 30 years. Estimates and mortality (9). Complications such as leg
based on the mortality in the CSSCD indicate ulcers and osteonecrosis of the hips and shoul-
a median survival of 42 years for males and ders cause chronic pain and disability, which
48 years for females with SCD-SS disease and require social and vocational adjustments
60 years and 68 years, respectively, for SCD- (10,11). Essentially unstudied are the pain
SC disease (1). Patients are now living into episodes that many women experience in asso-
the seventh and eighth decades. More than ciation with menstruation and the increased
90 percent of patients of all phenotypes will frequency and severity of pain episodes near
survive past age 20, and significant numbers menopause. Geriatric challenges in patients
are older than age 50 (1). Risk of early death with SCD are not well studied.
in adults with SCD is associated with acute
complications such as pain episodes, anemic Health maintenance activities must also
events, acute chest syndrome, chronic renal address interactions between SCD and other
failure, and pulmonary disease (2). common health problems of the adult popula-
tion. Individuals with relative hypertension
CHALLENGES and SCD have an increased risk of strokes
and increased mortality, and therefore treat-
Improved survival provides opportunities ment for hypertension is an important aspect
to improve the quality of life for patients with of health care (12) (see chapter 15, Cardio-
SCD; however, it also provides unique challenges vascular Manifestations). Patients with SCD
in health maintenance. The frequency of pain are not protected from developing cancer
41
Chapter 7: Adult Health Care Maintenance
as they age (13). Diabetes, asthma, arthritis, O NGOING H EALTH C ARE V ISITS
atherosclerotic vascular disease, and other Initially, a number of visits every 1 to 2 weeks
chronic illnesses may occur concurrently will facilitate developing rapport, discussing
and provide unique challenges in managing laboratory and other test results, completing
patients with SCD. the initial database, developing a problem list
Many adults are well adjusted socially and and care plan, and exploring active social or
psychologically. Others, however, experience psychological issues. Routine medical evalua-
problems including anxiety and depression, tions are scheduled approximately every
and have difficulty forming and maintaining 2 to 6 months, depending on the patient’s
relationships, finding and keeping employ- phenotype and active problems. The database
ment, and participating in usual daily activi- is updated at every visit. Blood counts, reticu-
ties (14-16). There is an increased need for locyte counts, and urinalysis are repeated at
social and psychological support services to each visit to establish a baseline and detect
maximize adjustment and productivity in problems. Pulse oximetry at each visit is also
adults with SCD (14-16). helpful. Routine chemistry tests should be
repeated at least annually. Complications such
as chronic organ failure, other medical prob-
RECOMMENDATIONS lems, or complex psychosocial problems often
Ongoing care of the adult patient includes require more frequent visits and more exten-
preventive health maintenance, early recogni- sive evaluations.
tion and treatment of complications, continu-
ous assessment of social status, psychological Patients with hypertension, proteinuria,
assessment and support, and continuing increased creatinine, renal tubular acidosis,
patient education. Such services can be effec- or hyperuricemia should have more extensive
tively accomplished only during regularly and regular evaluation of renal function (see
scheduled well-patient visits where effective chapter 19, Renal Abnormalities in Sickle Cell
doctor-patient relationships are established Disease). Individuals, especially those with
and medical, social, and psychological issues sleep apnea or chronic hypoxia requiring oxy-
are addressed. gen therapy with pulmonary disease or symp-
toms, should have regular pulmonary function
studies and evaluation of pulmonary hyperten-
I NITIAL H EALTH M AINTENANCE V ISIT
sion. Patients should have an annual ophthal-
The initial visit provides an opportunity to mology examination for retinopathy, increased
establish rapport with the patient and his or ocular pressure, and refraction errors. Followup
her family and to determine the patient’s med- examinations of patients with significant
ical and social needs, as well as psychological proliferative retinopathy is scheduled by the
strengths and challenges. A complete database ophthamalogist at more frequent intervals
should be developed that includes the infor- (see chapter 14, Sickle Cell Eye Disease).
mation outlined in table 1.
In many populations, tuberculosis screening
should be done annually. Tetanus immuniza-
tions are kept up to date, hepatitis vaccine is
given, and influenza vaccines are administered
annually based on recommendations of the
42
Table 1. Patient Database
43
Chapter 7: Adult Health Care Maintenance
44
that may contribute to risk of complications. with SCD to complete their studies; however,
There is anecdotal evidence that persons with more time may be required than is usual for
splenic function may be at higher risk during students without medical problems.
air travel.
Patients must also be encouraged to discuss
Childbearing and birth control should be their disease with their employers. Maintain-
discussed with patients and their partners ing employment may require intervention by
(see chapter 23, Contraception and Pregnancy). the health care provider to explain limitations
Discussions should include the risks during to the employer, provide excuses for absences
pregnancy, the potential for spontaneous from work, and complete forms for the
abortion, and the physical and emotional employer. Health care providers also should be
challenges of raising an infant. Resources for familiar with legal protection against discrimi-
patient support during and after the pregnan- nation in the workplace, as provided by the
cy should be explored. Preconception educa- Americans with Disabilities Act. Individuals
tion should include genetic counseling and with severe disease, cerebral vascular accidents,
testing of the partner. Pre- or postconception and avascular necrosis may truly be disabled.
genetic counseling should include discussion In these situations, the health care provider
of prenatal diagnosis. should actively assist in obtaining benefits
for the patient.
V OCATIONAL G OALS
Individuals with SCD should be encouraged C OUNSELING
to complete their education and pursue voca- Social services and psychologic support activi-
tions. Jobs requiring strenuous physical exer- ties are a critical component of comprehensive
tion, long work hours, exposure to hypoxia, or health maintenance in sickle cell patients (18).
extremes in temperature may not be tolerated These activities are best accomplished if social
and should be discouraged, especially if the workers and mental health professionals are
patient has increased symptoms when engaged integrated into the sickle cell care team. Social
in the vocation. workers are invaluable in solving a myriad
of social and family problems. Mental health
Higher education and advanced vocational workers can assist in managing psychiatric
training can provide vocations and professions problems such as depression, teaching coping
that are ideal for individuals with SCD. Many skills, and giving instruction in cognitive and
young adults seem to have more frequent and behavioral management of pain. Nurses are an
severe pain episodes during the first years of essential part of the support team because they
college. This may be related to the rigors of have ongoing interactions with the patients
academic pursuits, excesses because of and their families that facilitate identification
increased independence, or perhaps, directly of special patient and family needs. Nurses
related to the natural history of the disease (3). coordinate health care efforts and education
Carefully teaching the individual to establish about preventive health care, and provide
excellent study habits and to practice modera- ongoing psychosocial counseling.
tion in social activities usually will reduce the
frequency of complications. These changes, Vocational rehabilitation services are also
along with discussions with faculty and advi- important in adult health maintenance. Patients
sors, almost always allow motivated students with inadequate education can receive training
45
Chapter 7: Adult Health Care Maintenance
in order to acquire satisfying employment 6. Powars DR, Eliott-Mills DD, Chan L, et al.
that supports independent and productive life Chronic renal failure in sickle cell disease: risk
factors, clinical course, and mortality. Ann Intern
styles. This greatly improves their self-image Med 1991;115:614-20.
and often has a positive impact on their health 7. Falk J, Sheinmen J, Phillips GM, et al. Prevalence
and utilization of health care resources. For and pathologic features of sickle cell nephropathy
example, occurrence of avascular necrosis or and response to inhibition of angiotensin convert-
leg ulcers in patients with jobs that require ing enzyme. N Engl J Med 1992;326:910-15.
8. Gausch A, Cua M, Mitch WE. Early detection and
prolonged standing often requires training the course of glomerular injury in patients with
to allow them to qualify for desk jobs. sickle cell anemia. Kidney Int 1996;49:786-91.
9. Powars D, Weidman JA, Odom-Maryon T, et al.
Sickle cell chronic lung disease: prior morbidity
D ENTAL C ARE
and the risk of pulmonary failure. Medicine
Routine dental care is important to prevent 1988;67:66-7.
loss of teeth and infections that may lead to 10. Embury SH, Hebbel RB, Mohandas N, et al.
other SCD complications. Dental procedures Sickle Cell Disease. Basic Principles and Clinical
Practice. New York: Raven Press, 1994.
that require local anesthesia can be performed 11. Serjeant GR. Sickle Cell Disease. 2nd ed. Oxford:
in the dentist’s office as with any other patient. Oxford University Press, 1992.
Procedures requiring general anesthesia necessi- 12. Pegelow CH, Colangelo L, Steinberg M, et al.
tate hospitalization and may require the usual Natural history of blood pressure in sickle cell dis-
perioperative care recommended for sickle cell ease: risks for stroke and death associated with rela-
tive hypertension in sickle cell anemia. Am J Med
patients (see chapter 24, Anesthesia and 1997;103:171-7.
Surgery). Patients with a history of rheumatic 13. Dawkins FW, Him KS, Squires RS, et al. Cancer
heart disease, mitral valve proplapse, heart incidence rate and mortality rate in sickle cell
murmurs, or those with implanted venous disease patients at Howard University Hospital.
access catheters and orthopedic prothesis 1986-1996. Am J Hematol 1997;55:188-92.
14. Thompson RJ, Gil KM, Abrams MR, et al. Stress,
should receive antibodics for subacute bacterial coping, and psychologic adjustment of adults with
endocarditis (SBE) prophylaxis with tooth sickle cell disease. J Consult Psychol 1992;60:433-40.
extractions, aggressive dental hygiene activities, 15. Faber MD, Koshy M, Kinney TR. Cooperative
gum surgery, or root canal therapy. study of sickle cell disease: demographic of
adults with sickle cell disease. J Chronic Dis
1985;48:495-505.
REFERENCES 16. Abrams MR, Philips G, Whitworth E. Adaption
1. Platt OS, Brambilla DJ, Rosse WF, et al. and coping: a look at a sickle cell patient popula-
Mortality in sickle cell disease. Life expectancy tion over age 30-an integral phase of the life long
and risk factors for early death. N Engl J Med development process. J Health Soc Policy
1994;3430:1639-44. 1994;5:141-60.
2. Thomas AN, Pattison C, Serjeant GR. Causes of 17. Mahony BS, Githens JH. Sickle crisis and altitude:
death in sickle cell diseases in Jamaica. Br Med J occurrence in the Colorado patient population.
1982;285:633-5. Clin Pediatr 1979;18:431-8.
3. Platt OS, Thorington BD, Brambilla DJ, et al. 18. Koshy M, Dorn L. Continuing care for adult
Pain in sickle cell disease. Rates and risk factors. N patients with sickle cell disease. Hematol Clin
Engl J Med 1991;325:11-16. N Am 1996;10:1265-73.
4. Charache S, Barton FB, Moore RD, et al.
Hydroxyurea and sickle cell anemia. Medicine
1996;75:300-26.
O NLINE R ESOURCES
5. Charache S. Eye disease in sickling disorders. http://www.emory.edu/PEDS/SICKLE
Hematol/Oncol Clin N Am 1996;10:1357-62.
46
C OORDINATION OF C ARE : 8
R OLE OF M ID -L EVEL P RACTITIONERS
47
Chapter 8: Coordination of Care: Role of Mid-Level Practitioners
or Norplant. The MLP should ensure that they are less likely to try “shopping around”
patients use birth control properly and for multiple prescriptions. A team approach,
obtain annual PAP smears and STD checks which includes the primary care providers,
as required. pain management experts, and a social worker,
is ideal to help patients manage chronic pain.
Over time, as patients learn about their med-
ical history and the importance of regular
health care visits, they are encouraged to D AY T REATMENT C ENTER
M ANAGEMENT
be proactive. They should be empowered
to choose their own primary care providers When a painful event no longer can be treated
and make their own appointments. with oral analgesics, patients are encouraged
to go to a day treatment center or emergency
room (3,4). Hospitals with many sickle cell
MANAGEMENT
patients have dedicated day treatment clinics,
OF PAIN EPISODES but in locations without such facilities, sickle
( SEE CHAPTER 10, PAIN ) cell patients can be treated in chemotherapy
infusion suites that have been developed for
H OME M ANAGEMENT oncology patients. Outpatient day treatment
Painful events are the most common manifes- has advantages over the use of emergency
tation of SCD. Oral analgesics can be used to rooms, including the usually more prompt
manage most mild-to-moderate pain episodes administration of intravenous or intramuscular
at home. Nonmedical therapies, such as hot pain medications. The MLP, who is familiar
baths and showers, massage, distraction, and with the patient, acts as a resource for the day
relaxation techniques, also can relieve pain. treatment staff and provides key information
Patients should contact their health care and recommendations about each patient’s
providers for any symptoms such as fevers, needs. The MLP also assesses the patient for
chest pain, difficulty breathing, or pain that any complications that require referral to a
occurs in atypical locations or is more severe physician or admission. Again, the patient’s
than usual. Providers must educate patients need for preventive services, prescription
and their families about basic pain manage- refills, or any other general health issues should
ment principles, use of nonopioid medications be reviewed. Aggressive outpatient treatment
[such as nonsteriodal anti-inflammatory drugs of moderate-to-severe pain, coupled with con-
(NSAIDs) and antidepressants], use of opioid sistent, supportive care from familiar staff,
drugs, and the signs of overuse or abuse. often can prevent hospitalization.
Adults with SCD often experience chronic pain,
managed by daily use of prescription opioids. I NPATIENT M ANAGEMENT
The MLP must be vigilant in checking the When hospitalization is needed for a pain
patient’s intake of opioids at home, and should episode or any other SCD complication,
intervene if there is any suggestion of misuse. patients should be admitted consistently to the
A computerized pharmacy database can help same unit if possible. They should be treated
track usage over time. As few providers as pos- with intravenous opioids, by patient-con-
sible should write prescriptions for a patient. trolled analgesia pumps, or even by patient-
When patients know they can only receive controlled epidural analgesia pumps if avail-
pain medication from one or two providers, able and required (see chapter 10, Pain).
48
The MLP follows the patient and offers authority of a medical record. The card is lam-
background about the usual course of illness, inated to be carried at all times by the patient.
including the patient’s behavior and response
to treatment. This information makes patient TRANSFUSIONS AND
care a better experience for the in-house staff. CHELATION THERAPY
The MLP’s input can help the patient receive
( SEE CHAPTER 25, T RANSFUSION , I RON -O VERLOAD ,
appropriate and effective treatment, rather
AND C HELATION )
than being undertreated or viewed as “difficult”
or “drug seeking.” Regular phone contact or For patients being transfused regularly, MLPs
rounds with house staff provide education on coordinate the schedules and tests for iron
disease management. MLPs also should sched- overload. Persons on transfusion regimens usu-
ule in-service training for nurses to improve ally have few painful events, so they can go to
care for sickle cell patients. school or work full time. Ideally, transfusions
should not interfere with these activities, and
they are given on evenings or weekends at
E MERGENCY D EPARTMENT C ARE many sickle cell centers. If transfusions can
By adulthood, all SCD patients have had many be arranged only during regular business
emergency room visits. The most common hours, some patients will need help to discuss
complaint about emergency care is inappropri- this issue with school staff or their employer.
ate treatment of their disease (5,6). MLPs can
educate emergency department staff about the SCD patients should be transfused with
course and complications of SCD and proper leukocyte-poor, antigen-matched blood to
pain management. Emergency physicians often reduce the frequency of transfusion reactions
undertreat or overtreat painful episodes, not and the development of antibodies (8).
because of lack of knowledge about SCD but Finding antigen-matched blood is often diffi-
because of their unfamiliarity with certain cult in areas where blood donors are primarily
patients. Given the rapid pace in most emer- Caucasian. Providers should encourage blood
gency rooms, quick access to individual patient donations by African Americans as part of
care plans is essential. Computerized records, their community education efforts.
patient “identification” cards, or a phone call
When iron overload is documented, patients
to the patient’s health care provider are all ways
are started on iron chelation therapy. MLPs
to transmit information rapidly to emergency
should teach children and their families about
department personnel.
the serious complications of iron overload, and
A two-sided identification card (7), about the to understand that iron chelation is an integral
size of a business card, can contain enough part of transfusion therapy, not something to
information to ensure prompt initial treat- be ignored because of its inconvenience.
ment for most sickle cell patients. The card Desferal, the only iron chelator available at
contains pertinent medical history, baseline this time, is given by slow, daily, subcutaneous
labs, allergies, outpatient medications, the infusion. MLPs need to monitor compliance
usual treatment plan for the patient’s pain with chelation therapy. If children are begun
episodes, and the name and telephone number on Desferal soon after chronic transfusions
of the patient’s primary health care provider. start, compliance during the difficult teen
The latter also signs the card to give it the years may be greater.
49
Chapter 8: Coordination of Care: Role of Mid-Level Practitioners
50
REFERENCES
1. Castro O. Management of sickle cell disease;recent
advances and controversies. Br J Haematol
1999;107:2-11.
2. Shilalukey K, Kaufman M, Bradley S, et al.
Counseling sexually active teenagers treated with
potential human teratogens. J Adol Health
1997;21:143-6.
3. Benjamin LJ, Swinson GI, Nagel RL. Sickle cell
anemia day hospital: an approach for the manage-
ment of uncomplicated painful crises. Blood
2000;95:1130-7.
4. Ware MA, Hambleton I, Ochaya I, et al.
Day-care management of sickle cell painful crisis
in Jamaica: a model applicable elsewhere? Br J
Haematol 1999;104:93-6.
5. Maxwell K, Streetly A, Bevan D. Experiences
of hospital care and treatment seeking for pain
from sickle cell disease: qualitative study. BMJ
1999;318:1585-90.
6. Shapiro BS, Benjamin LJ, Payne R, Heidrich G.
Sickle cell-related pain: perceptions of medical prac-
titioners. J Pain Symptom Manage 1997;14:168-74.
7. Mandell E. Medical identification cards facilitate
emergency care for people with sickle-cell disease.
Oncol Nurs Forum (letter) 1997;24:1500-1.
8. Steinberg MH. Management of sickle cell disease.
N Engl J Med 1999;340:1021-30.
9. Koshy M, Burd L, Wallace D, et al. Prophylactic
red-cell transfusions in pregnant patients with
sickle cell disease. A randomized cooperative study.
N Engl J Med 1988;319:1447-52.
51
52
P SYCHOSOCIAL M ANAGEMENT 9
Sickle cell disease (SCD) is a complex condi- of the health care team. However, psychosocial
tion that affects the patient, the family, and interventions should be woven across the spec-
the patient’s and family’s relationship with trum of medical care.
health care providers and the community. It
is imperative that teaching the skills necessary Historically, psychosocial interventions were
for coping with this illness begin at the time reserved for emergency situations. Psychologists
of diagnosis and continue throughout the life or social workers were called for acting-out
of the patient, and that providers recognize behaviors, housing emergencies, noncompli-
that including the extended family and the ance issues, and other crises. Crisis situations
community in the education process will may be minimized by identifying specific
ensure the most positive outcome. points at which psychosocial interventions
may be necessary and planning for them, thus
eliminating the frustration and ineffectiveness
SUMMARY OF THE often experienced by patients and caregivers.
STATE OF THE ART
Pain, the most well-known symptom of SCD,
No interventions are proven to work with all
is the reason for most hospitalizations and
patients in all situations (1-15). While a team
precipitates many psychosocial crises. Skills
knowledgeable about chronic illness and exist-
for coping with pain and other complications
ing intervention models is ideal, available staff
of SCD must be taught early and reinforced
sensitive to the special needs of these patients
often (8,9). Which patients will have mild dis-
can provide effective interventions even in
eases and which will have a more severe course
primary care settings. Providers must recognize
is not predictable; however, stress is known
that the complexities of SCD necessitate
to play an important role in the severity of
a team approach to management. Clinical
chronic illness and pain. Absence of the physi-
management, pain control, coping skills,
cal appearance of trauma in severe SCD pain
genetic counseling, and community interac-
episodes can confound a patient’s ability to
tions, including school and work intervention,
cope. In addition, many health care providers
require different expertise. The establishment
are not knowledgeable about sickle cell pain,
of Comprehensive Sickle Cell Centers intro-
its causes, and the best management options.
duced the concept of comprehensive care for
This can lead to poorly controlled pain, con-
SCD and refined the multidisciplinary team
tinued treatment failure, and frustration of
approach to health care. Psychosocial support
patients and providers.
was recognized as a necessary, integral function
53
Chapter 9: Psychosocial Management
54
A DULT REFERENCES
As longevity of SCD patients increased, 1. Vichinsky EP. Comprehensive care in sickle cell
the need for continued comprehensive care disease: its impact on morbidity and mortality.
became evident; however, while pediatric cen- Semin Hematol 1991;28:220-6.
2. Vichinsky EP, Johnson R, Lubin BH.
ters thrive, adult providers are scarce. Long- Multidisciplinary approach to pain management
term management needs to focus not only on in sickle cell disease. Am J Pediatr Hematol Oncol
health care needs but on the other goals of 1982;4:328-33.
psychosocial well-being—education, indepen- 3. Adams RJ. Lessons from the Stroke Prevention
dence, and (eventually) marriage and family. Trial in Sickle Cell Anemia (STOP) study. J Child
Neurol 2000;15:344-9.
In adulthood, reproductive issues are of major 4. Britto MT, Garrett JM, Dugliss MA, et al. Risky
behavior in teens with cystic fibrosis or sickle cell
concern and often are not addressed in a posi- disease: a multi-center study. Pediatrics
tive manner. Most individuals, including those 1998;101:250-6.
with disabilities, hope to achieve normalcy, 5. Campbell MK, Motsinger BM, Ingram A, et al.
(e.g., independence, a meaningful job, and The North Carolina Black Churches United for
a family) (13). One barrier to care may be Better Health Project: intervention and process
evaluation. Health Educ Behav 2000;27:241-53.
providers’ lack of understanding of the multi- 6. Maunder R, Esplen MJ. Facilitating adjustment to
ple layers of learning needed to live with SCD inflammatory bowel disease: a model of psychoso-
and the realities of trying to be “normal” and cial intervention in non-psychiatric patients.
fitting in. The pain experienced by many Psychother Psychosom 1999;68:230-40.
patients with SCD can be demoralizing and 7. Schultz A, Liptak G. Helping adolescents who have
disabilities negotiate transitions to adulthood. Issues
overwhelming. In addition to the psychologi- Compr Nurs 1998;21:187-201.
cal effects of inadequately treated pain, 8. Gallagher RM. Treatment planning in pain medi-
patients have the added stress of continually cine. Integrating medical, physical, and behavioral
searching for effective pain relief, resulting in therapies. Med Clin North Am 1999;83:823-49, viii.
9. Benjamin LJ, Dampier CD, Jacox AK, et al.
frequent emergency room visits and episodic
Guideline for the Management of Acute and Chronic
care. This cycle can lead to depression, which Pain in Sickle-Cell Disease. APS Clinical Practice
is highest among the chronically ill and in Guidelines Series, No. 1. Glenview, IL, 1999.
the 20-40 age group, and is often not recog- 10. Ross-Lee B, Kiss LE, Weiser MA. Should health
nized or addressed. Continued comprehensive care reform be “color-blind”? Addressing the barri-
ers to improving minority health. J Am Osteopath
care—including a strong psychosocial
Assoc 1994;94:664-71.
component—for adults with SCD is most 11. Lillie-Blanton M, Hoffman SC. Conducting
important, since prevention of complications an assessment of health needs and resources in
is the key to longevity. a racial/ethnic minority community. Health Serv
Res 1995;30:225-36.
12. Bussing R, Aro H. Youth with chronic conditions
CONCLUSIONS and their transition to adulthood. Findings from
a Finnish cohort study. Arch Pediatr Adolesc Med
Psychosocial issues confronting patients, fami-
1996;150:181-6.
lies, providers, and the community, though 13. Gatchel RJ, Gardea MA. Psychosocial issues: their
multiple and multifactorial, can be addressed importance in predicting disability, response to
and result in positive patient outcomes. treatment, and search for compensation. Neurol
Clin 1999;17:149-66.
55
Chapter 9: Psychosocial Management
56
TREATMENT OF ACUTE AND
CHRONIC COMPLICATIONS
57
58
PAIN 10
Editors’ Note: The information in this chapter and use patients’ reports as the primary source
has been abstracted with permission from the for assessment, except in infants where behav-
1999 Guideline for the Management of Acute ioral observations are the main basis for evalu-
and Chronic Pain in Sickle Cell Disease, pub- ation. Most SCD pain can be managed well
lished by the American Pain Society (1). This if the barriers to assessment and treatment are
guideline is based on scientific evidence and the overcome; a comprehensive psychosocial clini-
clinical judgment of experts in the management cal assessment should be performed yearly
of acute and chronic pain in sickle cell disease (more often for patients with frequent pain).
(SCD). The information is provided in an
abbreviated form with several references in the TYPES AND CHARACTERISTICS
guideline, and additional comments in italics. OF PAIN ASSOCIATED WITH
The hallmark clinical manifestation of SCD SICKLE CELL DISEASE
is the acute vaso-occlusive event, or painful The most common pain states associated with
episode. This unique type of pain can start as SCD are summarized in table 1. When classi-
early as 6 months of age, recur unpredictably fied according to temporal characteristics,
over a lifetime, and require treatment with sickle cell pain can be described as acute,
opioids. Painful events are the top cause of chronic, or mixed.
emergency room visits and hospitalizations,
and are a major focus of home management
A CUTE PAIN
(2). Management of pain in childhood affects
a person’s ability to cope as an adolescent and The acute painful event is the most common
adult. Past, present, and anticipated experi- type of pain, characterized by an unpredictably
ences affect pain management, so pain must abrupt onset without any other explanation.
be assessed and treated in a developmental and Intensity varies from a mild ache to severe and
psychosocial context. debilitating pain. Uncomplicated acute pain
is self-limited and generally lasts hours to a
Major barriers to effective management of few days, but it can persist or recur and may
pain are clinicians’ limited knowledge of SCD, migrate from one site to another. With comor-
inadequate assessment of pain, and biases bid conditions or inadequate treatment, some
against opioid use. Biases are based on igno- painful events can last for weeks.
rance about opioid tolerance and physical
dependence, and confusion with addiction. C HRONIC PAIN
Unwarranted fear of addiction is common
Chronic pain often is defined as pain that
among patients and families, as well as health
lasts 3 to 6 months or more and that no
care workers. Clinicians should ask about pain
longer serves a warning function. The time
59
Chapter 10: Pain
distinction is arbitrary, and the condition may for patients with painful episodes due to SCD.
be difficult to distinguish from frequently Patients should undergo a thorough history and
recurring acute pain, as in SCD. Chronic pain physical examination to determine whether an
(e.g., from bone changes) can be debilitating, illness might have precipitated the pain, so that
both physically and psychologically. The the cause and symptom can be treated simultane-
involvement of sensation, emotion, cognition, ously. Patients should be seen immediately by
memory, and context can pose difficult man- a physician if they experience severe abdominal
agement problems (4). pain, recurrent vomiting, respiratory symptoms,
neurologic signs of paresis or paralysis, acute joint
M IXED PAIN swelling, priapism, or abrupt fall in hemoglobin.
Superimposition of acute pain on chronic pain
Pain frequently is mixed as to type and mecha-
may confound assessment and treatment.
nism due to confounding factors. Acute pain
can be superimposed on chronic pain, and Clinicians should understand the pain in detail
frequent episodes of acute pain can resemble to tailor therapy to the needs of the patient.
chronic pain. Neuropathic pain is insufficient- Assessment depends on chronologic age, devel-
ly diagnosed in SCD but can result from opmental stage, functional status, cognitive
nerve infarction, compression from bony ability, and emotional state, so these factors
structures, nociceptive substances, and/or should be considered in the choice of measure-
iron overload neuropathy. ment tools. Pain management should be aggres-
sive to relieve pain and achieve maximum
RECOMMENDATIONS function. Physicians should reassess pain fre-
FOR ASSESSMENT AND quently and adjust treatment to provide relief.
TREATMENT OF PAIN
A SSESSMENT OF PAIN IN SCD
A dedicated facility, such as a day hospital, which
includes experts to manage SCD pain, can The goals for assessment of acute and chronic
reduce overnight admissions and provide timely pain are to characterize a patient’s pain and
relief (5). Should this resource be unavailable, related experiences, provide a basis for thera-
the following approach is recommended peutic decisions, and document the efficacy
Table 1. Major Pain Syndromes in Patients with Sickle Cell Disease (3)
60
of pain control. Because pain is subjective, ■ Begin hydration. Total fluids should not
assessment requires patients’ self-reports, valid exceed 1.5 times maintenance (including
tools, and measurements repeated over time. volume for drug infusions). Initial fluid
Clinically, self-reports are supplemented by should be 5 percent dextrose + half-nor-
physical findings, laboratory data, and diag- mal saline + 20 mEq KCl/L, adjusted for
nostic procedures. Figure 1 is a flowchart to serum chemistry results.
guide clinicians in pain assessment.
■ Assess the patient for the cause of pain
There are two major kinds of assessment: and complications.
■ Rapidly assess pain intensity using
■ Rapid assessment of an acute painful
a simple measurement tool.
episode. This type of assessment deals with
an isolated pain event and focuses on pain
intensity, prompt treatment, and relief. E MERGENCY T REATMENT
OF A CUTE PAIN E PISODES
■ Comprehensive assessment for chronic Initial Treatment
pain or followup of persons who have acute The patient in acute pain at an emergency
pain. This type of assessment usually room or clinician’s office usually has exhausted
occurs at the end of a painful episode, all homecare options. Failure of home or out-
at office/clinic visits for chronic pain, or patient therapy signals the need for parenteral
between episodes. The objective is treat- medications, which include strong opioids like
ment planning (4), which involves the morphine. If a patient is on long-term opioids
patient, family (6), and health care team. at home, tolerance may have developed, so the
Assessment is multidimensional and new episode can be treated with a different
should include physiologic, sensory, opioid or with a higher dose of the same drug
affective, cognitive, behavioral, and if it is the only one the patient tolerates.
sociocultural factors.
In general, medications and loading doses
Figures 2 to 4 are examples of assessment
should be selected after assessment of the
instruments. Figure 2 is a unidimensional
patient’s current condition and consideration
“Faces’ Pain” intensity scale (7,8), and figures
of the patient’s history, including
3 and 4 show a visual analog scale (VAS) (9)
and multidimensional scales for either chronic ■ usual drugs, dosages, and side effects
or acute pain assessment. Diaries are also during acute pain.
useful for assessment of pain at home (10).
■ effective treatments at home.
Rapid Assessment of Acute Pain Episodes
■ medications taken since the onset
Severe pain should be considered a medical of present pain.
emergency that prompts timely and aggressive
management (figure 5) until the pain is tolera- For patients with recurrent pain, the best ini-
ble. The following recommendations are for tial dose of opioids for severe sickle cell pain
treatment in the emergency room, day treat- is that which provided adequate analgesia at
ment center, or hospital if the patient is a previous time. Some patients and clinicians
admitted directly. may prefer a loading dose of parenteral mor-
phine, usually equivalent to 5-10 mg (0.1-
0.15 mg/kg for children), depending on pain
61
Chapter 10: Pain
Acute Chronic
(Frequently
occurring acute or
Brief or Persistent? mixed acute superimposed
on chronic)
Brief Persistent
Determine Conduct
characteristics, comprehensive
Determine location, assessment
characteristics, intensity, and
location, and impact on
intensity based activities and
on self-report mood based on
self-report and Demographic and Impact of Pain
observation Psychosocial Factors on Functioning
• Age • Self-care
• Gender • School
• Developmental level • Work
Determine • Family factors • Social activities
related • Cultural factors • Relationships
symptoms • Adaptation to SCD • Parenting ability
• Coping styles (adults)
• Cognitive abilities
Physical factors • Mood
• Blood pressure • Pain sites • Level of distress
• Respiration • Tenderness
• Oxygen saturation level • Warmth
• Chest/abdomen • Swelling
• Mobility of joints • Heart rate Summarize,
• Lab/x-ray data assimilate, and
• Comorbidities/complications prioritize profile
Determine
probable cause(s) Identify appropriate
and precipitating interventions based on
factors comprehensive assessment
Conduct complete
No workup to determine
Related to SCD?
etiology of pain
Yes
Treatment
history
Treat based on
characteristics of episode
62
Figure 2. Wong-Baker Faces Pain Rating least 50 or 60 percent from the upper end of
Scale (7,8) the pain scale. Evaluate the response to therapy
15 to 30 minutes after each dose by assessing
pain intensity, relief, mood, and sedation level.
Frequency of reassessment should take into
account the route of administration. Record
the pain assessment and reassessments, along
0 1 2 3 4 5
with the patient’s other vital signs, in the
No Hurt Hurts
Little Bit
Hurts Little
More
Hurts Even
More
Hurts
Whole Lot
Hurts
Worst patient’s chart and/or on a bedside flowsheet,
so that the effectiveness of treatment can be
evaluated in a timely manner.
intensity, patients’ size, and prior opioid expe-
Titration to Relief
rience. Smaller doses of 2.5-5 mg (0.05-0.1
mg/kg for children) can be added later. The recurrent, lifelong nature of the pain
must be considered for consistent manage-
■ Intramuscular administration of medication ment of acute pain episodes, so the pain is
should be avoided, if possible, because made tolerable and side effects are minimized.
absorption is unpredictable and children Figure 6 presents three titration methods used
may find this method frightening and in different situations. Scheme 1 is an aggres-
painful. sive approach when close observation is possi-
ble. After the loading dose, one reassesses the
■ For severe pain, intravenous (IV) adminis-
patient at 30-minute intervals and, based on
tration is the route of choice. For patients
the results, treats with one-quarter to one-half
with poor venous access, many opioids
of the loading dose until the patient experi-
can be administered via the subcutaneous
ences relief. Scheme 2 is for more gradual
route by bolus dosing, continuous
titration. The patient is started immediately
infusion, or patient-controlled analgesia
on “by the clock” (BTC) doses based on prior
pumps (PCA).
history (e.g., morphine, 8 mg every 2 hours).
Patients who receive opioid agonists should “Rescue” doses are used for titration between
not be given mixed opioid agonist-antagonists BTC doses until relief is achieved. Scheme 3
(e.g., pentazocine, nalbuphine, butorphanol), is for titration using PCA.
because they can precipitate withdrawal
syndromes. Medications may be combined to enhance
the efficacy/safety ratio. Anti-inflammatory
Frequent Reassessment agents, acetaminophen, antihistamines, and
Assess the pain before pharmacological inter- other adjuvant medications can be used with
vention, at the peak effect of the medication, opioids. Side effects, such as respiratory
and at frequent intervals, until the adequacy depression, should be monitored and treated.
and duration of the medication’s effects have
been determined. Define the measure to be If a patient has pain between doses, the inter-
used in determining response to therapy. For vals could be decreased or the dose increased.
example, on a scale of 0 to 4 (0 = none, 1 = For patients on large doses of opioids, an alter-
little, 2 = moderate, 3 = good, and 4 = com- native approach is to change to one-half the
plete), relief could be defined as a score of 2 equianalgesic dose of another opioid and
or greater and a pain intensity reduction of at repeat titration to relief.
63
Chapter 10: Pain
4 3
Mood Scale Relief Scale
Worst Complete
Best No relief
mood relief
mood of pain
of pain
1 2
Moderate Just noticeable
Pain Scale
Strong No pain
Least Worst Mild
possible possible
pain pain
Excruciating Severe
Weak
1. Circle the number that describes your pain right now. 5. Shade the figure
where you feel pain.
0 1 2 3 4 5 6 7 8 9 10 6. Mark an X where
No pain Worst possible pain you hurt most.
FRONT
2. Circle the number that describes your pain relief.
0 1 2 3 4 5 6 7 8 9 10
RIGHT LEFT
No relief Complete relief
0 1 2 3 4 5 6 7 8 9 10
Worst mood Best mood
BACK
4. Circle the number that describes how drowsy you feel. LEFT RIGHT
0 1 2 3 4 5 6 7 8 9 10
Not drowsy Asleep
64
Change the medication delivery route or type of oral preparation used depends on the
regimen if the pain is poorly controlled with characteristics and expected duration of the
boluses, or if doses are required too frequently pain. If the patient’s pain typically is of short
for relief. Intraspinal analgesics, which require duration (less than 24 hours), opioids or for-
anesthesiology consultation, should not be mulations with a short duration of action are
considered before an adequate trial of maximal appropriate, with the advantage of quicker
doses of systemic opioids and adjuvant med- onset of action. For patients whose pain
ications; however, case studies suggest that requires several days to resolve, a sustained-
epidural anesthetics alone or with fentanyl can release opioid preparation is more convenient to
be effective in acute refractory pain of SCD (11). take and provides a more consistent analgesia.
Disposition The combination of nonopioid analgesics
After treatment in an emergency room, with opioids can permit lower doses of the
patients may be sent home or admitted latter. If an opioid like codeine is used, pain
as inpatients. Prescriptions for equianalgesic relief is accompanied by mild sedation that
doses of oral opioids should be written for can facilitate rest.
home use if needed to maintain pain relief.
NSAIDs and Acetaminophen
If pain does not diminish significantly after
rigorous therapy, the patient should be Mild-to-moderate pain in children with a fever
admitted as an inpatient. or viral syndrome generally is managed with
NSAIDs or acetaminophen; aspirin is avoided
due to a risk of Reye’s syndrome. Acetaminophen
P HARMACOLOGICAL M ANAGEMENT is an analgesic but not an anti-inflammatory
OF S ICKLE PAIN
drug, and both NSAIDs and acetaminophen
Analgesics are the foundation for the manage- have ceiling doses above which escalation does
ment of sickle cell pain, and their use should not result in increased relief. Most NSAIDs
be tailored to the individual patient. Sedatives are given only orally, except for ketorolac,
and anxiolytics alone should not be used to which can be used orally or parenterally.
manage pain, because they can mask the
behavioral response to pain without providing NSAIDs and acetaminophen are not benign.
analgesia. Many patients with SCD have varying degrees
of hepatic impairment, and acetaminophen
Management of pain associated with SCD may be toxic when liver disease is present.
consists of the use of nonsteroidal anti- NSAIDs also are contraindicated in patients
inflammatory drugs (NSAIDs), opioids, and with gastritis, peptic ulcers, coagulopathies,
adjuvant medications (12,13). Management of and renal failure. All NSAIDs are associated
mild-to-moderate pain should include NSAIDs with renal failure when used on a long-term
or acetaminophen, unless there is a contraindi- basis, and patients must be told not to exceed
cation; these are nonsedating, so patient activi- safe doses of these medications.
ties can continue. If mild-to-moderate pain
persists, an opioid can be added. Clinicians should monitor doses and frequen-
cy of treatment, and order urinalyses and
Treatment of persistent or moderate-to-severe renal function tests every 3 to 6 months in
pain relies on repeated assessments and appro- chronic users. Current trials have been incon-
priate increases in opioid strength or dose. The clusive regarding use of the parenteral NSAID
65
Chapter 10: Pain
Figure 5a.
Yes
Determine cause
Determine pain characteristics
(intensity, location, and quality
based on self-report)
Yes No
Related to SCD?
(continued)
66
Figure 5b.
Reassess
frequently
Continue to titrate with
Moderate No
1/4-1/2 loading dose to relief
pain relief?
Titrate plus coanalgesic
to relief
Yes
Yes
Breakthrough Yes
Provide rescue dosing
pain?
No
Treatment No
effective?
Yes
No
Can be
maintained at No
home with oral
medication?
2-8 Yes
hours
Send home with prescribed level
of medication (PO) to maintain
adequate pain relief
67
Chapter 10: Pain
ketorolac as a single agent. It may be added to meperidine use for acute sickle pain is contro-
opioids in situations in which opioids provide versial. Ideally, parenteral meperidine should
inadequate analgesia after optimal titration, no longer be used as first-line treatment of
or when the side effects of opioids are prob- acute pain in SCD because of CNS toxicity
lematic. Due to the need for more safety data, related to its metabolite, normeperidine. It has
the current recommendation is that ketorolac a long half-life and is a cerebral irritant, so
should not be used by any route or combina- accumulation can cause effects ranging from
tion of routes for longer than 5 days in a dysphoria and irritable mood to clonus and
given month because of the increased risk seizures. Thus, meperidine should be reserved
of toxicity (14). for brief treatments in patients who have
benefited, who have allergies, or who are
Opioids
intolerant to other opioids such as morphine
Moderate-to-severe pain is treated with opi- and hydromorphone.
oids (figure 6, tables 2-3), with or without
NSAIDs and adjuvant medications. Codeine- Meperidine should not be used for more than
equivalent opioids, such as oxycodone and 48 hours or at doses greater than 600 mg/24
hydrocodone, are used for moderate pain. hours (13). Because normeperidine is excreted
When opioids are given for the first time for by the kidneys, meperidine is contraindicated
severe pain, morphine sulfate or hydromor- for patients with impaired renal function as well
phone should be used. Other morphine-equiv- as for patients who are taking monoamine oxi-
alent opioids include oxymorphone, levor- dase inhibitor antidepressants.
phanol, meperidine, fentanyl, and methadone.
Fentanyl is in the same chemical family as
Considerations in opioid selection include meperidine and can be used parenterally. In
type of pain, analgesic history, pain intensity, addition, a transdermal fentanyl preparation
route of administration, cost, local availability, can be an adjunct for managing chronic sickle
provider comfort with analgesic modalities, pain because it has a 48-72 hour duration
and patient preference. Patient preference and provides continuous analgesic effect by
should not be ignored, because it is likely a noninvasive, nonoral route of administration.
that individual variations in drug metabolism Hypoventilation and respiratory depression can
contribute to differences in adverse effects occur with the use of fentanyl (14).
or dose-response to analgesia. The recurrent
Chronic Opioid Therapy. For patients with
nature of SCD pain often allows the patient
to experience multiple treatment options and several days of pain, or who require chronic
learn which regimen provides predictable relief. opioid therapy, sustained-release or long-half-
life opioid preparations are more convenient
Meperidine is the most commonly used opioid and provide more consistent analgesia. Short-
in hospitals for SCD patients with acute acting opioids may be used for rescue dosing
painful episodes. Many patients prefer meperi- early in the treatment regimen for break-
dine because of long-standing prescribing through pain, or until the sustained-release
practices of physicians, and they are apprehen- preparation reaches steady-state levels. In these
sive about changing to a different medication. situations, the administration of adjuvant
There is general agreement, however, that oral medications may be needed to control pre-
meperidine should not be used for acute or dictable opioid side effects such as pruritus,
chronic pain, and the indication for parenteral nausea, sedation, and constipation.
68
Figure 6. Titration Schemes
Start Calculate
Reassess in
by-the-clock 24-hour dosing
15-30 minutes
dosing
Reassess at 30
Yes Yes minute intervals
Continue maintenance
therapy and reassessment
69
Chapter 10: Pain
Table 2. Usual Starting Doses of Opioid Analgesics in Opioid-Naive Adults and Children ≤ 50 kg Body Weight1
Long-Acting Opioid Agonists Because is not possible to determine the appropriate starting dose
(e.g., morphine controlled-release, of controlled-release opioids without knowing the patients’s opioid
Levorphanol, methadone, and requirements as determined by immediate-release preparation,
oxycodone controlled-release) usual starting doses are not listed for these medications.
1Caution: Doses listed for patients with body weight less than 50 kg cannot be used as initial starting doses for babies younger than
6 months of age.
2Caution: Recommended doses do not apply to patient with renal or hepatic insufficiency, or other conditions affecting drug
metabolism and kinetics.
3Caution: For morphine, hydromorphone and oxymorphone, rectal administration is an alternate route for patients unable to take
oral medications. Equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences.
4Chronic administration of meperidine may result in central nervous system stimulation, including agitation, irritability, nervousness,
tremors, twitches myoclonus, or seizures, due to accumulation of the toxic metabolite normeperidine. The risk is much greater for
patients with renal or hepatic impairment.
5These products contain aspirin or acetaminophen. Total daily doses of acetaminophen that exceed 6 grams may be associated with
severe hepatic toxicity. Aspirin is contraindicated in children in the presence of fever or other viral disease because of its association
with Reye’s syndrome.
6Caution: Codeine doses higher than 65 mg often are not appropriate because of diminishing incremental analgesia with increasing
doses but continually increasing nausea, constipation, and other side effects.
70
Table 3. Usual Starting Doses of Opioid Analgesics in Opioid-Naive Adults and Children ≥ 50 kg Body Weight1
1Caution: Recommended doses do not apply to adult patients with body weight less than 50 kg. For recommended starting doses
for children and adults less than 50 kg body weight, see table 2.
2Caution: Recommended doses do not apply to patient with renal or hepatic insufficiency, or other conditions affecting drug
metabolism and kinetics.
3Caution: For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to
take oral medications. Equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences.
4Caution: Codeine doses higher than 65 mg often are not appropriate because of diminishing incremental analgesia with increasing
doses but continually increasing nausea, constipation, and other side effects.
5Chronic administration of meperidine may result in central nervous system stimulation, including agitation, irritability, nervousness,
tremors, twitches, myoclonus, or seizures, due to accumulation of the toxic metabolite normeperidine. The risk is much greater for
patients with renal or hepatic impairment.
Equianalgesic doses of oral opioids are pre- Side Effects of Opioids. Sedation usually pre-
scribed for home use if needed for the pain cedes one of the most feared side effects of
relief achieved in the emergency room or opioids, respiratory depression. Fortunately,
day hospital, or for recurrence of severe pain. tolerance to this side effect develops faster than
Opioid tolerance and physical dependence to the analgesic action; nevertheless, nurses
are expected with long-term opioid use and should monitor sedation levels when patients
should not be confused with psychological are at risk. If sedation persists after prompt
dependence (addiction). Opioids should be intervention, then pulse oximetry, apnea
tapered carefully in patients at risk for with- monitors, and blood gas levels may be needed.
drawal syndromes.
71
Chapter 10: Pain
72
■ Addiction is a not physical dependence As in the general population, some persons
but, rather, a psychologic dependence. with SCD will use illicit drugs, such as
Addiction is a complex phenomenon with cocaine. Patients who have problems with
genetic, psychologic, and social roots. The substance abuse require individual treatment
use of opioids for acute pain relief is not to provide competent and humane manage-
addiction, regardless of the dose or dura- ment of their pain. The treatment of patients
tion of time opioids are taken. Patients who have problems with substance abuse is
with SCD do not appear to be more likely complex and is beyond the scope of this chapter;
than others to develop addiction. The consultation with appropriate specialists should
denial of opioids to patients with SCD be considered.
due to fear of addiction is unwarranted
and can lead to inadequate treatment. PATIENT EDUCATION
■ Pseudoaddiction (16) applies to patients Education about pain management is the basis
who receive inadequate doses of opioids or for collaboration among patients, families, and
whose doses are not tapered, and therefore health care providers for optimal treatment.
they develop characteristics that resemble SCD is incurable, except possibly by bone
opioid addiction. marrow transplantation. Health care profes-
Understandably, some patients whose pain is sionals should tell patients about hydroxyurea,
managed poorly will try to persuade medical the drug that is used prophylactically to
staff to give them more analgesic, engage in reduce the frequency of acute painful events
clock-watching, and request specific medica- in severe cases. While no drug is approved
tions or dosages. Staff often regard this as for treatment of SCD itself during an acute
manipulative or demanding behavior. Patients episode, patients must be assured that when
with SCD often are quite knowledgeable they do experience pain, it will be taken seri-
about the medications they take for their con- ously and managed optimally with a plan.
dition and the doses that have worked in the Because patient needs change over time,
past. Requests for these specific medications the care plan must be assessed and modified
and doses should not be interpreted as indica- accordingly. Nurses and physicians who care
tions of drug-seeking behavior. In addition, for inpatients with sickle cell pain should be
patients who have had frequent painful trained to assess and manage pain so they do
episodes often behave in ways learned from not unwittingly dismiss a patient’s pain or
prior experiences. A patient, for example, who cause an exacerbation of pain-related behaviors.
believes that a medication will not be given Education of clinicians who work in emer-
unless he or she appears to be in severe pain gency rooms or day treatment centers is also
may lie quietly when alone but begin to important because inconsistent or adversarial
writhe and moan when a nurse or physician care given in these settings can cause mistrust
enters the room. Pseudoaddiction or clock- or other problems that affect patients’ relation-
watching behavior usually can be resolved by ships with other health care professionals.
effective communication with the patient to
ensure accurate assessment and by adequate
opioid doses.
73
Chapter 10: Pain
74
I NFECTION 11
75
Chapter 11: Infection
76
P REVENTION IN A DULTS F EVER W ITHOUT A S OURCE
Virtually all adults with sickle cell anemia Febrile patients with SCD should be evaluated
are functionally asplenic, but their immune and treated in the context of functional asple-
systems have matured to allow type-specific nia. In essence, this means more rapid and
polysaccharide antibody production. Because intensive evaluation (exam, blood counts,
they are not as susceptible as children to over- cultures, x rays) and lower threshold for
whelming sepsis and the incidence of sepsis is empiric therapy than in a general population.
relatively low, there is only anecdotal evidence Because minor febrile illnesses are common
about preventive strategies. Streptococcus pneu- in children, and the risk of death from over-
moniae vaccination is recommended for adults whelming Streptococcus pneumoniae sepsis is
with SCD. Some patients keep penicillin on so high, aggressive management is critical.
hand for fever, but most are not prescribed The following represent key principles in
penicillin prophylaxis routinely. the management of febrile children (13-15):
■ Parents and clinicians should be taught that
EMPIRIC THERAPY a temperature over 38.5˚C is an emergency.
Most antibiotic treatments are started empiri-
■ Basic laboratory evaluation includes CBC,
cally, before culture results are available. Table
U/A, chest x ray and/or oxygen saturation,
2 summarizes the pathogens that should be
and cultures of blood, urine, and throat.
covered in different clinical situations (9-12).
Additional information on some specific situa- ■ “Toxic-looking” children and those with
tions follows. temperatures above 40˚C should be treated
promptly with parenteral antibiotics—
before obtaining x rays or laboratory
results. They should be admitted to the
hospital for treatment.
Empiric therapy for: Should include coverage for: Consider broadening to include:
Fever without source Streptococcus pneumoniae Salmonella
(rule out sepsis) Hemophilus influenzae Gram-negative enterics
Meningitis Streptococcus pneumoniae Neisseria meningitidis
Hemophilus influenzae
Chest syndrome Streptococcus pneumoniae Legionella
Mycoplasma pneumoniae Respiratory syncytial virus
Chlamydia pneumoniae
Osteomyelitis/septic arthritis Salmonella
Staphylococcus aureus
Streptococcus pneumoniae
Urinary tract infection Escherichia coli
Other gram-negative enterics
77
Chapter 11: Infection
78
REFERENCES 11. Poncz M, Kane E, Gill FM. Acute chest syndrome
in sickle cell disease: etiology and clinical corre-
1. Leikin SL, Gallagher D, Kinney TR, et al. lates. J Pediatr 1985;107:861-6.
Mortality in children and adolescents with sickle 12. Miller ST, Hammerschlag MR, Chirgwin K, et al.
cell disease. Cooperative Study of Sickle Cell Role of chlamydia pneumoniae in acute chest
Disease. Pediatrics 1989;84:500-8. syndrome of sickle cell disease. J Pediatr
2. Gill FM, Sleeper LA, Weiner SJ, et al. Clinical 1991;118:30-3.
events in the first decade in a cohort of infants 13. Williams LL, Wilimas JA, Harris SC, et al.
with sickle cell disease. Cooperative study of sickle Outpatient therapy with ceftriaxone and oral
cell disease. Blood 1995;86:776-83. cefixime for selected febrile children with sickle cell
3. Bjornson AB, Falletta JM, Verter JI, et al. Serotype- disease. J Pediatr Hematol Oncol 1996;18:257-13.
specific immunoglobulin G antibody responses to 14. Rogers ZR, Morrison RA, Vedro DA, et al.
pneumococcal polysaccharide vaccine in children Outpatient management of febrile illness in
with sickle cell anemia: effects of continued peni- infants and young children with sickle cell anemia.
cillin prophylaxis. J Pediatr 1996;129:828-35. J Pediatr 1990;117:736-9.
4. Gaston MH, Verter JI, Woods G, et al. Prophylaxis 15. Platt OS. The febrile child with sickle cell disease:
with oral penicillin in children with sickle cell a pediatrician’s quandary. J Pediatr 1997;130:693.
anemia. A randomized trial. N Engl J Med
1986;314:1593-9.
5. Falletta JM, Woods GM, Verter JI, et al.
Discontinuing penicillin prophylaxis in children
with sickle cell anemia. Prophylactic Penicillin
Study II. J Pediatr 1995;27:685-90.
6. Chesney PJ, Wilimas JA, Presbury G, et al.
Penicillin- and cephalosporin-resistant strains
of Streptococcus pneumoniae causing sepsis and
meningitis in children with sickle cell disease.
J Pediatr 1995;127:526-32.
7. Steele RW, Warrier R, Unkel PJ, et al. Colonization
with antibiotic-resistant Streptococcus pneumoniae
in children with sickle cell disease. J Pediatr
1996;128:531-5.
8. Norris CF, Mahannah SR, Smith-Whitley K, et al.
Pneumococcal colonization in children with sickle
cell disease. J Pediatr 1996;29:821-7.
9. Wright J, Thomas P, Serjeant GR. Septicemia
caused by Salmonella infection: an overlooked
complication of sickle cell disease, J Pediatr
1997;130:394-.
10. Zarkowsky HS, Gallagher D, Gill FM, et al.
Bacteremia in sickle hemoglobinopathies. J Pediatr
1986;109:579-85.
79
80
T RANSIENT R ED C ELL A PLASIA 12
Because the life span of red blood cells is levels. However, the diagnosis of TRCA is
greatly shortened in sickle cell disease (SCD), supported by increased B19 parvovirus IgM
temporary suppression of erythropoiesis can levels. In at least 20 percent of patients with
result in severe anemia. Transient red cell serologic evidence of past B19 parvovirus
aplasia (TRCA) typically is preceded by or infection, there was no acute severe anemia.
associated with a febrile illness. The infectious Following B19 infection, parvovirus-specific
nature of TRCA is apparent from the fact that IgG concentrations are increased in most
several members of families with congenital patients and protective immunity appears
hemolytic anemia may be affected within to be life-long; no cases of recurrent disease
a period of several days. have been reported in children with SCD
(1,3). Recovery is often heralded by a massive
ROLE OF PARVOVIRUS B19 outpouring of nucleated red blood cells
(>100/100 white blood cells).
Between 70 and 100 percent of episodes of
TRCA are due to infection by human par- Although the majority of adults have acquired
vovirus B19, also the cause of erythema infec- immunity to B19 parvovirus, hospital workers
tiosum (“fifth disease”) (1). Aplasia is the result who are susceptible and are exposed to
of direct cytotoxicity of the parvovirus to ery- patients with TRCA are at high risk of con-
throid precursors, although other progenitors tracting nosocomial erythema infectiosum (4).
may be affected in some conditions. Patients Because infection during the mid-trimester
may present with increased headache, fatigue, of pregnancy may result in hydrops fetalis and
dyspnea, more severe anemia than usual, and stillbirth, isolation precautions for pregnant
a severe decrease in reticulocytes (usually <1 staff are a necessity if a parvovirus problem
percent or 10,000/µL). Patients may have is suspected (5).
fever, signs of upper respiratory infection,
and/or gastrointestinal symptoms. Skin rashes MANAGEMENT
are characteristically absent. Reticulocytopenia
begins about 5 days postexposure and contin- No experimental trials have been reported
ues for 7 to 10 days. Exacerbation of anemia regarding the management of TRCA. Although
develops shortly after reticulocytopenia. many patients recover spontaneously, red cell
Hemoglobin levels reached a mean nadir of transfusions should be considered for those
3.9 g/dL in one series (2). Patients who pre- who become symptomatic (see chapter 25,
sent in the convalescent phase may be thought Transfusion, Iron Overload, and Chelation).
mistakenly to have a hyperhemolytic process If patients are beginning to show evidence for
because of severe anemia and high reticulocyte red cell production, as determined by the reti-
culocyte count, they may not need transfusions.
81
Chapter 12: Transient Red Cell Aplasia
82
S TROKE AND C ENTRAL N ERVOUS S YSTEM D ISEASE 13
83
Chapter 13: Stroke and Central Nervous System Disease
Stroke Negative
Consider trans-
Consider chronic Observe vs. Chronic
MRI / MRA fusion or other
transfusion empiric therapy transfusion
empiric therapy
Chronic
PET / MRS
transfusion
84
its use in children with SCD where the patho- ease (5) or aneurysms. EEG is recommended
physiology may differ completely. Therefore, only if there is a clinical suspicion of seizure.
it is not recommended.
In the subacute phase, evaluations should be
The usual treatment for pediatric patients in undertaken to make a final determination of
the acute stage of ischemic stroke is hydration the cause. In many cases, evaluation of the
with transfusion, although there are no con- intracranial vessels will show occlusive vascu-
trolled treatment studies. Exchange transfusion lopathy characteristic of SCD. Even though
is preferred, as it avoids the theoretical risk of intracranial arterial vasculopathy is the most
increasing blood viscosity that may accompany likely cause of stroke in this setting, considera-
rapid elevations in hematocrit, but care must tion should be given to other etiologies that
be taken to avoid hypotension that may wors- cause stroke in young persons (6). If there is
en cerebral ischemia (4). Because fever increas- a history of head or neck trauma and arterial
es cerebral metabolism, any degree of hyper- dissection is suspected, the radiologist should
thermia should be treated. Hypothermia to be notified so that appropriate changes in the
treat stroke is promising but not supported magnetic resonance (MR) acquisition protocol
by data adequate to form a recommendation. can be made prior to study.
Acute treatment in an intensive care unit
(ICU) or stroke unit will facilitate close Other causes of stroke in children—such as
observation and treatment. Seizures should infection, cardiac embolism, and clotting dis-
be treated, but prophylactic therapy or corti- orders including anticardiolipin antibodies—
costeroids are not recommended. Hypoxemia should be considered (7). While hemiparesis
and hypotension should be treated and nor- typically improves, cognitive deficits are often
moglycemia maintained. There are no proven significant and long lasting; formal testing
neuroprotective therapies as yet to lessen should be carried out to identify rehabilitation
damage or promote recovery. and educational needs.
In early ischemia (less than 3 hours), the cranial TIAs have been defined as ischemic events
CT may be negative or show only subtle signs. in which the symptoms resolve in less than
Magnetic resonance imaging (MRI) provides 24 hours. Because TIAs are a strong predictor
better detail of the areas of ischemia, and dif- of stroke in other settings and in SCD as well,
fusion weighted imaging (DWI) shows hyper- there is a general recommendation that all
intense areas of brain ischemia within minutes patients with TIA receive appropriate therapy
after onset of severe ischemia. Unless the diag- for stroke prevention. In this particular setting
nosis is in doubt, MRI should be deferred until there are few data. The diagnosis of TIA is
treatment has been initiated. Evaluation within difficult in children, especially those who are
the first hours to days with MRI is recom- very young, and painful episodes can mimic
mended, because MRI-based studies provide hemiparesis or paraparesis. In cases where the
significant additional information, such as the history is weak for the event actually being
ability to detect very early and sometimes clini- a TIA, caution is advised, especially if long-
cally silent acute lesions with DWI and prior term transfusion is being considered.
infarction that may not be seen on CT. Imaging In the case of a child in which a TIA is observed
of the arteries by magnetic resonance angiography or strongly suspected, a prior recommendation
(MRA), may show large vessel occlusive dis- is reiterated as a reasonable approach (2): if
85
Chapter 13: Stroke and Central Nervous System Disease
the patient has significant large vessel disease sometimes be inferred by the location of blood.
on imaging, transfusion should be undertaken. Minor subarachnoid hemorrhages may have
If the patient has not been screened for stroke no identifiable cause even when angiography
risk by transcranial Doppler (TCD) ultra- is performed, but an angiogram is recom-
sound (8), this should be done and treatment mended to identify aneurysms or arteriove-
initiated according to the discussion under nous malformations (AVM) if surgery is being
“Prevention of Brain Infarction,” below, and considered. This is clinically relevant because
figure 2. Alternatively, other tests, if available, aneurysms may rebleed, and SCD patients
such as positron emission tomography (PET) may have multiple aneurysms that require
(9) or MR spectroscopy, could be employed. management. Surgical clipping, as well as
If these indicate significant “brain at risk,” AVM removal, has been successfully performed
prophylactic treatment with transfusion can in many patients with SCD. Although
be undertaken on the basis that the child’s aneurysms can be identified using MR, MRA
brain blood supply has already failed once, is not a definitive test for aneurysms unless
even if transiently, and is at significant risk special techniques are used (20). However,
for subsequent deterioration. MRI/MRA can reliably detect AVM.
Antiplatelet agents are usually recommended The initial treatment of subarachnoid hemor-
for TIAs in cases without SCD, but there are rhage is stabilization in a neurological inten-
very few data on efficacy in SCD. Agents sive care unit or pediatric ICU, depending on
such as aspirin, clopidogrel, and combination local expertise and the age of the child. Initial
dyprimadole/aspirin are used in adults and care includes intravenous normotonic fluids
in cases where transfusion is not undertaken. to avoid dehydration. The effect of transfusion
on the course and outcome of hemorrhage
I NTRACRANIAL H EMORRHAGE is not known; however, reduction of sickle
hemoglobin (Hb S) to less than 30 percent
The clinical presentation of intracranial
of total hemoglobin is recommended.
hemorrhage is dramatic and may include
Nimodopine, a calcium antagonist that
severe headache, vomiting, stupor, or coma.
improves outcome after SAH by counteracting
However, hemiparesis may be present, espe-
delayed arterial vasospasm, is indicated in
cially with intraparenchymal bleeding. A child
adults with SAH (10). Use in this setting
with such a presentation requires rapid but
with young children is not approved but
careful evaluation to rule out meningitis,
is reasonable on an empiric basis. The adult
sepsis, hypoxemia, drug intoxication, or other
dosage of 60 mg orally every 4 hours for
metabolic derangements. A noncontrast
21 days should be adjusted by weight.
cranial CT should be performed as soon as
possible. Intracranial hemorrhage should be Intraparenchymal Hemorrhage
approached based on the location of the blood If the CT shows blood primarily confined
on the CT scan, as described below. to the parenchyma, the cause may still be
an AVM, but an aneurysm is not likely
Subarachnoid hemorrhage (SAH)
unless there is also subarachnoid bleeding.
The usual cause of subarachnoid hemorrhage
Intraparenchymal bleeding may be associated
(SAH) is rupture of a berry aneurysm. The
with large vessel vasculopathy, especially if
aneurysm may not be seen on CT, but can
a moyamoya formation is present. In some
86
Figure 2. Child with Hb SS and No Symptoms
Evaluate
Neuropsychological TCD unavailable
educational needs
testing
based on results
Or treatment options:
MRI / MRA Abnormal exam ■ Observation
for progression
■ Hydroxyurea
■ Transfusion
■ Other (e.g.,
antiplatelet agents)
Chronic
transfusion
87
Chapter 13: Stroke and Central Nervous System Disease
88
Patients with stroke have received bone marrow used in STOP or with TCD attachments to
transplantation (19). The current indications, ultrasound imaging machines (transcranial
efficacy, and outcome of this therapy are Doppler imaging, or TCDI) that have also
discussed in chapter 27, Hematopoietic Cell been used in this setting (22).
Transplantation. Hydroxyurea is used for
reduction of painful episodes in adults with I DENTIFICATION OF PATIENTS AT R ISK
SCD, but the trial establishing its use provides
In addition to TCD, a number of other
no guidance on whether hydroxyurea is a suit-
approaches have been used to identify chil-
able alternative to transfusion for prevention of
dren at risk for stroke (figure 2). The CSSCD
stroke. Clinical studies in children have report-
identified five significant risk factors in a
ed short-term safety, but these studies have not
long-term prospective study: prior TIA, low
established hydroxyurea as an alternative to
steady-state hemoglobin, rate and recency
transfusion for stroke prevention in this setting
of acute chest syndrome (ACS), and elevated
(20). Anticoagulants and antiplatelet agents
systolic blood pressure. The newborn cohort
have not been studied in this indication.
of the CSSCD identified three early life (first
2 years) predictors of severe outcomes such
P RIMARY S TROKE P REVENTION as stroke (23). These were dactylitis, severe
The CSSCD established that patients with anemia, and leukocytosis.
SDC-SS have rates of stroke in childhood in
the range of 0.5-1 percent per year (1). In the Other clinical and laboratory indicators of
Stroke Prevention Trial in Sickle Cell Anemia stroke risk that have been reported include
(STOP) study, children between 2 and 16 stroke in a sibling, subtle neurological abnor-
years of age who were at risk for first-time malities, severe anemia, high leukocyte count,
stroke, as determined by having TCD velocity certain βs-gene haplotypes, and no α-gene
greater than 200 cm/sec, were randomized to deletion (2).
receive either periodic transfusions to maintain
the Hb S level below 30 percent or standard S UBCLINICAL B RAIN D ISEASE
supportive care (21). An interim analysis The CSSCD confirmed that about 13 percent
demonstrated that periodic transfusions were of children with SCD have “silent” brain
efficacious in preventing first-time stroke, lesions on MRI, in predominantly frontal and
in the children randomized to the transfusion parietal cortical, subcortical, and border-zone
arm. At the end of the trial, all participants locations (24,25). These lesions are associated
were offered periodic transfusion therapy. The with poor performance on neuropsychological
main side effects of the transfusion therapy testing. Recent evidence from the CSSCD
were iron accumulation and alloimmunization, confirms an earlier smaller study indicating
through the rate of occurrence was low. A that the risk of clinical stroke is increased if
new trial, known as STOP II, is now in place MRI is abnormal. The presence of these
to determine whether transfusions need to lesions should prompt evaluation of the child
be continued indefinitely of if they can be for learning and cognitive problems, and eval-
stopped after some period of time when risk uation of cerebral vessels for primary stroke
of stroke has diminished. prevention (see above). Silent lesions are evi-
dence of brain injury and should also lead to
TCD can be performed with either the
reevaluation of the patient’s history, which
dedicated 2-MHz pulsed Doppler device
89
Chapter 13: Stroke and Central Nervous System Disease
may reveal symptoms that were not previously reported. However, there is no clear justifica-
recognized, as well as reexamination of the tion to exclude SCD patients from t-PA thera-
patient’s clinical and laboratory risks for stroke. py, and it remains the only therapy approved
The rate of stroke in children with positive by the U.S. Food and Drug Administration
MRI and with TCD that do not reach current for treatment of ischemic stroke.
treatment guidelines is not clear, and the risks
and benefits of prophylactic transfusion based According to established guidelines,
on silent MRI lesions have not been deter- use of t-PA is indicated when:
mined. Intervention in patients with silent ■ the patient is at least 18 years old.
lesions and additional indicators of cerebral
dysfunction or abnormality have been suggest- ■ the patient’s National Institutes of Health
ed, but no recommendation for treatment can Stroke Scale score is greater than 4
be made at this time. (ischemic stroke in any vessel with
a clinically significant deficit).
STROKE AND BRAIN DISEASE ■ t-PA therapy can begin within 3 hours
IN ADULTS WITH SCD of symptom onset.
■ cranial CT shows no evidence
I NFARCTION of hemorrhage.
The CSSCD confirmed the relatively high Thrombolytic therapy cannot be
rates of stroke in adults with SCD and the recommended if:
predominance of hemorrhage compared with
infarction in adults with SCD. There is less ■ stroke duration is longer than 3 hours.
information on treatment and prevention in ■ INR is greater than 1.7 or PT of 15 seconds.
adults with SCD. The clinician must decide
whether to approach a patient with TIA or ■ patient received heparin in last 48 hours
stroke who has SCD in a manner similar to and has a prolonged aPTT.
that used in children with SCD, or along ■ platelet count is less than 100,000/µL.
guidelines established for adults without SCD
(26,27). The interaction of SCD-specific risk ■ patient has had a stroke or serious head
factors with risks factors for stroke seen in injury in the past 3 months.
adults without SCD has not been determined, ■ patient underwent major surgery within
although high blood pressure was identified the preceding 14 days.
as a stroke risk in the CSSCD. Specifically, the
■ pretreatment blood pressure is greater
role of chronic transfusion is unclear. The rec-
than 185 mmHg systolic or 110 mmHg
ommendations that follow are based primarily
diastolic.
on current recommendations for treatment and
prevention in patients without SCD (figure 3). ■ patient has rapidly improving neurological
signs or isolated ataxia, sensory loss,
Treatment of hyperacute ischemic stroke in dysarthria or minimal weakness.
adults is accomplished using recombinant tis-
sue plasminogen activator (t-PA). It is not ■ patient has a history of intracranial
clear whether t-PA, which has a significant risk hemorrhage.
of bleeding, is appropriate for patients with ■ blood glucose is less than 50 mg/dL or
SCD; no experience with its use has been greater than 400 mg/dL.
90
Figure 3. Adult with SCD and Symptoms
Ischemic stroke
Hemorrhage
or negative
Consider TPA
if < 3 hours
Evaluate/treat based from onset
ASA 325 mg if no TPA
on source of bleeding
Ischemic
Negative
stroke
Chronic Secondary
Clinical
blood OR prevention with
suspicion of TIA
transfusion antiplatelet
agents, warfarin
High Low
Observe
91
Chapter 13: Stroke and Central Nervous System Disease
■ patient had seizure at onset of symptoms. The acute evaluation of the patient requires
a noncontrast CT scan to rule out hemorrhage.
■ patient has experienced GI or GU bleed-
After the decision is made regarding t-PA, an
ing within the preceding 21 days.
MR study of the brain is recommended to
In addition, t-PA should not be given unless better delineate the area of ischemia/infarction.
emergent care and appropriate facilities are
available. Caution is advised before giving t-PA Prevention of stroke in patients with TIA or
to patients with severe stroke, and careful expla- stroke is accomplished with either antiplatelet
nation of the risk of bleeding to patient and agents or warfarin, based on the likely cause
family is advised. There is a 6.4 percent risk of of the symptoms.
symptomatic brain hemorrhage, and about half The following workup is recommended for
of these are fatal. If a hemorrhage occurs, the adults presenting with TIA or ischemic stroke:
guidelines suggest red cell transfusions as need- CBC with differential and platelet count;
ed (for extracranial bleeds) and urgent adminis- EKG; transthoracic echocardiogram with con-
tration of 4 to 6 units of cryoprecipitate or sideration given to transesophageal echocar-
fresh frozen plasma and 1 unit of single donor diogram, especially in younger patients; aPTT;
platelets. Surgical drainage of intracranial hem- PT; and a brain study to include MRI, DWI,
orrhage should be considered. Although t-PA and MRA, and/or TCD and carotid duplex
can be given to patients on antiplatelet agents, ultrasound or CT angiography to determine
these drugs, as well as any dose of heparin, the status of the intracranial and extracranial
should not be given for the first 24 hours after vessels. Blood tests for protein C and S defi-
using t-PA. There is evidence that aspirin (325 ciency, homocysteine elevation, and anticardi-
mg one-time dose) within the first 48 hours olipin antibodies may be appropriate. Health
after stroke onset has a small beneficial effect care providers also should consider etiologies
and is recommended if t-PA is not used. seen in young patients with stroke without
SCD, including CNS infection, illicit drug
use, and arterial dissection.
1 Neither ER-DP + ASA or ASA alone is recommended for patients who are allergic to aspirin or unable to take low-dose aspirin.
2 The recommended antithrombotic agents have not been specifically tested in patients who have experienced a TIA during ASA therapy.
92
There are currently three options for antiplatelet results do not meet criteria for treatment
therapy for secondary stroke prevention. Table in the presence of other strong indications
1 summarizes the American Stroke Association’s of high risk, consideration should be given
recommendations regarding these agents. to intervention on an individualized basis
unless enrollment in appropriate treatment
These guidelines are similar to those for trials is an option.
prevention of stroke after completed brain
infarction (26,28). ■ Children with ischemic stroke should
undergo acute evaluation with CT scan-
Alternative therapy is chronic blood transfu- ning followed by intravenous hydration
sion as used in children with SCD. Recently, and exchange transfusion to reduce
surgical bypass has been reported in a patient Hb S to <30 percent total hemoglobin.
with SCD. Surgical procedures that have been In most cases this should be followed
developed to treat moyamoya syndrome may by chronic transfusion (figure 1).
be considered, due to the similarity in
anatomic location of the arterial disease in ■ Children with intracranial hemorrhage
moyamoya and SCD (29). These procedures should be evaluated for a surgically cor-
may be last-resort options for patients who rectable lesion. Following this, chronic
cannot be otherwise treated or who continue transfusion is recommended in cases
to have brain infarction despite medical thera- of severe vasculopathy or unrepaired
py. However, risk and benefit in this setting aneurysm (figure 1). Acute hydration
have not been established and no recommen- and short-term exchange transfusion
dation can be made. may be beneficial as well.
A DULTS
I NTRACRANIAL H EMORRHAGE
■ Adults presenting with acute ischemic
Adults with intracerebral hemorrhage should stroke should be evaluated for t-PA treat-
be approached in the manner outlined above ment (figure 3). If t-PA is not used, aspirin
for children, with the exception that nimod- (325 mg) is appropriate. Adults with TIA
opine is recommended without qualification or ischemic stroke should be evaluated for
for patients with subarachnoid hemorrhage (11). the cause of the ischemia and therapy
should be guided by these findings.
SUMMARY OF Alternatives include antiplatelet agents and
RECOMMENDATIONS warfarin. Chronic transfusion is an option,
as used in pediatric stroke prevention.
C HILDREN
■ Primary prevention (figure 2). Children REFERENCES
with SCD 2 to 16 years of age should 1. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al.
be screened for stroke risk using TCD. Cerebrovascular accidents in sickle cell disease:
(Chronic transfusion should be strongly rates and risk factors. Blood 1998;91:288-94.
2. Powars DL. Management of cerebral vasculopathy
considered in those with confirmed in children with sickle cell disease. Br J Haematol
abnormal TCD.) If TCD is unavailable 2000;108:666-78.
or technically inadequate, or if TCD
93
Chapter 13: Stroke and Central Nervous System Disease
3. The National Institute of Neurologic Disorders 17. Wang WC, Kavaar EH, Tonkin IC, et al. High risk
and Stroke rt-PA Acute Stroke Study Group. Tissue of recurrent stroke after discontinuance of five to
plasminogen activator in acute ischemic stroke. twelve years of transfusion therapy in patients with
N Engl J Med 1995;333:1581-7. sickle cell disease. J Pediatr 1991;118:377-82.
4. Pavlakis SG. Neurologic complications of sickle 18. Rana S, Houston PE, Surana N. Discontinuation
cell disease. Adv Pediatr 1989;36:247-76. of long-term transfusion therapy in patients with
5. Kandeel AY, Zimmerman RA, Ohene-Frempong sickle cell disease. J Pediatr 1997;131:757-60.
K. Comparison of magnetic resonance angiograpy 19. Walters MC, Storb R, Patience M, et al. Impact
and conventional angiography in sickle cell disease: of bone marrow transplantation for symptomatic
clinical significance and reliability. Neuroradiol sickle cell disease: an interim report. Blood
1996;38:409-16. 2000;95:1918-24.
6. Williams LS, Garg BP, Cohen M, et al. Subtypes 20. Ware RE, Zimmerman SA, Schultz WH.
of ischemic stroke in children and young adults. Hydroxyurea as an alternative to blood transfusions
Neurol 1997;49:1541-5. for the prevention of recurrent stroke in children
7. Roach ES. Stroke in children. Curr Treat Options with sickle cell disease. Blood 1999;94:3022-6.
Neurol 2000;2:295-304. 21. Adams RJ, McKie VC, Hsu L, et al. Prevention of
8. Adams RJ, McKie VC, Carl EM, et al. Long-term a first stroke by transfusions in children with sickle
stroke risk in children with sickle cell disease cell anemia and abnormal results on transcranial
screened with transcranial doppler. Ann Neurol Doppler ultrasonography. N Eng J Med
1997;42:699-704. 1998;339:5-11.
9. Powars DR, Conti PS, Wong WY, et al. Cerebral 22. Seibert J, Glasier C, Kirby R, et al. Transcranial
vasculopathy in sickle cell anemia: diagnostic con- Doppler (TCD), MRA and MRI as a screening
tribution of positron emission tomography. Blood examination for cerebrovascular disease in patients
1999;93:71-9. with sickle cell anemia—an eight year study.
10. Mayberg MR, Batjer HH, Dacey R, et al. Pediatr Radiol 1998;28:138-42.
Guidelines for the management of aneurysmal 23. Miller ST, Sleeper LA, Pegelow CH, et al.
subarachnoid hemorrhage. Stroke 1994;25:231-2. Prediction of adverse outcomes in children with
11. Broderick JP, Adams HP, Barsan W, et al. sickle cell disease. N Engl J Med 2000;342:83-9.
Guidelines for the management of spontaneous 24. Moser FG, Miller ST, Bello JA, et al. The spectrum
intracerebral hemorrhage. Stroke 1999;30:905-15. of brain MR abnormalities in sickle cell disease:
12. Russell MO, Goldberg HI, Hodson A, et al. a report from the cooperative study of sickle cell
Effect of transfusion therapy on arteriographic disease. Am J Neuroradiol 1996;17:965-72.
abnormalities and on recurrence of stroke 25. Kinney TR, Sleeper LA, Wang WC, et al. Silent
in sickle cell disease. Blood 1984;63:162-9. cerebral infarcts in sickle cell anemia: a risk factor
13. Pegelow CH, Adams RJ, McKie V, et al. Risk of analysis. Pediatrics 1999;103:640-5.
recurrent stroke in patients with sickle cell disease 26. Wolf P, Clagett GP, Easton JD, et al. Preventing
treated with erythrocyte transfusions. J Pediatr ischemic stroke in patients with prior stroke and
1995;126:896-9. transient ischemic attack. A statement for health
14. Malinow MR, Bostom AG, Krauss RM. care professionals from the Stroke Council of the
Homocyst(e)ine, diet, and cardiovascular diseases: American Council of the American Heart
a statement for health care professionals from the Association. Stroke 1999;30:1991-4.
nutrition committee, American Heart Association. 27. Albers GW, Hart RG, Lutsep HL, et al. Scientific
Circulation 1999;99:178-82. statement: supplement to the guidelines for the
15. Westerman MP, Green D, Gilman-Sachs A, et al. management of transient ischemic attacks. Stroke
Antiphospholipid antibodies, proteins C and S, 1999;30:2502-11.
and coagulation changes in sickle cell disease. 28. Albers GW, Amarenco P, Easton JD, et al.
J Lab Clin Med 1999;134:352-62. Antithrombotic and thrombolytic therapy for
16. Tam DA. Protein C and protein S activity ischemic stroke. Chest 2001;119:300S-320S.
in sickle cell disease and stroke. J Child Neurol 29. Vernet O, Montes JL, O’Gorman AM, et al.
1997;12:19-21. Encephaloduroarterio-synangiosis in a child with
sickle cell anemia and moyamoya disease. Pediatr
Neurol 1996;14:226-30.
94
S ICKLE C ELL E YE D ISEASE 14
Sickle cell vaso-occlusive events can affect atrophy, retinal hemorrhages, retinal pigmen-
every vascular bed in the eye, often with dev- tary changes, and other abnormalities of the
astating visual consequences. Because early retinal vasculature, macula, choroid, and optic
stages of sickle cell eye disease do not usually disc. These clinical findings are readily appar-
result in visual symptoms, the disease can go ent on dilated ophthalmoscopy, and all occur
undetected unless a formal eye exam is per- due to local vaso-occlusive events but rarely
formed by an ophthalmologist. The examina- have visual consequences.
tion should include an accurate measurement
of visual acuity, assessment of pupillary P ROLIFERATIVE D ISEASE
reactivity, careful evaluation of the anterior
Progression to neovascularization or to the
structures of the eye using a slit-lamp biomi-
proliferative stage involves the growth of
croscope, and a thorough examination of
abnormal vascular fronds that place patients
the posterior and peripheral retina through
at risk of vitreous hemorrhage and retinal
a dilated pupil. This last examination should
detachment. The initiating event in the patho-
include fluorescein angiography. Patients with
genesis of proliferative disease is thought to be
sickle hemoglobinopathies should have yearly
peripheral retinal arteriolar occlusions. Local
eye examinations beginning in childhood and
ischemia from repeated episodes of arteriolar
continuing through adulthood.
closure is presumed to trigger angiogenesis
through the production of endogenous vascu-
CLINICAL FINDINGS lar growth factors, such as vascular endothelial
The clinical manifestations of sickle hemoglo- growth factor and basic fibroblast growth fac-
binopathies are grouped according to the tor (1,2). Goldberg has defined five stages of
presence or absence of neovascularization in proliferative retinopathy (3). In stage I, periph-
the eye. The distinction is clinically relevant eral arteriolar occlusion is present. In stage II,
because proliferation of new blood vessels on vascular remodeling occurs at the boundary
the retina is the key biological event that sets between perfused and nonperfused peripheral
the stage for progression to vitreous hemor- retina with the formation of arteriovenous
rhage and retinal detachment. anastomoses. In stage III, actual preretinal neo-
vascularization occurs. The neovascular fronds
N ONPROLIFERATIVE D ISEASE typically assume a shape that resembles the
marine invertebrate Gorgonia flabellum,
Non-neovascular ocular manifestations of sickle known commonly as the “sea fan.” Stage IV
hemoglobinopathies include conjunctival is defined by the presence of vitreous hemor-
vascular occlusions that transform smooth rhage, and stage V is defined by the presence
vessels into comma-shaped fragments, iris of retinal detachment. This last complication
95
Chapter 14: Sickle Cell Eye Disease
96
INDICATIONS FOR within minutes to hours after the onset of
URGENT OPHTHALMOLOGIC symptoms. Treatment consists of hyperoxy-
genation combined with rapid reduction of
CONSULTATION
eye pressure utilizing surgical and medical
Immediate consultation with an ophthalmolo- techniques. Vision loss from hemorrhage or
gist familiar with the management of individ- retinal detachment also calls for urgent care,
uals with hemoglobinopathies is required for but, unlike acute vascular occlusion, can be
any individual with a sickle hemoglobinopa- addressed appropriately within 24 to 48
thy, including sickle trait, who sustains eye hours. Any individual with a sickle hemoglo-
trauma. Anterior segment trauma may result binopathy who sustains ocular or periocular
in hemorrhage into the anterior chamber of trauma should be examined immediately by
the eye, allowing sickled erythrocytes to clog an ophthalmologist because of the increased
the trabecular outflow channels and raise the risk of visual loss from elevated eye pressure
intraocular pressure, producing glaucoma. In associated with hemorrhage into the anterior
patients with sickle hemoglobinopathies, even chamber (hyphema).
a moderate increase in eye pressure may cause
a significant reduction in perfusion of the REFERENCES
optic nerve and retina, putting the eye at risk
1. Cao J, Mathers MK, McLeod DS, et al.
for ischemic optic atrophy and retinal artery Angiogenic factors in human proliferative sickle
occlusion. In such instances patients may cell retinopathy. Br J Ophthalmol 1999;83:838-46.
require an emergent surgical washout of the 2. Aiello LP. Clinical implications of vascular growth
anterior chamber. factors in proliferative retinopathies. Curr Opin
Ophthalmol 1997;8:19-31.
Trauma considerations aside, any patient with 3. Goldberg MF. Classification and pathogenesis of
a sickle hemoglobinopathy who has an acute proliferative sickle retinopathy. Am J Ophthalmol
1971;71:649-55.
change in vision always should be referred 4. McLeod DS, Goldberg MF, Lutty GA. Dual per-
immediately to an ophthalmologist for a full spective analysis of vascular formations in sickle
evaluation. retinopathy. Arch Ophthalmol 1993;111:1234-45.
5. Condon PI, Serjeant GR. Photocoagulation in
proliferative sickle retinopathy: results of a 5
RECOMMENDATIONS year study. Br J Ophthalmol 1980;64:832-40.
Beginning in childhood, all patients with 6. Clarkson JG. The ocular manifestations of sickle
cell disease: a prevalence and natural history study.
sickle hemoglobinopathies should have yearly
Trans Am Ophthalmol Soc 1992;90:481-504.
dilated examinations by an ophthalmologist 7. Rednam KRV, Jampol LM, Goldberg MF. Scatter
with expertise in retinal diseases. Any patient retinal photocoagulation for proliferative sickle cell
with a sickle hemoglobinopathy who experi- retinopathy. Am J Ophthalmol 1982;93:594-9.
ences a change in vision should be referred 8. Charache S. Eye disease in sickling disorders.
Hematol Oncol Clin North Am 1996;10:1357-62.
for ophthalmologic consultation immediately.
Central retinal artery occlusion, an event which
usually results in permanent, devastating loss of O NLINE R ESOURCE
vision, is one of the few bona fide ophthalmic http://www.dr4eyes.com/sickle-cell.htm
emergencies which demands intervention
97
98
C ARDIOVASCULAR M ANIFESTATIONS 15
99
Chapter 15: Cardiovascular Manifestations
patients with SCD. When this is added to the Currently, no trials in patients with sickle cell
apparent risks of even relative hypertension anemia can guide decisions regarding when to
and the fact that reducing blood pressure in begin antihypertensive treatment, what agents
people without SCD can prevent the conse- are most effective, what the blood pressure
quence of hypertension, it seems reasonable to goals of treatment should be, and whether
consider antihypertensive therapy in patients blood pressure reduction can reduce the inci-
with SCD with borderline hypertension. dence of stroke or prolong life. A reasonable
approach, based on experience in the general
RECOMMENDATIONS hypertensive population where the risk of
stroke begins well below the normal blood
Chest pain, a common entity in SCD, often pressure of 140/90 mmHg, is to carefully
leads to patients being told they have had a evaluate the patient and consider beginning
heart attack. Obvious myocardial infarction is antihypertensive treatment when systolic blood
unusual, but it has been reported. Paradoxically, pressure rises by 20 mmHg or the diastolic
coronary artery occlusion is not common, sug- blood pressure increases by 10 mmHg. When
gesting that small vessel disease is responsible there is evidence of target organ damage from
for the cardiac damage (2). Ischemic heart heart disease, nephropathy and peripheral
disease can be present in patients with SCD vascular disease, treatment might be started
and should be considered in all individuals at pressures above 130/85 mmHg. Treatment
with chest pain (8). at pressures of 120/75 mmHg may be indicat-
Sudden unexpected and unexplained death is ed when proteinuria is higher than 1 gram
common in adults with sickle cell anemia (9,10). per day. ACE inhibitors and calcium antago-
Patients with SCD can have autonomic nervous nists may be especially useful treatments; the
system dysfunction that may contribute to sud- former appears to reduce proteinuria and pre-
den death. A recent study in 24 patients found serve renal function, and the latter may induce
14 patients (58.3 percent) to have cardiovascu- a higher rate of response in black patients.
lar autonomic dysfunction based on abnormal Theoretically, diuretics, by causing hemocon-
values for at least two cardiovascular autonomic centration, might predispose to vaso-occlu-
function tests, whereas 10 (41.7 percent) had sion. In practice, it is not clear whether this
preserved cardiovascular autonomic function. occurs, and their use is not contraindicated.
In contrast, all control subjects had normal Diuretic dosing should take into consideration
cardiac autonomic function (9). the additive effects of obligate hyposthenuria
in patients with SCD. β-adrenergic receptor
Documented congestive heart failure in sickle blocking agents can also be used. Renin-
cell anemia should be treated with the usual dependent hypertension can result from focal
methods. Severely anemic patients with symp- areas of renal ischemia. Severe blood pressure
toms of congestive heart failure or angina pec- increases in individuals with SCD should be
toris may be helped by cautiously increasing evaluated thoroughly to exclude this and other
their hemoglobin concentration by transfusion forms of secondary hypertension.
or, if possible, with hydroxyurea (see chapter
25, Transfusion, Iron Overload, and Chelation
and chapter 26, Hydroxyurea, for general
information about treating anemia).
100
REFERENCES
1. Leight L, Snider TH, Clifford GO, Hellems HK.
Hemodynamic studies in sickle cell anemia.
Circulation 1994;10:653-62.
2. Covitz W. Cardiac Disease. In: Embury SH,
Hebbel RP, Mohandas N, et al., eds. Sickle
Cell Disease: Basic Principles and Clinical Practice.
New York: Lippincott-Raven, 1994:725-34.
3. Covitz W, Espeland M, Gallagher D, et al.
The heart in sickle cell anemia. The cooperative
study of sickle cell disease (CSSCD). Chest
1995;108:1214-9.
4. Braden DS, Covitz W, Milner PF. Cardiovascular
function during rest and exercise in patients with
sickle-cell anemia and coexisting alpha thalassemia-
2. Am J Hematol 1996;52:96-102.
5. Johnson CS, Giorgio AJ. Arterial blood pressure
in adults with sickle cell disease. Arch Intern Med
1981;141:891-3.
6. Pegelow CH, Colangelo L, Steinberg M, et al.
Natural history of blood pressure in sickle cell dis-
ease: risks for stroke and death associated with rela-
tive hypertension in sickle cell anemia. Am J Med
1997;102:171-7.
7. Rodgers GP, Walker EC, Podgor MJ. Is “relative”
hypertension a risk factor for vaso-occlusive com-
plications in sickle cell disease. Am J Med Sci
1993;305:150-6.
8. Martin CR, Johnson CS, Cobb C, et al.
Myocardial infarction in sickle cell disease.
J Natl Med Assoc 1996;88:428-32.
9. Romero Mestre JC, Hernandez A, Agramonte O,
et al. Cardiovascular autonomic dysfunction in
sickle cell anemia: a possible risk factor for sudden
death? Clin Auton Res 1999;7:121-5.
10. James TN, Riddick L, Massing GK. Sickle cells
and sudden death: morphologic abnormalities of
the cardiac conduction system. J Lab Clin Med
1994;124:507-20.
101
102
A CUTE C HEST S YNDROME 16
AND O THER P ULMONARY C OMPLICATIONS
The lung is a major target organ for acute may not be recognized immediately. A major
and chronic complications of sickle cell disease risk factor for the development of ACS is the
(SCD). Acute chest syndrome (ACS) is a hemoglobin genotype: the highest incidence
frequent cause of death in both children and is seen in βs/βs genotype (12.8 events/100 per-
adults (1-3) with SCD. Pulmonary problems son-years) and the lowest in βs/β+ thalassemia
not directly related to sickle cell vaso-occlu- genotype (3.9 events/100 person-years) (4).
sion, such as pneumonia or asthma, can wors- ACS is the second most common cause of
en SCD because local or systemic hypoxia hospitalization in sickle cell patients and the
increases sickle hemoglobin (Hb S) polymer- most common complication of surgery and
ization. Multiorgan failure often is preceded anesthesia (5). Children have higher inci-
or accompanied by pulmonary involvement, dences of ACS (21 events/100 person-years,
as observed with fat embolization in pain βs/βs genotype) but lower mortality (<2 per-
episodes. There is more frequent recognition cent) than adults (8.7 events /100 person-years
of chronic pulmonary hypertension in adult and 4-9 percent mortality) (3,6). In SCD-SS
patients, as this complication gives a poor persons, the incidence of ACS is related to
prognosis even though pulmonary artery pres- low fetal hemoglobin (Hb F) levels and high
sures are not very high compared to those in steady-state hematocrits and white cell counts,
patients with primary pulmonary hypertension. but not to coexistent α-thalassemia (4).
Children have seasonal variation in ACS
Few of the management recommendations incidence: lower in the summer, but higher
below are based on randomized clinical trials, in winter when respiratory infections are
since such trials are largely unavailable. The frequent (6). The seasonal pattern is less
proposed guidelines are based on reviews of marked in adults. Even though the ACS
small case series in the literature, and on con- usually is self-limited, it can present with or
sensus among clinicians with experience in progress to respiratory failure, characterized
SCD treatment. by noncardiogenic pulmonary edema and
severe hypoxemia. These critically ill patients
ACUTE CHEST SYNDROME need both respiratory support and emergency
transfusions (see below).
S UMMARY OF THE S TATE
OF K NOWLEDGE The Multicenter Acute Chest Syndrome
ACS is an acute illness characterized by fever Study (MACSS) group enrolled 538 patients
and respiratory symptoms, accompanied by with 671 ACS episodes in a comprehensive,
a new pulmonary infiltrate on a chest x ray. standardized diagnostic and management
Because the appearance of radiographic protocol (3). The protocol included bacteriol-
changes may be delayed (3), the diagnosis ogy, virology, and serologic studies, as well as
103
Chapter 16: Acute Chest Syndrome and Other Pulmonary Complications
104
Table 1. Clinical Presentation and Course of Acute Chest Syndrome: Cooperative Study
of Sickle Cell Disease (CSSCD) and Multicenter Acute Chest Syndrome Study (MACSS)
* Tachypnea was an inclusion criterion in the MACSS but not in the CSSCD series.
** Not reported.
*** SCD-SS patients.
**** Only 56 percent had arterial blood gas determinations.
105
Chapter 16: Acute Chest Syndrome and Other Pulmonary Complications
Table 2. Mean Room Air PaO2 in ACS before and after Transfusions
106
Anemia (STOP) showed that patients ran- R ECOMMENDATIONS
domized to receive transfusions had signifi- Because SFE is life-threatening but difficult to
cantly fewer ACS events (2.2/100 person- recognize, a proposal for management includes
years), compared to patients in the nontrans- the following:
fused arm (15.7/100 person-years, p<0.001).
■ A high index of suspicion for SFE should
SYSTEMIC FAT EMBOLIZATION be maintained, and all cases of ACS are
considered to be at risk. Treatment of SFE
SYNDROME
should not await proof of diagnosis, since
only two premortem findings prove SFE
S UMMARY OF THE S TATE OF THE A RT
in sickle cell or trauma patients: detection
Bone marrow infarction and necrosis is of fat droplets within retinal vessels and
a known complication of SCD (19). When a biopsy of petechiae (22) that shows
an infarct is massive, necrotic marrow and fat microvascular fat. Urine fat stains are
embolize to the pulmonary vasculature. Fat unreliable. Indirect evidence of SFE in
droplets can enter the systemic circulation, sickle cell patients includes positive fat
which results in systemic fat embolization stain in bronchial macrophages, lung
(SFE) syndrome. Thus, in addition to respirato- microvascular cells, or venous blood buffy
ry insufficiency, patients can develop multior- coat (23) and multiple areas of necrosis
gan failure from emboli in organs such as the on bone marrow scans. The descriptions
brain and kidneys. SFE can affect patients of these signs are anecdotal in SCD-related
with even the mildest forms of SCD. Few case SFE (and in non-SCD patients with fat
reports are available (20,21), but risk factors for emboli due to trauma).
SFE appear to be a βs/βc genotype, pregnancy,
and prior corticosteroid treatment. Clinical ■ As in cases of severe ACS, support in a
signs of SFE vary and depend on the organs critical care setting is essential to manage
involved and the degree of involvement. respiratory insufficiency and multiorgan
Initially there may be a painful event, but failure. Case reports suggest that prompt
patients can present with or develop a fever, transfusion or exchange transfusion may
hypoxemia, azotemia, liver damage, altered prevent some deaths from SFE (20). Since
mental state, or coma. Hematologic signs fat embolism causes severe hypoxemia
include progressive anemia, normoblastemia, which promotes Hb S polymerization,
thrombocytopenia, and disseminated intravas- it seems likely that transfused normal
cular coagulation. A high index of suspicion for blood will dilute the patient’s sickle cells
SFE should be maintained, even though this and improve pulmonary and systemic
diagnosis is hard to prove. Fortunately, SFE microvascular circulation. Survival in sick-
is often preceded or accompanied by pul- le cell patients with SFE has been reported
monary involvement (severe chest syndrome, only in those treated with transfusions.
pulmonary fat embolism), so that transfusions
given to hypoxemic ACS patients may prevent REACTIVE AIRWAY DISEASE
or inhibit its development. Airway hyperreactivity (asthma) is not a classi-
cal feature of SCD, but transgenic mouse
models of SCD have airway obstruction that
is responsive to albuterol. Cold air challenge
107
Chapter 16: Acute Chest Syndrome and Other Pulmonary Complications
108
with SCD-related PHT to respond during 6. Vichinsky EP, Styles LA, Colangelo LH, et al.
cardiac catheterization (31), but there are no Acute chest syndrome in sickle cell disease: clinical
presentation and course. Blood 1997;89:1787-92.
published data on long-term use. Other agents 7. Vichinsky E, Williams R, Das M, et al.
used to treat primary PHT are the calcium- Pulmonary fat embolism: a distinct cause
channel blockers nifedipine and diltiazem of severe acute chest syndrome in sickle cell
(32), and these or similar medications could anemia. Blood 1994;83:3107-12.
be tried in responsive sickle cell patients. 8. Godeau B, Schaeffer, A, Bachir D, et al.
Bronchoalveolar lavage in adult sickle cell patients
Long-term anticoagulation with warfarin with acute chest syndrome: value for diagnostic
[to an international normalized ratio (INR) assessment of fat embolism. Am J Respir Crit Care
of 2-3] is used in primary PHT because of Med 1996;153:1691-6.
the risk of thromboembolism (29) and also 9. Bellet PS, Kalinyak KA, Shukla R, et al.
may be useful for SCD-related PHT (27). Incentive spirometry to prevent acute pulmonary
complications in sickle cell diseases. N Engl J Med
Continuous or nocturnal oxygen therapy 1995;333:699-703.
decreases pulmonary artery pressure in patients 10. Emre U, Miller ST, Rao SP, et al. Alveolar-arterial
who are hypoxemic from various lung disor- oxygen gradient in acute chest syndrome of sickle
ders. It should be used in SCD-related PHT cell disease. J Pediatr 1993;123:272-5.
11. Emre U, Miller ST, Gutierrez M, et al. Effect of
if it lowers pulmonary pressure at cardiac
transfusion in acute chest syndrome of sickle cell
catheterization, and in chronically hypoxemic disease. J Pediatr 1995;127:901-4.
patients (PaO2 <60 mmHg, O2 saturation 12. Uchida K, Rackoff WR, Ohene-Frempong K, et al.
<90 percent). A red cell transfusion program Effect of erythrocytapheresis on arterial oxygen sat-
would help to reduce the incidence of vaso- uration and hemoglobin oxygen affinity in patients
with sickle cell disease. Am J Hematol 1998;59:5-8.
occlusive events, ACS, lung scarring, and
13. Bernini JC, Rogers ZR, Sandler ES, et al.
PHT in some patients. Hydroxyurea would Beneficial effect of intravenous dexamethasone
be expected to have the same effect, but it in children with mild to moderately severe acute
does not seem to prevent the development chest syndrome complicating sickle cell disease.
of PHT in SCD. Blood 1998;92:3082-9.
14. Sullivan KJ, Goodwin SR, Evangelist J, et al. Nitric
oxide successfully used to treat acute chest syn-
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hyperreactivity in children with sickle cell disease. hypertension: a case series. Ann Intern Med
J Pediatr 1997;131:278-83. 1999;130:740-3.
25. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality 31. Kaur K, Brown B, Lombardo F. Prostacyclin for
in sickle cell disease. Life expectancy and risk secondary pulmonary hypertension. Ann Intern
factors for early death. N Engl J Med Med 2000;132:165.
1994;330:1639-44. 32. Rich S, Kaufmann E, Levy PS. The effect of high
26. Samuels MP, Stebbens VA, Davies, SC, et al. Sleep doses of calcium-channel blockers on survival in
related upper airway obstruction and hypoxaemia primary pulmonary hypertension. N Engl J Med
in sickle cell disease. Arch Dis Child 1992;67:925-9. 1992;327:76-81.
110
G ALL B LADDER AND L IVER 17
Dysfunction of the liver and biliary tract is Ultrasound surveys of patient populations
a common complication of sickle cell disease indicate the onset of cholelithiasis occurs as
(SCD) and its variants. Despite nearly 200 early as 2 to 4 years of age and progressively
reports in the past 15 years on the hepato- increases in prevalence with age (4); nearly
biliary aspects of the sickling disorders, the 30 percent of patients develop cholelithiasis
frequency and pathophysiology responsible by age 18. African populations appear to have
for hepatic lesions remain unclear. a substantially lower prevalence than that of
Jamaican or North American patients (5); this
Hepato-biliary complications of the sickling variation is attributed to differences in dietary
disorders can be separated into broad cate- cholesterol or fiber, although other factors
gories of disorders related to hemolysis, the (genetic or environmental) also may have an
problems of anemia and transfusion manage- influence. Xenobiotics such as the third gener-
ment, the consequences of sickling and vaso- ation cephalosporins may crystallize in the
occlusion, and diseases unrelated to sickle gallbladder, and differences in the use of such
hemoglobin (Hb S). These complications of antibiotics could account for some of the geo-
the sickling disorders are most common in graphic variation in cholelithiasis frequency.
sickle cell anemia (SCD-SS), but also occur to The coinheritance of α-thalassemia appears
a lesser extent in the compound heterozygous to reduce the frequency of stones as the result
sickle diseases, SCD-SC and the β-thalassemia of a lesser degree of hemolysis (6). Common
syndromes (SCD-S βo thal and SCD-S β+ thal). duct obstruction is frequently incomplete
because pigment stones are small but they
CHOLELITHIASIS AND still can cause the characteristic biochemical
BILIARY SLUDGE changes of cholestasis. Gallstones have been
Chronic hemolysis, with its accelerated biliru- known to pass with or without pancreatitis.
bin turnover, leads to a high incidence of pig- Biliary sludge is a viscous material detectable
ment gallstones. Ordinarily, bilirubin levels in by nonacoustic shadowing on ultrasonography
SCD patients do not exceed 4 mg/dL from (7) and may be a precursor of gallstone devel-
hemolysis alone, and the conjugated fraction is opment. Certain antibiotics such as ceftriax-
less than 10 percent (1,2). Marked increases in one seem to promote sludge formation.
the unconjugated fraction have been reported Studies in patients with SCD indicate that
in association with the UDP-glucuronyltrans- sludge is often found with stones, but sludge
ferase genetic defect of Gilbert’s syndrome (3). alone may or may not progress to stone for-
mation. However, the period of followup of
such studies is short (8,9).
111
Chapter 17: Gall Bladder and Liver
ACUTE AND CHRONIC The Tc-99 RBC scan may prove more useful
CHOLECYSTITIS in detecting the hyperemia of acute cholecys-
titis, but its use with these patients has not
Fever, nausea, vomiting, and abdominal pain been reported.
are common events with a wide differential
diagnosis, including hepatic, intestinal, pan- Treatment of acute cholecystitis does not
creatic, vertebral, neurologic, and pulmonary differ from that for the general population
disorders (table 1). and consists of antibiotics and general sup-
portive care with consideration for elective
A careful clinical evaluation is necessary to cholecystectomy several weeks after the acute
establish a clear diagnosis. Biliary scintigraphy episode subsides.
might be helpful, but its use is controversial
because of a high false positive rate and low
C HOLECYSTECTOMY
positive predictive value. However, it has a
high negative predictive value since a normal Laparoscopic cholecystectomy on an elective
study indicates that the cystic duct is patent. basis in a well-prepared patient has become
False positives can result from prolonged fast- the standard approach to symptomatic
ing, severe hepatocellular disease, extrahepatic patients. However, symptoms attributed to
obstruction, chronic cholecystitis, or narcotic- cholecystitis often persist after cholecystecto-
induced spasm of the sphincter of Oddi (10). my. Because intraoperative cholangiography
(IOC) has a false positive rate estimated at 25
percent, endoscopic retrograde cholangiopan-
creatography (ERCP) at the time of laparo-
Table 1. Unusual Causes of Right Upper Quadrant
scopic cholecystectomy is preferred. IOC is
(RUQ) Pain and Abnormal Liver Tests
Reported in Sickling Disorders still useful, however, for delineating the anato-
my of the cystic duct and its artery. The deci-
sion to proceed to cholecystectomy should be
Biloma based on the natural history of the disorder in
Focal nodular hyperplasia of the liver in children this patient population. The Jamaican data (4)
Fungal ball provide the strongest argument for a conserva-
tive approach, but Jamaican patients seem to
Hepatic artery stenosis
be substantially less symptomatic than are
Hepatic infarct/abscess North American patients. An aggressive
Hepatic vein thrombosis approach provides the benefit of reducing the
Mesenteric/colonic ischemia risk of the morbid complications of cholelithi-
asis, as well as eliminating gallbladder disease
Pancreatitis
as a confounding item in the differential
Periappendiceal abscess
diagnosis of right upper quadrant pain. For
Pericolonic abscess asymptomatic patients, the data support a
Pulmonary infarct/abscess conservative approach, but there is consider-
Renal vein thrombosis
able controversy.
112
VIRAL HEPATITIS the inflammatory process, and slows the
subsequent development of cirrhosis and
Acute viral hepatitis has the same clinical
hepatocellular carcinoma.
course in patients with sickling disorders as
in the general population, but with a higher Indications for treatment of hepatitis B
peak bilirubin level because of hemolysis. include HBsAg positivity for more than
6 months, HBV DNA positivity, and persis-
Surveys for serologic evidence of hepatitis
tent elevation of ALT or biopsy evidence for
B infection show a wide range of prevalence,
chronic hepatitis.
related to the endemicity of the virus as well
as to past transfusion practices (1). Fulminant For hepatitis C, persistent elevation of
hepatitis occurs with a high mortality in AST/ALT, positive PCR for viral RNA,
0.5 percent of the general population, and or biopsy evidence of chronic hepatitis
chronicity is inversely related to age. Thus are indications for treatment.
vaccination early in life seems to be indicated;
patients with SCD respond as well as the AUTOIMMUNE HEPATITIS
general population.
Autoimmune hepatitis has been reported in
Similar surveys for hepatitis C infection indi- 5 patients (15). It is characterized histologically
cate that this infection is clearly related to by dense T-cell infiltrates in periportal areas
transfusion practice and geographic location with bridging fibrosis and piecemeal necrosis
and that chronic hepatitis is as frequent in and by a marked polyclonal gammopathy. It
patients with SCD as in the general popula- is associated with extrahepatic manifestations
tion (11). In the general population, fulmi- of arthropathy, rash, and leg ulcers. Treatment
nant hepatitis is unusual, but as many as 65 of sickle cell patients with plasma exchange
percent will develop chronic hepatitis and cir- has been successful. Data from the hepatology
rhosis. Chronic hepatitis is subtle, with only literature indicate that prednisone and
25 percent of patients having AST/ALT as azathioprine given for 24 months initially
high as twice normal values. In SCD, cirrhosis induce a clinical remission that is followed
occurs, and liver transplants are now being by biochemical, then histological, remission.
done (12). Chronic hepatitis C is associated
with extrahepatic manifestations that can HEMOSIDEROSIS/
confound the management of SCD. These HEMOCHROMATOSIS
include a cutaneous leucocytoclastic vasculitis
and essential mixed cryoglobulinemia with Iron overload develops as a result of frequent
purpura, arthralgias, glomerulonephritis, and transfusions, although genetic hemochromato-
peripheral neuropathy. sis does occur. Hepatic iron stores can be mea-
sured biochemically or by a superconducting
In studies of patients with persistent elevations quantum interference device susceptometer,
of AST/ALT, biopsy invariably shows evidence but this instrument is not widely available.
of chronic hepatitis (13,14). Treatment of Magnetic resonance imaging (MRI) compar-
chronic viral hepatitis is based upon observa- ing the signal intensity of liver, pancreas, and
tions that sustained suppression of viral repli- spleen to that of muscle is useful for detecting
cation renders patients noninfectious, reduces iron overload, but MRI is not very sensitive
113
Chapter 17: Gall Bladder and Liver
114
HEPATIC SEQUESTRATION CHOLESTASIS
Acute hepatic sequestration, a rarely recog- Acute and chronic cholestatic syndromes
nized complication of VOC, is characterized have been attributed to a wide variety of
by a rapidly enlarging liver accompanied by a clinical entities in patients with SCD.
decrease in hemoglobin/hematocrit and a rise
in reticulocyte count. The liver is smooth and A benign cholestatic picture has been described
variably tender. The bilirubin may be as high in which there are striking elevations of biliru-
as 24 mg/dL (or even higher) with a predomi- bin with only modest elevations of alkaline
nance of the conjugated fraction. The alkaline phosphatase and transaminases; there is no
phosphatase can be as high as 650 IU/L or impairment of hepatic synthetic function, as
may be normal; the transaminases may be reflected by the prothrombin time and activat-
elevated only minimally but are often normal. ed partial thromboplastin time. The patients
Ultrasonography and CT scanning show only are asymptomatic except for jaundice or
diffuse hepatomegaly. Liver biopsy shows pruritus. Fever, abdominal pain, and gastroin-
massively dilated sinusoids with sickled ery- testinal upset are conspicuously absent. Drug
throcytes and Kupffer cell erythrophagocyto- reactions can be implicated in some cases,
sis. Intrahepatic cholestasis with bile plugs and measurement of anti-kidney/liver micro-
in canaliculi may be seen. Hepatocyte necrosis somal antibodies can assist in diagnosis. In
is unusual. Recurrence is common. all instances, resolution of cholestasis occurs
within months in the absence of specific
Simple transfusion, exchange transfusion, therapy (1,23).
or supportive care alone can resolve hepatic
sequestration. In one patient, treated with In contrast, progressive cholestasis in the
simple transfusion, resolution of sequestration absence of cirrhosis has been reported in a
was accompanied by a rapid increase in the number of cases. These cases are characterized
concentration of circulating hemoglobin, by RUQ pain, extreme elevation of bilirubin,
representing return of sequestered red cells striking elevation of alkaline phosphatase, and
to the circulation; this resulted in a fatal acute variable elevation of transaminases. Renal fail-
hyperviscosity syndrome (22). Because of this ure, thrombocytopenia, and severe prolonga-
risk with simple transfusion, exchange transfu- tion of coagulation test results are present.
sion is preferred; however, careful monitoring Liver histology in both benign and progressive
still is required. forms of cholestasis shows intrasinusoidal sick-
ling and Kupffer cell hyperplasia with phago-
Acute hepatic failure has been reported in cytosis of sickled erythrocytes. Mortality due
several cases where massive hepatic necrosis to uncontrollable bleeding or hepatic failure
was seen in the absence of markers for viral is common (1,24). All survivors have been
hepatitis. However, clinical and biological treated with exchange red cell transfusion;
profiles improved rapidly after exchange plasmapheresis with fresh frozen plasma and
transfusion therapy. platelet transfusion support have been used
to control bleeding due to hemostatic failure.
115
Chapter 17: Gall Bladder and Liver
RECOMMENDATIONS REFERENCES
Biliary sludge is best managed by serial 1. Johnson CS, Omata M, Tong MJ, et al. Liver
ultrasound examinations at 12- to 24-month involvement in sickle cell disease. Medicine
(Baltimore) 1985;64:349-56.
intervals unless cholestasis occurs; at that 2. West MS, Wethers D, Smith J, et al. Laboratory
point, laparoscopic cholecystectomy is indict- profile of sickle cell disease: a cross-sectional
ed. Elective laparoscopic cholecystectomy has analysis. J Clin Epidemiol 1992;45:893-909.
become the procedure of choice for sympto- 3. Passon RG, Howard TA, Zimmerman SA, et al.
The effect of UDP-glucuronosyltransferase
matic cholelithiasis (25) because of the short-
(UGTIA) promoter polymorphisms on serum
ened hospital stay, lower cost, and fewer imme- bilirubin levels and cholelithiasis in patients with
diate surgical complications. One approach sickle cell anemia. Blood 1999;94(Supp l):645a.
to asymptomatic or minimally symptomatic 4 Walker TM, Hambleton IR, Serjeant GR.
cholelithiasis is careful observation until symp- Gallstones in sickle cell disease: Observations from
the Jamaican cohort study. J Pediatr 2000;136:80-5.
toms dictate surgery. Bacteremia, ascending
5. Nzeh DA, Adedoyin MA. Sonographic pattern of
cholangitis, empyema, and other hyperacute gallbladder disease in children with sickle cell
biliary complications require surgery on anaemia. Pediatr Radiol 1989;19:290-2.
a more urgent basis, consistent with good 6. Haider MZ, Ashebu S, Aduh P, et al. Influence of
surgical practice. α-thalassemia on cholelithiasis in SS patients with
elevated Hb F. Acta Haematol 1998;100:147-50.
The management of chronic hepatitis is 7. Lee SP, Maher K, Nicholls JF. Origin and fate of
biliary sludge. Gastroenterology 1988;94:170-6.
beyond the scope of this treatise but requires
8. Al-Salem AH, Qaisruddin S. The significance of
close coordination with gastroenterologists biliary sludge in children with sickle cell disease.
and the judicious use of liver biopsy to guide Pediatr Surg Int 1998;13:14-6.
diagnosis and therapeutic decisions. 9. Walker TM, Serjeant GR. Biliary sludge in sickle
cell disease. J Pediatr 1996;129:443-5.
Iron overload can be managed by the standard 10. Serafini AN, Spoliansky G, Sfakianakis N, et al.
subcutaneous protocols, but the intensive Diagnostic studies in patients with sickle cell ane-
mia and acute abdominal pain. Arch Intern Med
intravenous approach is attractive because
1987;147:1061-2.
of the claim of improved compliance (19). 11. Hasan MF, Marsh F, Posner G, et al. Chronic
hepatitis C in patients with sickle cell disease.
The syndromes attributable to intrahepatic Am J Gastroenterol 1996;91:1204-6.
vaso-occlusion appear to be treated best with 12. Emre S, Kitibayashi K, Schwartz M, et al. Liver
exchange red cell transfusion because of the transplantation in a patient with acute liver failure
remote risk of acute hyperviscosity (22). due to sickle cell intrahepatic cholestasis.
Transplantation 2000;69:675-6.
Plasmapheresis and platelet transfusion support
13. Mills LR, Mwakyusa D, Milner PF.
are useful in cases associated with coagulopathy. Histopathologic features of liver biopsy specimens
in sickle cell disease. Arch Pathol Lab Med
1988;112:290-4.
116
14. Omata M, Johnson CS, Tong MJ, et al. The O NLINE R ESOURCES
pathological spectrum of liver diseases in sickle cell
American Association for the Study of Liver Diseases
disease. Dig Dis Science 1986;31:247-56.
http://www.aasld.org
15. Chuang E, Ruchelli E, Mulberg AE. Autoimmune
liver disease and sickle cell anemia in children: A The American Gastroenterological Association
report of three cases. Am J Pediatr Hematol Oncol http://www.gastro.org
1997;19:159-62.
16. Brittenham GM, Cohen AR, McLaren CE, et al. American Liver Foundation
Hepatic iron stores and plasma ferritin concentra- http://www.liverfoundation.org
tion in patients with sickle cell anemia and tha-
lassemia major. Am J Hematol 1993;42:81-5. Centers for Disease Control and Prevention
17. Harmatz P, Butensky E, Quirolo K, et al. Severity http://www.cdc.gov
of iron overload in patients with sickle cell disease
Hepatitis B Coalition
receiving chronic red blood cell transfusion thera-
http://www.immunize.org
py. Blood 2000;96:76-9.
18. Yeomans E, Lowe T, Eigenbrodt EH, et al. Liver Hepatitis B Foundation
histopathologic findings in women with sickle cell http://www.hepb.org
disease given prophylactic transfusion during preg-
nancy. Am J Obstet Gynecol 1990;163:958-64. Hepatitis Foundation International
19. Silliman CC, Peterson VM, Mellman DL, et al. http://www.hepfi.org
Iron chelation by desferoxamine in sickle cell
patients with severe transfusion-induced hemo- National Institutes of Health Consensus Statement
siderosis: a randomized double-blind study of http://www.consensus.nih.gov
the dose-response relationship. J Lab Clin Med
1993;122:48-54.
20. Serjeant GR. Sickle Cell Disease, 3rd ed. Oxford:
Oxford University Press, 2001.
21. Ojuawo A, Adeoyin MA, Fagbule D. Hepatic
function tests in children with sickle cell anaemia
during vaso occlusive crisis. Cent Afr J Med
1994;40:342-5.
22. Lee ESH, Chu PCM. Reverse sequestration
in a case of sickle cell crisis. Postgrad Med J
1996;72:487-8.
23. Buchanan GR, Glader BE. Benign course of
extreme hyperbilirubinemia in sickle cell anemia:
Analysis of six cases. J Pediatr 1977;91:21-4.
24. Shao SH, Orringer EP. Sickle cell intrahepatic
cholestasis: approach to a difficult problem.
Am J Gastroenterol 1995;90:2048-50.
25. Jawad AJ, Kurban K, El-Bakry A, et al.
Laparoscopic cholecystectomy for cholelithiasis
during infancy and childhood: cost analysis and
review of current indications. World J Surg
1998;22:69-73.
117
118
S PLENIC S EQUESTRATION 18
Acute exacerbation of anemia in the patient episode, and the mortality rate in these
with sickle cell disease (SCD) is a significant patients may be 20 percent (5). There are no
cause of morbidity and mortality. The most clear prognostic factors for the occurrence of
common process leading to this complication ASSC, although the fetal hemoglobin (Hb F)
is acute splenic sequestration. level at 6 months of age is somewhat lower
in children who develop this complication
ACUTE SPLENIC SEQUESTRATION (3). Although ASSC occurs most commonly
COMPLICATION among children with SCD-SS, it has been
reported in 5 percent of children with SCD-
Acute splenic sequestration complication SC disease at a mean age of approximately 9
(ASSC) is caused by intrasplenic trapping of years (6) and in adults with SCD-SC disease
red cells which causes a precipitous fall in and SCD-S β+-thalassemia (7).
hemoglobin level and the potential for hypox-
ic shock. ASSC remains a leading cause of
T REATMENT OF A CUTE S PLENIC
death in children with SCD. ASSC may be S EQUESTRATION
defined by a decrease of at least 2 g/dL from
the steady-state hemoglobin concentration, The immediate treatment of acute splenic
evidence of increased erythropoiesis such as a sequestration is directed toward correction of
markedly elevated reticulocyte count, and an hypovolemia with red blood cell transfusion.
acutely enlarging spleen. ASSC has been Because severe ASSC can be fatal within a few
reported as early as 5 weeks of age (1) and in hours, emergent transfusion is required (see
adults (2), but in most cases the first episodes chapter 25, Transfusion, Iron Overload, and
in SCD-SS patients occur between 3 months Chelation). Once transfusion is employed, red
and 5 years of age. The attacks are often asso- cells sequestered in the spleen are remobilized,
ciated with viral or bacterial infections. Acute splenomegaly regresses, and the hemoglobin
chest syndrome occurred in 20 percent in one level increases, often to a level greater than
series (3). The usual clinical manifestations are predicted on the basis of the volume of red
sudden weakness, pallor, tachycardia, tachyp- cells administered.
nea, and abdominal fullness. ASSC has been The rate of recurrent splenic sequestration is
reported in 30 percent of children with sickle high and greatly influences subsequent man-
cell anemia in Jamaica (3) and 7.5 percent agement, which may be divided into observa-
of children seen at Duke University (4). In tion only, chronic transfusion, and splenecto-
Jamaica, the mortality rate for first attacks was my. Indications for these approaches are not
12 percent (5). Recurrent splenic sequestration clearly defined. Questions which bear on man-
events are common, occurring in approximate- agement decisions include: Does splenectomy
ly 50 percent of those who survive the first
119
Chapter 18: Splenic Sequestration
increase the risk of invasive infection above Grover and Wethers (10), who advised a year
that of the patient with functional asplenia? or more of long-term transfusion therapy for
Does a partial splenectomy allow maintenance the child with ASSC under age 3 and prompt
of some splenic function? Does chronic trans- splenectomy after the first episode of ASSC
fusion effectively restore splenic function? in the child 5 years of age or older.
Does chronic transfusion maintain the spleen’s
potential for sequestration by delaying autoin- Topley et al. (5) reported that one third of
farction? patients with ASSC develop hypersplenism.
They noted that chronic transfusion may
Observation simply delay episodes of ASSC to a later age
Children who have ASSC are at risk for and may not restore splenic function. In fact,
recurrent, potentially fatal episodes and Rogers et al. (11) reported that pitted red cell
should receive immediate medical attention. counts rose to asplenic levels after an episode
Observation for adults is common because of ASSC and rarely, if ever, returned to values
episodes tend to be mild (8). compatible with normal splenic function.
Chronic Transfusion Splenectomy
Rao and Gooden (9) treated 11 children with Powell et al. (8) described 12 patients with
subacute splenic sequestration with short-term ASSC. One patient died; 3 patients with
transfusion for 1 to 3 years. Seven patients had minor episodes had no recurrences, and
recurrent sequestration when transfusions were 8 patients had prompt splenectomy. The
discontinued near 5 years of age and subse- researchers recommended splenectomy after
quently underwent splenectomy. There were the first major episode of ASSC and reasoned
no deaths. The authors concluded that the that removal of a poorly or nonfunctioning
time gained from short-term transfusion ther- spleen does not increase susceptibility to
apy was beneficial in reducing the risk of acute infections. Although chronic blood transfusion
sequestration and temporarily reversing splenic can delay splenectomy and temporarily restore
dysfunction. In contrast, Kinney et al. (4) splenic function, these advantages were
compared short-term transfusion (n=12) with thought to be outweighed by the risks of
observation (n=7) and immediate splenectomy chronic blood administration. In addition,
(n=4) in a group of 23 children with ASSC. Topley et al. (5) suggested that any child
Despite a reduction in the concentration of with a history of one classical episode of
sickle hemoglobin (Hb S) to less than 30 per- ASSC or a minor episode followed by the
cent in the chronically transfused patients, development of sustained hypersplenism
the risk of recurrent sequestration appeared should undergo splenectomy.
unaffected by transfusion. Seven of 10 evalu-
able patients with chronic transfusion had An analysis of 130 Jamaican patients with
recurrences either during the transfusion period SCD-SS treated by splenectomy (46 for recur-
or shortly after transfusion was discontinued; rent ASSC), and a control group matched for
4 of 7 patients who were observed had recur- sex, age, and duration of followup in a retro-
rences. Overall, splenectomy was performed in spective review by Wright et al. (12) found
61 percent of patients. The authors concluded that mortality and bacteremic episodes did not
that short-term transfusion to prevent recurrent differ between the splenectomy and control
splenic sequestration was of limited benefit. groups. Painful events and acute chest syn-
An intermediate recommendation came from drome were more common in the splenectomy
120
group. The authors concluded that splenectomy ■ Alternatively, patients who have a severe
does not increase the risk of death or bac- episode of ASSC and are below 2 years of
teremic illness in patients with SCD-SS and, age should be placed in a chronic transfu-
if otherwise indicated, should not be deferred. sion program to keep Hb S levels below
30 percent until a splenectomy can be
Partial splenectomy has been recommended considered after 2 years of age.
for children with recurrent ASSC as a means
of preventing further recurrence and retaining ■ Patients with chronic hypersplenism also
splenic function (13,14). However, one should be considered for splenectomy.
patient died of overwhelming sepsis when
this approach was used (15). REFERENCES
1. Airede AI. Acute splenic sequestration in a five-
week-old infant with sickle cell disease. J Pediatr
E DUCATION
1992;120:160.
Emond et al. (3) describe a parental education 2. Solanki DL, Kletter GG, Castro O. Acute splenic
program in Jamaica to facilitate early diagnosis sequestration crises in adults with sickle cell
of ASSC. The program, which involved more disease. Am J Med 1986;80:985-90.
3. Emond AM, Collis R, Darvill D, et al. Acute
than 300 children with SCD-SS, led to an splenic sequestration in homozygous sickle cell
increase in the incidence of ASSC from 4.6 disease: natural history and management. J Pediatr
to 11.3/100 patient-years, probably reflecting 1985;107:201-6.
increased awareness of the complication. 4. Kinney TR, Ware RE, Schultz WH, et al.
However, the mortality rate fell from 29.4/100 Long-term management of splenic sequestration
in children with sickle cell disease. J Pediatr
events to 3.1/100 events, a dramatic decline 1990;117:194-9.
resulting from improved medical management 5. Topley JM, Rogers DW, Stevens MCG, et al.
and earlier detection. Acute splenic sequestration and hypersplenism
in the first five years in homozygous sickle cell
disease. Arch Dis Child 1981;56:765-9.
RECOMMENDATIONS 6. Aquino VM, Norvell JM, Buchanan GR. Acute
All reports regarding the management of splenic complications in children with sickle cell-
hemoglobin C disease. J Pediatr 1997;130:961-5.
ASSC (and chronic hypersplenism) were 7. Orringer EP, Fowler VG Jr, Owens CM, et al.
descriptive, retrospective, and uncontrolled. Case report: splenic infarction and acute splenic
Clinical evidence derived from controlled sequestration in adults with hemoglobin SC dis-
clinical trials is relatively weak. ease. Am J Med Sci 1991;302:374-9.
8. Powell RW, Levine GL, Yang Y-M, et al. Acute
The following are current recommendations: splenic sequestration crisis in sickle cell disease:
early detection and treatment. J Pediatr Surg
■ Early education should be provided to 1992;27:215-9.
parents of infants with SCD regarding pal- 9. Rao S, Gooden S. Splenic sequestration in sickle
cell disease: role of transfusion therapy. Am J
pation of the spleen, symptoms of progres-
Pediatr Hematol Oncol 1985;7:298-301.
sive anemia, and appropriate action for 10. Grover R, Wethers DL. Management of acute
obtaining rapid evaluation and treatment. splenic sequestration crisis in sickle cell disease.
J Assoc Acad Minor Phys 1990;1:67-70.
■ Patients who have a life-threatening 11. Rogers DW, Serjeant BE, Serjeant GR. Early rise
episode of ASSC that requires transfusion in ‘pitted’ red cell count as a guide to susceptibility
support should have a splenectomy shortly to infection in childhood sickle cell anemia. Arch
after the event or be placed on a chronic Dis Child 1982;57:338-42.
transfusion program.
121
Chapter 18: Splenic Sequestration
122
R ENAL A BNORMALITIES IN S ICKLE C ELL D ISEASE 19
The kidney in patients with sickle cell disease it may occur later in life. This dysfunction
(SCD) exhibits numerous structural and func- in urinary concentrating ability is frequently
tional abnormalities, changes that are seen associated with nocturia.
along the entire length of the nephron. The
medullary region of the kidney is composed As a result of the inability to maximally
of renal tubules and medullary blood vessels concentrate the urine, patients with SCD
that are collectively referred to as the vasa recta are more susceptible than are normal individ-
system. The environment of the renal medulla uals to dehydration, a factor that often pre-
is characterized by hypoxia, acidosis, and cipitates vaso-occlusive events. Patients with
hypertonicity. Because these conditions SCD should therefore be encouraged to
promote hemoglobin S (Hb S) polymerization drink liberal amounts of liquids in order to
and red cell sickling, this area of the kidney compensate for the fluid loss that is brought
is particularly susceptible to malfunction. on by hyposthenuria.
Microradioangiographic studies carried out
on the kidneys of patients with SCD show TUBULE DYSFUNCTION
significant loss of the vasa recta. Those few Defective urinary acidification also is well
medullary blood vessels that remain are described in SCD (3). Typically, however,
markedly dilated with a spiral configuration, patients have normal aldosterone and renin
and appear to end blindly (1). Changes are responses (4). The primary abnormality is
most marked in patients with homozygous an incomplete distal renal tubular acidosis
sickle cell anemia (SCD-SS), but are also seen (RTA), and the severity of the acidification
in those with compound heterozygous states defect is related, at least in part, to the
(SCD-SC, thalassemia) and the sickle cell severity of the hyposthenuria.
trait. Table 1 summarizes renal abnormalities
associated with SCD. Defects in potassium excretion also are seen
in SCD. Although not clinically apparent
HYPOSTHENURIA under normal circumstances, hyperkalemia
does become manifest as overall renal function
Hyposthenuria, an inability to concentrate deteriorates. In addition, even SCD patients
urine maximally, is perhaps the most com- with normal renal function are at risk for
mon renal abnormality in SCD (2). In indi- hyperkalemia following administration of
viduals with SCD-SS, hyposthenuria typical- drugs such as ACE inhibitors, beta-blockers,
ly becomes apparent during early childhood and potassium-sparing diuretics (2).
as enuresis, whereas in the other syndromes,
123
Chapter 19: Renal Abnormalities in Sickle Cell Disease
124
Vasopressin and epsilon-amino caproic acid GLOMERULAR ABNORMALITIES
(EACA) have both been used with variable AND CHRONIC RENAL FAILURE
success (7,8). However, caution must be exer-
cised when using EACA as this antifibrinolytic Proteinuria, which can progress to the nephrot-
agent may predispose to the formation of ic syndrome, is the most common manifesta-
clots that can obstruct the urinary collecting tion of glomerular injury in SCD patients.
system. If prolonged and life-threatening Moreover, as many as 40 percent of SCD-SS
bleeding is coming from one kidney, local patients with nephrotic syndrome may go
resection of the bleeding segment is preferred. on to develop end-stage renal disease (ESRD)
Unilateral nephrectomy is a last resort since (12). Therefore, patients with persistent
bleeding may recur from the other kidney. proteinuria should have a urine collection
obtained for the determination of 24-hour
Hematuria that occurs in SCD is not always protein excretion, and a nephrology consulta-
a consequence of red cell sickling and papillary tion should be requested for consideration of
necrosis. Other, nonsickling causes also should other, nonsickling causes of proteinuria and
be considered. For example, renal medullary possible renal biopsy.
carcinoma in young subjects with SCD and
sickle cell trait (Hb AS) has been reported ACE inhibitors ameliorate pathological
(9,10). Therefore, a thorough evaluation is changes such as perihilar focal and segmental
recommended when hematuria is initially glomerulosclerosis. They also decrease urinary
found in individuals with SCD and Hb AS. protein excretion in patients with early mani-
festations of sickle cell nephropathy (13).
ACUTE RENAL FAILURE Renal insufficiency occurs earlier in SCD-SS
Acute renal failure occurs as a component patients than it does in SCD-SC patients (12).
of the acute multiorgan failure syndrome Factors that appear to predict renal failure
(AMOFS) in patients with SCD (11). This in SCD-SS patients include hypertension,
syndrome is characterized by the sudden onset proteinuria, increasingly severe anemia, and
of severe dysfunction of at least two major hematuria (13). Finally, the risk of renal
organ systems (e.g., kidney, lung, liver) during failure is increased in those SCD-SS patients
an acute painful vaso-occlusive episode in with the Central African Republic (CAR)
patients with SCD. The pathophysiology βs-gene cluster haplotype.
of AMOFS appears to be due to diffuse, small As there is no proven treatment for sickle cell
vessel occlusion, which in turn results in tissue nephropathy, every attempt should be made
ischemia and organ dysfunction. The renal to slow its rate of progression. The amount of
failure in this syndrome also may be related proteinuria can be decreased by the adminis-
to the accompanying rhabdomyolysis. Prompt tration of ACE inhibitors, and it is conceivable
initiation of transfusion therapy or exchange that the progression of sickle cell nephropathy
transfusion may reverse this syndrome. may be slowed by a prolonged course of these
drugs. Patients should avoid nonsteroidal anti-
inflammatory drugs (NSAIDs) because NSAIDs
have been shown to produce significant
declines in the rates of glomerular filtration and
renal blood flow in patients with SCD (5,14).
125
Chapter 19: Renal Abnormalities in Sickle Cell Disease
Effective control of blood pressure has been have reported graft and patient survival rates
reported to slow the progression of ESRD comparable to those of other nondiabetic
in patients with SCD; they should be treated patients (19). A more recent study of renal
with standard approaches (15). Optimum transplantation in SCD reported short-term
target blood pressure has not been defined. patient and allograft outcomes comparable
Because dehydration can precipitate vaso- to other age-matched African Americans.
occlusive events, caution should be exercised However, there was a shorter cadaveric graft
in the use of diuretic agents in an individual survival and high risk of graft loss with longer
with obligate hyposthenuria. followup in the SCD patient group (20).
There was a trend toward improved survival
Every effort must be made to avoid additional in those SCD patients who received trans-
renal damage due to urinary tract infection. plants compared to those on chronic dialysis.
Infection must be recognized and treated
vigorously. Followup should be maintained Although many SCD patients have done
longer than for patients without SCD. well after renal transplantation, several unique
complications have been described. Patients
Although erythropoietin levels are generally may experience a resumption of frequent
high in steady-state SCD-SS patients, they are vaso-occlusive events which presumably are
not increased to the level that would be expect- related to an increase in whole blood viscosity
ed for the degree of anemia (16). One explana- accompanying a higher hemoglobin level.
tion for the relatively decreased erythropoietin Renal infarction, a probable secondary conse-
levels is the right-shifted hemoglobin-oxygen quence of Hb S polymerization, cell sickling,
dissociation curve seen in SCD patients (17). and vaso-occlusion, has been reported to
Erythropoietin levels in SCD patients fall still occur as early as 6 days following transplanta-
further as renal function worsens, and these tion (21). The reappearance of sickle cell
patients may require substantially higher doses nephropathy in the donor kidney has also
of erythropoietin than are required for patients been reported (22).
with other forms of ESRD (18). If erythropoi-
etin is ineffective, transfusions can be given; It is possible that the availability of new
they must be done carefully, however, to avoid immunosuppressive drugs may further
volume overload (see chapter 25, Transfusion, improve the outcome renal transplantation
Iron Overload, and Chelation). in SCD patients. Hydroxyurea is excreted by
the kidney and thus its use in patients with
As with all patients who develop ESRD, SCD renal failure requires careful monitoring.
patients can be treated with both hemodiaylsis SCD patients receiving renal transplants may
and peritoneal dialysis, and they can undergo benefit from exchange transfusion or even
renal transplantation. Although early reports from periodic phlebotomy, particularly when
suggested poor allograft survival and other dis- hemoglobin levels are high.
ease-specific problems in SCD patients, others
126
REFERENCES 14. De Jong PE, de Jong-van den Berg TW,
Sewrajsingh GS, et al. The influence of
1. Statius van Eps LW, Pinedo-Veels C, deVries CH, indomethacin on renal hemodynamics in
et al. Nature of the concentrating defect in sickle sickle cell anemia. Clin Sci 1980;59:245-50.
cell nephropathy. Microradioangiographic studies. 15. Nissenson AR, Port FK. Outcome of end-stage
Lancet 1970;1:450-2. renal disease in patients with rare causes of renal
2. Allon M. Renal abnormalities in sickle cell disease. failure. I. Inherited and metabolic disorders. Quart
Arch Intern Med 1990;150:501-4. J Med 1989;271:1055.
3. Kontessis P, Mayopoulou-Symvoulidis D, 16. Sherwood JB, Goldwasser E, Chilcote R, et al.
Symvoulidis A, et al. Renal involvement in sickle Sickle cell anemia patients have low erythropoietin
cell-β thalassemia. Nephron 1992;61:10-5. levels for their degree of anemia. Blood
4. DeFronzo RA, Taufield PA, Black H, et al. 1986;67:46-9.
Impaired renal tubular potassium secretion in sick- 17. Morris J, Dunn D, Beckford M, et al. The haema-
le cell disease. Ann Intern Med 1979;90:310-6. tology of homozygous sickle cell disease after the
5. Allon M, Lawson L, Eckman JR, et al. Effects age 40. Br J Haematol 1991;77:382-5.
of nonsteroidal anti-inflammatory drugs on 18. Steinberg MH. Erythropoietin for the anemia of
renal function in sickle cell anemia. Kidney Int renal failure in sickle cell disease. N Engl J Med
1988;34:500-6. 1991;324:1369-70.
6. Case records of the Massachusetts General 19. Chatterjee SN. National study in natural
Hospital: Weekly Clinicopathological Exercises. history of renal allografts in sickle cell disease
N Engl J Med 1985;312:1623-31. or trait: a second report. Transplant Proc
7. John EG, Schade SG, Spigos DG, et al. 1987;19(2 Suppl 2):33-5.
Effectiveness of triglycyl vasopressin in persistent 20. Ojo AO, Govaerts TC, Schmouder RL, et al.
hematuria associated with sickle cell hemoglobin. Renal transplantation in end-stage sickle cell
Arch Intern Med 1980;140:1589-93. nephropathy. Transplantation 1999;67:291-5.
8. Immergut MA, Stevenson T. The use of epsilon 21. Donnelly PK, Edmunds ME, O’Reilly K. Renal
aminocaproic acid in the control of hematuria transplantation in sickle cell disease. Lancet (letter)
associated with hemoglobinopathies. J Urol 1988;2:229.
1965;93:110. 22. Miner DJ, Jorkasky DK, Perloff LJ, et al.
9. Herring JC, Schmetz MA, Digan AB, et al. Renal Recurrent sickle cell nephropathy in a transplanted
medullary carcinoma: a recently described highly kidney. Am J Kidney Dis 1987;10:306-13.
aggressive renal tumor in young black patients.
J Urol 1997;157:2246-7.
10. Coogan CL, McKiel CF Jr, Flanagan MJ, et al. O NLINE R ESOURCES
Renal medullary carcinoma in patients with SCT. The Sickle Cell Information Center: Problem Oriented
Urology 1998;51:1049-50. Clinical Guidelines
11. Hassell KL, Eckman JR, Lane PA. Acute multior- http://www.emory.edu/PEDS/SICKLE/prod04.htm
gan failure syndrome: a potentially catastrophic
complication of severe sickle cell pain episodes. Sickle Cell Disease
Am J Med 1994;96:155-62. http://www.familyvillage.wisc.edu/lib_scd.htm
12. Foucan L, Bourhis V, Bangou J, et al. A random-
ized trial of captopril for microalbuminuria in
normotensive adults with sickle cell anemia. Am
J Med 1998;104:339-42.
13. Powars DR, Elliott-Mills DD, Chan L, et al.
Chronic renal failure in sickle cell disease: risk
factors, clinical course, and mortality. Ann Intern
Med 1991;115:614-20.
127
128
P RIAPISM 20
Priapism, defined as a sustained, painful, and experienced priapism knew that it could be
unwanted erection, is a well recognized com- a complication of SCD (1). This information
plication of sickle cell disease (SCD) (1-3). prompted the authors to prepare a brochure
According to one study, the mean age at explaining priapism, which was distributed
which priapism occurs is 12 years, and by the to all males and their families. Boys and young
age of 20, as many as 89 percent of males with men, as well as their families, need to know
SCD will have experienced one or more that they should be prepared to seek medical
episodes of priapism (1). Priapism in males attention as soon as an episode begins and that
with SCD is due to vaso-occlusion, which if untreated, priapism can result in impotence
causes obstruction of the venous drainage in the future. The males should know that
of the penis. Priapism can be classified as a full bladder can trigger priapism, and they
prolonged if it lasts for more than three hours therefore need to urinate regularly. They also
or stuttering if it lasts for more than a few should avoid prolonged sexual activity, which
minutes but less than three hours and resolves can trigger an episode. If they have had
spontaneously; however, such stuttering more than one episode, medications can
episodes may recur or develop into more pro- be prescribed that may prevent recurrences.
longed events. Prolonged priapism is an emer-
gency that requires urologic consultation. EVALUATION AND TREATMENT
Recurrent episodes of priapism can result in
fibrosis and impotence, even when adequate When evaluating a patient with priapism, the
treatment is attempted. Currently, there is no physician or nurse should document the time
single standard of care for the treatment of of onset of the episode as well as the presence
priapism; the information provided below of any other inciting factors, such as trauma,
represents current efforts with respect to the infections, or the use of drugs (e.g., cocaine,
treatment of this complication of SCD. alcohol, psychotropic agents, sildenafil, testos-
terone) (4-6). A careful physical examination
should reveal a hard penis with a soft glans.
PSYCHOSOCIAL AND
COUNSELING ASPECTS The goal of therapy is to ease pain, make the
OF PRIAPISM erection go away, and preserve future erectile
function. If treatment is given within 4 to 6
Beginning in early boyhood, males need to hours, the erection can generally be reduced
know that priapism is one aspect of SCD and with medication and conservative therapy.
that this is not an event that should embarrass Most of the articles in the literature concern
them. One study found that only 7 percent anecdotal reports and few randomized trials
of boys and men with SCD who had not are available.
129
Chapter 20: Priapism
130
PREVENTING FUTURE EPISODES 7. Mantadakis E, Ewalt DH, Cavender JD, et al.
Outpatient penile aspiration and epinephrine irri-
There are no large clinical studies document- gation for young patients with sickle cell anemia
ing ways to prevent priapism. Some physicians and prolonged priapism. Blood 2000;95:78-82.
prescribe 30 mg of oral pseudoephedrine 8. Walker EM Jr, Mitchum EN, Rous SN, et al.
at night as an attempt to prevent further Automated erythrocytopheresis for relief of pri-
apism in sickle cell hemoglobinopathies. J Urol
episodes in those who have had priapism and
1983;130:912-6.
have required aspiration and irrigation (7). 9. Rackoff WR, Ohene-Frempong K, Month S,
Injections of leuprolide, a gonadotropin- et al. Neurologic events after partial exchange
releasing hormone analogue that suppresses transfusion for priapism in sickle cell disease.
the hypothalamic-testicular axis and the pro- J Pediatr 1992;120:882-5.
10. Winter CC. Priapism cured by creation of fistulas
duction of testosterone, also has also been between glans penis and corpora cavernosa. J Urol
used with some degree of success as prophy- 1978;119:227-8.
laxis against further episodes (15). A small 11. Lowe FC, Jarow JP. Placebo controlled study of
(11 patients) double-blind, placebo-controlled oral terbutaline and pseudoephedrine in manage-
crossover study found that oral stilbestrol ment of prostaglandin E1-induced prolonged
erections. Urology 1993;42:51-3.
in doses of 5 mg daily for 3 to 4 days could 12. Virag R, Bachir D, Floresco J, et al. Ambulatory
abort episodes of priapism and that much treatment and prevention of priapism using alpha-
smaller doses could prevent recurrence (16). agonists. Apropos of 172 cases. Chirurgie
Although hydroxyurea may potentially be of 1997;121;648-52.
benefit (17), clinical studies to determine its 13. Jarmon JD, Ginsberg PC, Nachmann MM, et al.
Stuttering priapism in a liver transplant patient
efficacy in preventing priapism have not been with toxic levels of FK506. Urology 1999;54:366.
performed. 14. Douglas L, Fletcher H, Serjeant GR. Penile pros-
theses in the management of impotence in sickle
cell disease. Br J Urol 1990;65:533-5.
REFERENCES 15. Levine LA, Guss SP. Gonadotropin-releasing hor-
1. Mantadakis E, Cavender JD, Rogers ZR, et al. mone analogues in the treatment of sickle-cell ane-
Prevalence of priapism in children and adolescents mia associated priapism. J Urol 1993;150:475-7.
with sickle cell anemia. Am J Pediatr Hematol 16. Serjeant GR, DeCeulaer K, Maude GH. Stilbestrol
Oncol 1999;21:518-22. and stuttering priapism in homozygous sickle-cell
2. Powars DR, Johnson CS. Priapism. Hematol disease. Lancet 1985;2:1274-6.
Oncol Clin North Am 1996;10:1363-72. 17. Al Jam’a AH, Al Dobbous IA. Hydroxyurea in the
3. Miller ST, Rao SP, Dunn EK, et al. Priapism treatment of sickle cell associated priapism. J Urol
in children with sickle cell disease. J Urol 1998;159:1642.
1995;154:844-7.
4. Saenz-de-Tejada I, Ware JC, Blanco R, et al. G ENERAL R EFERENCE
Pathophysiology of prolonged penile erection asso- Steidle C. Priapism. In: The Impotence Sourcebook.
ciated with trazodone use. J Urol 1991;145:60-4. New York: RGA Publishing Group, 1998.
5. Kassim AA, Fabry ME, Nagel RL. Acute priapism
associated with the use of sildenafil in a patient
with sickle cell trait. Blood 2000;95:1878-9.
6. Slayton W, Kedar A, Schatz D. Testosterone
induced priapism in two adolescents with sickle
cell disease. J Pediatr Endocrinol Metab
1995;8:199-203.
131
132
B ONES AND J OINTS
21
133
Chapter 21: Bones and Joints
osteomyelitis (7), close followup examinations, to genotype; patients with SCD-SS α-tha-
blood cultures, aspiration of the affected site, lassemia present at 28 years of age, those with
and repeated white blood cell counts are appro- SCD-SS present at age 36, and those with
priate until a diagnosis is firmly established. SCD-SC present at age 40. The natural histo-
ry of symtomatic hip disease in SCD patients
D ACTYLITIS , OR THE who are treated conservatively varies with the
“H AND -F OOT ” S YNDROME patient’s age. In skeletally immature patients
Dactylitis, or the “hand-foot” syndrome, is a who are 12 years of age or younger, treatment
limited phenomenon that occurs in the hands with analgesics, nonsteroidal anti-inflammatory
and feet of infants and young children. One to drugs, and protected weight-bearing usually
four extremities may be involved at the same results in healing and remodeling of the
time. The syndrome presents with pain in the involved capital epiphysis, similar to what is
metacarpals, metatarsals, and phalanges of the observed in Legg-Calve-Perthes disease (1,11).
hands and feet. Swelling typically occurs over This approach results in preservation of the
the dorsum of the hands and feet, extending joint despite the persistence of deformity such
into the fingers and toes. Radiographs eventual- as coxa magna and coxa plana (1,12).
ly reveal periosteal elevation and a moth-eaten In contrast, conservative management of
appearance of involved bone (3). Symptoms osteonecrosis usually fails in patients in late
usually resolve in 1 to 4 weeks, and the condi- adolescence and in adulthood. Progressive flat-
tion results in no long-term sequelae (8). The tening and collapse of the femoral head results
patient should receive analgesia and hydration, in painful secondary degenerative arthritis.
and the parents should be given reassurance. The use of joint-preserving surgical procedures
Transfusions, antibiotics and other measures such as core decompression and osteotomy
are usually not necessary. Although it is rare, has been reported anecdotally in sickle cell
infection should be considered if conservative patients who have precollapse femoral head
management yields no benefit. At least one involvement (13). As yet, there have been
study has indicated that an episode of dactyli- no prospective, randomized studies in sickle
tis within the first two years of life, particular- cell patients to critically assess the safety and
ly in association with leukocytosis and severe efficacy of such procedures.
anemia, may predict severe manifestations of
SCD later in life (9). Hip arthroplasty is reserved for patients with
advanced disease who are severely sympto-
O STEONECROSIS matic. Earlier studies have reported high rates
of early and late deep sepsis, mechanical loos-
Ischemic necrosis of juxta-articular bone arises
ening of implants, and high reoperation rates
from thrombosis of the endarterial vessels and
(14-18). In these studies, there was a high rate
often leads to painful destruction of the adja-
of postoperative events, averaging 10 percent.
cent joint. The femoral and humeral heads
In more recent reports, patients have been
are most often involved. Osteonecrosis of the
treated with newer surgical techniques, includ-
femoral head may occur in any of the genetic
ing the use of cementless prostheses, and peri-
variants of SCD, but is most prevalent in
operative medical management has received
patients with SCD-SS α-thalassemia (10).
greater emphasis (19-21). These studies report
The mean age at diagnosis varies according
lower rates of infection, fewer risky reoperations,
134
and fewer salvage resection arthroplasties. in patients with SCD and further elevations
Despite these encouraging recent reports, may be seen with infarcts and infection. A
most orthopedists continue to reserve pros- left shift in the differential is usually present
thetic arthroplasty for those patients in whom in infection, but not in infarction. Positive
all other measures have failed to yield relief. blood cultures frequently accompany acute
osteomyelitis, and a positive culture from local
Osteonecrosis of the humeral head occurs bone aspiration is diagnostic. Radiographs
commonly in SCD, especially in patients with rarely reveal bone changes early on, and the
femoral head involvement (22). The prevalence only abnormality may be evidence of soft tis-
of humeral head osteonecrosis on radiographs sue swelling. Radionuclide bone scans usually
was 28 percent in one population of patients do not differentiate infection from infarction
(23); in another study, 48 percent of adults in the acute phase (6), but marrow scans may
with SCD-SS were found to have radiographic be helpful (28).
abnormalities suggestive of healed and remod-
eled osteonecrotic lesions (24). Treatment of Surgical drainage is the primary treatment
symptomatic humeral head osteonecrosis is once the diagnosis is made. Intravenous thera-
similar to that described for femoral head py with antibiotics, chosen according to the
osteonecrosis, but because the forces on the sensitivity of the organism, is carried out for
shoulder joint are smaller, morbidity is less 2 to 6 weeks, depending upon the nature and
pronounced (25). extent of the infection. Protected weight-
bearing and bracing are sometimes required
HEMATOGENOUS INFECTION when there is significant bone destruction.
Chronic undiagnosed infections may involve
O STEOMYELITIS bone extensively, resulting in the formation of
Blood-borne bacteria may proliferate in the a so-called “bone within a bone” radiographic
sinusoids of the marrow spaces where flow appearance, reflecting the presence of a shell of
is sluggish. Previously infarcted bone may periosteal new bone (involucrum) surrounding
provide a protected environment for bacterial a core of dead bone (sequestrum).
infection, and the likelihood of osteomyelitis
may be increased further by a diminished S EPTIC A RTHRITIS
immune response in SCD. The prevalence Septic arthritis, like osteomyelitis, may
of osteomyelitis may be rare or as high as result from hematogenous spread of bacteria
61 percent in sickle cell populations (26,27). or, alternatively, from direct spread from
The predisposition of sickle cell patients to a contiguous focus of osteomyelitis. Severe
salmonella osteomyelitis is well known. pain, tenderness, joint swelling, local warmth,
and marked limitation of motion are charac-
As noted earlier, acute osteomyelitis must teristic findings.
be differentiated from acute bone infarction.
Although acute bone “crisis” is much more Septic arthritis must be differentiated from
common, a high index of suspicion for other types of arthropathy including synovial
osteomyelitis is warranted. Local tenderness, infarction, synovitis associated with adjacent
warmth, and swelling are present in both. osteonecrosis, and nonspecific synovitis, which
Fever is generally high in acute infection. is usually self-limited and rarely progresses to
The white blood cell count is often elevated chondrolysis (29). The use of radiography and
135
Chapter 21: Bones and Joints
136
17. Gunderson C, D’Ambrosia RD, Shaoji H. Total
hip replacement in patients with sickle cell disease.
J Bone Joint Surg Am 1977;59:760-1.
18. Hanker GJ, Nuys V, Amstutz HC. Osteonecrosis
of the hip in sickle cell disease. J Bone Joint Surg Am
1988;70:499-506.
19. Hickman JM, Lachiewicz PF. Results and
complications of total hip arthroplasties in patients
with sickle-cell hemoglobinopathies. J Arthroplasty
1997;12:420-5.
20. Moran MC, Huo MH, Garvin KL, et al. Total hip
arthroplasty in sickle cell hemoglobinopathy. Clin
Orthop 1993;294:140-8.
21. Sanjay BKS, Moreau PG. Bipolar hip replacement
in sickle cell disease. Int Orthop 1996;20:222-6.
22. Wingate J, Schiff CF, Friedman RJ. Osteonecrosis
of the humeral head in sickle cell disease. J South
Orthop Assoc 1996;5:101-7.
23. David HG, Bridgman SA, Davies SC, et al. The
shoulder in sickle-cell disease. J Bone Joint Surg Br
1993;75:538-45.
24. Hernigou P, Allain J, Bachir D, et al. Abnormalities
of the adult shoulder due to sickle cell osteonecrosis
during childhood. Rev Rhum Engl 1996;65:27-32.
25. Chung SM, Ralston EL. Necrosis of the humeral
head associated with sickle cell anemia and its
genetic variants. Clin Orthop 1971;80:105-17.
26. Bennett OM, Namnyak SS. Bone and joint mani-
festations of sickle cell anaemia. J Bone Joint Surg
Br 1990;72:494-9.
27. Mallouh A, Talab Y. Bone and joint infection in
patients with sickle cell disease. J Pediatr Orthop
1985;5:158-62.
28. Rao S, Solomon N, Miller S, et al. Scintigraphic
differentiation of bone infarction from
osteomyelitis in children with sickle cell
disease. J Pediatr 1985;107:685-8.
29. Schumacher HR, Dorwart BB, Bond J, et al.
Chronic synovitis with early cartilage destruction in
sickle cell disease. Ann Rheum Dis 1977;36:413-9.
30. Sidhu P, Rich PM. Sonographic detection and
characterization of musculoskeletal and subcuta-
neous tissue abnormalities in sickle cell disease.
Br J Radiol 1999;72:9-17.
31. Rao VM, Mitchell DG, Steiner RM, et al. Femoral
head avascular necrosis in sickle cell anemia MR
characteristics. Magn Reson Imaging 1988;6:661-7.
32. Rao VM, Sebes JI, Steiner RM, et al. Noninvasive
diagnostic imaging in hemoglobinopathies.
Hematol Oncol Clin North Am 1991;5:517-33.
137
138
L EG U LCERS 22
Between 10 and 20 percent of patients with the neighboring skin appears to be healthy, but
sickle cell disease (SCD) due to a homozygous as the ulcer persists, the surrounding skin shows
hemoglobin S (Hb S) genotype (SCD-SS) hyperpigmentation with loss of subcutaneous
develop painful, disfiguring, and indolent leg fat and hair follicles. These ulcers can be very
ulcers. The ulcers usually appear between ages painful and often are accompanied by reactive
10 and 50 years and are seen more frequently cellulitis and regional (inguinal) adenitis.
in males than in females. Leg ulcers are rare
in individuals with SCD-SC, SCD-S β+-tha- A general physical examination should search
lassemia, and patients under 10 years of age, for other causes of leg ulcers such as varicose
but occur in other hemolytic anemias, such veins, diabetes mellitus, and collagen vascular
as thalassemia major. In the United States, disease. Before therapy, a radiograph of the
SCD is the main hemoglobinopathy that leg is performed to rule out osteomyelitis,
causes leg ulcers. which is rare, even though periosteal thicken-
ing is common.
PATHOLOGIC MECHANISMS
TREATMENT
The etiology of leg ulcers is unclear. In sickle
cell anemia, poorly deformable red cells may The number of well controlled trials for treat-
cause hypoxia and infarction of distal ankle ment of leg ulcers is small, the number of
skin, which can be ameliorated by increased patients in most of them is too low, and there
fetal hemoglobin (1). Trauma, infection, severe have been almost no confirmatory studies.
anemia, and warmer temperatures also may Methods considered to be effective in more
predispose to ulcer formation. Decreased common conditions (burns, venous stasis, and
blood flow after the ulcer has healed often diabetic ulcers) have been used, but evidence
results in recurrence. of efficacy is often absent. In most cases, the
patient’s history has been used as his control
in a condition notorious for unexplained
CLINICAL FINDINGS remissions and relapses. Thus, most evidence
Sickle cell ulcers usually begin as small, elevat- is relatively weak.
ed, crusting sores on the lower third of the
leg, over the medial or lateral malleolus of the There have been many proposed treatments,
ankle. Occasionally, ulcers are seen over the including topical honey or topical granulocyte
tibia or the dorsum of the foot. They can be macrophage-colony stimulating factor (GM-
single or multiple. Some heal rapidly, others CSF), zinc oxide impregnated dressings (Unna
persist for years, and others heal only to recur boots), various types of natural dressings (such
in the area of scarred tissue. In the early phase, as lyophilized pig skin), synthetic matrices (2)
139
Chapter 22: Leg Ulcers
that foster healing, full-thickness skin flaps care; 13 cases in the zinc group improved,
attached with microsurgical techniques, compared to 8 in the placebo group. No sta-
parenteral erythropoietin, and intravenous tistical analysis of the difference was reported.
antithrombin III concentrate. Localized infec- Later, topical antibiotic spray was compared
tion is an invariant feature (3), and proposed to sodium chloride solution in 28 patients (6);
approaches range from acetic acid wet-to-dry 6 of the control patients were taking oral zinc
dressings to gentle surgical debridement to sulfate. For ulcers of the same initial size,
systemic antibiotics. Anemia is, of course, those treated with the topical antibiotic were
a problem; most therapeutic regimens involve 66 percent smaller (p<0.05) after 8 weeks.
transfusion to raise the patient’s hemoglobin A later trial compared Solcoseryl, Duoderm,
concentration, and some more aggressive and conventional therapy (7); patients did not
programs attempt to dilute sickle cells below tolerate Duoderm, and results with Solcoseryl
some arbitrary limit, as in treatment and were not significantly different from conven-
prevention of stroke. tional therapy.
There are no published trials of various types Perhaps the most useful but frustrating con-
of conventional therapy, no reports that assess trolled trial of treatment for ankle ulcers was
the efficacy of transfusion, and no reports that of Wethers and coworkers (2). Fifty-five
that compare skin grafting with conventional patients with chronic nonhealing ulcers were
therapy aside from comparisons of pretreat- randomized to treatment with or without a
ment and posttreatment courses in individual gel composed of an arginine-glycine-aspartate
patients. Particularly when evaluating surgical (RGD) peptide (a binding site for integrins
regimens, it is important to remember that on cell surfaces) and sodium hyaluronate for
ulcers heal with bed rest alone, and that rela- cell attachment. Healing was accelerated in
tively prolonged bed rest is often part of post- patients treated with the RGD peptide matrix
grafting regimens. (p=0.0085), and the gel was as effective in
ulcers of long duration as it was in those of
Any treatment for a chronic condition that shorter duration. Although the study appears
causes many patients to be economically to have been well designed, the manufacturer
disadvantaged must be practical and cost- of the RGD matrix for clinical use is defunct,
effective. Complete bed rest for weeks may and the compound is no longer available.
be effective, but it is not practical; moderately
expensive dressings used for an outpatient
might be cost-effective, but inpatient therapy
SUMMARY
probably is not (4). Issues of cost and practi- Studies to prove the efficacy of treatment of
cality are not considered in the following leg ulcers are difficult to perform. One reason
review of several controlled trials, but they is that healing depends on blood circulation,
underlie any choice of treatment. and the cumulative time of bed rest and leg
elevation is not easily monitored. In addition,
Most of the controlled trials were carried out the variable extent of wound debridement is
by Serjeant and coworkers in Jamaica (5), difficult to quantify, and a short period of
where the frequency of ankle ulcers is very dependency could erase any gains made in
high and their etiology is complex. In the first the previous period. Thus, no treatments
trial, 29 patients received either zinc sulfate or have been proven to work well or consistently.
placebo for 6 months in addition to wound
140
Stated differently, the “strength of evidence” helpful, but topical antibiotics invite growth
that any available treatment except bed rest of treatment-resistant strains and should be
and wound cleansing is really effective is not avoided. In acutely infected patients, vigorous
good, a conclusion similar to that of a recently systemic antibiotic therapy is indicated.
published comprehensive review (3). Periosteal thickening is usually present beneath
the ulcer, but osteomyelitis is unusual.
Since the one apparently effective compound
is unavailable, practice is empirical, rather than After pain and swelling have subsided, the use
based on firm evidence. Outpatient treatment of Unna boots can be helpful. Patients can be
is cheaper than hospitalization and can be taught to change the dressing themselves, and
achieved with intermittent clinic visits for must be instructed to remove it promptly if
supervision. Some patients will be unable to swelling recurs. Patients need to know before
follow medical advice if they cannot stay off a boot is first applied that a shoe may no
their feet because of employment or domestic longer fit when the boot is in place, and a
duties, afford to buy dressings, or follow loose sneaker or sandal may fit more easily.
instructions on how to change dressings. If there is much exudate, the boot may need
In such cases, considerable ingenuity on the to be changed 2 or 3 times a week; as ulcers
part of the physician or nurse may be needed. improve, weekly changes are sufficient. The
The caregiver can provide encouragement ulcer size should be measured at every clinic
and understanding, which can help the patient visit; seeing the dimensions shrink can provide
accept the long duration of treatment. encouragement to the patient.
Some ulcers will not heal. Rigorous studies
RECOMMENDATIONS have not been done to assess the utility of
Ankle ulcers are painful, and the patient transfusions for treating leg ulcers (see chapter
should be given moderately potent analgesics 25, Transfusion, Iron Overload, and Chelation),
such as oxycodone. Bed rest and elevation of but the ulcers seem to correlate with degree
the leg to reduce edema are useful, though not of anemia, which suggests transfusions may
always practical. Wet-to-dry dressings, even help. They should be considered for recalci-
if applied only 2 or 3 times a day, can provide trant or recurrent skin ulcers if conservative
gentle debridement; cooperation of patients therapy fails. If transfusions are used, they
increases when they are permitted to dampen probably should be continued for 3 to 6
the dressing slightly before removal, since it months. There is no evidence that a specified
is a painful process. Oral zinc sulfate (200 mg posttransfusion hemoglobin concentration
3 times a day) probably does no harm if it does or percentage of sickle cells is better than
not cause nausea, and may be worth using. another, but a hemoglobin concentration
above 10 g/dL with Hb S levels less than
Ankle ulcers are always colonized with patho- 50 percent can be achieved.
genic bacteria, usually Pseudomonas aeruginosa,
Staphylococcus aureus, and/or Streptococcus More complete bed rest, systemic antibiotics,
species (8), and sometimes the ulcers are transfusions, and skin grafts sometimes help.
acutely infected. The infection also can be If split thickness or pinch grafts are to be used,
systemic. In the colonized patient, topical preoperative preparation of the ulcer bed is
antiseptics (dressings soaked with dilute acetic probably quite important. Quantitative bacter-
acid, silver sulfadiazine cream, etc.) may be ial cultures of biopsies of the bed and margin
141
Chapter 22: Leg Ulcers
are advocated by some (9) but not all (10) 6. Baum KF, MacFarlane DE, Maude GH, et al.
surgeons as a guide to the time for surgery. Topical antibiotics in chronic sickle cell leg ulcers.
Trans Roy Soc Trop Med Hyg 1987;81:847-9.
Microsurgical attachment of myocutaneous 7. La Grenade L, Thomas PW, Serjeant GR.
flaps may sometimes succeed when all else A randomized trial of solcoseryl and duoderm
fails (11), but this rather heroic procedure in chronic sickle-cell ulcers. West Indian Med J
is not always successful (12). 1993;42:121-3.
8. MacFarlane DE, Baum KF, Serjeant GR.
Because leg ulcers are less common in patients Bacteriology of sickle cell leg ulcers. Trans
with high fetal hemoglobin (Hb F) levels, it Roy Soc Trop Med Hyg 1986;80:553-6.
9. Majewski W, Cybulski Z, Napierala M, et al. The
would seem logical to try to raise Hb F con- value of quantitative bacteriological investigations
centrations. Intravenous arginine butyrate in the monitoring of treatment of ischaemic ulcera-
infusions have been reported to cause rapid tions of lower legs. Int Angiol 1995;14:381-4.
healing of ankle ulcers (13). Hydroxyurea is 10. Steer JA, Papini RPG, Wilson APR, et al.
not a good choice because it appears to cause Quantitative microbiology in the management of
burn patients II. Relationship between bacterial
leg ulcers in patients with myeloproliferative counts obtained by burn wound biopsy culture and
disease (14). surface alginate swab culture, with clinical outcome
following burn surgery and change of dressings.
Burns 1996;22:177-81.
REFERENCES 11. Heckler FR, Dibbell DG, McCraw JB. Successful
1. Koshy M, Entsuah R, Koranda A, et al. Leg ulcers use of muscle flaps or myocutaneous flaps in
in patients with sickle cell disease. Blood patients with sickle cell disease. Plast Reconst Surg
1989;74:1403-8. 1977;59:902-8.
2. Wethers DL, Ramirez GM, Koshy M, et al. 12. Richards RS, Bowen CVA, Glynn MFX.
Accelerated healing of chronic sickle-cell leg Microsurgical free flap transfer in sickle cell
ulcers treated with RGD peptide matrix. disease. Ann Plastic Surg 1992;29:278-81.
Blood 1994;84:1775-9. 13. Sher GD, Olivieri NF. Rapid healing of chronic leg
3. Eckman JR. Leg ulcers in sickle cell disease. ulcers during arginine butyrate therapy in patients
Hem/Onc Clin N Amer 1996;10:1333-44. with sickle cell disease and thalassemia. Blood
4. Cackovic M, Chung C, Bolton LL, et al. Leg 1994;84:2378-80.
ulceration in the sickle cell patient. J Am Coll 14. Best PJ, Daoud MS, Pittelkow MR, et al.
Surg 1998;187:307-9. Hydroxyurea-induced leg ulceration in 14
5. Serjeant GR, Galloway RE, Gueri MC. Oral zinc patients. Ann Intern Med 1998;128:29-32.
sulphate in sickle cell ulcers. Lancet 1970;2:891-2.
142
SPECIAL TOPICS
143
144
C ONTRACEPTION AND P REGNANCY 23
145
Chapter 23: Contraception and Pregnancy
Data are based on a study of 445 pregnancies in 297 women (predominantly in women with SCD-SS) recorded
between 1979 and 1986 at 19 centers participating in the Cooperative Study of Sickle Cell Disease (1).
previous uterine surgery. Adequate nutritional tuberculin skin test, Pap smear, cervical
assessment and the avoidance of precipitating smear, and gonococcus culture and screening
factors that cause painful events should be out- for other sexually transmitted diseases, and
lined with this initial visit as well as all subse- bacterial vaginosis also should be performed.
quent visits. The patient’s prepregnant weight,
height, and optimal weight gain in pregnancy Hepatitis vaccine should be administered
will be recorded. Physical exam should also when appropriate for patients who are nega-
include determination of splenic size. tive for hepatitis B. If asymptomatic bacteri-
uria is found, the patient should receive
Initial comprehensive laboratory studies antibiotics in order to prevent urinary tract
include complete blood count with a reticulo- infection and pyelonephritis.
cyte index, hemoglobin electrophoresis, serum
iron, total iron binding capacity (TIBC), Return visits are recommended 2 weeks after
ferritin levels, liver function tests, urine exami- the initial visit. Low-risk patients are sched-
nation and culture, electrolytes, blood urea uled for monthly visits until the second
nitrogen (BUN), creatinine, blood type and trimester, when they should be seen every
group, red cell antibody screen, and measure- two weeks; in the third trimester, they should
ment of antibodies to hepatitis A, B, and C, be seen every week.
as well as to HIV. Rubella antibody titre,
146
R ECOGNITION OF P REGNANCY-I NDUCED additional study, also retrospective in nature,
H YPERTENSION AND D IABETES concluded that prophylactic transfusions, if
For women with SCD, preeclampsia and initiated at about 20 weeks, may be beneficial
severe anemia have been identified as risk (7). A realistic approach may be to avoid rou-
factors for delivering infants that are small for tine prophylactic transfusions for uncompli-
their gestational age (1). In the study summa- cated pregnancies but to consider initiation
rized in table 1, the incidence of preeclampsia of transfusions for women who have complica-
(defined as blood pressure >140/90 mmHg, tions such as preeclampsia, severe anemia,
proteinuria of >300 mg/2 hours, and patho- or increasing frequency of pain episodes (8).
logic edema), and eclampsia (seizures in addi- Women who have had previous pregnancy
tion to features of preeclampsia) in pregnant losses or who have multiple gestations may
women with SCD was 15 percent (1). The benefit from the early use of transfusions to
mechanisms for the high incidence of hyper- maintain a hemoglobin level above 9 g/dL (8).
tension in this patient population remain Women should receive leukoreduced packed
unclear; multiple factors such as placental red blood cells that have been phenotyped for
ischemia and endothelial injury have been major and minor antigens. If the primary goal
implicated. Other known risk factors for of transfusions is to reduce the percent of sick-
preeclampsia, even in women without SCD, le hemoglobin (Hb S), and the hemoglobin
are nulliparity, a history of renal disease or level is high, one approach is to remove 500
hypertension, multiple gestation, and diabetes. mL of whole blood and transfuse 2 units of
Pregnant women with SCD should be packed red blood cells. This procedure can
observed closely if blood pressure rises above be done manually or by automated methods
125/75 mmHg, if the systolic blood pressure to obtain a posttransfusion hemoglobin level
increases by 30 mmHg, or diastolic blood ranging between 10 and 11 g/dL and to reduce
pressure increases by 15 mmHg, in association the percentage of Hb S to between 30 and 40
with edema and proteinuria in the second percent of the total hemoglobin concentration.
trimester. Preeclampsia, which requires
frequent monitoring, can be treated with S ICKLE C ELL -R ELATED E VENTS
bed rest at home or in the hospital, if needed. D URING P REGNANCY
If preeclampsia is worsening, delivery of the The clinical problems of SCD, such as new-
fetus may be required if the gestational age is onset seizures, hepatopathy, acute anemia, and
greater than 32 weeks. Expedited delivery is painful episodes should be evaluated and man-
recommended for uncontrolled hypertension. aged for pregnant women in the same fashion
as for women who are not pregnant.
I NDICATIONS FOR B LOOD
T RANSFUSION D URING P REGNANCY The frequency of previous acute vaso-occlusive
painful events is usually predictive of the events
The role of prophylactic transfusions in preg- during pregnancy, although some patients
nancy is controversial. One randomized trial may experience an increased frequency of
(5) and a retrospective study (6) concluded pain episodes (9,10). Patients with a chronic
that routine prophylactic transfusions from pain syndrome should be identified; they
the onset of pregnancy do not alter the out- may benefit from an individualized care plan.
come for the fetus or mother. However, one
147
Chapter 23: Contraception and Pregnancy
148
A NESTHESIA AND S URGERY 24
Patients with sickle cell disease (SCD) may study of aggressive (exchange) versus simple
require surgery for complications such as asep- transfusion in SCD-SS patients, with both
tic necrosis or cholelithiasis, or for conditions treatments performed to achieve a hemoglobin
unrelated to SCD. Multiple authors (1-5) have level of 10 g/dL. The authors found no differ-
reported that the risk of morbidity and mor- ence in complication rates. The protocol speci-
tality in these patients is greater than in the fied a minimum of “8 hours of preoperative
general population because of anemia, the hydration, with intraoperative monitoring
propensity for red blood cells to sickle and of temperature, blood pressure, electrocardio-
obstruct the microvasculature, the presence of graphic features, and oxygenation.” Postoper-
chronic organ damage in some patients, the ative care included the administration of
risks of hypoxia, and the effects of asplenia. oxygen, intravenous hydration, monitoring
Risks have been said to be greater for patients with pulse oximetry, and respiratory therapy.
with SCD-SS or SCD-S βo-thalassemia. These guidelines are now generally accepted
Various suggestions for risk reduction have as the standard of perioperative care.
been made, including correction of anemia by
simple or exchange transfusion, attention to Koshy et al. (8), reporting for the Cooperative
hydration and oxygenation, postoperative res- Study of Sickle Cell Disease on 717 patients
piratory care, and selection of less aggressive or with SCD-SS, SCD-SC, SCD-S βo-thalassemia,
extensive surgical procedures. It also has been and SCD-S β+-thalassemia, reported no deaths
suggested (6) that patients undergoing minor in patients under the age of 14 (42 percent
surgical procedures (excluding tonsillectomy of the population was under the age of 20).
and adenoidectomy) may not require transfu- This nonrandomized study also showed that
sion if special attention is paid to oxygenation postoperative complications increased with
and acid-base status. Several recent reports age, with an “estimated odds ratio 1.3 times
of larger series have begun to quantify the increased risk of postoperative complications
magnitude of risks and provide some guidance per ten years of age, p<0.0001.” Furthermore,
for management (7-9). SCD-related complications were more com-
mon in those who received regional compared
with general anesthesia and preoperative trans-
SUMMARY OF THE fusion resulted in a lower complication rate for
STATE OF THE ART those undergoing low-risk surgery (p=0.006).
Two reports published in 1995 and one in
Preoperative transfusions were beneficial for
1998 have added greatly to our understanding
SCD-SC patients undergoing any risk level
of the magnitude of risk and the management
of surgery (p=0.009) (8). Neumayer et al. (9),
of surgery in SCD patients. Vichinsky et al.
reporting on SCD-SC patients in the same
(7) reported on a multicenter randomized
149
Chapter 24: Anesthesia and Surgery
150
Table 1. Outcome of Surgery in Patients With Sickle Cell Disease Who Received Perioperative Transfusions
Ref. Yrs Hb Ages No. of Surgical ACS Pain CVA Infection Death
Procedures /Renal /Fever
Koshy
et al. (8) 1978-88 SS* 0-59 650 2.2 3.5 0.15 4.3 0.46
Vichinsky
et al. (7) 1988-93 SS* All 604 10.0 5.0 >2.0 6.0 >0.5
Koshy
et al. (8) 1978-88 SC 0-62 81 0.0 2.5 0.0 20.0 0.0
Neumayr
et al. (9) 1988-93 SC** All 92 5.0 3.0 not 9.0 2.0**
reported
151
152
T RANSFUSION , I RON O VERLOAD , AND C HELATION 25
153
Chapter 25: Transfusion, Iron Overload, and Chelation
154
CONTROVERSIAL INDICATIONS ■ Infections.
Transfusions are sometimes suggested for con- ■ Minor surgery that does not require
ditions in which efficacy is unproven, but may prolonged general anesthesia (e.g.,
be considered under extreme circumstances myringotomy).
as described in chapter 20, Priapism; chapter ■ Aseptic necrosis of the hip or shoulder
22, Leg Ulcers; and chapter 23, Contraception (except when surgery is required).
and Pregnancy.
■ Uncomplicated pregnancies.
155
Chapter 25: Transfusion, Iron Overload, and Chelation
and recipient is a major factor (7). Limited chronic iron burden (6,10). The volume of
matching for E, C, and Kell antigens is usually blood needed can be calculated from the
performed, unless patients have antibodies (8). patient’s weight, initial hematocrit, target
hematocrit, and desired percentage of Hb A.
Prestorage leukodepletion of red cells is An adult exchange usually takes about 6 to 8
standard practice to reduce febrile reactions, units, and children require about 50 to 60
platelet refractoriness, infections, and cytokine- mL/kg of blood. Whole blood or packed cells
induced complications (9). Washed red cells reconstituted to hematocrits of 30 to 40 per-
should be reserved for patients who had aller- cent are used to conserve units, but exchanges
gic reactions after prior transfusions. Irradiated will take longer than with packed cells alone.
blood should be considered in patients likely Blood can be removed from the adult patient
to be candidates for bone marrow transplanta- in 500 mL aliquots, followed by infusion of
tion, but relatives should not be used as blood 500 mL of reconstituted blood, repeated for
donors for children who are such candidates. 6 to 8 cycles, or another schedule can be used.
The use of autologous blood transfusions in The following is an example:
SCD should be avoided. Red cell substitutes
are experimental and generally not indicated. Step 1. Bleed one unit (500 mL) of blood
from patient, infuse 500 mL of saline.
TRANSFUSION METHODS Step 2. Bleed a second unit from the patient,
Simple transfusions can be used for acute infuse two units of blood.
anemia or hypovolemia. Packed red cells
Step 3. Repeat steps 1 and 2; if the patient has
are preferred, except when marked volume
expansion is needed. a large red blood cell mass, repeat once more.
For children, smaller, more precise volumes
C HRONIC S IMPLE T RANSFUSION should be calculated and used in order not
Once a sufficient level of transfused normal to remove or transfuse too much blood at one
cells [60-70 percent normal hemoglobin (Hb time. In some patients, whole blood can be
A)] is achieved, simple transfusions every 2 to taken from one arm at the same time that
4 weeks may maintain this proportion of nor- donor cells are transfused into the other.
mal cells for years. The level of Hb A must be For adults, this procedure can be performed
monitored regularly by quantitative hemoglo- in 500 mL units, whereas in children, smaller
bin electrophoresis. Significant variation in amounts are practical. Automated erythrocyta-
transfusion requirements for each patient is pheresis is safe and is being used fairly often
common, but the pretransfusion hematocrit because it prevents iron overload, despite
should be between 25 and 30 percent. The concerns about increased red cell utilization,
posttransfusion hematocrit should be 36 per- venous access, and increased cost. When
cent or less to prevent hyperviscosity, especially exchange transfusion is performed, the final
for initial transfusions. hemoglobin value should not exceed 10 to 12
g/dL to avoid hyperviscosity, and the percent-
E XCHANGE T RANSFUSION age of Hb A should meet the goals of therapy.
Exchange transfusion is used to remove sickle
cells and replace them with normal red cells
without increasing whole blood viscosity or
156
TRANSFUSION COMPLICATIONS A CUTE H EMOLYTIC
T RANSFUSION R EACTIONS
Transfusion complications, such as
alloimmunization, hyperviscosity, and relative The causes of acute hemolytic transfusion
hypertension, may be higher for sickle cell reactions in sickle cell patients are not differ-
patients than for members of the general ent from those in other patients. Major
population (1). Transfusions have precipitated hemolytic reactions occur mainly with major
pain episodes, strokes, and acute pulmonary blood group (ABO) mismatches and must be
insufficiency. treated aggressively to maintain blood pressure
and glomerular filtration. Most reactions can
be prevented by avoiding clerical and sample
V OLUME O VERLOAD
identification errors in the cross-matching and
This condition occurs when a large volume transfer of units from the donor site to the
of blood is transfused too quickly. Congestive patient. Minor hemolytic reactions occur
heart failure and pulmonary edema tend to when the amount of antibody in the patient’s
occur in patients who have cardiac dysfunc- serum is limiting and causes the transfused
tion or poor cardiac reserve. Administration blood to disappear over several days, followed
of intravenous furosemide, partial removal by hyperbilirubinemia. The hematocrit
of red cell supernatant fluid before transfusion, decreases, but no further treatment is needed
and a slow transfusion rate can help to prevent unless the hematocrit falls greatly.
this problem.
Any of these reactions, particularly the delayed
A LLOIMMUNIZATION AND D ELAYED variety, can initiate a pain episode in patients
H EMOLYTIC T RANSFUSION R EACTIONS with SCD. In all cases, a patient’s blood
should be examined very carefully by
The incidence of alloimmunization to red
immunohematologists to document the anti-
blood cell antigens in transfused patients with
body or antibodies responsible for the reac-
sickle cell anemia is approximately 20 to 25
tion. The patient must be told of the compli-
percent, which is greater than in the general
cation and be given a card describing the anti-
population (7). This condition causes difficulty
bodies found.
in obtaining compatible blood and results in
a high incidence of delayed hemolytic transfu- Alloimmunization and hemolytic transfusion
sion reactions (12,13). Reactions occur 5 reactions can be reduced by:
to 20 days after transfusion and are due to
antibodies undetectable at the time of com- ■ Acquiring and maintaining adequate
patibility testing. More than 30 percent of records of previous transfusions and
antibodies disappear with time, but recipients complications arising from them.
can mount anamnestic responses to further ■ Limiting the number of transfusions
stimulation by transfusion. Delayed hemolytic administered.
transfusion reactions may cause severe anemia,
painful events, and even death. ■ Screening for newly acquired antibodies
1 to 2 months after each transfusion
to detect transient antibodies that cause
a subsequent delayed reaction.
157
Chapter 25: Transfusion, Iron Overload, and Chelation
■ Diminishing the opportunities for alloim- antibody and requires special blood bank tests
munization because of a mismatch in to find the least incompatible units for transfu-
the antigens of donors and patients (14). sion. Although transfusion may be necessary in
This may be accomplished by: some patients, an alternative course may be to
avoid transfusion and to administer corticos-
– Typing the patient before transfusion
teroids, large doses of erythropoietin, and pos-
(if this has not already been done) for Rh
sibly intravenous immune globulin.
and Kell blood group antigens to avoid
transfusion of cells with these antigens
(particularly E, C, and Kell) if the patient A LLOANTIBODIES TO W HITE C ELLS ,
lacks them. P LATELETS , AND S ERUM P ROTEINS
Patients who are transfused may become
– More extensive antigen matching in
alloimmunized to antigens present on leuko-
patients who are already alloimmunized.
cytes or platelets but absent from red blood
– Increasing the numbers of African- cells. Such antibodies may cause febrile reac-
American blood donors because of the tions that can be prevented by the removal
similarity of their blood cell antigenic of leukocytes by filtration or washing. These
phenotypes. Family members and commu- antibodies, and those for serum proteins,
nity groups can assist in accomplishing can cause allergic reactions that can be pre-
this objective. vented by prophylaxis with an antihistamine
Patients alloimmunized to one red cell antigen (Benadryl®), leukodepletion, or removal
are more likely to become alloimmunized to of plasma.
others. Transfusions should be given only for
clearcut indications, and care should be taken I NFECTION
in the selection of units of blood. Patients Hepatitis and other transfusion-transmitted
should be counseled to advise any new physi- viral diseases in blood occur with the same
cian of their history of alloimmunization and frequency in sickle cell patients as in other
to carry a card or identification bracelet that patients who receive transfusions. The conse-
lists their red blood cell phenotype and any quences may be more severe with concurrent
identified antibodies. SCD, however. Patients who have received
multiple transfusions should be monitored
A UTOIMMUNE A NEMIA F OLLOWING serially for hepatitis C and other infections
A LLOSENSITIZATION (15,16). Parvovirus occurs in 1 in every 40,000
In a highly alloimmunized patient, a syndrome units, and is associated with acute anemic
of autoimmune hemolytic anemia may occur. events and multiple sickle cell complications.
In this case, the patient may become more Transfusion-induced bacterial infections are
anemic than before transfusion, and the direct uncommon. Repeatedly transfused hemoglo-
antiglobulin (Coombs’) test remains positive binopathy patients are particularly vulnerable
even after the incompatible transfused cells to Yersinia entercolitica and bacteremia from
have been destroyed. Autoimmune anemia poor skin cleansing before phlebotomy. All
occurs because the recipient produces antibod- patients who develop fever after transfusion
ies against self-antigens, which may persist up need to be assessed immediately for potential
to 2 to 3 months before disappearing. Further bacterial infection.
transfusion is complicated by the autoimmune
158
IRON OVERLOAD Exchange transfusions and chelation therapy
AND CHELATION are the only two accepted methods to manage
transfusion-related iron overload. Phlebotomy
Iron overload in sickle cell patients is often will remove iron in abnormal red cells, which
undetected or not treated. In contrast to tha- are replaced by normal red cells. The initial
lassemia patients, most patients are iron over- dose of the chelator deferoxamine (Desferal™)
loaded because of intermittent transfusions is 25 mg/kg per day, over 8 hours subcuta-
throughout their lives. There is no evidence neously (17); dose and duration of infusion
that SCD patients are spared the fatal conse- can be increased, depending on patient age and
quences of iron overload. Therefore, a compre- iron load. Supplementation with vitamin C,
hensive program to monitor and treat iron 100 to 200 mg per day, may help to increase
overload is necessary. excretion, especially in those who are vitamin
There is no simple test to determine iron C deficient. New methods of delivery, includ-
overload. Measurement of serial serum fer- ing twice-daily subcutaneous injections and
ritins may help but can be unreliable because intravenous home parenteral access, are being
ferritin is an acute phase reactant and values studied. Deferoxamine is generally safe, but has
are altered by liver disease, inflammation, been associated with ototoxicity, eye toxicity,
and vitamin C stores. Liver biopsy is the most allergic reactions, growth failure, unusual infec-
accurate test for iron overload and can be tions, and pulmonary hypersensitivity; there-
performed safely by an experienced physician. fore, patients should be monitored annually for
The sample should be of adequate size and growth and eye toxicity. Iron chelation always
sent to a reference lab familiar with liver iron should be discontinued during an acute infec-
quantitation. Some programs recommend liver tion. Other chelators are experimental and are
biopsies at the start of chelation and every 2 not recommended at this time.
years thereafter. As a noninvasive method, the
superconducting quantum interference device REFERENCES
(SQUID) is acceptable for quantitating liver 1. Ohene-Frempong K. Indications for red cell
iron (10). There is progress with MRI and transfusion in sickle cell disease. Sem Hematol
CT, but their clinical use is unproven. The 2001;38(Suppl 1):5-13.
2. Hassell KL, Eckman JR, Lane PA. Acute multior-
best indication to begin chelation therapy is
gan failure syndrome: a potentially catastrophic
a rise in liver iron stores to 7 mg/g dry weight. complication of severe sickle cell pain episodes.
Alternatively, cumulative transfusions of 120 Am J Med 1994;96:155-62.
cc of pure red cells per kilogram of body 3. Vichinsky EP, Haberkern CM, Neumayr L, et al.
weight can be used (5). Serum ferritin levels A comparison of conservative and aggressive trans-
fusion regimens in the perioperative management
above 1,000 ng/mL in the steady state are of sickle cell disease. The Preoperative Transfusion
helpful, but the risk of under- and over- in Sickle Cell Disease Study Group. N Engl J Med
treatment occurs. All iron-overloaded patients 1995;333:206-13.
should be followed at comprehensive sickle 4. Styles LA, Vichinsky E. Effects of a long-term
cell centers that can monitor organ toxicity transfusion regimen on sickle cell-related illnesses.
J Pediatr 1994;125:909-11.
and provide ongoing education and support. 5. Vichinsky E. Guest editor. Consensus document
for transfusion-related iron overloads. Sem Hematol
2001;38(Suppl 1):2-4.
159
Chapter 25: Transfusion, Iron Overload, and Chelation
6. Singer ST, Quirolo K, Nishi K, et al. Erythrocyta- 12. King KE, Shirey RS, Lankiewicz MW, et al.
pheresis for chronically transfused children with Delayed hemolytic transfusion reactions in sickle
sickle cell disease: an effective method for main- cell disease: simultaneous destruction of recipients’
taining a low hemoglobin S level and reducing iron red cells. Transfusion 1997;37:376-81.
overload. J Clin Apheresis 1999;14:122-5. 13. Petz LD, Calhoun L, Shulman IA, et al. The sickle
7. Rosse WF, Gallagher D, Kinney TR, et al. cell hemolytic transfusion reaction syndrome.
Transfusion and alloimmunization in sickle cell Transfusion 1997;37:382-92.
disease. The Cooperative Study of Sickle Cell 14. Tahhan HR, Holbrook CT, Braddy LR, et al.
Disease. Blood 1990;76:1431-7. Antigen-matched donor blood in the transfusion
8. Sosler SD, Jilly BJ, Saporito C, et al. A simple, prac- management of patients with sickle cell disease.
tical model for reducing alloimmunization Transfusion 1994;34:562-9.
in patients with sickle cell disease. Am J Hematol 15. Hasan MF, Marsh F, Posner G, et al. Chronic
1993;43:103-6 hepatitis C in patients with sickle cell disease.
9. Brand A. Passenger leukocytes, cytokines, and trans- Am J Gastroenterol 1996;91:1204-6.
fusion reactions. N Engl J Med 1994;331:670-1. 16. Schreiber GB, Busch MP, Kleinman SH, et al.
10. Brittenham GW, Cohen AR, McLaren CE, et al. The risk of transfusion-transmitted viral infections.
Hepatic iron stores and plasma ferritin concentra- The Retrovirus Epidemiology Donor Study.
tion in patients with sickle cell anemia and tha- N Engl J Med 1996;334:1685-90.
lassemia major. Am J Hematol 1993;42:81-5. 17. Silliman CC, Peterson VM, Mellman DL, et al.
11. Pegelow CH, Colangelo L, Steinberg M, et al. Iron chelation by desferrioxamine in sickle cell
Natural history of blood pressure in sickle cell patients with severe transfusion-induced hemo-
disease: risks for stroke and death associated with siderosis: a randomized, double-blind study of
relative hypertension in sickle cell anemia. Am J the dose-response relationship. J Lab Clin Med
Med 1997;102:171-7. 1993;122:48-54.
160
F ETAL H EMOGLOBIN I NDUCTION 26
161
Chapter 26: Fetal Hemoglobin Induction
162
Twenty-nine infants, with a median age of less than 1 year of drug exposure, and 1 in
14 months, were treated with hydroxyurea at a patient who never received hydroxyurea.
a dose of 20 mg/kg for 2 years, escalating to New adverse effects have not been found.
30 mg/kg thereafter. After 2 years, all parents Pulmonary disease was the most common
elected to continue treatment, and 19 children cause of death.
completed a median treatment period of 148
weeks. Changes in hemoglobin concentration, We do not know whether hydroxyurea will
MCV, Hb F, and leukocyte count were com- prevent or reverse organ damage (4). After 1
pared with the changes observed in a historical year of treatment, splenic function in a group
control group. Hemoglobin increased from of children who averaged 12 years of age did
8.5 to 8.9 g/dL (predicted, 8.2 g/dL), MCV not change. Of 10 patients with sickle cell
increased from 82 to 93 fL (predicted, 88 fL), anemia who received hydroxyurea for 21
and Hb F fell from 21.3 to 19.6 percent months and had an increase in Hb F from
(predicted, 12.3 percent). Functional asplenia 8 to 17 percent, only 1 recovered splenic
was found in 24 percent of patients before function. In another prospective study, some
treatment and in 47 percent after treatment patients had partial return of splenic function,
(predicted, 80 percent). Nine patients were possibly related to Hb F levels. Splenic regen-
dropped from the study because of poor eration was reported in 2 adults with sickle
compliance or parental refusal to continue; cell anemia who had Hb F levels of about
one child died of splenic sequestration. One 30 percent after hydroxyurea treatment.
patient had a transient ischemic attack, one Hydroxyurea does not appear to prevent
had a mild stroke, eight had episodes of acute the cerebrovascular complications of SCD.
chest syndrome, two had splenic sequestration, However, in children ages 5 to 15 years with-
and three had episodes of sepsis. Growth was out a history of overt CVA and with more
normal. Despite moderate levels of Hb F, than three painful episodes yearly, hydroxyurea
acute complications of sickle cell anemia still maintained cognitive performance comparable
occurred in these very young patients. Perhaps to sibling controls. Performance was found
functional asplenia is delayed by treatment, to deteriorate in untreated patients.
but risks of splenic sequestration and other
complications may persist.
A DVERSE E VENTS
Long-term effects of hydroxyurea are still
M ORTALITY AND M ORBIDITY
poorly defined. The multicenter trial had
The best data on the complications of hydroxy- power to detect only 100-fold increases in the
urea treatment and its effect on morbidity and incidence of leukemia or cancer. Hydroxyurea
mortality come from the followup of patients has been given to 64 children with cyanotic
in the Multicenter Study of Hydroxyurea in congenital heart disease for a mean duration
Sickle Cell Disease. After 8 years of followup of more than 5 years without any reports of
the data strongly suggest that treatment of malignancies. In myeloproliferative disorders,
moderately-to-severely affected adults with however, the drug may have helped to trans-
sickle cell anemia with hydroxyurea is associat- form premalignant conditions into acute
ed with reduced mortality. Twelve strokes have leukemia in about 10 percent of patients.
occured, 9 in patients with more than 1 year There are at least three patients with SCD
of hydroxyurea treatment, 2 in patients with treated with hydroxyurea who developed
163
Chapter 26: Fetal Hemoglobin Induction
164
Table 1. Hydroxyurea in Sickle Cell Anemia
Baseline Evaluation
Blood counts, red cell indices, percent Hb F, serum chemistries, pregnancy test, willingness to follow
treatment recommendations, nonparticipation in a chronic transfusion program.
Initiation of Treatment
Hydroxyurea, 10-15 mg/kg/day in a single daily dose for 6-8 weeks; CBC every 2 weeks; percent Hb F
every 6-8 weeks; serum chemistries every 2-4 weeks.
Continuation of Treatment
If no major toxicity, escalate dose every 6-8 weeks until the desired endpoint is reached.
Treatment Endpoints
Less pain, increase in Hb F to 15-20 percent, increased hemoglobin level if severely anemic,
improved well-being, acceptable myelotoxicity.
Cautions
Special caution should be taken in patients with compromised renal or hepatic function. Contraception
should be practiced by both men and women since hydroxyurea is a teratogen and its effects during
pregnancy are unknown. After a stable, nontoxic dose of hydroxyurea is reached, blood counts may be
done at 4-8 week intervals. Granulocytes should be ≥ 2,500/µL, platelets ≥ 95,000/µL.
165
166
H EMATOPOIETIC C ELL T RANSPLANTATION 27
Hematopoietic cell transplantation (HCT) nation of SCD. In the decade and longer that
has curative potential for a broad spectrum of followed, there was considerable discussion
genetic disorders, including sickle cell disease about who should be considered and when
(SCD) (1). The goal is to eliminate the sickle they should be referred for transplantation
erythrocyte and its cellular progenitors and (13-15). The first limited series of patients
replace them with donor hematopoietic who underwent transplantation because
pluripotent stem cells that give rise to erythro- they had SCD comprised a group of families
cytes that express no sickle hemoglobin (Hb from Africa living at the time in Belgium (4).
S), thereby reducing Hb S levels to those asso- Based in part on the very good outcome
ciated with the trait condition. The possibility experienced by these initial patients, several
of preventing serious complications from SCD, multicenter phase II studies for children with
which can cause extensive morbidity and early symptomatic SCD were conducted in North
death, is balanced by the risk of severe adverse America and Europe (7,9). It was reasoned
events after transplantation. The first case that children might have a superior outcome
reports of successful outcomes after transplan- compared to adult patients because of chil-
tation have been extended by several multicen- dren’s lower risk of transplant-related compli-
ter investigations (table 1). To date, nearly all cations such as graft-versus-host disease
transplants have utilized HLA-identical sibling (GvHD) and because of a presumed lower
donors, which has limited the number of eligi- burden of sickle-related organ damage. The
ble sickle cell patients. Thus, there are no ran- inclusion and exclusion criteria for enrollment
domized, controlled studies that support this adapted from one multicenter study (7) are
therapeutic option for SCD. However, with summarized in table 2.
the development of new therapies that prevent
and treat graft-versus-host and host-versus-graft RESULTS OF HCT FROM HLA-
reactions, it is likely that transplantation will IDENTICAL SIBLING DONORS
take on added importance for selected patients
with SCD. Approximately 150 patients have undergone
HCT from HLA-identical siblings worldwide
(9,10,16,17). The combined results of three
INDICATIONS FOR HCT
studies have demonstrated that transplant-
The first published reports of HCT for SCD related mortality is about 5 percent, and that
involved patients who had other hematological more than 90 percent of patients survive.
or genetic disorders that were the primary Approximately 85 percent survive free from
indication for transplantation (2,3). From this SCD after transplantation with a period of
initial experience it was learned that engraft- followup that extends to 11 years, but about
ment of donor cells was associated with elimi- 10 percent of patients experience recurrence
167
Chapter 27: Hematopoietic Cell Transplantation
Inclusions
Patients < 16 years of age with sickle cell anemia (SCD-SS or SCD-S βo-thalassemia)
One or more of the following complications:
Stroke or central nervous system (CNS) event lasting longer than 24 hours
Impaired neuropsychologic function and abnormal cerebral magnetic resonance imaging (MRI) scan
Recurrent acute chest syndrome or Stage I or II sickle lung disease
Recurrent vaso-occlusive painful episodes
Sickle nephropathy [glomular filtration rate (GFR) 30-50 percent of predicted normal]
Osteonecrosis of multiple joints
Exclusions
Patients >16 years of age
HLA-non-identical donor
One or more of the following conditions:
Lansky performance score <70 percent
Acute hepatitis or biopsy evidence of cirrhosis
Renal impairment (GFR <30 percent predicted normal)
Stage III or IV sickle lung disease
168
of SCD. Neurologic complications, such as This advantage is balanced by somewhat
seizures, occurred frequently after transplanta- lengthier periods for hematopoietic engraft-
tion, leading to the development of preventive ment and perhaps a higher rate of graft rejec-
measures (18-20). tion, especially when nonidentical donors
are used and when cell doses are low (26).
Among patients who had stable engraftment Strategies for transplantation from unrelated
of donor cells, there were no subsequent sickle volunteer stem cell donors will need to over-
cell-related clinical events, and there was stabi- come histocompatibility barriers associated
lization of preexisting sickle cell-related organ with higher rates of GvHD and graft rejec-
damage (9,10,21). There was also recovery tion. There are no established protocols for
of splenic function (22). Some patients transplantation from alternative sources of
developed mixed donor-host hematopoietic stem cells; however, pilot clinical investiga-
chimerism after transplantation that was stable tions are being designed.
(23). Of interest, these patients also had no
symptoms from SCD.
HCT FOR ADULTS
About 5 percent of patients developed Grade There is very limited information about the
III acute or extensive chronic GvHD; the outcome after HCT among adult patients.
others had no graft-vs-host response or mild However, they might have a higher risk of
GvHD. Primary and secondary amenorrhea dying due, in part, to the increased frequency
were common among females after transplan- of GvHD in adults (27). Compared to
tation and it is likely that most patients will younger patients with β-thalassemia major,
be infertile (9,10). The risk of secondary can- adult patients had an increased risk of dying
cers after HCT remains uncertain, but it is after HLA-identical bone marrow transplanta-
estimated to be less than 5 percent (24). Linear tion (28), but ethnic factors might have con-
growth was normal or accelerated after trans- tributed to the risk. The use of nonmyeloabla-
plantation in the majority of patients (9,10). tive preparation before HCT may lower the
risk of complications (29). The intent is to
ALTERNATIVE SOURCES establish stable donor-host hematopoietic
OF STEM CELLS chimerism after transplantation, which might
Umbilical cord blood (UCB) and hematopoi- provide a significant clinical benefit. If suc-
etic cells from volunteer donors represent cessful, the nonmyeloablative approach might
alternative sources of hematopoietic stem cells improve the safety profile of HCT for older
that might increase the number of donors individuals who have advanced organ damage
for SCD patients. Successful hematological from SCD. Several investigations have been
reconstitution has been observed after UCB initiated to test this hypothesis.
transplantation for SCD (11). However, there
are no published reports of transplantation SUMMARY OF THE
to treat SCD using UCB from volunteer, STATE OF THE ART
unrelated donors. Currently, HCT is the only therapy for
There is evidence to suggest that the incidence SCD that has curative potential. The results
of GvHD is lower after UCB transplantation of transplantation are best when performed
than after bone marrow transplantation (25). in children with a sibling donor who is
169
Chapter 27: Hematopoietic Cell Transplantation
170
15. Platt OS, Guinan EC. Bone marrow transplanta- 27. Sullivan KM, Agura E, Anasetti C, et al.
tion in sickle cell anemia—the dilemma of choice. Chronic graft-versus-host disease and other late
N Engl J Med 1996;335:426-8. complications of bone marrow transplantation.
16. Giardini C, Galimberti M, Lucarelli G, et al. Sem Hematol 1991;28:250-9.
Bone marrow transplantation in sickle-cell 28. Lucarelli G, Clift RA, Galimberti M, et al.
anemia in Pesaro. Bone Marrow Transplant Bone marrow transplantation in adult thalassemic
1993;12(Suppl 1):122-3. patients. Blood 1999;93:1164-7.
17. Bernaudin F. Resultats et indications actuelles 29. Storb R, Yu C, Sandmaier BM, et al. Mixed
de l’allogreffe de moelle dans la drepanocytose. hematopoietic chimerism after marrow allografts.
Path Biolog 1999;47:59-64. Transplantation in the ambulatory care setting.
18. Walters MC, Sullivan KM, Bernaudin F, et al. Ann N York Acad Sci 1999;872:372-6.
Neurologic complications after allogeneic marrow 30. Lubin BH, Eraklis M, Apicelli G. Umbilical cord
transplantation for sickle cell anemia. Blood blood banking. Advan Pediatr 1999;46:383-408.
1995;85:879-84.
19. Ferster A, Christophe C, Dan B, et al. Neurologic
complications after bone marrow transplantation
for sickle cell anemia. Blood 1995;86:408-9.
20. Abboud MR, Jackson SM, Barredo J, et al.
Neurologic complications following bone marrow
transplantation for sickle cell disease. Bone Marrow
Transplant 1996;17:405-7.
21. Hernigou P, Bernaudin F, Reinert P, et al. Bone-
marrow transplantation in sickle-cell disease.
Effect on osteonecrosis: a case report with a four-
year follow-up. J Bone Joint Surg 1997;79:1726-30.
22. Ferster A, Bujan W, Corazza F, et al. Bone marrow
transplantation corrects the splenic reticuloen-
dothelial dysfunction in sickle cell anemia. Blood
1993;81:1102-5.
23. Sullivan K, Walters MC, Patience M, et al.
Collaborative study of marrow transplantation for
sickle cell disease: aspects specific for transplanta-
tion of hemoglobin disorders. Bone Marrow
Transplant 1997;19(Suppl 2):102-5.
24. Curtis RE, Rowlings PA, Deeg HJ, et al. Solid
cancers after bone marrow transplantation.
N Engl J Med 1997;336:897-904.
25. Rocha V, Chastang C, Souillet G, et al. Related
cord blood transplants: the Eurocord experience
from 78 transplants. Eurocord Transplant Group.
Bone Marrow Transplant 1998;21(Suppl 3):S59-62.
26. Gluckman E, Rocha V, Boyer-Chammard A,
et al. Outcome of cord-blood transplantation
from related and unrelated donors. Eurocord
Transplant Group and the European Blood and
Marrow Transplantation Group. N Engl J Med
1997;337:373-81.
171
172
G ENETIC M ODULATION OF P HENOTYPE 28
BY E PISTATIC G ENES
A unique mutation is responsible for sickle gene cluster haplotypes, chromosome 6 locus),
hemoglobin (Hb S), but sickle cell disease and 2) the copresence of α-thalassemia. These
(SCD) is clinically pleiotropic and can be known factors explain only a small fraction
considered a multigene disease. Polymerization of the diversity of sickle cell anemia, however.
of Hb S can injure red cells and cause a cas- Other epistatic genes must exist, and based
cade of pleiotropic effects that determines the on our knowledge of the pathophysiology of
clinical picture (1,2). Some patients are always SCD, candidate genes have been suggested (3).
sick, and others infrequently ill. What is the
basis of this variability? An environmental FETAL HEMOGLOBIN
effect on the course of SCD is dramatically MODULATION OF
apparent in tropical Africa. Provided there is
SICKLE CELL ANEMIA
good access to medical care, survival to adult-
hood and a decent quality of life is possible.
T HE β-G LOBIN G ENE C LUSTER
Still, SCD in Africa remains a childhood
AND G LOBIN G ENE S WITCHING
disease since premature death, often from
malaria, is common. Hb F levels in sickle cell anemia vary over two
orders of magnitude. Initially only very high
Most of the pleiotropic effects result from levels of Hb F were considered capable of
the activity of other genes—which also may influencing the phenotype of sickle cell ane-
be polymorphic—that differ among patients. mia (4,5), but any increment in Hb F appears
These epistatic (or modifier) genes may to be clinically and perhaps therapeutically
account for the interindividual variation that important (6).
characterizes SCD. Another source of genetic
variation in SCD derives from the multicen- Hemoglobin gene switching is the process of
tric origin of the Hb S gene. Because it arose sequential globin gene activation and inactiva-
more than once, the gene had the opportunity tion. It involves complex interactions of stage-
to interact with different (polymorphic) linked specific transcription factors, chromosomal
genes, particularly the two γ-globin genes that gene order, gene proximity to the β-globin
ameliorate SCD through expression of fetal locus control region (LCR), cis-acting sequences
hemoglobin (Hb F). that positively and negatively regulate tran-
scription, and erythroid-specific and ubiqui-
The two best understood genetic factors that tous trans-acting factors (7). By interacting
influence the clinical expression of the Hb S with promoters of the β-like globin genes,
mutation are 1) those linked to the synthesis the LCR plays a critical role in gene expression;
of fetal hemoglobin (Hb F) (gender, β-globin polymorphisms in some of their sequences
173
Chapter 28: Genetic Modulation of Phenotype by Epistatic Genes
are considered vital elements of γ-globin gene Most of the detailed and larger studies of the
regulation in sickle cell anemia. Nevertheless, clinical and hematological effects of haplotype
the full picture of this process is not known. in sickle cell anemia have been in regions
where the Hb S gene arrived by gene flow.
β-G LOBIN G ENE C LUSTER After many years of miscegenation, patients
H APLOTYPES —E FFECTS ON H B F are commonly haplotype heterozygotes,
L EVELS , H EMATOLOGY, AND complicating the interpretation of potential
C LINICAL C OURSE associations of haplotype with phenotype.
Four β-globin gene cluster haplotypes are Therefore, reports of the clinical and hemato-
linked with the independent emergence of four logical effects of haplotype in sickle cell
βs genes in Africa. The three most common are anemia should be interpreted carefully. Often
the Senegal haplotype in Atlantic West Africa, too few patients are studied, the patients’ ages
the Benin haplotype in central West Africa, differ among series, clinical events are not
and the Bantu haplotype in all Bantu-speaking sharply defined, age-dependence of their
African societies (equatorial and southern phenotype is not considered, and the distinc-
Africa) (8). The Arab-Indian haplotype is tion between haplotype homozygotes and
found in the Middle East and India. heterozygotes is not clearly drawn.
Although β-globin gene cluster haplotypes In longitudinal studies from the United States,
are convenient markers for genetic regulators the Senegal haplotype was associated with
of γ-globin gene expression, most polymorphic fewer hospitalizations and painful episodes.
endonuclease restriction sites used to assign a The relationship between the Senegal haplo-
haplotype have no known role in the differen- type and reduced frequency of acute chest
tial transcription and temporal regulation of syndrome was of marginal significance. The
these genes. An exception is the Xmn I site Bantu haplotype was associated with the high-
that is 5' to the Gγ-globin gene in the Senegal est incidence of organ damage and was strong-
and Arab-India haplotypes (9-11). This site is ly associated with renal failure in a study that
strongly associated with high expression of the used robust statistics and a large number of
Gγ-globin gene compared with the Aγ-globin patients (13-15). Most work suggests that the
gene. In adults and neonates lacking the Hb S Arab-India haplotype is associated with milder
gene, this polymorphism is associated with disease, although vaso-occlusive events are not
small but significant increases in the synthesis rare. In India the almost fixed (approaching
of Hb F and Gγ-globin chains. More recently, 100 percent) haplotype frequency of α-tha-
twin studies have implicated it as a major lassemia adds considerably to the benign
factor in defining the level of Hb F expression picture of SCD (16).
(see below).
Considerable variation also exists among
patients who have Senegal or Arab-India
haplotypes, although they tend to have higher
Hb F levels than those who have Benin and
Bantu haplotypes. A patient’s sex, in addition
to his or her haplotype, also may modulate
Hb F production (12).
174
H B F M ODULATION U NLINKED TO in part, for the higher Hb F levels in females
THE β-G LOBIN G ENE C LUSTER : G ENDER compared to males, an observation found in
E FFECTS AND R OLE OF C HROMOSOMAL both the normal population and in patients
S ITES O THER THAN C HROMOSOME 11 with sickle cell anemia. More recent multi-
Hb F is restricted to a subset of red cells, point linkage analysis with seven polymorphic
called F-cells, whose numbers are determined markers has further localized the FCP within
genetically, although exactly how is unknown. 2 to 3 cM between DXS452 and APXL, with
There are likely to be genetic determinants a maximum LOD score of 3.3.
of Hb F level not linked to the β-globin gene
cluster that influence Hb F concentrations α-THALASSEMIA
in sickle cell anemia. The Hb F level in sickle
α-thalassemia in individuals of African descent
cell anemia is set by the number of F-cells, the
is usually a result of the deletion of one or
amount of Hb F per F-cell, and the differen-
two α-globin genes. Missing even two of the
tial survival of F-cells and non-F-cells (17).
normal complement of four α-globin genes is
Family studies have shown that this consider-
not clinically significant in normal individuals.
able variation is inherited, but the number of
About a third of African Americans carry an
genes involved and the mode of inheritance
α-globin gene deletion, and this prevalence
are largely unknown. Identical-twin studies
is even higher in some populations, so α-
showed that the heritability of F-cell numbers
thalassemia and sickle cell anemia frequently
is very high and that gender, age, and the -158
coexist (22).
T-to-C mutation 5' to the Gγ-globin gene
account for close to 40 percent of the variance. The hematological and clinical consequences
of interactions between these two disorders
Other trans-acting autosomal loci, termed
have been studied intensively. The presence
quantitative trait loci (QTL), also appear to
of α-thalassemia with sickle cell anemia is
influence the amounts of Hb F in F-cells (18).
associated with less hemolysis, higher hemo-
Two such QTLs have been mapped by linkage
globin concentration, lower mean corpuscular
analysis, one to chromosome 6q23 (19).
volume (MCV), and lower reticulocyte count,
Genetic studies originally localized this QTL
when compared to individuals with normal
to a region approximately 4 Mb or 11 cM
α-globin gene numbers. α-thalassemia does
between markers D6S408 and D6S292. More
not appear to modify the effect of haplotype
recently, novel polymorphic markers plus
on Hb F levels in sickle cell anemia despite an
existing markers have further localized the
early report to the contrary, but it can further
QTL within an interval of 0.8-1 Mb between
ameliorate the disease. Therefore, it is unlikely
D6S270 and D61626 (20). Further analysis
that any clinical benefit α-thalassemia confers
suggests an additional QTL on chromosome 8q
upon sickle cell anemia is mediated through
(20). It is clear that further QTLs affecting the
its effect on Hb F level.
expression of Hb F will be found in the future.
α-thalassemia has a strong effect upon the
The second possible F-cell production locus
phenotype of sickle cell anemia by reducing
(FCP) is X-chromosome-linked and has been
the erythrocyte Hb S concentration. Hb S
localized between DXS143 and DXS16 within
polymerization depends on hemoglobin
the short arm of chromosome X (Xp22.3-
concentration, so concurrent α-thalassemia
22.20) (21). The FCP locus may account,
should diminish the polymerization potential
175
Chapter 28: Genetic Modulation of Phenotype by Epistatic Genes
of sickle hemoglobin in sickle cell anemia. picture of sickle cell anemia (12,25,26). Most
When these conditions coexist, there is less often there is little interaction besides minor
hemolysis, and anemia is less severe. Clinically, reductions in MCV and reticulocyte count and
the copresence of α-thalassemia and sickle cell increases in PCV. One exception was a study
anemia is a paradoxical outcome. Vaso-occlu- of two western Indian populations with high
sive events appear undiminished in SCD with Hb F levels in which the coexistence of α-tha-
α-thalassemia, and in some studies, even lassemia was associated with milder disease (16).
appeared to be increased. Fewer dense and
poorly deformable cells as a result of α-tha- H EMOGLOBIN A 2
lassemia raise the packed cell volume (PCV),
Hb A2, the tetramer of α- and δ-globin
and because the cells contain Hb S, blood
chains, impairs the polymerization of Hb S
viscosity is increased. Raising the number of
to the same extent as the γ-globin chain of
sickle cells, as occurs with α-thalassemia, might
Hb F. When Hb A2 and Hb F levels are high,
promote vaso-occlusion since younger sickle
the combination of these two hemoglobins
cells are more adherent (a critical phenome-
may potentially modulate SCD and cause
non in painful episodes) (23). On the other
a mild phenotype.
hand, a higher PCV may have beneficial
effects in some organs, so that skin ulcers
of the leg, childhood stroke, and retinal E RYTHROCYTE G-6-PD D EFICIENCY
vascular disease may be less common in Glucose-6-phosphate dehydrogenase (G-6-
carriers of α-thalassemia and sickle cell ane- PD) deficiency is common in sickle cell ane-
mia. The effect of α-thalassemia on cellular, mia. In a study of 800 males over age 2 with
hematological, and clinical aspects of sickle SCD, G-6-PD deficiency was not associated
cell anemia have been reviewed recently (22). with differential survival, reduced hemoglobin
levels, increased hemolysis, more pain episodes,
Some but not all studies suggest that the septic episodes, or a higher incidence of acute
combination of α-thalassemia and sickle cell anemia episodes (27,28). It now seems clear
anemia may increase survival (24). A recent that there is little, if any, modulation of the
followup study of the age-dependency of phenotype of sickle cell anemia by coincident
α-globin gene frequency is compatible with G-6-PD deficiency, particularly in males
the following interpretation: as medical care where the expression of this X-linked trait
improves, the advantage of α-thalassemia on is most apparent.
survival disappears, a phenomenon that could
explain the contradiction in the available data. INHERITED DISORDERS
OF THROMBOSIS
INTERACTIONS OF β-GLOBIN
GENE HAPLOTYPE AND Some have postulated that thrombosis and
hemostasis could play roles in the pathophysi-
α-THALASSEMIA ology of SCD. Coincidental mutations that
Some studies have examined how α-thalassemia favor blood coagulation or thrombosis could
interacts with different β-globin gene haplo- influence disease phenotype (29), particularly
types to modify the hematological and clinical the occurance of SCD-related stroke.
176
Recent studies attempting to relate the pres- A case-control candidate gene association study
ence of mutations in genes for factor V, involving patients with SCD and ischemic
platelet glycoprotein IIIa, and 5,10 methyl- stroke suggested an association with ischemic
enetetrahydrofolate reductase (MTHFR) to stroke and angiotensinogen repeat alleles
the pathogenesis of specific complications of 3 and 4 (p<0.05) and plasminogen activator
SCD have had disparate results. In one report, inhibitor (PAI-I) 4/4 alleles (p<0.01) (35).
a C→T mutation at position 677 of the
MTHFR gene that is associated with enzyme GENETIC PREDICTION
thermolability and a putative hypercoagulabile OF PHENOTYPE IN
state due to hyperhomocystenemia was found
SICKLE CELL ANEMIA
in 36 percent of 45 adults with SCD and
osteonecrosis but in only 13 percent of 62 As with other diseases, the sickle cell diseases
SCD patients without osteonecrosis—a signif- are variable in their presentation due to differ-
icant difference (30). However, smaller studies ences in the genetic makeup and the environ-
reported that the same mutation was not asso- mental exposure of the affected individual.
ciated with vascular complications of SCD, Although the exact genes have yet to be iden-
including osteonecrosis and stroke (31-33). tified, extensive advances in understanding the
Studies of the platelet glycoprotein IIIa gene pathophysiology of SCD suggest that genes
have not found a link between a C→T muta- involved in numerous mechanisms might have
tion at position 1565 (which is associated epistatic potential in SCD. These include:
with premature coronary artery disease) and
1. Genes involved in the adhesion of young
osteonecrosis. Factor V Leiden, a common
sickle cells to the vascular endothelium
cause of thrombosis in Caucasians, is rare in
(e.g., genes related to integrin and other
African Americans; limited studies have not
adhesive molecules).
linked this mutation to stroke in SCD.
2. Genes that affect the density of sickle cells,
High levels of antiphospholipid antibodies including transporter genes such as those
were found in patients with SCD and individ- involved in Ca-dependent K efflux, K:Cl
uals with sickle cell trait (33), but no relation- cotransport, Na/H exchange.
ship to disease complications was noted.
Clearly, further work is needed to resolve 3. Genes involved in thrombosis,
the role of genetic risk factors for thrombosis, particularly in sickle cell stroke.
many of which have been examined only 4. Genes involved in angiogenesis,
in pilot studies or reported in abstract. particularly in sickle cell retinopathy.
The potential genetic contribution to stroke 5. Genes involved in hemopoiesis,
risk in SCD can be estimated from clinical particularly marrow response to anemia.
stroke risk observed in sibling pairs with SCD. 6. Genes involved in vascular reactivity,
In 210 pairs among 2,353 patients with SCD, particularly genes involved in the effects
167 pairs had no history of stroke, 33 pairs of endothelin and NO.
had a stroke in one sib, and 10 pairs had his-
tory of stroke in both sibs (34).
177
Chapter 28: Genetic Modulation of Phenotype by Epistatic Genes
Eventually, researchers may develop a reliable 9. Gilman JG, Huisman TH. DNA sequence
method of predicting severity of disease. This variation associated with elevated fetal Gγ globin
production. Blood 1985;66:783-7.
would allow better grounds for decisions 10. Nagel RL, Fabry ME, Pagnier J, et al.
pertaining to termination of pregnancy in Hematologically and genetically distinct forms of
the context of prenatal diagnosis and the sickle cell anemia in Africa. The Senegal type and
establishment of risk/benefit ratios when the Benin type. N Engl J Med 1984;312:880-4.
contemplating bone marrow transplantation, 11. Labie D, Srinivas R, Dunda O, et al. Haplotypes
in tribal Indians bearing the sickle gene: evidence
chemotherapeutic manipulation of Hb F for the unicentric origin of the beta S mutation
level, and even gene therapy, all of which and the unicentric origin of the tribal populations
have potentially serious complications. of India. Hum Biol 1989;61:479-91.
12. Steinberg MH, Hsu H, Nagel RL, et al. Gender
and haplotype effects upon hematological manifes-
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UK: Cambridge University Press, 2001. the Arab-Indian haplotype in India. Am J Hematol
4. Noguchi CT, Rodgers GP, Serjeant G, et al. Levels 1997;55:104-9.
of fetal hemoglobin necessary for treatment of sick- 17. Dover GJ, Boyer SH, Charache S, et al.
le cell disease. N Engl J Med 1988;318:96-9. Individual variation in the production
5. Powars DR, Weiss JN, Chan LS, et al. Is there and survival of F cells in sickle-cell disease.
a threshold level of fetal hemoglobin that amelio- N Engl J Med 1978;299:1428-35.
rates morbidity in sickle cell anemia? Blood 18. Garner C, Tatu T, Reittie JE, et al. Genetic influ-
1984;63:921-6. ences on F cells and other hematologic variables: A
6. Platt OS, Brambilla DJ, Rosse WF, et al. Mortality twin heritability study. Blood 2000;95:342-6.
in sickle cell disease. Life expectancy and risk factors 19. Game L, Close J, Stephens P, et al. An integrated
for early death. N Engl J Med 1994;330:1639-44. map of human 6q22.3-q24 including a 3-Mb high-
7. Weiss M, Blobel G. Nuclear factors that regulate resolution BAC/PAC contig encompassing a QTL
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Higgs DR, et al., eds. Disorders of Hemoglobin: 20. Tang W, Smith K, Dover G. The F-cell production
Genetics, Pathophysiology, Clinical Management. locus is mapped between DXS 452 and APXL, and
Cambridge, UK: Cambridge University Press, 2001. interval of 2-3 cM on Xp22.2. Abstract. The 12th
8. Nagel RL, Steinberg MH. Genetics of the βs gene: Conference on Hemoglobin Switching. 2000.
Origins, genetic epidemiology, and epistasis in 21. Dover GJ, Smith KD, Chang YC, et al. Fetal
sickle cell anemia. In: Steinberg MH, Forget BG, hemoglobin levels in sickle cell disease and normal
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22. Steinberg MH. Compound heterozygous and other 34. Driscoll MC, Hurlet A, Berman B, et al. Stroke
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Hemoglobin: Genetics, Pathophysiology, Clinical 35. Tang DC, Prauner R, Liu W, et al. The
Management. Cambridge, UK: Cambridge angiotensinogen GT dinucleotide repeat is
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23. Adekile AD, Tuli M, Haider MZ, et al. Influence cell anemia. Abstract. National Sickle Cell
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1996;53:1-5.
24. Mears JG, Lachman HM, Labie D, et al. α-tha-
lassemia is related to prolonged survival in sickle
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25. Rieder RF, Safaya S, Gillette P, et al. Effect of β-
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26. Steinberg MH, Embury SH. α-thalassemia
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1986;68:985-90.
27. Steinberg MH, West MS, Gallagher D, et al.
Effects of glucose-6-phosphate dehydrogenase
deficiency upon sickle cell anemia. Blood
1988;71:748-52.
28. Bouanga JC, Mouélé R, Préhu C, et al. Glucose-
6-phosphate dehydrogenase deficiency and
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Cell Disease: Basic Principles and Clinical Practice.
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30. Kutlar A, Kutlar F, Turker I, et al. The methlylene
tetrathydrofolate reductase (C677T) mutation as
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in sickle cell disease. Hemoglobin 2001:25:213-7.
31. Zimmerman SA, Ware RE. Inherited DNA muta-
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32. Andrade FL, Annichino-Bizzacchi JM, Saad STO,
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in Brazil. Am J Hematol 1998;59:46-50.
33. Nsiri B, Ghazouani E, Gritli N, et al. Antiphos-
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179
180
H IGHLIGHTS F ROM F EDERALLY F UNDED S TUDIES 29
Many of the observational studies and thera- risk factors responsible for the increased mor-
peutic trials that have contributed to the bidity and early mortality of SCD (table 1).
understanding of syndromes associated with Below are just a few of the findings from the
sickle cell disease (SCD) have been federally CSSCD studies, which have resulted in 39
funded. This chapter highlights some of the papers (1-39).
research funded by the National Heart, Lung,
and Blood Institute (NHLBI) that has led to L ABORATORY R EFERENCE VALUES
a clearer understanding of the clinical course
The CSSCD described reference values and
of SCD and appropriate interventions to
hematologic changes from birth to 5 years
reduce morbidity. Specifically, it describes
of age (2). Anemia was observed by 10 weeks
a large multi-year observational study, known
of age in infants with SCD-SS and was associ-
as the Cooperative Study of Sickle Cell
ated with a rising reticulocyte count, exceeding
Disease (CSSCD), as well as several interven-
12 percent by 5 years of age. The fetal hemo-
tional clinical trials. The discussions are not
globin (Hb F) concentration in SCD-SS infants
inclusive but rather highlight successful efforts
declined more gradually than did that of infants
in the study and treatment of the disorder.
with SCD-SC. Infants with SCD-SS had evi-
dence of abnormal splenic function after 6
COOPERATIVE STUDY OF SICKLE months of age, and by 1 year, 28 percent of
CELL DISEASE—EPIDEMIOLOGY SCD-SS infants had evidence of poor splenic
COHORT STUDY function. By the time the children had reached
3 years of age, this percentage had increased to
The CSSCD, started in 1979 after years
78 percent for SCD-SS children and 32 percent
of planning, was a large multi-institutional
for those with SCD-SC. Children with SCD-
prospective study of the clinical course of
SC were mildly affected, and displayed mild
SCD (1). The recruitment goals included indi-
anemia (10.5 g/dL), slightly elevated mean
viduals with major phenotypes of sickle cell
reticulocyte counts (3 percent), and fetal hemo-
disease (SCD-SS, SCD-SC, and SCD-S β+/o
globin levels (3 percent) during early childhood.
thalassemia); 3,200 subjects, with an SCD-SS
sample of 2100; individuals from different
geographic areas (including rural areas); and PAINFUL E VENTS
inclusion of individuals at all stages of life One of the major accomplishments of the
(including newborns and pregnant women). CSSCD was an analysis of the epidemiology
The CSSCD completed its third phase in of pain episodes (3). The natural history of
1999; it followed the newborn cohort of 694 3,578 individuals ranging in age from new-
children who were identified through screen- borns to 66 years was evaluated. The average
ing programs. The CSSCD has identified the pain rate was 0.8 episode per person-year in
181
Chapter 29: Highlights From Federally Funded Studies
Table 1. Risk Factors for Major Organ Dysfunction or Event (Results from the CSSCD)
* ↓=decreased, ↑=increased
sickle cell anemia (SCD-SS), 1.0 episode all episodes. Among persons over the age
per person-year in SCD-S βo-thalassemia, of 20, those with high pain rates tended to
and 0.4 episode per person-year in SCD-SC die earlier than did those with low pain rates.
β+-thalassemia and SCD-SS β+-thalassemia. High pain rates were associated with high
hematocrit and low Hb F levels, and α-tha-
The rates varied widely within each of these
lassemia had no effect on pain rates apart
four groups. Thirty-nine percent of persons
from its association with an increased hemat-
with sickle cell anemia had no episodes of
ocrit. The data indicated that the Hb F level
pain, and 1 percent had more than six episodes
was predictive of the pain rate, prompting
per year. The 5.2 percent of persons with 3
attempts to increase Hb F levels with pharma-
to 10 episodes per year had 32.9 percent of
cologic agents such as hydroxyurea.
182
M AJOR O RGAN D YSFUNCTION A LLOIMMUNIZATION R ISKS
Leg Ulcers OF T RANSFUSION
The incidence of leg ulcers was evaluated at In 1,814 persons with SCD who had been
study entry in 2,075 persons 10 years and transfused, the rate of alloimmunization to
older between 1979 and 1986 (4). Leg ulcers erythrocyte antigens was 18.6 percent (6).
were most prevalent in persons with SCD-SS The rate of alloimmunization increased expo-
and SCD-SS α-thalassemia. Prevalence rates nentially with increasing numbers of transfu-
per 100 persons were: SCD-SS (4-5 α genes) sions. However, the rate of alloimmunization
= 4.97; SCD-SS (2-3 α genes) = 3.9; SCD-SS in persons whose first transfusion occurred
unmapped = 1.5; SCD-S βo-thalassemia = 0.9. at less than 10 years of age was less than
Individuals with SCD-SC and SCD-S β+-tha- expected based on the number of transfusions
lassemia did not have leg ulcers at entry. The administered.
incidence rates of leg ulceration among males
were significantly higher than among females D EMOGRAPHICS
(15 versus 5 per 100 person-years). Persons An analysis of socioeconomic status of 3,538
who had SCD-SS experienced a sharp increase African-American SCD persons enrolled in
in incidence of leg ulcers after the second the CSSCD revealed the following: there were
decade of life. At any given total hemoglobin fewer two-parent families than in the total
concentration, rates were lower in individuals United States black population (USBP) (40
with fetal hemoglobin (Hb F) levels greater than percent versus 54 percent); twice as many
5 percent. persons of both sexes with SCD worked in
Osteonecrosis of the Humeral Head white-collar positions; a higher percentage of
Osteonecrosis of the humeral head was deter- SCD persons were unemployed and disabled
mined in a study of 2,524 persons in the (compared to the USBP); and men with
CSSCD cohort (5). At entry, 5.6 percent had SCD patients had lower median incomes
radiologic evidence of osteonecrosis in one or than all black males in the United States (7).
both shoulders. The highest age adjusted inci- The percentage of high school graduates was
dence rates were observed in SCD-SS persons similar (71 percent SCD versus 75 percent
with concomitant α-thalassemia (4.9 per 100 USBP), and female heads of household
person-years), followed by SCD-S βo-thalas- employed full time earned about the same
semia (4.8 per 100 person-years), SCD-SS salary as USBP females.
without α-thalassemia (2.5 per 100 person-
years), and SCD-SC (1.7 per 100 person- CLINICAL TRIALS IN
years). Most were asymptomatic, with 20.9 SICKLE CELL DISEASE
percent reporting pain or limited range of
Interventional trials grew partly from needs
motion at time of diagnosis.
and observations related to the CSSCD.
Examples of clinical trials funded by the
NHLBI are described below and are summa-
rized in table 2.
183
Chapter 29: Highlights From Federally Funded Studies
184
received the drug had an average yearly lower decreasing morbidity for patients undergoing
cost of health care than did those originally surgical procedures, simple transfusions
randomized to receive placebo (46). Other are associated with significant cost savings.
areas being explored by the MSH investiga-
tors include effects of hydroxyurea usage on S TROKE P REVENTION T RIAL IN
quality of life and the effect of hydroxyurea S ICKLE C ELL A NEMIA (STOP T RIAL )
on analgesia use. Stroke is the second leading cause of death
in children with SCD. In the STOP trial, an
P HASE I/II S TUDY OF H YDROXYUREA investigator-initiated multicentered trial fund-
IN C HILDREN (PED HUG) ed by the NHLBI, children between the ages
Children between the ages of 5 and 15 years of 2 and 16 who were at risk for first-time
with sickle cell anemia were entered into a stroke, as determined by having transcranial
multicenter safety and dosing study of hydrox- Doppler velocity greater than 200 cm/sec,
yurea in 1994 (47). A total of 84 children were randomized to receive either periodic
were enrolled, 68 reached MTD, and 52 were transfusions to maintain the Hb S level below
treated at MTD for 1 year. This study demon- 30 percent or standard supportive care (49).
strated significant increases in hemoglobin An interim analysis demonstrated that period-
concentration, Hb F levels, and decreases ic transfusions were efficacious in preventing
in white blood cell, neutrophil, platelet, and first-time stroke in the children randomized
reticulocyte counts. Laboratory toxicities were to the transfusion arm. At the end of the trial,
transient and were reversible with cessation of all participants were offered periodic transfu-
hydroxyurea, as had been seen in adults. This sion therapy. The main side effects of the
study set the stage for the design of phase III transfusion therapy were iron accumulation
trials of hydroxyurea in even younger children and alloimmunization, although the rate of
to determine whether hydroxyurea can prevent occurrence was low. A new trial, known as
chronic end-organ damage. STOP II, is now in place to determine whether
transfusions need to be continued indefinitely
P ERIOPERATIVE T RANSFUSION S TUDY or if they can be stopped after some period of
time when risk of stroke has diminished.
Perioperative transfusions are used frequently
to prevent morbidity in patients with sickle cell
anemia. A prospective multicenter study that SUMMARY
ran from 1988 to 1993 randomly assigned 692 The trials discussed are examples of only some
patients to receive either exchange transfusions of the major clinical efforts in SCD research.
to decrease their Hb S levels below 30 percent The NHLBI funds 10 Comprehensive Sickle
or simple transfusions to increase their hemo- Cell Centers, whose mission is to perform
globin levels to 10 g/dL (48). The conservative basic research in SCD, conduct clinical studies,
transfusion regimen was as effective as exchange and provide community outreach and education.
transfusion in preventing perioperative com- It also supports a variety of other endeavors.
plications, and the conservative regimen was
associated with a much lower rate of transfu-
sion-associated complications. In addition to
185
Chapter 29: Highlights From Federally Funded Studies
Perioperative Simple blood transfusions to raise the Simple blood transfusions can be safely
Transfusion Trial total Hb level to 10 g/dL regardless of Hb S given during the perioperative period
concentration, compared to aggressive to raise Hb concentration to 10 g/dL (48)
blood transfusions to suppress Hb S level
to below 30 percent at time of surgery
in children and adults
(Phase III)
STOP Trial Blood transfusions to prevent stroke First-time stroke can be prevented
in children in children found to be at risk by periodic
(Phase III) blood transfusions to suppress Hb S
concentraion to less than 30 percent (49)
186
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Web: http://www.nhlbi.nih.gov
DISCRIMINATION PROHIBITED: Under provisions of applicable public laws enacted by Congress since 1964,
no person in the United States shall, on the grounds of race, color, national origin, handicap, or age, be excluded from
participation in, be denied the benefits of, or be subjected to discrimination under any program or activity (or, on the basis
of sex, with respect to any education program and activity) receiving Federal financial assistance. In addition, Executive
Order 11141 prohibits discrimination on the basis of age by contractors and subcontractors in the performance of Federal
contracts, and Executive Order 11246 States that no federally funded contractor may discriminate against any employee or
applicant for employment because of race, color, religion, sex, or national origin. Therefore, the National Heart, Lung, and
Blood Institute must be operated in compliance with these laws and Executive Orders.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
National Institutes of Health
National Heart, Lung, and Blood Institute