IDF Patient & Family Handbook for Primary Immunodeficiency ... - IDFA

Patient
& Family
Handbook
For Primary
Immunodeficiency
Diseases

This book contains general medical information which cannot be applied safely to any individual case. Medical knowledge and
practice can change rapidly. Therefore, this book should not be used as a substitute for professional medical advice.
FOURTH EDITION
COPYRIGHT 1987, 1993, 2001, 2007 IMMUNE DEFICIENCY FOUNDATION
Copyright 2007 by Immune Deficiency Foundation, USA.
Readers may redistribute this article to other individuals for non-commercial use, provided that the text, html codes, and this
notice remain intact and unaltered in any way. The Patient & Family Handbook may not be resold, reprinted or redistributed
for compensation of any kind without prior written permission from Immune Deficiency Foundation. If you have any questions
about permission, please contact: Immune Deficiency Foundation, 40 West Chesapeake Avenue, Suite 308, Towson, MD
21204, USA; or by telephone at 1-800-296-4433.

Patient &
Family Handbook
For Primary Immunodeficiency Diseases
4th Edition
This publication has been made possible
through a generous grant from
Baxter Healthcare Corporation
40 West Chesapeake Avenue, Suite 308
Towson, Maryland 21204
800-296-4433
www.primaryimmune.org
idf@primaryimmune.org

EDITORS
R. Michael Blaese, MD
Immune Deficiency Foundation
Towson, MD
Jerry A. Winkelstein, MD
Johns Hopkins University
School of Medicine
Baltimore, MD
Katherine A. Antilla, MAEd
Immune Deficiency Foundation
Towson, MD
ASSOCIATE EDITORS
CONTRIBUTORS
Christine M. Belser
Immune Deficiency Foundation
Towson, MD
Melvin Berger, MD, PhD
Rainbow Babies &
Children’s Hospital
Cleveland, OH
Francisco A. Bonilla, MD, PhD
Boston Children’s Hospital
Boston, MA
Marcia Boyle, MS
Immune Deficiency Foundation
Towson, MD
Rebecca H. Buckley, MD
Duke University
School of Medicine
Durham, NC
Mary Ellen Conley, MD
St. Jude
Children’s Research Hospital
Memphis, TN
Charlotte Cunningham-Rundles,
MD, PhD
Mt. Sinai Medical Center
New York, NY
Robert Dash
Baxter Healthcare Corporation
Deerfield, IL
Carol Ernst, RN, OCN
Mercy Anderson Hospital
Cincinnati, OH
Thomas A. Fleisher, MD
National Institutes of Health
Bethesda, MD
Michael Frank, MD
Duke University
School of Medicine
Durham, NC
Ramsay Fuleihan, MD
Northwestern University
Chicago, IL
Serrie L. Krash, MS
Immune Deficiency Foundation
Towson, MD
Howard M. Lederman, MD, PhD
Johns Hopkins University
School of Medicine
Baltimore, MD
Harry Malech, MD
National Institutes of Health
Bethesda, MD
Steven Miles, MD
All Seasons Allergy, Asthma
and Immunology Center
Woodlands, TX
Hans D. Ochs, MD
University of Washington
School of Medicine
Seattle, WA
Jordan S. Orange, MD, PhD
Children’s Hospital of Philadelphia
Philadelphia, PA
Kenneth Paris, MD, MPH
Louisiana State University
New Orleans, LA
Jennifer M. Puck, MD
University of California
San Francisco, CA
John W. Seymour, PhD, LMFT
Mankato State University
Mankato, MN
Ricardo U. Sorensen, MD
Louisiana State University
New Orleans, LA
E. Richard Stiehm, MD
University of California
Los Angeles, CA
Kathleen Sullivan, MD, PhD
Children’s Hospital of Philadelphia
Philadelphia, PA

Patient and Family Handbook
i
Preface
The first edition of the Patient & Family Handbook was written nearly two decades ago in response to
requests from patients with primary immunodeficiency diseases, their families and their physicians. We
hoped that it would help patients and their families to learn more about the immune system, the primary
immunodeficiency diseases, currently available therapies and possible future treatments. Since then, tens
of thousands of copies have been distributed to patients and their families!
This fourth edition, like those editions that have come before, has been inspired by the many new and
exciting advances in the diagnosis and therapy of the primary immunodeficiencies. Many chapters in this
edition are new and all of the existing chapters have been revised to include important new information.
We hope that the first chapter will be useful to all who read this book. It explains how the immune system
works and how the failure of the immune system leads to primary immunodeficiency diseases. Individual
chapters on most of the specific primary immunodeficiencies follow. We have included three new chapters
on disorders that were not covered in previous editions and updated the existing chapters to include
information on new diagnostic tools, more precise clinical information, and new therapies. The General
Care chapter has been updated to reflect new nutritional guidance and conveys commonsense guidelines
that the patient and family may find useful. The chapter on Specific Medical Therapy has been revised to
reflect recent advances in treatments available to the primary immunodeficient individual, including newer
methods of treatment with immunoglobulin. A new chapter dedicated to the adolescent with a primary
immunodeficiency has been added, making three chapters that deal with issues relating to patients
from infancy through adult life. The Health Insurance chapter has been expanded and updated to reflect
changes in reimbursement and insurance; it should be a good place to start when trying to understand
this complex and important area. Resources includes additional information available both in printed form
and on the Internet. Finally, the Glossary offers definitions of the more common, and possibly confusing,
medical terms.
A few words on how to use this book: this book is not a substitute for a dialogue between the patient, his/
her family, their physician, and other members of the healthcare team. Rather, it is intended to provide the
patient and family with tools to enhance the communication process and to understand the information
they receive from the healthcare team. Most importantly, this book is not intended to suggest diagnostic
approaches or to recommend specific therapy for any patient. Each patient’s condition and treatment is
unique and the management of their illness should be customized to their individual medical needs.
We thank all those individuals who contributed to this book: those who wrote specific chapters, the
members of the Medical Advisory Committee who reviewed the chapters, the Board of Trustees and the
staff of the Immune Deficiency Foundation who made this book a high priority, and finally, the patients and
their families whose suggestions will make this edition even better than the last three!
The Editors
Baltimore 2007

ii
Patient and Family Handbook
The Immune Deficiency Foundation
The Immune Deficiency Foundation (IDF) was founded in 1980 by parents of children with primary
immunodefiency diseases and their physicians. At that time, there were no educational materials or
programs for patients and no public advocacy initiatives. One of the greatest challenges faced by people
who find themselves or their children diagnosed with a primary immunodeficiency is getting the right
information at the right time. To fill this void, one of the most important publications developed by IDF is
the Patient & Family Handbook and we are proud to offer this fourth edition. We know that this book has
served as the basis of understanding primary immunodeficiency diseases for over two decades and we
are pleased to present this updated version.
A few years ago, Kinsey Moore, then an eighth grader, had the assignment of writing an essay on what
book she would choose to be. Kinsey wrote:
“The book I would want to be turned into is the Immune Deficiency Foundation (IDF) Family Handbook.
When I was born, I was very ill and almost died several times. In all of my baby pictures, I have cords and
wires connected to me. One time when I was in the hospital and I had a life-threatening infection for the
third time that month, my mom walked into the library and saw a little blue and white book poking off
the shelf. It was the IDF’s family handbook. Everything in that book applied to me. When my mom told
the doctors, they did not believe her. After two years of going to different doctors, I was finally diagnosed
when I was four. This book saved my life. I would want to become this book so I could save more people
in my situation. My family knows what it is like to feel lost and not know whether I would live till tomorrow,
but this book gave us hope.”
We hope this handbook gives you hope, knowledge and empowerment to help cope with the challenges
of living with a primary immunodeficiency disease. As a patient-focused organization dedicated to our
community, we encourage you to contact IDF to help meet your needs. Whether you want to talk to
a peer support volunteer, need assistance from a patient advocate or want to attend an educational
meeting, know that IDF is the place to turn for help and information.
Marcia Boyle
President & Founder
Immune Deficiency Foundation

Patient and Family Handbook
iii
About the Immune Deficiency Foundation
The Immune Deficiency Foundation, founded in 1980, is the national non-profit patient organization
dedicated to improving the diagnosis and treatment of patients with primary immunodeficiency diseases
through research, education and advocacy.
Educational Publications
• Patient & Family Handbook for Primary Immunodeficiency Diseases
• Our Immune System
• A Guide for School Personnel on Primary Immune Deficiency Diseases
• Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases
• IDF Guide for Nurses on Immunoglobulin Therapy for Primary Immunodeficiency Diseases
• IDF Advocate—newsletter
• Primary Immune Tribune—e-newsletter
Services for Patients and Families
• Patient Advocacy—inquiries related to diagnosis, treatment, health insurance, peer support and
literature requests
• IDF Educational Meetings—local and regional patient meetings, national conference
• IDF Volunteer Network—Peer Support, Grassroots Advocacy and Fundraising
• Student Scholarships—post-secondary education
Services for Medical Professionals
• Consulting Immunologist Program (877-666-0866) provides physicians with a free consult or second
opinion on patients with primary immunodeficiency diseases
• LeBien Visiting Professor Program offers Grand Rounds and clinical presentations at medical
institutions throughout North America
• United States Immunodeficiency Network (USIDNET). IDF administers this National Institute of Health
contract for research and mentoring for primary immunodeficiency diseases
• National Registries of Primary Immunodeficiency Diseases
Public Policy Initiatives
• Advocacy efforts on public policy issues at national and state levels by monitoring issues that are
critical to patients
• IDF Grassroots Advocacy Program mobilizes the primary immunodeficiency community to contact their
government representatives to promote healthcare legislation that will positively affect the community.
• Advocacy for increased funding for research on primary immunodeficiency diseases
• Work with other organizations on quality of care initiatives for users of plasma products
www.primaryimmune.org
800-296-4433

iv
Patient and Family Handbook
Contents
Chapter 1 The Immune System and Primary Immunodeficiency Diseases . . . . . . . . . . . . . . . . .1
Chapter 2 Common Variable Immune Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11
Chapter 3 X-Linked Agammaglobulinemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15
Chapter 4 Selective IgA Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19
Chapter 5 Severe Combined Immune Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23
Chapter 6 Chronic Granulomatous Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .30
Chapter 7 Wiskott-Aldrich Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36
Chapter 8 Hyper IgM Syndromes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .42
Chapter 9 DiGeorge Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .46
Chapter 10 IgG Subclass Deficiency and Specific Antibody Deficiency . . . . . . . . . . . . . . . . . . . .50
Chapter 11 Ataxia Telangiectasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54
Chapter 12 Hyper IgE Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .58
Chapter 13 Complement Deficiencies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .62
Chapter 14 Other Important Primary Immunodeficiency Diseases . . . . . . . . . . . . . . . . . . . . . . . .66
Chapter 15 Inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .71
Chapter 16 Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79
Chapter 17 General Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .84
Chapter 18 Specific Medical Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .92
Chapter 19 Infants and Children with Primary Immunodeficiency Diseases . . . . . . . . . . . . . . . .104
Chapter 20 Adolescents with Primary Immunodeficiency Diseases . . . . . . . . . . . . . . . . . . . . . .111
Chapter 21 Adults with Primary Immunodeficiency Diseases . . . . . . . . . . . . . . . . . . . . . . . . . .119
Chapter 22 Health Insurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .125
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .134
Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .138

The Immune System and
Primary Immunodeficiency
Diseases
chapter
1
The immune system is composed of a variety of different cell types
and proteins. Each component performs a special task aimed at
recognizing and/or reacting against foreign material.

2 The Immune System And Primary Immunodeficiency Diseases
Components of the Immune System
The immune system is composed of a variety of
different cell types and proteins. Each component
performs a special task aimed at recognizing
foreign material (antigens) and/or reacting
against foreign material. For some components,
recognition of the material as foreign to the body is
their primary and only function. Other components
function primarily to react against the foreign
material. Still, other components function to both
recognize and react against foreign materials.
These foreign materials, or antigens, include
microorganisms that cause infections (such as
bacteria and viruses), pollen, and transplanted
organs from other individuals. Since the functions
of the immune system are so critical to survival,
many of them can be performed by more than
one component of the system. This redundancy
acts as a back-up mechanism. Therefore, if
one component of the whole system is missing
or functioning poorly, another component can
partially take over at least some of its functions.
The major components of the immune system are:
• B-lymphocytes
• T-lymphocytes
• NK cells
• Phagocytes (Macrophages and Neutrophils)
• Complement
B-lymphocytes
B-lymphocytes (sometimes called B-cells) are
specialized cells of the immune system whose
major function is to produce antibodies (also
called immunoglobulins or gammaglobulins).
B-lymphocytes develop from primitive cells
(stem cells) in the bone marrow (see Figure 2).
When mature, B-lymphocytes can be found in
the bone marrow, lymph nodes, spleen, some
areas of the intestine, and to a lesser extent,
in the bloodstream. When B-lymphocytes are
stimulated by a foreign material (antigens), they
respond by maturing into another cell type called
plasma cells. Plasma cells are the mature cells that
actually produce the antibodies. Antibodies, the
major product of plasma cells, find their way into
the bloodstream, tissues, respiratory secretions,
intestinal secretions, and even tears. Antibodies
are highly specialized serum protein molecules.
For every foreign antigen, there are antibody
molecules specifically designed for that antigen.
For example, like a lock and key, there are
antibody molecules that physically fit the
poliovirus, others that are aimed specifically at
the bacteria that cause diphtheria and still others
that match the measles virus. The variety of
different antibody molecules is so extensive that
B-lymphocytes have the ability to produce them
against virtually all possible microorganisms in our
environment. When antibody molecules recognize
the microorganism as foreign, they physically
attach to the microorganism and set off a complex
chain of reactions involving other components of
the immune system (see Figure 3) that eventually
destroy the microorganism. The chemical names
for antibody proteins are “immunoglobulins” or
“gammaglobulins.” Antibodies vary from molecule
to molecule with respect to which microorganisms
they bind. They can also vary with respect to their
specialized functions in the body (see Figure 4).
This kind of variation in specialized function is
determined by the antibody’s chemical structure,
which in turn determines the class of the antibody
(or immunoglobulin). There are four major classes
of antibodies or immunoglobulins:
• Immunoglobulin G (IgG)
• Immunoglobulin A (IgA)
• Immunoglobulin M (IgM)
• Immunoglobulin E (IgE)
Each immunoglobulin class has special chemical
characteristics that provide it with specific
advantages. For example, antibodies in the IgG
fraction are formed in large quantities, last for over
a month and travel from the blood stream to the
tissues easily. The IgG class is the only class of
immunoglobulins which crosses the placenta and
passes immunity from the mother to the newborn.
Antibodies of the IgA fraction are produced
near mucus membranes and find their way
into secretions such as tears, bile, saliva, and
mucus, where they protect against infection in the
respiratory tract and intestines.
Antibodies of the IgM class are the first antibodies
formed in response to infection. They are important
in protection during the early days of an infection.
Antibodies of the IgE class are responsible for
allergic reactions.

The Immune System And Primary Immunodeficiency Diseases 3
CHAPTER 1; FIGURE 1
Major Organs of the Immune System
A
D
B
E
C
F
G
A. Thymus: The thymus is an organ located in the upper chest. Immature
lymphocytes leave the bone marrow and find their way to the thymus
where they are “educated” to become mature T-lymphocytes.
B. Liver: The liver is the major organ responsible for synthesizing proteins
of the complement system. In addition, it contains large numbers of
phagocytic cells which ingest bacteria in the blood as it passes through
the liver.
C. Bone Marrow: The bone marrow is the location where all cells of the
immune system begin their development from primitive stem cells.
D. Tonsils: Tonsils are collections of lymphocytes in the throat.
E. Lymph Nodes: Lymph nodes are collections of B-lymphocytes and
T-lymphocytes throughout the body. Cells congregate in lymph nodes
to communicate with each other.
F. Spleen: The spleen is a collection of T-lymphocytes, B-lymphocytes
and monocytes. It serves to filter the blood and provides a site for
organisms and cells of the immune system to interact.
G. Blood: Blood is the circulatory system that carries cells and proteins of
the immune system from one part of the body to another.

4 The Immune System And Primary Immunodeficiency Diseases
Components of the Immune System continued
Antibodies protect the host against infection in
a number of different ways. For example, some
microorganisms, such as viruses, must attach
to body cells before they can cause an infection,
but antibody bound to the surface of a virus can
interfere with the virus’s ability to attach to the host
cell. In addition, antibody attached to the surface
of some microorganisms can cause the activation
of a group of proteins, called the complement
system, that directly kills the bacteria or viruses.
Antibody-coated bacteria are also much easier
for phagocytic cells to ingest and kill than bacteria
that are not coated with antibody. All of these
actions of antibodies prevent microorganisms from
successfully invading body tissues and causing
serious infections. The long life of B-lymphocytes
enables us to retain immunity to viruses and
bacteria that infected us many years ago. For
example, once a person has been infected with
chicken pox, he or she will seldom catch it again
because they retain the B-lymphocytes and
antibodies for many years and the antibodies
prevent infection a second time.
T-lymphocytes
T-lymphocytes (sometimes called T-cells) are
another type of immune cell. T-lymphocytes do not
produce antibody molecules. The specialized roles
of T-lymphocytes are to directly attack foreign
antigens such as viruses, fungi, or transplanted
tissues, and to act as regulators of the immune
system. T-lymphocytes develop from stem cells in
the bone marrow. Early in fetal life, the immature
cells migrate to the thymus, a specialized organ
of the immune system in the chest. Within the
thymus, immature lymphocytes develop into
mature T-lymphocytes (the “T” stands for the
thymus). The thymus is essential for this process,
and T-lymphocytes cannot develop if the fetus
does not have a thymus. Mature T-lymphocytes
leave the thymus and populate other organs
of the immune system, such as the spleen,
lymph nodes, bone marrow, and blood. Each
T-lymphocyte reacts with a specific antigen, just
as each antibody molecule reacts with a specific
antigen. In fact, T-lymphocytes have molecules
on their surfaces that are similar to antibodies
and recognize antigens. The variety of different
T-lymphocytes is so extensive that the body has
T-lymphocytes that can react against virtually
any antigen.
T-lymphocytes also vary in their function. There
are “killer” or cytotoxic T-lymphocytes, helper
T-lymphocytes, and regulatory T-lymphocytes.
Each has a different role to play in the immune
system. Killer, or cytotoxic, T-lymphocytes are
the T-lymphocytes which perform the actual
destruction of the invading microorganism. Killer
T-lymphocytes protect the body from certain
bacteria and viruses that have the ability to survive
and even reproduce within the body’s own cells.
Killer T-lymphocytes also respond to foreign
tissues in the body, such as a transplanted kidney.
Killer T-lymphocytes migrate to the site of an
infection or the transplanted tissues. Once there,
the killer cell directly binds to its target and kills it.
Helper T-lymphocytes assist B-lymphocytes in
producing antibody and assist killer T-lymphocytes
in their attack on foreign substances. The helper
T-lymphocyte “helps” or enhances the function of
B-lymphocytes, causing them to produce more
antibodies more quickly and switch from the
production of IgM to IgG and IgA.
Regulatory T-lymphocytes suppress or turn off
other T-lymphocytes. Without regulatory cells, the
immune system would keep working even after
an infection had been cured and overreact to the
infection. Regulatory T-lymphocytes act as the
thermostat of the lymphocyte system to keep it
turned on just enough—not too much and not
too little.
NK Cells
NK cells are so named because they easily
kill cells infected with viruses. They are said
to be Natural Killer (NK) cells as they do not
require the same thymic education process that
T-lymphocytes require. NK cells are derived from
the bone marrow and are present in relatively
low numbers in the bloodstream and in tissues.
They are extremely important in defending against
viruses and many people believe that they act to
prevent cancer.
They act to kill viruses by attaching to the cell
that contains the virus and injecting it with a
killer potion of chemicals. They are particularly
important in the defense against herpes viruses.
This family of viruses includes the traditional cold
sore form of herpes as well as Epstein Barr virus
(the cause of most infectious mononucleosis) and
the varicella virus which causes chicken pox.

The Immune System And Primary Immunodeficiency Diseases 5
CHAPTER 1; FIGURE 2
Cells of the Immune System
D
B
A B
C
S
Thymus
Bone Marrow
PMN M
RBC Platelet DC
I J K L M
PC
T-CD4
T-CD8
G H
IgG
IgM
IgE
IgA
F
E
A Bone Marrow: The site in the body where
most of the cells of the immune system
are produced as immature or stem cells
B Stem Cells: These cells have the
potential to differentiate and mature into
the different cells of the immune system
C Thymus: An organ located in the chest
which instructs immature lymphocytes to
become mature T-lymphocytes
D B-Lymphocytes: These lymphocytes
arise in the bone marrow and differentiate
into plasma cells which in turn produce
immunoglobulins (antibodies)
E Effector/Cytotoxic: These lymphocytes
arise in the bone marrow but migrate to
the thymus where they are instructed to
mature into T-lymphocytes
F T-helper Lymphocytes: These specialized
lymphocytes “help” other T-lymphocytes
and B-lymphocytes to perform their
functions
G Plasma Cells: These cells develop from
B-lymphocytes and are the cells that
make immunoglobulin
H Immunoglobulins: These highly specialized
protein molecules, also known as
antibodies, fit foreign antigens, such as
polio, like a lock and key. Their variety is
so extensive that they can be produced to
match all possible microorganisms in our
environment
I Polymorphonuclear (PMN) Cell: A type of
phagocytic cell found in the blood stream
J Monocytes: A type of phagocytic cell
found in the blood stream which develops
into a macrophage when it migrates to
tissues
K Red Blood Cells: The cells in the blood
stream which carry oxygen from the lungs
to the tissues
L Platelets: Small cells in the blood stream
which are important in blood clotting
M Dendritic Cells: Important cells in presenting
antigen to immune system cells

6 The Immune System And Primary Immunodeficiency Diseases
Components of the Immune System continued
Phagocytes
Phagocytes are specialized cells of the immune
system whose primary function is to ingest and kill
microorganisms. These cells, like the others in the
immune system, develop from primitive stem cells
in the bone marrow. When mature, they migrate to
all tissues of the body but are especially prominent
in the bloodstream, spleen, liver, lymph nodes,
and lungs.
There are several different types of phagocytic
cells. Polymorphonuclear leukocytes (neutrophils
or granulocytes) are found in the bloodstream and
can migrate into sites of infection within a matter
of minutes. It is this phagocytic cell that increases
in number in the bloodstream during infection
and is in large part responsible for an elevated
white blood cell count during infection. It also is
the phagocytic cell that leaves the bloodstream
and accumulates in the tissues during the first
few hours of infection, and is responsible for the
formation of “pus.”
Monocytes, another type of phagocytic cell, are
also found circulating in the bloodstream. They
also line the walls of blood vessels in organs
like the liver and spleen. Here they capture
microorganisms as they pass by in the blood.
When monocytes leave the bloodstream and
enter the tissues, they change shape and size and
become macrophages. Macrophages are essential
for killing fungi and the class of bacteria to which
tuberculosis belongs (mycobacteria).
Phagocytic cells serve a number of critical
functions in the body’s defense against infection.
They have the ability to leave the bloodstream and
move into the tissues to the site of infection. Once
at the site of infection, they ingest the invading
microorganisms. Ingestion of microorganisms
by phagocytic cells is made easier when the
microorganisms are coated with either antibody or
complement or both. Once the phagocytic cell has
engulfed or ingested the microorganism, it initiates
a series of chemical reactions within the cell which
result in the death of the microorganism.
Complement
The complement system is composed of 30
proteins, which function in an ordered and
integrated fashion to defend against infection
and produce inflammation. Most proteins in the
complement system are produced in the liver.
The complement components must be converted
from inactive forms to activated forms in order
to perform their protective functions. In some
instances, microorganisms must first combine
with antibody in order to activate complement.
In other cases, the microorganisms can activate
complement without the need for antibody. As
mentioned above, one of the proteins of the
complement system coats microorganisms to
make them more easily ingested by phagocytic
cells. Other components of complement act to
send out chemical signals to attract phagocytic
cells to the sites of infection.
When the complement system is assembled on
the surface of some microorganisms, a complex
is created which can puncture the microorganism
and cause it to burst.

The Immune System And Primary Immunodeficiency Diseases 7
CHAPTER 1; FIGURE 3
Normal Anti-bacterial Action
A
Key:
Neutrophil
Antibody
B
Bacteria
Complement
In most instances, bacteria are destroyed by the cooperative efforts of
phagocytic cells, antibody and complement.
A. Neutrophil (Phagocytic Cell) Engages Bacteria (Microbe): The
microbe is coated with specific antibody and complement. The
phagocytic cell then begins its attack on the microbe by attaching to
the antibody and complement molecules.
B. Phagocytosis Of The Microbe: After attaching to the microbe, the
phagocytic cell begins to ingest the microbe by extending itself around
the microbe and engulfing it.
C. Destruction Of The Microbe: Once the microbe is ingested, bags of
enzymes or chemicals are discharged into the vacuole where they kill
the microbe.
C

8 The Immune System And Primary Immunodeficiency Diseases
Examples of How the Immune System
Fights Infections
Bacteria
Our bodies are covered with bacteria and our
environment contains bacteria on most surfaces.
Our skin and internal mucous membranes act
as a physical barrier and prevent infection with
those bacteria in most cases. When the skin or
mucous membranes are broken due to disease,
inflammation, or injury, bacteria can enter the
body. An infecting bacteria is usually coated with
complement and antibody once it enters the
tissues and this allows the neutrophil to easily
recognize the bacteria as foreign. The neutrophil
then engulfs the bacteria and destroys it. When
the antibody, complement, and neutrophils are
all functioning normally, this is typically the end
of the process. When the number of bacteria is
overwhelming, or there are defects in antibody,
complement, and/or neutrophils, recurrent
bacterial infections can occur.
Viruses
Most of us are exposed to viruses frequently. The
way our bodies defend against viruses is slightly
different than how we fight bacteria. Viruses
can only survive and multiply inside our cells.
This allows them to hide somewhat from our
immune system. When a virus infects a cell, the
cell releases chemicals to alert other cells to the
infection and prevent other cells from becoming
infected. Many viruses have outsmarted this
protective strategy and they continue to spread
the infection. Circulating T-cells become alerted
to the infection and migrate to the site where they
kill the cells harboring the virus. This is a very
destructive manner to kill the virus since many
of our own cells are sacrificed in the process.
Nevertheless, it is an efficient mechanism to
eradicate the virus. Our bodies have a back-up
strategy so that we do not have to go through the
process of T-lymphocytes killing so many cells
each time we are infected. At the same time, the
T-lymphocytes are killing the virus, they are also
instructing the B-lymphocytes to make antibody.
When we are exposed to the same virus a second
time, the antibody will prevent the infection.

The Immune System And Primary Immunodeficiency Diseases 9
CHAPTER 1; FIGURE 4
Immunoglobulin Structure
A
B
Each class or type of immunoglobulin shares properties in common with
the others. They all have antigen binding sites which combine specifically
with the foreign antigen.
A. IgG: IgG is the major immunoglobulin class in the body and is found in
the blood stream as well as in tissues.
B. Secretory IgA: Secretory IgA is composed of two IgA molecules joined
by a J-chain and attached to a secretory piece. These modifications
allow the secretory IgA to be secreted into mucus, intestinal juices and
tears where it protects those areas from infection.
C. IgM: IgM is composed of five immunoglobulin molecules attached to
each other. It is formed very early in infection and activates complement
very easily.
C

10 The Immune System And Primary Immunodeficiency Diseases
The Immune System and Primary
Immunodeficiency Diseases
When part of the immune system is either absent
or its function is hampered, an immune deficiency
disease may result. An immune deficiency disease
may be caused either by an intrinsic (inborn)
defect in the cells of the immune system or an
extrinsic (coming from the outside) environmental
factor or agent. In the case of an inborn or
congenital defect, the immune deficiency disease
is a primary immune deficiency disease. When
the damage is caused by an extrinsic force, such
as an environmental factor or agent, it is called
a secondary immune deficiency disease. For
example, AIDS is a secondary immune deficiency
disease caused by the HIV virus. Secondary
immune deficiencies can also be caused by
irradiation, chemotherapy, malnutrition, and burns.
The secondary immune deficiencies are not
discussed in this handbook.
The primary immunodeficiency diseases are a
group of disorders caused by basic defects in
immune function that are intrinsic to, or inherent in,
the cells and tissues of the immune system. There
are over 150 primary immunodeficiency diseases.
Some are relatively common, while others are
quite rare. Some affect a single cell or protein of
the immune system and others may affect more
than one component of the immune system.
Although primary immunodeficiency diseases may
differ from one another in many ways, they share
one important feature. They all result from a defect
in one of the functions of the normal immune
system. The primary immunodeficiencies result
from defects in T-lymphocytes, B-lymphocytes, NK
cells, phagocytic cells or the complement system.
Most of them are inherited diseases and may run
in families, such as X-linked agammaglobulinemia
(XLA) or Severe Combined Immunodeficiency
(SCID). Other primary immunodeficiencies, such
as Common Variable Immunodeficiency (CVID)
and Selective IgA Deficiency are not always
inherited in a clear cut or predictable fashion. In
these disorders, the cause is unknown but the
interaction of genetic and environmental factors
may play a role in their causation.
Because one of the most important functions of
the normal immune system is to protect us against
infection, patients with primary immunodeficiency
diseases commonly have an increased susceptibility
to infection. This increased susceptibility to infection
may include too many infections, infections
that are difficult to clear, or unusually severe
infections. The infections may be located in the
sinuses (sinusitis), the bronchi (bronchitis), the
lung (pneumonia) or the intestinal tract (infectious
diarrhea). Another function of the immune system
is to discriminate between the individual (“self”) and
foreign material (“non-self”), such as microorganisms,
pollen or even a transplanted kidney from another
individual. In some immunodeficiency diseases, the
immune system is unable to discriminate between
“self” and “non-self.”
Therefore, in addition to an increased susceptibility
to infection, patients with immune deficiencies may
have autoimmune diseases in which their immune
system attacks their own cells or tissues as if they
were foreign or “non-self.” There are also a few
types of immune deficiencies in which the ability
to respond to an infection is intact, but the ability
to regulate that response is abnormal. Examples
of this are autoimmune lymphoproliferative
syndrome (ALPS) and IPEX (immunodeficiency,
polyendocrinopathy, X-linked syndrome).
Primary immunodeficiency diseases can occur in
individuals of any age. The original descriptions of
these diseases were in children, but as medical
experience has grown, many adolescents
and adults have been diagnosed with primary
immunodeficiency diseases. This is partly due
to the fact that some of the disorders, such as
Common Variable Immunodeficiency Disease
and Selective IgA Deficiency, may have their initial
clinical presentation in adult life. Another factor
is that effective therapy exists for nearly all of the
disorders and patients who were diagnosed in
infancy and childhood now reach adult life as
productive members of society.
Finally, the primary immunodeficiency diseases
were originally felt to be very rare. However, they
are more common than originally thought. In fact,
Selective IgA deficiency, occurs as often as one in
500 individuals, translating into 500,000 patients in
the United States alone. With so many individuals
affected with primary immunodeficiencies, it is no
surprise that research in the field of immunology
is advancing rapidly. Each year brings better
diagnostic strategies, and hope for more cures.

Common Variable
Immune Deficiency
chapter
2
Common Variable Immune Deficiency is a disorder characterized
by low levels of serum immunoglobulins (antibodies) and an
increased susceptibility to infections. The genetic causes of the
low levels of serum immunoglobulins are not known in most cases.
It is a relatively common form of immunodeficiency, hence, the
word “common.” The degree and type of deficiency of serum
immunoglobulins, and the clinical course, varies from patient to
patient, hence, the word “variable.”

12 Common Variable Immune Deficiency
Definition of Common Variable Immune Deficiency
Common Variable Immune Deficiency (CVID) is
a disorder characterized by low levels of serum
immunoglobulins (antibodies) and an increased
susceptibility to infections. The exact cause
of the low levels of serum immunoglobulins is
usually not known. It is a relatively common
form of immunodeficiency, hence, the word
“common.” The degree and type of deficiency of
serum immunoglobulins, and the clinical course,
varies from patient to patient, hence, the word
“variable.” In some patients, there is a decrease in
both IgG and IgA; in others, all three major types
(IgG, IgA and IgM) of immunoglobulins may be
decreased. The clinical signs and symptoms also
vary from severe to mild. Frequent and unusual
infections may first occur during early childhood,
adolescence or adult life. In the majority of
patients, the diagnosis is not made until the 3rd or
4th decade of life. However, about 20% of patients
have symptoms of disease or are found to be
immunodeficient under the age of 16.
Due to the relatively late onset of symptoms
and diagnosis, other names that have been
used for this disorder include “acquired”
agammaglobulinemia, “adult onset”
agammaglobulinemia, or “late onset”
hypogammaglobulinemia. The term “acquired
immunodeficiency” is now used to refer to a
syndrome caused by the AIDS virus (HIV) and
should not be used for individuals with CVID as
these two disorders are very different.
The causes of CVID are largely unknown although
recent studies have shown the involvement of
a small group of genes in some of the patients
(see chapter titled Inheritance). Over the past
few decades, studies on the cells of the immune
system in patients with CVID have revealed a
spectrum of lymphocyte abnormalities. Most
patients appear to have normal numbers of
B-lymphocytes, but they fail to undergo normal
maturation into plasma cells capable of making the
different types of immunoglobulins and antibodies.
Other patients lack enough function from helper
T-lymphocytes necessary for a normal antibody
response. A third group of patients have excessive
numbers of cytotoxic T-lymphocytes, although the
role of these cells in the disease is unclear.
Clinical Presentation of Common Variable
Immune Deficiency
Both males and females may have CVID. Some
patients have symptoms in the first few years of life
while many patients may not develop symptoms
until the second or third decade, or even later. The
presenting features of most patients with CVID
are recurrent infections involving the ears, sinuses,
nose, bronchi and lungs. When the lung infections
are severe and occur repeatedly, permanent
damage to the bronchial tree may occur and
a chronic condition of the bronchi (breathing
tubes) develops, causing widening and scarring
of these structures. This condition is known as
bronchiectasis. The organisms commonly found in
these infections are bacteria that are widespread
in the population and that often cause pneumonia
(Haemophilus influenzae, pneumococci, and
staphylococci). The purpose of treatment of lung
infections is to prevent their recurrence and the
accompanying chronic damage to lung tissue.
A regular cough in the morning that produces
yellow or green sputum may suggest the presence
of chronic infection or bronchiectasis (widening,
scarring and inflammation of the bronchi).
Patients with CVID may also develop enlarged
lymph nodes in the neck, the chest or abdomen.
The specific cause is unknown, but enlarged
lymph nodes may be driven by infection, immune
dysregulation, or both. Similarly, enlargement of
the spleen is relatively common, as is enlargement
of collections of lymphocytes in the walls of the
intestine called Peyer’s patches.
Although patients with CVID have a depressed
antibody response and low levels of immunoglobulin
in their blood (hypogammaglobulinemia), some of
the antibodies that are produced by these patients
may attack their own tissues (autoantibodies).
These autoantibodies may attack and destroy
blood cells (e.g. red cells, white cells or platelets).
Although, most individuals with CVID present first
with recurrent bacterial infections, in about 20% of
cases the first manifestation of the immune defect
is a finding of very low platelets in the blood, or
perhaps severe anemia due to destruction of red
cells. The autoantibodies may also cause arthritis
or endocrine disorders, such as thyroid disease.

Common Variable Immune Deficiency 13
Clinical Presentation of Common Variable Immune Deficiency continued
Some patients with CVID who may not be
receiving optimal immunoglobulin replacement
therapy may also develop a painful inflammation
of one or more joints. This condition is called
polyarthritis. In the majority of these cases, the
joint fluid does not contain bacteria. To be certain
that the arthritis is not caused by a treatable
infection; the joint fluid may be removed by
needle aspiration and studied for the presence of
bacteria. In some instances, a bacterium called
Mycoplasma may be the cause and can be difficult
to diagnose. The typical arthritis associated with
CVID may involve the larger joints such as knees,
ankles, elbows and wrists. The smaller joints (i.e.
the finger joints) are rarely affected. Symptoms
of joint inflammation usually disappear with
adequate immunoglobulin therapy and appropriate
antibiotics. In some patients, however, arthritis
may occur even when the patient is receiving
adequate immunoglobulin replacement.
Some patients with CVID report gastrointestinal
complaints such as abdominal pain, bloating,
nausea, vomiting, diarrhea and weight loss. Careful
evaluation of the digestive organs may reveal
malabsorption of fat and certain sugars. If a small
sample (biopsy) of the bowel mucosa is obtained,
characteristic changes may be seen. These
changes are helpful in diagnosing the problem and
treating it. In some patients with digestive problems,
a small parasite called Giardia lamblia has been
identified in the biopsies and in the stool samples.
Eradication of these parasites by medication may
eliminate the gastrointestinal symptoms.
Finally, patients with CVID may have an increased
risk of cancer, especially cancer of the lymphoid
system, skin and gastrointestinal tract.
Patients with CVID do not have physical
abnormalities unless complications have
developed. Some patients with CVID may have
an enlarged spleen and lymph nodes. If chronic
lung disease has developed, the patient may have
a reduced ability to exercise and decreased vital
capacity (the maximum amount of air that can
be taken into the lung voluntarily). Involvement of
the gastrointestinal tract may, in some instances,
interfere with normal growth in children or lead to
weight loss in adults.
Diagnosis of Common Variable
Immune Deficiency
CVID is suspected in children or adults who
have a history of recurrent infections involving
ears, sinuses, bronchi, and lungs. The diagnosis
is confirmed by finding low levels of serum
immunoglobulins, including IgG, IgA and usually
IgM. Patients who have received complete
immunizations against polio, measles, diphtheria
and tetanus will usually have very low or absent
antibody levels to one or more of these vaccines.
Immunization with other vaccines, such as the
pneumococcal vaccine, is done to define the
degree of immunodeficiency. In some instances,
these tests help the physician decide if the patient
will benefit from immunoglobulin replacement
therapy. The number of T-lymphocytes may also
be determined and their function tested in samples
of blood. With special laboratory techniques, it is
possible to determine if B-lymphocytes produce
antibody in a test tube (tissue culture) and if
T-lymphocytes have normal functions.

14 Common Variable Immune Deficiency
Genetics and Inheritance of Common Variable
Immune Deficiency
Due to the unclear genetic nature of CVID, a clear
pattern of inheritance has not been defined. In
some instances, more than one family member
is found to be deficient in one or more types of
immunoglobulins. For example, it is not unusual
for one family member to have CVID while another
may have selective IgA deficiency (see chapter
titled Selective IgA Deficiency).
In the past few years, mutations in several different
genes have been found to be associated with
CVID. These include inducible co-stimulatory
(ICOS) in one family and a protein on B-cells
(CD19) in several families as causes of autosomal
recessive CVID. Mutations in a cell receptor (TACI)
for two factors (BAFF or APRIL) needed for normal
growth and regulation of B-cells have also been
found in about 10% of patients with CVID. A
causative role of these mutations in the immune
defect is not yet clear since some of these
mutations can be found in people with normal
immunoglobulins.
Treatment for Common Variable
Immune Deficiency
The treatment of CVID is similar to that of
other disorders characterized by low levels
of serum immunoglobulins. In the absence
of a significant T-lymphocyte defect or organ
damage, immunoglobulin replacement therapy
almost always brings improvement of symptoms.
Immunoglobulin is extracted from a large pool
of human plasma consisting mostly of IgG and
containing all the important antibodies present in
the normal population (see chapter titled Specific
Medical Therapy).
Patients with chronic sinusitis or chronic lung
disease may also require long-term treatment
with broad-spectrum antibiotics. If mycoplasma
or chlamydia infections are suspected, antibiotics
specific for those organisms may be indicated. If
bronchiectasis has developed, physical therapy
and daily postural drainage are needed to remove
the secretions from the lungs and bronchi.
Patients with gastrointestinal symptoms and
malabsorption are evaluated for the presence of
Giardia lamblia, rotavirus and a variety of other
gastrointestinal infections.
Most patients with immunodeficiency and
arthritis respond favorably to treatment with
immunoglobulin replacement therapy.
Expectations for Common Variable
Immune Deficiency Patients
Immunoglobulin replacement therapy combined
with antibiotic therapy has greatly improved the
outlook of patients with CVID. The aim of the
treatment is to keep the patient free of infections
and to prevent the development of chronic lung
disease. The outlook for patients with CVID
depends on how much damage has occurred
to their lungs or other organs before diagnosis
and treatment with immunoglobulin replacement
therapy and how successfully infections can be
prevented in the future by using immunoglobulin
and antibiotic therapy.

X-Linked
Agammaglobulinemia
chapter
3
The basic defect in X-Linked Agammaglobulinemia is a failure of
B-lymphocyte precursors to mature into B-lymphocytes and
ultimately plasma cells. Since they lack the cells that are responsible
for producing immunoglobulins, these patients have severe
deficiencies of immunoglobulins.

16 X-Linked Agammaglobulinemia
Definition of X-Linked Agammaglobulinemia
X-Linked Agammaglobulinemia (XLA) was
first described in 1952 by Dr. Ogden Bruton.
This disease, sometimes called Bruton’s
Agammaglobulinemia or Congenital
Agammaglobulinemia, was one of the first
immunodeficiency diseases to be identified. XLA
is an inherited immunodeficiency disease in which
patients lack the ability to produce antibodies,
proteins that make up the gamma globulin or
immunoglobulin fraction of blood plasma.
Antibodies are an integral part of the body’s
defense mechanism against certain microorganisms
(e.g. bacteria, viruses). Antibodies are important
in the recovery from infections and also protect
against getting certain infections more than once.
There are antibodies specifically designed to
combine with each and every microorganism—
much like a lock and key. When microorganisms,
such as bacteria, land on a mucus membrane
or enter the body, antibody molecules specific
for that microorganism stick to the surface of the
microorganism. Antibody bound to the surface
of a microorganism can have one or more effects
that are beneficial to the person. For example,
some microorganisms must attach to body cells
before they can cause an infection and antibody
prevents the microorganism from “sticking” to the
cells. Antibody attached to the surface of some
microorganisms will also cause the activation of
other body defenses (such as a group of blood
proteins called serum complement) which can
directly kill the bacteria or viruses. Finally, antibody
coated bacteria are much easier for white blood
cells (phagocytes) to ingest and kill than bacteria
which are not coated with antibody. All of these
actions prevent microorganisms from invading body
tissues where they may cause serious infections
(see chapter titled The Immune System and Primary
Immunodeficiency Diseases).
The basic defect in XLA is an inability of the patient
to produce antibodies. Antibodies are proteins that
are produced by specialized cells in the body, called
the plasma cells (see chapter titled The Immune
System and Primary Immunodeficiency Diseases).
The development of plasma cells proceeds in an
orderly fashion from stem cells located in the bone
marrow. The stem cells give rise to immature
lymphocytes called pro-B-lymphocytes.
Pro-B-lymphocytes give rise to Pre-B-lymphocytes,
which in turn give rise to B-lymphocytes. Each
B-lymphocyte bears on its cell surface a sample
of the immunoglobulin that it is able to produce.
This cell surface immunoglobulin can bind
foreign substances, called antigens. When the
B-lymphocyte comes into contact with its specific
antigen, like the pneumococcus or tetanus toxoid,
it matures into an antibody secreting plasma cell.
Each B-cell makes a slightly different antibody (or
immunoglobulin) to allow the body to respond to
millions of different foreign substances.
Most patients with XLA have B-lymphocyte
precursors, but very few of these go on to become
B-lymphocytes. As a result, the underlying defect
in XLA is a failure of B-lymphocyte precursors
to mature into B-cells. Patients with XLA have
mutations in the gene that is necessary for the
normal development of B-lymphocytes. This gene,
discovered in 1993, is named BTK, or Bruton’s
Tyrosine Kinase, in honor of the discoverer of the
disorder, Dr. Ogden Bruton. As the name of the
disorder suggests, the BTK gene is located on the
X chromosome.

X-Linked Agammaglobulinemia 17
Clinical Presentation of X-Linked
Agammaglobulinemia
Patients with X-Linked Agammaglobulinemia (XLA)
are prone to develop infections because they lack
antibodies. The infections frequently occur at or
near the surfaces of mucus membranes, such as
the middle ear, sinuses and lungs, but in some
instances can also involve the bloodstream or
internal organs. As a result, patients with XLA may
have infections that involve the sinuses (sinusitis),
the eyes (conjunctivitis), the ears (otitis), the nose
(rhinitis), the airways to the lung (bronchitis) or the
lung itself (pneumonia). Gastrointestinal infections
can also be a problem, especially with the parasite
Giardia. Giardia may cause abdominal pain,
diarrhea, poor growth or loss of serum proteins
like gamma globulin. Some patients with XLA also
have problems with skin infections.
In patients without antibodies, any of these infections
may invade the bloodstream and spread to other
organs deep within the body, such as the bones,
joints or brain. Infections in XLA patients are usually
caused by microorganisms that are killed or
inactivated very effectively by antibodies in normal
people. The most common bacteria that cause
infection are the pneumococcus, the streptococcus,
the staphylococcus and Hemophilus influenzae.
Some specific kinds of viruses may also cause
serious infections in these patients.
On physical examination, most patients with XLA
have very small tonsils and lymph nodes (the
glands in your neck). This is because most of the
bulk of tonsils and lymph nodes is made up of
B-lymphocytes. In the absence of B-lymphocytes,
these tissues are reduced in size.
Diagnosis of X-Linked Agammaglobulinemia
The diagnosis of XLA should be considered in any
boy with recurrent or severe bacterial infections,
particularly if he has small or absent tonsils and
lymph nodes.
The first screening test should be an evaluation
of serum immunoglobulins. In most patients with
XLA all of the immunoglobulins (IgG, IgM and
IgA) are markedly reduced or absent. However,
there are exceptions; some patients make
some IgM or IgG. In addition, unaffected babies
make only small quantities of immunoglobulins
in the first few months of life, making it difficult
to distinguish an unaffected baby with a normal
delay in immunoglobulin production from a
baby with a true immunodeficiency. If the serum
immunoglobulins are low or if the physician
strongly suspects the diagnosis of XLA, the
number of B-cells in the peripheral blood should
be tested. A low percentage of B-cells (nearly
absent) in the blood is the most characteristic and
reliable laboratory finding in patients with XLA.
If a baby boy has a brother, maternal cousin or
maternal uncle with XLA, the newborn baby is at
risk to have XLA and his family and his physicians
should immediately determine the percentage
of B-cells in the blood so that treatment can be
started before an affected infant gets sick.
The diagnosis of XLA can be confirmed by
demonstrating the absence of BTK protein in
monocytes or platelets or by the detection of a
mutation in BTK in DNA. Almost every family has
a different mutation in BTK; however, members of
the same family usually have the same mutation.

18 X-Linked Agammaglobulinemia
Inheritance of X-Linked Agammaglobulinemia
X-Linked Agammaglobulinemia (XLA) is a genetic
disease and can be inherited or passed on in a
family. It is inherited as an X-linked recessive trait.
(For more information on how X-Linked recessive
traits are inherited, see chapter titled Inheritance.)
It is important to know the type of inheritance so
the family can better understand why a child has
been affected, the risk that subsequent children
may be affected and the implications for other
members of the family.
Now that the precise gene that causes XLA has
been identified, it is possible to test the female
siblings (sisters) of a patient with XLA, and other
female relatives such as the child’s maternal aunts,
to determine if they are carriers of the disease.
Carriers of XLA have no symptoms, but have a
50% chance of transmitting the disease to each of
their sons (see chapter titled Inheritance). In some
instances, it is also possible to determine if a fetus
of a carrier female will be born with XLA. Currently,
these genetic tests are being performed in only a
few laboratories.
Treatment for X-Linked Agammaglobulinemia
At this time, there is no way to cure patients who
have X-Linked Agammaglobulinemia (XLA). The
defective gene cannot be repaired or replaced, nor
can the maturation of B-lymphocyte precursors
to B-lymphocytes and plasma cells be induced.
However, patients with XLA can be given some of
the antibodies that they are lacking. The antibodies
are supplied in the form of immunoglobulins (or
gamma globulins), and can be given directly
into the blood stream (intravenously) or under
the skin (subcutaneously) (see chapter titled
Specific Medical Therapy). The immunoglobulin
preparations contain antibodies that substitute for
the antibodies that the XLA patient can not make
himself. They contain antibodies to a wide variety
of microorganisms. Immunoglobulin is particularly
effective in preventing the spread of infections
into the bloodstream and to deep body tissues or
organs. Some patients benefit from the use of oral
antibiotics every day to protect them from infection
or to treat chronic sinusitis or chronic bronchitis.
Patients with XLA should not receive any
live viral vaccines, such as live polio, or the
measles, mumps, rubella (MMR) vaccine.
Although uncommon, it is possible that live
vaccines (particularly the oral polio vaccine) in
agammaglobulinemia patients can transmit the
diseases that they were designed to prevent.
Expectations for X-Linked
Agammaglobulinemia Patients
Most X-Linked Agammaglobulinemia (XLA)
patients who receive immunoglobulin on a
regular basis will be able to lead relatively
normal lives. They do not need to be isolated or
limited in their activities. Active participation in
team sports should be encouraged. Infections
may require some extra attention from time to
time, but children with XLA can participate in all
regular school and extracurricular activities, and
when they become adults can have productive
careers and families. A full active lifestyle is to be
encouraged and expected.

Selective IgA Deficiency
chapter
4
Individuals with Selective IgA Deficiency lack IgA, but usually have
normal amounts of the other types of immunoglobulins. Most
affected people have no illness as a result. Others may develop a
variety of significant clinical problems. Selective IgA Deficiency is
relatively common in Caucasians.

20 Selective IgA Deficiency
Definition of Selective IgA Deficiency
Selective IgA Deficiency is the complete absence
of the IgA class of immunoglobulins in the blood
serum and secretions. There are five types
(classes) of immunoglobulins or antibodies in
the blood: IgG, IgA, IgM, IgD, and IgE. The
immunoglobulin class present in the largest
amount in blood is IgG, followed by IgM and
IgA. IgD is much lower, and IgE is present in only
minute amounts in the blood.
Of these immunoglobulin classes, it is primarily
IgM and IgG that protect us internally from
infection. It is also important that the body is
protected at surfaces that come into contact
with the environment. These sites are the
mucosal surfaces, which include: mouth, ears,
sinuses and nose, throat, airways within the
lung, gastrointestinal tract, eyes, and genitalia.
IgA antibodies are transported in secretions
to mucosal surfaces and play a major role in
protecting these surfaces from infection. Other
immunoglobulin classes are also found in
secretions at mucosal surfaces, but not in nearly
the same amount as IgA. This is why IgA is known
as the secretory antibody. If our mucosal surfaces
were spread out they would cover an area equal to
one and one-half tennis courts, so the importance
of IgA in protecting our mucosal surfaces cannot
be overstated.
IgA has some special chemical characteristics. It
is present in secretions as two antibody molecules
attached by a component called the J chain (“J”
for “joining”). In order for these antibodies to be
secreted, they must also be attached to another
molecule called the secretory piece. The IgA unit
that protects the mucosal surfaces is actually
composed of two IgA molecules joined by the J
chain and attached to the secretory piece.
Although individuals with Selective IgA Deficiency
do not produce IgA, they do produce all the other
immunoglobulin classes. In addition, the function
of their T-lymphocytes, phagocytic cells and
complement system are normal. Hence, the term
Selective IgA Deficiency.
The causes of Selective IgA Deficiency are
unknown. It is likely that there are a variety of
causes for Selective IgA Deficiency and the cause
may vary from individual to individual.
Low serum IgA, like absent serum IgA, is also
relatively common. Similarly, most people with
low serum IgA have no apparent illness. Some
people with low serum IgA have a clinical course
very similar to people with common variable
immunodeficiency (see chapter titled Common
Variable Immune Deficiency).
Clinical Features of Selective IgA Deficiency
Selective IgA Deficiency is one of the most
common primary immunodeficiency diseases.
Studies have indicated that as many as one in
every five hundred people have Selective IgA
Deficiency. Many of these individuals appear
healthy, or have relatively mild illnesses and
are generally not sick enough to be seen by a
doctor and may never be discovered to have IgA
deficiency. In contrast, there are individuals with
Selective IgA Deficiency who have significant
illnesses. Currently, it is not understood why some
individuals with IgA deficiency have almost no
illness while others are very sick. Also, it is not
known precisely what percent of individuals with
IgA deficiency will eventually develop complications;
estimates range from 25% to 50% over 20 years
of observation. Studies have suggested that
some patients with IgA deficiency may be missing
a fraction of their IgG (the IgG2 and/or IgG4
subclasses), and that may be part of the explanation
of why some patients with IgA deficiency are more
susceptible to infection than others.
A common problem in IgA deficiency is
susceptibility to infections. This is seen in about
half of the patients with IgA deficiency that come
to medical attention. Recurrent ear infections,
sinusitis, bronchitis and pneumonia are the
most common infections seen in patients with
Selective IgA Deficiency. Some patients also have
gastrointestinal infections and chronic diarrhea.
The occurrence of these kinds of infections is
easy to understand since IgA protects mucosal
surfaces. These infections may become chronic.
Furthermore, the infection may not completely
clear with treatment, and patients may have to
remain on antibiotics for longer than usual.

Selective IgA Deficiency 21
Clinical Features of Selective IgA Deficiency continued
A second major problem in IgA deficiency is the
occurrence of autoimmune diseases. These are
found in about 25% to 33% of patients who seek
medical help. In autoimmune diseases, individuals
produce antibodies or T-lymphocytes which react
with their own tissues with resulting inflammation and
damage. Some of the more frequent autoimmune
diseases associated with IgA deficiency are:
Rheumatoid Arthritis, Systemic Lupus Erythematosis
and Immune Thrombocytopenic Purpura (ITP).
These autoimmune diseases may cause sore and
swollen joints of the hands or knees, a rash on
the face, anemia (a low red blood cell count) or
thrombocytopenia (a low platelet count). Other kinds
of autoimmune disease may affect the endocrine
system and/or the gastrointestinal system.
Allergies may also be more common among
individuals with Selective IgA Deficiency than
among the general population. These occur in
about 10-15% of these patients. The types of
allergies vary. Asthma is one of the common
allergic diseases that occurs with Selective IgA
Deficiency. It has been suggested that asthma
may be more severe, and less responsive to
therapy, in individuals with IgA deficiency than it
is in normal individuals. Another type of allergy
associated with IgA deficiency is food allergy, in
which patients have reactions to certain foods.
Symptoms associated with food allergies are
diarrhea or abdominal cramping. It is not certain
whether there is an increased incidence of allergic
rhinitis (hay fever) or eczema in Selective IgA
Deficiency.
Patients with IgA Deficiency are often considered
to be at increased risk of anaphylactic reactions
when they receive blood products (including IVIG)
that contain some IgA. This is thought to be due
to IgG (or possibly IgE) anti-IgA antibodies which
may be found in some of these people. However,
it has been observed that many patients with IgA
deficiency do not have adverse reactions to blood
products or IVIG. There is no agreement among
experts in this field regarding the magnitude of the
risk of these types of reactions in IgA deficiency, or
the need for caution or measurement of anti-IgA
antibodies before administration of blood or IVIG
to these individuals.
Diagnosis of Selective IgA Deficiency
The diagnosis of Selective IgA Deficiency is usually
suspected because of either chronic or recurrent
infections, allergies, autoimmune diseases, chronic
diarrhea, or some combination of these problems.
The diagnosis is established when tests of the
patient’s blood serum demonstrate absence of
IgA with normal levels of the other major classes
of immunoglobulins (IgG and IgM). Most patients
make antibodies normally. An occasional patient
may also have IgG2 and/or IgG4 subclass
deficiency and associated antibody deficiency
(see chapter titled IgG Subclass Deficiency and
Specific Antibody Deficiency). The numbers and
functions of T-lymphocytes are normal. Several
other tests that may be important include a
complete blood count, measurement of lung
function, and urinalysis. Other tests that may be
obtained in specific patients include measurement
of thyroid function, measurement of kidney
function, measurements of absorption of nutrients
by the GI tract, and the test for antibodies directed
against the body’s own tissues (autoantibodies).

22 Selective IgA Deficiency
Treatment of Selective IgA Deficiency
It is not currently possible to replace IgA in IgA
deficient patients, although research toward
purification of human IgA is ongoing. However,
it remains to be seen if replacement of IgA by
any route (IV, oral, or topical) will be beneficial
for humans with IgA deficiency. Treatment of
the problems associated with Selective IgA
Deficiency should be directed toward the particular
problem. For example, patients with chronic or
recurrent infections need appropriate antibiotics.
Ideally, antibiotic therapy should be directed
at the specific organism causing the infection.
Unfortunately, it is not always possible to identify
these organisms, and the use of broad-spectrum
antibiotics may be necessary. Certain patients who
have chronic sinusitis or chronic bronchitis may
need to stay on long term preventive antibiotic
therapy. It is important that the doctor and the
patient communicate closely so that appropriate
decisions can be reached for therapy.
As mentioned above, some patients with IgA
deficiency also have IgG2 and/or IgG4 subclass
deficiency and/or a deficiency of antibody
production. However, these laboratory findings do
not always predict a greater frequency or severity of
infections. For patients with IgA and IgG2 deficiency
who do not respond adequately to antibiotics, the
use of replacement gamma globulin may be helpful
in diminishing the frequency of infections (see
chapter titled Specific Medical Therapy).
There are a variety of therapies for the treatment
of autoimmune diseases. Anti-inflammatory drugs,
such as aspirin or ibuprofen, are used in diseases
that cause joint inflammation. Steroids may be
helpful in a variety of autoimmune diseases. If
autoimmune disease results in an abnormality of
the endocrine system, replacement therapy with
hormones may be necessary. Treatment of the
allergies associated with IgA deficiency is similar
to treatment of allergies in general. It is not known
whether immunotherapy (allergy shots) is helpful in
the allergies associated with Selective IgA Deficiency,
although there is no evidence of any increased risk
associated with this therapy in these patients.
The most important aspect of therapy in IgA
deficiency is close communication between
the patient (and/or the patient’s family) and the
physician so that problems can be recognized and
treated as soon as they arise.
Expectations for Selective IgA Deficiency Patients
Although Selective IgA Deficiency is usually
one of the milder forms of immunodeficiency,
it may result in severe disease in some people.
Therefore, it is difficult to predict the long-term
outcome in a given patient with Selective IgA
Deficiency. In general, the prognosis in Selective
IgA Deficiency depends on the prognosis of the
associated diseases. It is important for physicians
to continually assess and reevaluate patients
with Selective IgA Deficiency for the existence of
associated diseases and the development of more
extensive immunodeficiency. For example, rarely,
IgA deficiency will progress to become Common
Variable Immunodeficiency with its deficiencies of
IgG and/or IgM. The physician should be notified
of anything unusual, especially fever, productive
cough, skin rash or sore joints. The key to a good
prognosis is adequate communication with the
physician and the initiation of therapy as soon as
disease processes are recognized.

Severe Combined
Immunodeficiency
chapter
5
Severe Combined Immunodeficiency is an uncommon primary
immunodeficiency in which there is combined absence of T-lymphocyte
and B-lymphocyte function. There are a number of different genetic
defects that can cause Severe Combined Immunodeficiency. These
defects lead to extreme susceptibility to very serious infections. This
condition is generally considered to be the most serious of the primary
immunodeficiencies. Fortunately, effective treatments, such as bone
marrow transplantation, exist that can cure the disorder and the future
holds the promise of gene therapy.

24
Severe Combined Immunodeficiency
Definition of Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID,
pronounced “skid”) is a rare, potentially fatal
syndrome of diverse genetic cause in which
there is combined absence of T-lymphocyte and
B-lymphocyte function (and in many cases also
natural killer, or NK lymphocyte function). These
defects lead to extreme susceptibility to serious
infections. There are currently twelve known
genetic causes of SCID. Although they vary
with respect to the specific defect that causes
the immunodeficiency, some of their laboratory
findings and their pattern of inheritance, these all
have severe deficiencies in both T-cell and B-cell
function (see chapter titled Inheritance).
Deficiency of the Common
Gamma Chain of the T-cell
Receptor
The most common form of SCID, affecting nearly
45% of all cases, is due to a mutation in a gene
on the X chromosome that encodes a component
(or chain) shared by the T-cell growth factor
receptor and other growth factor receptors. This
component is referred to as cg, for common
gamma chain. Mutations in this gene result in
very low T-lymphocyte and NK-lymphocyte
counts, but the B-lymphocyte count is high
(a so-called T-, B+, NK-phenotype). Despite the
high number of B-lymphocytes, there is no
B-lymphocyte function since the T-cells are not
able to “help” the B-cells to function normally (see
chapter titled The Immune System and Primary
Immunodeficiency Diseases). This deficiency is
inherited as an X-linked recessive trait. Only males
have this type of SCID, but females may carry the
gene and have a 1 in 2 chance (50%) of passing it
on to each son.
Adenosine Deaminase
Deficiency
Another type of SCID is caused by mutations in a
gene that encodes an enzyme called adenosine
deaminase (ADA). ADA is essential for the
metabolic function of a variety of body cells, but
especially T-cells. The absence of this enzyme
leads to an accumulation of toxic metabolic
by-products within lymphocytes that cause the
cells to die. ADA deficiency is the second most
common cause of SCID, accounting for 15% of
cases. Babies with this type of SCID have the
lowest total lymphocyte counts of all, and T, B and
NK-lymphocyte counts are all very low. This form
of SCID is inherited as an autosomal recessive
trait. Both boys and girls can be affected.
Deficiency of the Alpha Chain
of the IL-7 Receptor
Another form of SCID is due to mutations in a
gene on chromosome 5 that encodes another
growth factor receptor component, the alpha
chain of the IL-7 receptor (IL-7Ra). When T, B and
NK cell counts are done, infants with this type
have B and NK cells, but no T-cells. However, the
B-cells don’t work because of the lack of T-cells.
IL-7Ra deficiency is the third most common cause
of SCID accounting for 11% of SCID cases. It is
inherited as an autosomal recessive trait. Both
boys and girls can be affected.
Deficiency of Janus Kinase 3
Another type of SCID is caused by a mutation
in a gene on chromosome 19 that encodes an
enzyme found in lymphocytes called Janus kinase
3 (Jak3). This enzyme is necessary for function
of the above-mentioned cg. Thus, when T, B and
NK-lymphocyte counts are done, infants with this
type look very similar to those with X-linked SCID,
i.e. they are T-, B+, NK-. Since this form of SCID
is inherited as an autosomal recessive trait both
boys and girls can be affected. Jak3 deficiency
accounts for less than 10% of cases of SCID.
Deficiencies of CD3 Chains
Three other forms of SCID are due to mutations
in the genes that encode three of the individual
protein chains that make up another component
of the T-cell receptor complex, CD3. These SCIDcausing
gene mutations result in deficiencies of
CD3d, e or z chains. These deficiencies are also
inherited as autosomal recessive traits.
Deficiency of CD45
Another type of SCID is due to mutations in the
gene encoding CD45, a protein found on the
surface of all white cells that is necessary for T-cell
function. This deficiency is also inherited as an
autosomal recessive trait.

Severe Combined Immunodeficiency
25
Definition of Severe Combined Immunodeficiency continued
Other Causes of SCID
Four more types of SCID for which the molecular
cause is known are those due to mutations
in genes that encode proteins necessary for
the development of the immune recognition
receptors on T- and B-lymphocytes. These are:
recombinase activating genes 1 and 2 (RAG1 and
RAG2) deficiency (in some instances also known
as Ommen’s Syndrome), Artemis deficiency and
Ligase 4 deficiency. Infants with these types of
SCID lack T- and B-lymphocytes but have NK
lymphocytes, i.e. they have a T-B-NK+ phenotype.
These deficiencies are all inherited as autosomal
recessive traits.
Finally, there are probably other SCID-causing
mutations that have not yet been identified.
Less Severe Combined
Immunodeficiencies
There is another group of genetic disorders of
the immune system that results in combined
immunodeficiencies that usually do not reach
the level of clinical severity to qualify as severe
combined immunodeficiency. A list of several of
these disorders follows, although there may be
additional syndromes that qualify for inclusion as
combined immunodeficiency (CID) that are not
listed. These disorders include Bare Lymphocyte
syndrome (MHC class-II deficiency); purine
nucleoside phosphorylase (PNP) deficiency;
ZAP70 deficiency; CD25 deficiency; Cartilage-Hair
Hypoplasia; and MHC class I deficiency.
Clinical Presentation of Severe Combined
Immunodeficiency
An excessive number of infections is the most
common presenting symptom of infants with
SCID. These infections are not usually the same
sorts of infections that normal children have,
e.g., frequent colds. The infections of the infant
with SCID can be much more serious and even
life threatening and may include pneumonia,
meningitis or bloodstream infections. The widespread
use of antibiotics even for minimal infections has
changed the pattern of presentation of SCID, so
the doctor seeing the infant must have a high
index of suspicion in order to detect this condition.
Organisms that cause infections in normal children
may cause infections in infants with SCID, or
they may be caused by organisms or vaccines
which are usually not harmful in children who have
normal immunity. Among the most dangerous is
an organism called Pneumocystis jiroveci which
can cause a rapidly fatal pneumonia (PCP) if not
diagnosed and treated promptly. Another very
dangerous organism is the chickenpox virus
(varicella). Although chickenpox is annoying and
causes much discomfort in healthy children,
it usually is limited to the skin and mucous
membranes and resolves in a matter of days. In
the infant with SCID, it can be fatal because it
doesn’t resolve and can then infect the lung, liver
and the brain. Cytomegalovirus (CMV), which
nearly all of us carry in our salivary glands, may
cause fatal pneumonia in infants with SCID.
Other dangerous viruses for SCID infants are
the cold sore virus (Herpes simplex), adenovirus,
parainfluenza 3, Epstein-Barr virus (EBV or the
infectious mononucleosis virus), polioviruses, the
measles virus (rubeola) and rotavirus.
Since vaccines that infants receive for chickenpox,
measles and rotavirus are live virus vaccines, infants
with SCID can contract infections from those
viruses through the immunizations. If it is known
that someone in the family has had SCID in the
past, or currently has SCID, these vaccines should
not be given to new babies born into the family
until SCID has been ruled out in those babies.
Fungal (yeast) infections may be very difficult to
treat. As an example, candida fungal infections of
the mouth (thrush), are common in most babies
but usually disappear spontaneously or with
simple oral medication. In contrast, for the child
with SCID, oral thrush usually persists despite
all medication; it may improve but it doesn’t
go completely away or recurs as soon as the
medication is stopped. The diaper area may also
be involved. Occasionally, candida pneumonia,
abscesses, esophageal infection or even
meningitis may develop in SCID infants.

26
Severe Combined Immunodeficiency
Clinical Presentation of Severe Combined Immunodeficiency continued
Persistent diarrhea resulting in failure to thrive
is a common problem in children with SCID. It
may lead to severe weight loss and malnutrition.
The diarrhea may be caused by the same
bacteria, viruses or parasites which affect normal
children. However, in the case of SCID, the
organisms are very difficult to get rid of once they
become established.
The skin may be involved in children with SCID.
The skin may become chronically infected with
the same fungus (candida) that infects the mouth
and causes thrush. SCID infants may also have a
rash that is mistakenly diagnosed as eczema, but
is actually caused by a reaction of the mother’s
T-cells (that entered the SCID baby’s circulation
before birth) against the baby’s tissues. This
reaction is called graft-versus-host disease (GVHD).
Diagnosis of Severe Combined Immunodeficiency
The diagnosis is usually first suspected in children
because of the above clinical features. However,
in some instances there has been a previous child
with SCID in the family and this positive family
history may prompt the diagnosis even before the
child develops any symptoms. One of the easiest
ways to diagnose this condition is to count the
peripheral blood lymphocytes in the child (or those
in the cord blood). This is done by two tests; the
complete blood count and the manual differential
(or a count of the percentage of each different type
of white cell in the blood), from which the doctor
can calculate the absolute lymphocyte count (or
total number of lymphocytes in the blood). There
are usually more than 4000 lymphocytes (per
cubic millimeter) in normal infant blood in the first
year of life, 70% of which are T-cells. Since SCID
infants have no T-cells, they usually have many
fewer lymphocytes than this. The average for all
types of SCID is 1500 lymphocytes (per cubic
millimeter). If a low lymphocyte count is found, this
should be confirmed by repeating the test once
more. If the count is still low, then tests that count
T-cells and measure T-cell function should be done
promptly to confirm or exclude the diagnosis.
The different types of lymphocytes can be
identified with special stains and counted. In this
way, the number of total T-lymphocytes, helper
T-lymphocytes, killer T-lymphocytes, B-lymphocytes
and NK-lymphocytes can be counted. Since
there are other conditions that can result in lower
than normal numbers of the different types of
lymphocytes, the most important tests are those
of T-cell function. The most definitive test to
examine the function of the T-lymphocytes is to
place blood lymphocytes in culture tubes, treat
them with various stimulants and then incubate
them for several days. Normal T-lymphocytes react
to these stimulants by undergoing cell division.
In contrast, lymphocytes from patients with SCID
usually do not react to these stimuli.
Immunoglobulin levels are usually very low in
SCID. Most commonly (but not always), all
immunoglobulin classes are depressed (i.e. IgG,
IgA, IgM and IgE). Since IgG from the mother
passes into the baby’s blood through the placenta,
it will be present in the newborn’s and young
infant’s blood at nearly normal levels. Therefore,
the immunoglobulin deficiency may not be
recognized for several months until the transferred
maternal IgG has been metabolized away.

Severe Combined Immunodeficiency
27
Diagnosis of Severe Combined Immunodeficiency continued
The diagnosis of SCID can also be made in
utero (before the baby is born) if there has been
a previously affected infant in the family and
if the molecular defect has been identified. If
mutational analysis had been completed on the
previously affected infant, a diagnosis can be
determined for the conceptus (an embryo or fetus
with surrounding tissues). This can be done by
molecular testing of cells from a chorionic villous
sampling (CVS) or from an amniocentesis, where
a small amount of fluid (which contains fetal
cells) is removed from the uterine cavity. Even
if the molecular abnormality has not been fully
characterized in the family, there are tests that can
rule out certain defects. For example, adenosine
deaminase deficiency can be ruled in or out by
enzyme analyses on the above-mentioned CVS
or amnion cells. If there is documentation that the
form of SCID is inherited as an X-linked recessive
trait and the conceptus is a female, she would not
be affected.
In a majority of cases, unless termination of the
pregnancy is a consideration if the fetus is affected,
the diagnosis is best made at birth on cord blood
lymphocytes. This is because there is some risk
to the fetus by the above procedures if blood is
collected for lymphocyte studies while he or she is
in utero.
Early diagnosis, before the infant has had a
chance to develop any infections, is extremely
valuable since bone marrow transplants given in
the first 3 months of life have a 96% success rate.
In fact, screening all newborns to detect SCID
soon after birth is technically possible because of
recent scientific advances. In fact, pilot programs
to test the feasibility of newborn screening in
all infants are planned. If simple screening tests
were done on the cord blood of all babies born in
the United States, all infants with SCID could be
diagnosed at birth and transplantation could be
accomplished shortly after that with expectation of
a greater than 96% success rate.
Inheritance of Severe Combined
Immunodeficiency
All types of SCID are probably due to genetic
defects. These defects can be inherited from the
parents or can be due to new mutations that arise
in the affected infant. As already noted, the defect
can be inherited either as an X-linked (sex-linked)
defect where the gene is inherited from the mother
or as one of multiple types of autosomal recessive
defects (see previous section on the causes SCID)
where both parents carry a defective gene. The
reader should turn to the chapter titled Inheritance
to more fully understand how autosomal recessive
and sex-linked recessive diseases are inherited,
the risks for having other children with the disease
and how these patterns of inheritance affect other
family members. Parents should seek genetic
counseling so that they are aware of the risks of
future pregnancies.
It should be emphasized that there is no right
or wrong decision about having more children.
The decision must be made in light of the special
factors involved in the family structure, the basic
philosophy of the parents, their religious beliefs
and background, their perception of the impact of
the illness upon their lives, and the lives of all the
members of the family. There are countless factors
that may be different for each family.

28
Severe Combined Immunodeficiency
General Treatment of Severe Combined
Immunodeficiency
Infants with this life-threatening condition
need all the support and love that parents can
provide. They may have to tolerate repeated
hospitalizations which, in turn, may be associated
with painful procedures. Parents need to call upon
all of their inner resources to learn to handle the
anxiety and stress of this devastating problem.
They must have well-defined and useful coping
mechanisms and support groups. The demands
on the time and energies of the parents caring
for a patient with SCID can be overwhelming. If
there are siblings, parents must remember that
they need to share their love and care with them.
Parents also need to spend energy in maintaining
their own relationship with each other. If the stress
of the child’s illness and treatment destroys the
family structure, a successful therapeutic outcome
for the patient is a hollow victory indeed.
The infant with SCID needs to be isolated from
children outside the family, especially from young
children. If there are siblings who attend daycare,
religious school, kindergarten or grade school, the
possibility of bringing chickenpox into the home
represents the greatest danger. Fortunately, this
threat is being diminished by the widespread use
of the chickenpox vaccine (Varivax). Nevertheless,
the parents need to alert the school authorities as
to this danger, so that they can be notified if and
when chickenpox is in the school. If the siblings
have been vaccinated or have had chickenpox,
there is no danger. If the siblings have a close
exposure and they have not been vaccinated
nor had chickenpox themselves, they should live
in another house during the incubation period
(11 to 21 days). Examples of close contacts for
the sibling would be sitting at the same reading
table, eating together or playing with a child who
breaks out in the “pox” anytime within 72 hours of
that exposure. If the sibling breaks out with “pox”
at home and exposes the patient, the patient
should receive varicella immunoglobulin (VZIG) or
immunoglobulin replacement therapy immediately.
If, despite this, the SCID infant breaks out with
“pox”, he or she should be given intravenous
acyclovir in the hospital for 5-7 days. Children who
have been vaccinated with live polio vaccine may
excrete live virus which could be dangerous to
the SCID infant. Therefore, children who come in
contact with the patient (such as siblings) should
receive the killed polio vaccine.
Usually the infant with SCID should not be taken
to public places (daycare nurseries, church
nurseries, doctors’ offices, etc.) where they are
likely to be exposed to other young children who
could be harboring infectious agents. Contact with
relatives should also be limited, especially those
with young children. Neither elaborate isolation
procedures nor the wearing of masks or gowns
by the parents is necessary at home. However,
frequent hand-washing is essential.
Although no special diets are helpful, nutrition is
nevertheless very important. In some instances,
the child with SCID cannot absorb food normally,
which in turn can lead to poor nutrition. As a
result, in some instances the child may need
continuous intravenous feedings to maintain
normal nutrition. Sick children generally have poor
appetites, so maintaining good nutrition may not
be possible in the usual fashion (see chapter titled
General Care).
Death from infection with Pneumocystis jiroveci, a
widespread organism which rarely causes infection
in normal individuals, but causes pneumonia in
SCID patients, used to be a common occurrence
in this syndrome. Pneumonia from this organism
can be prevented by prophylactic treatment with
trimethoprim-sulfamethoxazole. All infants with
SCID should receive this preventive treatment until
their T-cell defect has been corrected.
Live virus vaccines and non-irradiated blood
or platelet transfusions are dangerous. If
you or your doctor suspect that your child has a
serious immunodeficiency, you should not allow
rotavirus, chickenpox, mumps, measles, live virus
polio or BCG vaccinations to be given to your child
until their immune status has been evaluated. As
mentioned above, the patient’s siblings should not
receive live poliovirus vaccine or the new rotavirus
vaccine. If viruses in the other live virus vaccines
are given to the patient’s siblings, they are not
likely to be shed or transmitted from the sibling
to the patient. The exception to this could be the
chickenpox vaccine if the sibling develops a rash
with blisters.
If your SCID infant needs to have a blood or
platelet transfusion, your infant should always get
irradiated (CMV-negative, leukocyte-depleted)
blood or platelets. This precaution is necessary
in order to prevent fatal GVHD from T-cells in
blood products and to prevent your infant from
contracting an infection with CMV.

Severe Combined Immunodeficiency
29
Specific Therapy for Severe Combined
Immunodeficiency
Immunoglobulin (IVIG) replacement therapy should
be given to SCID infants who are more than 3
months of age and/or who have already had
infections. Although immunoglobulin therapy will
not restore the function of the deficient T-cells, it
does replace the missing antibodies resulting from
the B-cell defect and is, therefore, of some benefit.
For patients with SCID due to ADA deficiency,
replacement therapy with a modified form of
the enzyme (from a cow, called PEG-ADA) has
been used with some success. The immune
reconstitution effected by PEG-ADA is not a
permanent cure and requires 2 subcutaneous
injections weekly for the rest of the child’s life.
PEG-ADA treatment is not recommended if the
patient has an HLA-matched sibling available as a
donor for a marrow transplant.
The most successful therapy for SCID is immune
reconstitution by bone marrow transplantation.
Bone marrow transplantation for SCID is best
performed at medical centers that have had
experience with SCID and its optimal treatment
and where there are pediatric immunologists
overseeing the transplant. In a bone marrow
transplant, bone marrow cells from a normal donor
are given to the immunodeficient patient to replace
the defective lymphocytes of the patient’s immune
system with the normal cells of the donor’s
immune system. The goal of transplantation in
SCID is to correct the immune dysfunction. This
contrasts with transplantation in cancer patients,
where the goal is to eradicate the cancer cells and
drugs suppressing the immune system are used
heavily in that type of transplant.
The ideal donor for a SCID infant is a perfectly
HLA-type matched normal brother or sister.
Lacking that, techniques have been developed
over the past three decades that permit good
success with half-matched related donors
(such as a mother or a father). Pre-transplant
chemotherapy is usually not necessary. Several
hundred marrow transplants have been performed
in SCID infants over the past 30 years, with an
overall survival rate of 60-70%. However, the
outcomes are better if the donor is a matched
sibling (>85% success rate) and if the transplant
can be performed soon after birth or less than 3.5
months of life (>96% survival even if only halfmatched).
HLA-matched bone marrow or cord
blood transplantation from unrelated donors has
also been used successfully to treat SCID.
There does not appear to be any advantage to
in utero marrow stem cell transplantation over
transplantaion performed immediately after birth.
Moreover, the mother would probably not be able
to be used as the donor since anesthesia would
cause some risk to the fetus, the procedures carry
risk to both mother and fetus, and there would be
no way to detect GVHD.
Finally, another type of treatment that has been
explored over the past two decades is gene
therapy. There have been successful cases of
gene therapy in both X-linked and ADA-deficient
SCID. However, research in this area is still being
conducted to make this treatment safer. One
cannot perform gene therapy unless the abnormal
gene is known, hence the importance of making a
molecular diagnosis.
Expectations for Severe Combined
Immunodeficiency Patients
Severe combined immunodeficiency syndrome
is generally considered to be the most serious
of the primary immunodeficiencies. Without a
successful bone marrow transplant or gene
therapy, the patient is at constant risk for a severe
or fatal infection. With a successful bone marrow
transplant, the patient’s own defective immune
system is replaced with a normal immune system,
and normal T-lymphocyte function is restored.
The first bone marrow transplantation for SCID
was performed in 1968. That patient is alive and
well today.

chapter
6
Chronic Granulomatous
Disease
Chronic Granulomatous Disease (CGD) is a genetically determined
(inherited) disease characterized by an inability of the body’s
phagocytic cells (also called phagocytes) to make hydrogen
peroxide and other oxidants needed to kill certain microorganisms.

Chronic Granulomatous Disease 31
Definition of Chronic Granulomatous Disease
Chronic Granulomatous Disease (CGD) is
a genetically determined (inherited) disease
characterized by an inability of the body’s
phagocytic cells (also called phagocytes) to
make hydrogen peroxide and other oxidants
needed to kill certain microorganisms. As a result
of this defect in phagocytic cell killing, patients
with CGD have an increased susceptibility to
infections caused by certain bacteria and fungi.
The condition is also associated with an excessive
accumulation of immune cells into aggregates
called granulomas (hence the name of the disease)
at sites of infection or other inflammation.
The term “phagocytic” (from the Greek, phagein,
“to eat”) is a general term used to describe any
white blood cell in the body that can surround
and ingest microorganisms into tiny membrane
packets in the cell. The membranes packets
(also called phagosomes) are filled with digestive
enzymes and other antimicrobial substances.
In general, there are two main categories of
phagocytic cells found in the blood, neutrophils
and monocytes. Neutrophils (also called
granulocytes or polymorphonuclear leukocytes
[PMNs]) comprise 50-70% of all circulating white
blood cells and are the first responders to bacterial
or fungal infections. Neutrophils are short lived,
lasting only about three days in the tissues after
they kill microorganisms. Monocytes are the other
type of phagocyte, making up about 1-5% of
circulating white blood cells. Monocytes entering
the tissues can live a long time, slowly changing
into cells called macrophages or dendritic cells
which help to deal with infections.
Phagocytes look very much like amoeba in that
they can easily change shape and crawl out of
blood vessels and into tissues, easily squeezing
between other cells. They can sense the presence
of bacteria or fungus pathogens that cause an
infection in the tissues and then, crawl rapidly
to the site of infection. When the phagocytes
arrive at the site of infection, they approach the
microorganism and attempt to engulf it and
contain it inside a pinched off piece of membrane
that forms a sort of bubble, or membrane packet,
inside the cell called a phagosome. The cell is
then triggered to dump packets of digestive
enzymes and other antimicrobial substances
into the phagosome. The cell also produces
hydrogen peroxide and other toxic oxidants that
are secreted directly into the phagosome. The
hydrogen peroxide works together with the other
substances to kill and digest the infection microbe.
Although phagocytes from patients with CGD
can migrate normally to sites of infection, ingest
infecting microbes and even dump digestive
enzymes and other antimicrobial substances into
the phagosome, they lack the enzyme machinery
to make hydrogen peroxide and other oxidants.
Thus, CGD patients’ phagocytes can defend
against some types of infections, but not infections
which specifically require hydrogen peroxide for
control of the infection. Their defect in defense
against infection is limited to only certain bacteria
and fungi. CGD patients do have normal immunity
to most viruses and to some kinds of bacteria and
fungi. This is why CGD patients are not infected
all the time. Instead they may go months to years
without infections, and then experience episodes
of severe life-threatening infections with microbes
that especially require hydrogen peroxide for
control. CGD patients make normal amounts and
types of antibodies, so that unlike patients with
inherited defects in lymphocyte function, CGD
patients are not particularly susceptible to viruses.
In summary, the phagocytic cells of patients with
CGD fail to produce hydrogen peroxide, but
otherwise retain many other types of antimicrobial
activities. This leads CGD patients to be
susceptible to infections with a special subset of
bacteria and fungi. They have normal antibody
production, normal T-cell function, and a normal
complement system; in short, much of the rest of
their immune system is normal.

32 Chronic Granulomatous Disease
Clinical Presentation of Chronic
Granulomatous Disease
Children with Chronic Granulomatous Disease
(CGD) are usually healthy at birth. Then, sometime
in their first few months or years of life, they may
develop recurrent bacterial or fungal infections.
The most common presentation of CGD in
infancy is a skin or bone infection with bacteria
called Serratia marcescens. In fact, any infant
with a major soft tissue or bone infection with
this particular organism is usually tested for CGD.
Similarly, if an infant develops an infection with an
unusual fungus called Aspergillis, this may result in
testing for CGD.
The infections in CGD may involve any organ
system or tissue of the body, but the skin, lungs,
lymph nodes, liver, bones and occasionally brain
are the usual sites of infection. Infected lesions
may have prolonged drainage, delayed healing
and residual scarring. Infection of a lymph node is
a common problem in CGD, often requiring either
drainage of the lymph node or in many cases
surgical removal of the affected lymph node to
achieve cure of the infection.
Pneumonia is a recurrent and common problem
in patients with CGD. Almost 50% of pneumonias
in CGD patients are caused by fungi, particularly
Aspergillus. Other organisms such as Burkholderia
cepacia, Serratia marcescens, Klebsiella
pneumoniae and Nocardia also commonly cause
pneumonia. Fungal pneumonias may come on
very slowly, initially only causing a general sense
of fatigue, and only later causing cough or chest
pain. Surprisingly, many fungal pneumonias
do not cause fever in the early phases of the
infection. By contrast bacterial infections usually
present acutely with fever and cough. Nocardia
in particular, causes high fevers and can also
result in lung abscesses that can destroy parts of
lung tissue. Since pneumonias can be caused by
so many different organisms and it is important
to catch these infections early and treat them
aggressively for a long period of time, it is critical
to seek medical attention early. There should be
a low threshold for getting a chest X-ray or even
a computerized tomography (CAT) scan of the
chest, followed by other diagnostic procedures
to make a specific diagnosis. Treatment often
requires more than one antibiotic and effective
treatment to cure an infection may require many
weeks of antibiotics.
Liver abscess can also occur in patients with
CGD. This may present with generalized malaise,
but often is associated with mild pain over the liver
area of the abdomen. Imaging scans are required
for diagnosis and needle biopsy is necessary to
determine the organism causing the abscess.
Staphylococcus causes about 90% of liver
abscesses. Often the liver abscesses do not form
a large easily drained pocket of pus, but instead
forms a hard lump or granuloma and multiple tiny
abscesses in the liver. This solid mass of infection
may require surgical removal for cure.
Osteomyelitis (bone infections) frequently involves
the small bones of the hands and feet, but can
involve the spine, particularly in cases that spread
from an infection in the lungs, such as with fungi
such as Aspergillus.
There are many potent new antibacterial and
antifungal antibiotics, many of them very active in
oral form, which treat CGD infections. Due to this,
there has been significant improvement in the rates
of successful cure of infection without significant
organ damage from the infection. However, this
requires prompt diagnosis of the infection and
prolonged administration of antibiotics.
Some infections may result in the formation of
localized, swollen collections of infected tissue.
In some instances, these swellings may cause
obstruction of the intestine or urinary tract. They
often contain microscopic groups of cells called
granulomas. In fact, it is the granuloma formation
that was the basis for the name of the disease.
Granulomas can also form without any clear
infection cause and may result in sudden blockage
of the urinary system in small children. In fact,
about 20% of CGD patients develop some type
of inflammatory bowel disease as a result of CGD
granulomas and in some cases is indistinguishable
from Crohn’s Disease.

Chronic Granulomatous Disease 33
Diagnosis of Chronic Granulomatous Disease
Because the most common genetic type of CGD
affects only boys, it may be mistakenly assumed that
CGD cannot affect girls. However, there are several
genetic types of CGD, and some do affect girls. In
fact, about 15% of all CGD patients are girls.
CGD can vary in its severity and there is a certain
amount of chance as to when a patient with
CGD develops a severe infection. For this reason
there are some CGD patients that may not have
an infection that draws attention to the disease
until late adolescence or even adulthood. While
it is more common to see infections that lead
to diagnosis in early childhood, surprisingly, the
average age of diagnosis of boys with CGD is
about three years old and of girls, seven years
old. It is important for pediatricians and internists
caring for adolescents and young adults not to
completely dismiss the possibility of a diagnosis of
CGD in a young adult patient who gets pneumonia
with an unusual organism like the Aspergillus
fungus. Any patient of any age who presents with
an Aspergillus, Nocardia or Burkholderia cepacia
pneumonia, a staphylococcus liver abscess or
pneumonia, or a bone infection with Serratia
marcescens should be tested to rule out CGD.
These are the usual combinations of organisms
and sites of infection that commonly trigger testing
for CGD. By contrast, merely having an occasional
staphylococcal infection of the skin is not
particularly a special sign of CGD, nor is recurrent
middle ear infections, though CGD patients can
also suffer from these problems.
The most accurate test for CGD measures the
production of hydrogen peroxide in phagocytic
cells. Hydrogen peroxide produced by normal
phagocytes oxidizes a chemical called
Dihydrorhodamine, making it fluorescent and the
fluorescence is measured with a sophisticated
machine. In contrast, phagocytic cells from
CGD patients cannot produce enough hydrogen
peroxide to make the dihydrorhodamine fluoresce.
There are other types of tests still used to
diagnose CGD, such as the Nitroblue Tetrazolium
(NBT) slide test. The NBT is a visual test in which
phagocytes producing oxidants turn blue and are
scored manually using a microscope. It is more
prone to human subjective assessment and can
lead to false negatives, occasionally missing the
diagnosis of CGD in patients with mild forms
of CGD, where cells may turn slightly blue, but
actually are abnormal.
Once a diagnosis of CGD is made, there are
a few specialized labs that can confirm the genetic
sub-type of CGD.
Inheritance Pattern of Chronic
Granulomatous Disease
Chronic Granulomatous Disease (CGD) is a
genetically determined disease and can be
inherited or passed on in families. There are two
patterns for transmission. One form of the disease
affects about 75% of cases and is inherited in
a sex-linked (or X-linked) recessive manner;
i.e. it is carried on the “X” chromosome. Three
other forms of the disease are inherited in an
autosomal recessive fashion. They are carried on
chromosomes other than the “X” chromosome
(see chapter titled Inheritance). It is important to
understand the type of inheritance so families can
understand why a child has been affected, the risk
that subsequent children may be affected, and the
implications for other members of the family.

34 Chronic Granulomatous Disease
Treatment of Chronic Granulomatous Disease
A mainstay of therapy is the early diagnosis
of infection and prompt, aggressive use of
appropriate antibiotics. Initial therapy with
antibiotics aimed at the most likely offending
organisms may be necessary while waiting for
results of cultures. A careful search for the cause
of infection is important so that sensitivity of the
microorganism to antibiotics can be determined.
Intravenous antibiotics are usually necessary for
treating serious infections in CGD patients and
clinical improvement may not be obvious for a
number of days in spite of treatment with the
appropriate antibiotics. In the past, granulocyte
transfusions have been used for some CGD
patients when aggressive antibiotic therapy fails
and the infection is life-threatening. Fortunately,
this is not commonly needed any more because of
the availability of newer, more potent antibacterial
and antifungal antibiotics.
Some patients with CGD have such frequent
infections, especially as young children, that
continuous daily administered oral antibiotics
(prophylaxis) are often recommended. CGD
patients who receive prophylactic antibiotics may
have infection-free periods and prolonged intervals
between serious infections. The most effective
antibiotic to prevent bacterial infection in CGD is
a formulation of the combination of trimethoprim
and sulfamethoxasole, sometimes also called
co-trimazole or under the trade names, Bactrim
or Septra. This reduces frequency of bacterial
infection by almost 70%. It is a safe and effective
agent for CGD patients because it provides
coverage for most of the bacterial pathogens
that cause infection in CGD, but does not have
much effect on normal bowel flora, leaving most
of the normal protective bacterial ecology of the
gut in place. The other important thing about
co-trimazole prophylaxis is that it does not seem
to wane in its effectiveness. This is because the
bacteria that it protects against in CGD are not
normally found in patients except in the setting
of an actual infection. So, the antibiotic does not
usually cause the organisms it is protecting against
to become resistant.
A natural product of the immune system, gamma
interferon, is also used to treat patients with
CGD to boost their immune system. Patients
with CGD who are treated with gamma interferon
have been shown to have more than 70% fewer
infections, and when infections do occur, they
may be less serious (see chapter titled Specific
Medical Therapy). CGD patients are not deficient
in gamma interferon, and gamma interferon is not
a cure for CGD. It augments immunity in a number
of general ways that partially compensate for the
defect in hydrogen peroxide production. Gamma
interferon may have side effects such as causing
fever, nightmares, fatigue and problems with
concentration. Antipyretics such as ibuprofren may
help. Some patients choose not to take gamma
interferon because they do not like injections,
because of the cost or because they have
unacceptable side effects. There is some evidence
that even doses of gamma interferon lower than
the standard recommendation may provide
some protection against infection. Due to this, a
number of experts in the field have suggested that
patients, who decide not to take gamma interferon
for any of the above reasons, should at least first
consider trying lower or less frequent dosing. In
particular, side effects are usually dose dependent
and may be decreased or eliminated by lowering
the dose of gamma interferon which will likely still
provide infection prophylaxis even at the lower
dose or frequency of administration.
More recently it has been demonstrated that daily
doses of the oral antifungal agent, Itraconazole,
can reduce the frequency of fungal infections in
CGD. Maximum infection prophylaxis for CGD
involves treatment with daily oral doses of cotrimazole
and itraconazole together, plus three
times weekly injections of gamma interferon.
On this regimen, the average rate of infection
in CGD patients drops to an average of one
severe infection approximately every four years.
Of course individual genetic factors and chance
result in some CGD patients having more frequent
infections while others have infections even less
frequently than every four years.

Chronic Granulomatous Disease 35
Treatment of Chronic Granulomatous Disease (continued)
CGD can be cured by successful bone marrow
transplant, but most CGD patients do not seek
this option. This may be because they lack a
fully tissue matched normal sibling, or because
they are doing well enough with conventional
therapy that it is inappropriate to assume the risks
associated with transplantation. But it is important
for that subset of CGD patients who do have
constant problems with life threatening infections
to know that bone marrow transplantation could
be a treatment option. Gene therapy is not yet an
option to cure CGD. However, some laboratories
are working on this new therapy and gene therapy
might be an option in the future.
Many physicians suggest that swimming should
be confined to well chlorinated pools. Fresh
water lakes in particular and even salt water
swimming may expose patients to organisms
which are not virulent (or infectious) for normal
swimmers but may be infectious for CGD
patients. Aspergillus is present in many samples
of marijuana, so CGD patients should be
discouraged from smoking marijuana.
A major risk to CGD patients is the handling of
garden mulch (shredded moldy tree bark); this
type of exposure is the cause of a grave and
life-threatening form of full lung acute inhalation
Aspergillus pneumonia. Households with CGD
patients should never use garden mulch at all if
possible and CGD patients should remain indoors
during its application in neighboring yards. Once
the mulch is settled firmly on the ground and is not
being spread or raked, it is much less of a danger
to CGD patients. Patients should also avoid
turning manure or compost piles, repotting house
plants, cleaning cellars or garages, performing
demolition for construction, dusty conditions, and
spoiled or moldy grass and hay (including avoiding
“hay rides”). Since early treatment of infections is
very important, patients are urged to consult their
physicians about even minor infections.
Expectations for the Chronic
Granulomatous Disease Patient
The quality of life for many patients with Chronic
Granulomatous Disease (CGD) has improved
remarkably with knowledge of the phagocytic
cell abnormality and appreciation of the need
for early, aggressive antibiotic therapy when
infections occur. Remarkable improvements in
morbidity and mortality have occurred in the last
20 years. The great majority of CGD children can
expect to live into adulthood, and many adult
CGD patients hold responsible jobs, get married
and have children. However, most CGD patients
remain at significant risk for infections and must
take their prophylaxis and be vigilant to seek early
diagnosis and treatment for possible infection.
Recurrent hospitalization may be required in CGD
patients since multiple tests are often necessary
to locate the exact site and cause of infections,
and intravenous antibiotics are usually needed
for treatment of serious infections. Disease-free
intervals are increased by prophylactic antibiotics
and treatment with gamma interferon. Serious
infections tend to occur less frequently when
patients reach their teenage years. Again it must
be emphasized that many patients with CGD
complete high school, attend college, and are
carrying on relatively normal lives.

chapter
7
Wiskott-Aldrich Syndrome
Wiskott-Aldrich syndrome is a primary immunodeficiency disease
involving both T- and B-lymphocytes. In addition, the blood cells that
help control bleeding, called platelets are also affected. The classic form
of Wiskott-Aldrich syndrome has a characteristic pattern of findings that
include an increased tendency to bleed caused by a reduced number of
platelets, recurrent bacterial, viral and fungal infections and eczema of
the skin. With the identification of the gene responsible for this disorder,
we now recognize that milder forms of the disease also occur that
express some, but not all, of the above symptoms.

Wiskott-Aldrich Syndrome 37
Definition of Wiskott-Aldrich Syndrome
In 1937, Dr. Wiskott described three brothers
with low platelet counts (thrombocytopenia),
bloody diarrhea, eczema and recurrent ear
infections. Seventeen years later, in 1954, Dr.
Aldrich demonstrated that this syndrome was
inherited as an X-linked recessive trait (see chapter
titled Inheritance). In the 1950s and 60s, the
features of the underlying immunodeficiency were
identified, and Wiskott-Aldrich syndrome joined
the list of primary immunodeficiency diseases.
Wiskott-Aldrich syndrome (WAS) is a primary
immunodeficiency disease involving both T- and
B-lymphocytes. Platelets—blood cells responsible
for controlling bleeding—are also severely affected.
In its classic form, WAS has a characteristic
pattern of findings that include:
1. Increased tendency to bleed caused by a
significantly reduced number of platelets
2. Recurrent bacterial, viral and fungal infections
3. Eczema of the skin
In addition, long term observations of patients
with WAS have revealed an increased incidence of
malignancies, including lymphoma and leukemia,
and an increased incidence of a variety of
autoimmune diseases in many patients.
The WAS is caused by mutations (or mistakes)
in the gene which produce a protein named
in honor of the disorder, the Wiskott-Aldrich
Syndrome Protein (WASP). The WASP gene is
located on the short arm of the X chromosome.
The majority of these mutations are “unique.”
This means that almost every family has its own
characteristic mutation of the WASP gene. If
the mutation is severe and interferes almost
completely with the gene’s ability to produce the
WAS protein, the patient has the classic, more
severe form of WAS. In contrast, if there is some
production of mutated WAS protein, a milder form
of the disorder may result.
Clinical Presentation of Wiskott-Aldrich Syndrome
The clinical presentation of Wiskott-Aldrich
syndrome (WAS) varies from patient to patient.
Some patients present with all three classic
manifestations, including low platelets and
bleeding, immunodeficiency and infection, and
eczema. Other patients present with low platelet
counts and bleeding. In past years, the patients
who presented with just low platelet counts were
felt to have a different disease called X-linked
thrombocytopenia (XLT). After the identification
of the WAS gene, it was realized that both the
WAS and X-linked thrombocytopenia are due to
mutations of the same gene, and thus are different
clinical forms of the same disorder. The initial
clinical manifestations of WAS may be present
soon after birth or develop in the first year of life.
These early clinical signs are directly related to any
or all of the classic clinical triad including bleeding
because of the low platelet count, itchy and scaly
skin rashes and eczema and/or infections because
of the underlying immunodeficiency.
Bleeding Tendency with Wiskott-Aldrich Syndrome
A reduced number of platelets of small size is a
characteristic hallmark of all patients with WAS.
Since WAS is the only disorder where small
platelets are found, their presence is a useful
diagnostic test for the disease. Bleeding into the
skin caused by the thrombocytopenia may cause
pinhead sized bluish-red spots, called petechiae, or
they may be larger and resemble bruises. Affected
boys may also have bloody bowel movements
(especially during infancy), bleeding gums, and
prolonged nose bleeds. Hemorrhage into the brain
is a dangerous complication and some physicians
recommend that toddlers with very low platelet
counts (

38 Wiskott-Aldrich Syndrome
Infections with Wiskott-Aldrich Syndrome
Due to a profound deficiency of T- and
B-lymphocyte function, infections are common
in classic WAS and may involve all classes of
microorganisms. These infections may include
upper and lower respiratory infections such as
otitis media, sinusitis and pneumonia. More severe
infections such as sepsis (bloodstream infection
or “blood poisoning”), meningitis and severe viral
infections are less frequent. Infrequently, patients
with classic WAS may develop pneumonia with
pneumocystis jiroveci (carinii). The skin may also
become infected with various bacteria as a result of
intense scratching of areas involved with eczema.
A viral infection of the skin called molluscum
contagiosum is also commonly seen in WAS.
Eczema with Wiskott-Aldrich Syndrome
Eczema is commonly found in patients with classic
WAS. In infants, the eczema may resemble “cradle
cap”, a severe diaper rash, or be generalized,
occurring on the body and/or extremities. In older
boys, eczema may be limited to the skin creases
around the front of the elbow, around the wrist and
neck and behind the knees or the eczema may
involve much of the total skin area. Since eczema
is extremely itchy (pruritic), affected boys often
scratch themselves until they bleed, even while
asleep. In extreme cases, the eczema may cause
so much reddened skin inflammation that the boys
“radiate” heat to the environment and have difficulty
maintaining normal body temperature. Eczema may
also be mild or absent in some patients.
Autoimmune Manifestations with
Wiskott-Aldrich Syndrome
A problem observed frequently in infants, as
well as adults with WAS is a high incidence
of “autoimmune-like” symptoms. The word
“autoimmune” describes conditions that appear
to be the result of a dysregulated immune
system reacting against part of the patient’s own
body. Among the most common autoimmune
manifestations observed in WAS patients is a type
of blood vessel inflammation (vasculitis) associated
with fever and skin rash on the extremities—
sometimes worsened following episodes of
exercise. Another autoimmune disorder is anemia
caused by antibodies that destroy the patient’s
own red blood cells (hemolytic anemia). The low
platelets can also be worsened by autoimmunity
in which the patient makes antibodies to attack
his remaining platelets (commonly called ITP or
idiopathic thrombocytopenic purpura). Some
patients have a more generalized disorder in
which there may be high fevers in the absence
of infection, associated with swollen joints,
tender lymph glands, kidney inflammation, and
gastrointestinal symptoms such as diarrhea.
Occasionally, inflammation of arteries (vasculitis)
occurring primarily in the muscles, heart, brain or
other internal organs develops and causes a wide
range of symptoms. These autoimmune episodes
may last only a few days or may occur in waves
over a period of many years and may be difficult
to treat.

Wiskott-Aldrich Syndrome 39
Malignancies with Wiskott-Aldrich Syndrome
Malignancies can occur in young children, in
adolescents and adults with WAS. Most of these
malignancies involve the B-lymphocytes resulting
in lymphoma or leukemia.
Diagnosis of Wiskott-Aldrich Syndrome
Due to the wide spectrum of findings, the
diagnosis of Wiskott-Aldrich syndrome (WAS)
should be considered in any boy presenting with
unusual bleeding and bruises, congenital or early
onset thrombocytopenia and small platelets.
The characteristic platelet abnormalities, low
numbers and small size, are almost always
already present in the cord blood of newborns.
The simplest and most useful test to diagnose
WAS is to obtain a platelet count and to carefully
determine the platelet size. WAS platelets are
significantly smaller than normal platelets. In older
children, over the age of two years, a variety of
immunologic abnormalities can also be identified
and used to support the diagnosis. Certain
types of serum antibodies are characteristically
low or absent in boys with WAS. They often
have low levels of antibodies to blood group
antigens (isohemagglutinins; e.g. antibodies
against type A or B red cells) and fail to produce
antibodies against certain vaccines that contain
polysaccharides or complex sugars such as
the vaccine against streptococcus pneumonae
(pneumovax). Skin tests to assess T-lymphocyte
function may show a negative response and
laboratory tests of T-lymphocyte function may
be abnormal. The diagnosis is confirmed by
demonstrating a decrease or absence of the WAS
protein in blood cells or by the presence of a
mutation within the WASP gene. These tests are
done in a few specialized laboratories and require
blood or other tissue.
Inheritance of Wiskott-Aldrich Syndrome
WAS is inherited as an X-linked recessive disorder
(see chapter titled Inheritance). Only boys are
affected with this disease. Since this is an inherited
disease transmitted as an X-linked recessive trait,
there may be brothers or maternal uncles (the
patient’s mother’s brother) with similar findings. It
is possible that the family history may be entirely
negative because of small family size or because
of the occurrence of a new mutation. It is felt
that about 1/3 of newly diagnosed WAS patients
result from a new mutation occurring at the time
of conception. If the precise mutation of WASP is
known in a given family, it is possible to perform
prenatal DNA diagnosis on cells obtained by
amniocentesis or chorionic villus sampling.

40 Wiskott-Aldrich Syndrome
Treatment of Wiskott-Aldrich Syndrome
All children with serious chronic illness need the
support of the parents and family. The demands on
the parents of boys with WAS and the decisions
they have to make may be overwhelming. Progress
in nutrition and antimicrobial therapy, prophylactic
use of immunoglobulin replacement therapy and
bone marrow transplantation have significantly
improved the life expectancy of patients with
WAS. Due to increased blood loss, iron deficiency
anemia is common and iron supplementation is
often necessary.
When there are symptoms of infection, a thorough
search for bacterial, viral and fungal infections
is necessary to determine the most effective
antimicrobial treatment. Since patients with WAS
have abnormal antibody responses to vaccines
and to invading microorganisms, the prophylactic
administration of immunoglobulin replacement
therapy may be indicated for those patients who
suffer from frequent bacterial infections. It should
be noted that if the patient has low platelet counts,
most physicians would prescribe intravenous
immunoglobulin therapy because the injection
of subcutaneous immunoglobulin may cause
bleeding. Immunoglobulin replacement therapy is
particularly important if the patient has been treated
with splenectomy (surgical removal of the spleen).
The eczema can be severe and persistent,
requiring constant care. Excessive bathing should
be avoided because frequent baths can cause
drying of the skin and make the eczema worse.
Bath oils should be used during the bath and
a moisturizing cream should be applied after
bathing, and several times daily to areas of dry
skin/eczema. Steroid creams applied sparingly
to areas of chronic inflammation are often helpful
but their overuse should be avoided. Do not use
strong steroid creams, e.g. fluorinated steroids, on
the face. If certain foods make the eczema worse
and if known food allergies exist, attempts should
be made to remove the offending food items.
Platelet transfusions may be used in some
situations to treat the low platelet count and
bleeding. For example, if serious bleeding cannot
be stopped by conservative measures, platelet
transfusions are indicated. Hemorrhages into
the brain usually require immediate platelet
transfusions. Surgical removal of the spleen (a
lymphoid organ in the abdomen that “filters the
blood”) has been performed in WAS patients and
has been shown to correct the low platelet count,
or thrombocytopenia, in over 90% of the cases.
Splenectomy does not cure the other features
of WAS and should only be used to control
thrombocytopenia in patients with particularly
low platelet counts. The ability of high dose
immunoglobulin replacement therapy to raise the
platelet count in WAS boys has been shown to
improve considerably once the spleen has been
removed. Removal of the spleen increases the
susceptibility of WAS patients to certain infections,
especially infections of the blood stream and
meningitis caused by encapsulated bacteria like
S pneumonae or H influenzae. If splenectomy is
used, it is imperative that the child be placed on
prophylactic antibiotics and possibly immunoglobulin
replacement therapy, potentially, for the rest of their
lives to prevent these serious infections.
The symptoms of autoimmune diseases
may require treatment with drugs that further
suppress the patient’s immune system. High
dose immunoglobulin replacement therapy and
systemic steroids may correct the problem and it
is important that the steroid dose be reduced to
the lowest level that will control symptoms as soon
as possible.
As with all children with primary immunodeficiency
diseases involving T-lymphocytes and/or
B-lymphocytes, boys with WAS should not receive
live virus vaccines since there is a possibility that
a vaccine strain of the virus may cause disease.
Complications of chicken pox infection occur
occasionally and may be prevented by early
treatment following exposure with antiviral drugs,
high dose immunoglobulin replacement therapy or
Herpes Zoster Hyper Immune Serum.

Wiskott-Aldrich Syndrome 41
Treatment of Wiskott-Aldrich Syndrome continued
The only “permanent cure” for WAS is bone
marrow transplantation or cord blood stem cell
transplantation (see chapter titled Specific Medical
Therapy) and the search for an HLA-matched
donor should be undertaken as soon as the
diagnosis of WAS has been established.
Because patients with WAS have some
residual T-lymphocyte function in spite of their
immunodeficiency, immunosuppressive drugs
and/or total body irradiation are required to
“condition” the patient before transplantation.
If the affected boy has healthy siblings with
the same parents, the entire family should be
tissue typed to determine whether there is an
HLA-identical sibling (a good tissue match) who
could serve as bone marrow transplant donor.
The results with HLA-identical sibling donor bone
marrow transplantation in WAS are excellent with
an overall success (cure) rate of 80-90%. This
procedure is the treatment of choice for boys
with significant clinical findings of the WAS. The
decision to perform an HLA-matched sibling
bone marrow transplant in patients with milder
clinical forms, such as isolated thrombocytopenia,
is more difficult and should be discussed with
an experienced immunologist. Success with
matched-unrelated donor (MUD) transplants has
improved substantially over the past two decades.
Fully matched-unrelated donor transplants are
now almost as successful as matched sibling
transplants if they are performed while the patient
is under 5-6 years of age and before they have
acquired a significant complication such as
severe viral infections or cancer. The success
rate of fully matched-unrelated donor transplants
decreases with age making the decision to
transplant teenagers or adults with WAS difficult.
Cord blood stem cells, fully or partially matched,
have successfully been used for immune
reconstitution and the correction of platelet
abnormalities in a few WAS patients and may be
considered if a matched sibling or fully matched
unrelated donor is not available. In contrast to the
excellent outcome of HLA-matched transplants,
haploidentical bone marrow transplantation (the
use of a parent as a donor) has been much less
successful than are HLA-matched transplants.
Expectations for Wiskott-Aldrich
Syndrome Patients
Three decades ago, the classic Wiskott-Aldrich
syndrome was one of the most severe primary
immunodeficiency disorders with a life
expectancy of only 2-3 years. Although it remains
a serious disease in which life-threatening
complications may occur, many affected males
go through puberty and enter adulthood, live
productive lives and have families of their own.
The oldest bone marrow transplanted patients
are now in their twenties and thirties and seem
to be cured, without developing malignancies or
autoimmune diseases.

chapter
8
Hyper IgM Syndrome
Patients with the Hyper IgM Syndrome have an inability to switch
their antibody (immunoglobulin) production from IgM to IgG, IgA,
and IgE. As a result, patients have decreased levels of IgG and IgA
and normal or elevated levels of IgM. A number of different genetic
defects can cause the Hyper IgM Syndrome. The most common
form is inherited as an X-chromosome linked trait and affects only
boys. Most of the other forms are inherited as autosomal recessive
traits and affect both girls and boys.

Hyper IgM Syndrome 43
Definition of Hyper IgM Syndrome
Patients with Hyper IgM (HIM) syndrome have
an inability to switch production of antibodies
of the IgM type to antibodies of the IgG, IgA, or
IgE type. As a result, patients with this primary
immunodeficiency disease have decreased levels
of serum IgG and IgA and normal or elevated
levels of IgM. B-lymphocytes can produce
IgM antibodies on their own, but they require
interactive help from T-lymphocytes in order to
switch antibody production from IgM to IgG, IgA
and IgE. The hyper IgM syndrome results from a
variety of genetic defects that affect this interaction
between T-lymphocytes and B-lymphocytes.
The most common form of hyper IgM syndrome
results from a defect or deficiency of a protein that is
found on the surface of activated T-lymphocytes.
The affected protein is called “CD40 ligand”
because it binds to a protein on B-lymphocytes
called CD40. CD40 ligand is made by a gene
on the X-chromosome. Therefore, this primary
immunodeficiency disease is inherited as an
X-linked recessive trait and usually found only
in boys. As a consequence of their deficiency in
CD40 ligand, affected patients’ T-lymphocytes are
unable to instruct B-lymphocytes to switch their
production of immunoglobulins from IgM to IgG,
IgA and IgE. In addition, CD40 ligand is important
for other T-lymphocyte functions, and therefore,
patients with X-linked hyper IgM syndrome (XHIM)
also have a defect in some of the protective
functions of their T-lymphocytes.
Other forms of HIM syndrome are inherited as
autosomal recessive traits (see chapter titled
Inheritance) and have been observed in females
and males. The molecular bases for some of the
other forms of HIM have been discovered. These
forms of HIM syndrome result from defects in
the genes that are involved in the CD40 signaling
pathway. Genetic defects in CD40 are very rare
and have been described in few families. The
resulting disease is almost identical to XHIM
because although the CD40 ligand is present on
T-lymphocytes, the CD40 found on B-lymphocytes
and other cells of the immune system is either not
present or does not function normally. Two other
genes (AID and UNG) have been identified that
are necessary for B-lymphocytes to switch their
antibody production from IgM to IgG, IgA or IgE.
Defects in both of these genes have been found
in patients with HIM syndrome. Since the function
of these genes is limited to antibody switching,
the other T-lymphocyte functions of CD40 ligand
are not affected, and these patients are less likely
to have infections caused by organisms that are
controlled by T-cells.
Finally, a defect in another X-linked gene that
is necessary for the activation of the signaling
molecule NF-qB has been identified in a form
of HIM that is associated with a skin condition
called ectodermal dysplasia. Patients have
immunodeficiency with sparse hair and conical
teeth among other abnormalities. NF-qB is
activated by CD40 and is necessary for the
signaling pathway that results in antibody
switching. NF-qB is also activated by other
signaling pathways that are important in fighting
infections. Therefore, these affected boys are
susceptible to a variety of serious infections.
Clinical Presentation of Hyper IgM Syndrome
Most patients with Hyper IgM (HIM) syndrome
develop clinical symptoms during their first or
second year of life. The most common problem
is an increased susceptibility to infection including
recurrent upper and lower respiratory tract
infections. The most frequent infective agents
are bacteria. A variety of other microorganisms
can also cause serious infections. For example,
Pneumocystis jiroveci (carinii) pneumonia, an
opportunistic infection, is relatively common during
the first year of life and its presence may be the
first clue that the child has the X-linked form of
HIM syndrome (XHIM). Lung infections may also
be caused by viruses such as Cytomegalovirus
and fungi such as Cryptococcus. Gastrointestinal
complaints, most commonly diarrhea and
malabsorption, have also been reported in
some patients. One of the major organisms
causing gastrointestinal symptoms in XHIM is
Cryptosporidium that may cause sclerosing
cholangitis, a severe disease of the liver.
Approximately half of the patients with XHIM
syndrome develop neutropenia (low white blood
cell count), either transiently or persistently. The
cause of the neutropenia is unknown, although
most patients respond to treatment with the

44 Hyper IgM Syndrome
Clinical Presentation of Hyper IgM Syndrome contined
colony stimulating factor, G-CSF. Neutropenia
is often associated with oral ulcers, proctitis
(inflammation and ulceration of the rectum) and
skin infections. Enlargement of the lymph nodes
is seen more frequently in patients with autosomal
recessive HIM syndrome than in most of the other
primary immunodeficiency diseases.
As a result, patients often have enlarged tonsils,
a big spleen and liver, and enlarged lymph
nodes. Autoimmune disorders may also occur in
patients with HIM syndrome. Their manifestations
may include chronic arthritis, low platelet
counts (thrombocytopenia), hemolytic anemia,
hypothyroidism, and kidney disease.
Diagnosis of Hyper IgM Syndrome
The diagnosis of X-linked Hyper IgM (XHIM)
syndrome should be considered in any boy
presenting with hypogammaglobulinemia,
characterized by low or absent IgG and IgA and
normal or elevated IgM levels. Failure to express
CD40 ligand on activated T-cells is a characteristic
finding. However, some patients with other
forms of immunodeficiency may have a markedly
depressed expression of CD40 ligand while their
CD40 ligand gene is perfectly normal. Therefore,
the final diagnosis of XHIM syndrome depends on
the identification of a mutation affecting the CD40
ligand gene. This type of DNA analysis can be
done in several specialized laboratories.
The autosomal recessive forms of HIM can be
suspected if a patient has the characteristics of
XHIM but is either a female patient and/or has a
normal CD40 ligand gene with normal expression
on activated T-lymphocytes.
Ectodermal Dysplasia with Immunodeficiency,
another X-linked form of HIM, can be suspected
in a patient who has features of ectodermal
dysplasia (e.g. sparse hair and conical teeth) and
recurrent infections, normal or elevated IgM and
low IgG, IgA and IgE.
The diagnosis of the different forms of autosomal
recessive HIM or of Ectodermal Dysplasia with
Immunodeficiency can be confirmed by mutation
analysis of the genes known to cause these disorders.
Inheritance of Hyper IgM Syndrome
X-linked Hyper IgM (XHIM) and Ectodermal
Dysplasia with Immunodeficiency are inherited
as X-linked recessive disorders. As a result, only
boys are affected. See chapter titled Inheritance
for more complete information on how X-linked
recessive disorders are passed on from generation
to generation. Since these are inherited diseases,
transmitted as an X-linked recessive trait, there
may be brothers or maternal uncles (mother’s
brothers) who have similar clinical findings. As in
other X-linked disorders, there also may be no
other affected members of the family.
Since the autosomal recessive forms of HIM require
that the gene on both chromosomes be affected,
they are less frequent than the X-linked conditions.
If the precise mutation in the affected gene is
known in a given family, it is possible to make a
prenatal diagnosis or test family members to see if
they are carriers of the mutation.

Hyper IgM Syndrome 45
Treatment of Hyper IgM Syndrome
Patients with Hyper IgM (HIM) syndrome have a
severe deficiency in IgG. Regular treatment with
immunoglobulin replacement therapy every 3 to
4 weeks is effective in decreasing the number
of infections (see chapter titled Specific Medical
Therapy). The immunoglobulin replaces the
missing IgG and often results in a reduction
or normalization of the serum IgM level. Since
patients with the XHIM syndrome also have a
marked susceptibility to Pneumocystis jiroveci
(carinii) pneumonia, many physicians feel it is
important to initiate prophylactic or preventative
treatment for Pneumocystis jiroveci pneumonia
by starting affected infants on trimethoprimsulfamethoxazole
(Bactrim, Septra) prophylaxis
as soon as the diagnosis of XHIM syndrome is
made. Sometimes, neutropenia may improve
during treatment with IVIG. Patients with persistent
neutropenia may also respond to granulocyte
colony stimulating factor (G-CSF) therapy.
However, G-CSF treatment is only necessary
in selected patients and long-term treatment
with G-CSF is usually not recommended. Boys
with HIM, similar to other patients with primary
immunodeficiency diseases, should not receive
live virus vaccines since there is a remote
possibility that the vaccine strain of the virus may
cause disease. It is also important to reduce the
possibility of drinking water that is contaminated
with Cryptosporidium because exposure to this
organism may cause severe gastrointestinal
symptoms and chronic liver disease. The family
should be proactive and contact the authorities
responsible for the local water supply and ask if
the water is safe and tested for Cryptosporidium.
Patients with XHIM syndrome have defects in
T-lymphocyte function in addition to their antibody
deficiency, and patients with Ectodermal Dysplasia
with Immunodeficiency also have defects in
other aspects of their immune system. Treatment
with immunoglobulin may not fully protect these
patients against all infections. In recent years,
bone marrow transplantation or cord blood stem
cell transplantation have been advocated (see
chapter titled Specific Medical Therapy). More
than a dozen patients with XHIM have received
an HLA identical sibling bone marrow transplant
with excellent success. Thus, a permanent cure
for this disorder is possible. Cord blood stem cell
transplants, fully or partially matched, have also
been successfully performed, resulting in complete
immune reconstitution. Matched unrelated donor
(MUD) transplants are nearly as successful as
matched sibling transplants. Since patients
with the XHIM syndrome may have strong T-cell
responses against organ transplants, including
bone marrow transplants, immunosuppressive
drugs or low dose irradiation are usually required.
Expectation for the Hyper IgM Syndrome Patient
Although patients with the Hyper IgM syndrome
may have defects in the production of IgG and
IgA antibodies and in some aspects of their
T-lymphocyte function (XHIM), a number of
effective therapies exist which allow these children
to grow into happy and successful adults.

chapter
9
DiGeorge Syndrome
DiGeorge Syndrome is a primary immunodeficiency disease which
is caused by abnormal migration and development of certain cells
and tissues during fetal development. As part of the developmental
defect, the thymus gland may be affected and T-lymphocyte
production may be impaired, resulting in recurrent infections.

DiGeorge Syndrome 47
Definition of DiGeorge Syndrome
The DiGeorge Syndrome is a primary
immunodeficiency disease which is caused by
abnormal migration and development of certain
cells and tissues during growth and differentiation
of the fetus. Different tissues and organs often
arise from a single group of embryonic cells.
Although the tissues and organs that ultimately
develop from a single group of embryonic cells
may appear to be unrelated in the fully formed
child, they are related in that they have developed
from the same embryonic or fetal tissues.
Although many different organs may be involved in
the DiGeorge Syndrome, they all evolve from the
same embryonic cells.
Most, but not all patients with the DiGeorge
Syndrome have a small deletion in a specific
part of chromosome number 22 at position
22q11.2. Another name for this syndrome is the
chromosome 22q11.2 deletion syndrome. Patients
with the DiGeorge Syndrome do not all show the
same organ involvement. A given organ may be
uninvolved, or so mildly involved that the organ
appears to be normal. Thus, patients with the
DiGeorge Syndrome may not all have the same
organs involved or the same severity. Patients
with the DiGeorge Syndrome may have any or all
of the following:
Facial Appearance
Affected children may have an underdeveloped
chin, eyes with heavy eyelids, ears that are rotated
back and defective upper portions of their ear
lobes. These facial characteristics vary greatly from
child to child and may not be very prominent in
many affected children.
Parathyroid Gland Abnormalities
Affected children may have underdeveloped
parathyroid glands (hypoparathyroidism). The
parathyroids are small glands found in the front of
the neck near the thyroid gland (hence the name
“parathyroid”). They function to control the normal
metabolism and blood levels of calcium. Children
with the DiGeorge Syndrome may have trouble
maintaining normal levels of calcium, and this
may cause them to have seizures (convulsions).
In some cases, the parathyroid abnormality is
relatively mild or not present at all. The parathyroid
defect often becomes less severe with time.
Heart Defects
Affected children may have a variety of heart
(or cardiac) defects. For the most part, these
anomalies involve the aorta and the part of the
heart from which the aorta develops. As with other
organs affected in the DiGeorge Syndrome, heart
defects vary from child to child. In some children,
heart defects may be very mild or absent.
Thymus Gland Abnormalities
Affected infants and children may have
abnormalities of their thymus. The thymus gland
is normally located in the upper area of the front
of the chest. The thymus begins its development
high in the neck during the first three months of
fetal development. As the thymus matures and
gets bigger, it drops down into the chest to its
ultimate location under the breastbone and over
the heart.
The thymus controls the development and
maturation of one kind of lymphocyte, the
T-lymphocyte (“T” for “Thymus”) (see chapter
titled The Immune System and Primary Immune
Deficiency Diseases). The size of the thymus
affects the number of T-lymphocytes that can
develop. Patients with a small thymus produce
fewer T-lymphocytes than someone with a
normally sized thymus. T-lymphocytes are
essential for resistance to certain viral and fungal
infections. Some T-lymphocytes, the cytotoxic
T-lymphocytes, directly kill viruses. T-lymphocytes
also help B-lymphocytes to develop into plasma
cells and produce immunoglobulins or antibodies.
Patients with the DiGeorge Syndrome may have
poor T-cell production compared to their peers,
and as a result, they may have an increased
susceptibility to viral, fungal and bacterial infections.
As with the other defects in the DiGeorge
Syndrome, the T-lymphocyte defect varies from
patient to patient. In addition, small or mild
deficiencies may disappear with time.
Miscellaneous Clinical Features
In addition to the above features, patients with
the DiGeorge Syndrome may occasionally have
a variety of other developmental abnormalities
including cleft palate, poor function of the palate,
delayed acquisition of speech and difficulty in
feeding and swallowing. In addition, some patients
have learning disabilities, behavioral problems,
and hyperactivity.

48
DiGeorge Syndrome
Diagnosis of DiGeorge Syndrome
The diagnosis of the DiGeorge Syndrome is
usually made on the basis of signs and symptoms
that are present at birth or develop soon
after birth. Some children may have the facial
features that are characteristic of the DiGeorge
Syndrome. Affected children may also show signs
of low blood calcium levels as a result of their
hypoparathyroidism. This may show up as low
blood calcium on a routine blood test, or the infant
may be “jittery” or have seizures (convulsions) as
a result of the low calcium. Affected children may
also show signs and symptoms of a heart defect.
They may have a heart murmur that shows up
on a routine physical exam, they may show signs
of heart failure, or they may have low oxygen
content of their arterial blood and appear “blue” or
cyanotic. Finally, affected children may show signs
of infection because of the underdevelopment of
their thymus gland and low T-lymphocyte levels.
Some children have signs or symptoms at birth or
while they are still in the hospital nursery. Others
may not show signs or symptoms until they are
a few weeks or months older. Some children and
adults are diagnosed at a much older age due
to speech delay, qualitative speech problems, or
feeding problems.
There is a great deal of variation in the DiGeorge
Syndrome from child to child. In some children,
all of the different organs and tissues are
affected. These children have the characteristic
facial characteristics, low blood calcium from
hypoparathyroidism, heart defects and a
deficiency in their T-lymphocyte number and
function. In other children, all of the different
organs and tissues may not be affected, and
the organs and tissues that are affected may be
affected to different degrees.
Not only do children with the DiGeorge Syndrome
differ in the organs and tissues that are affected,
but they also differ in terms of how severely a
given organ or tissue is affected.
In the past, the diagnosis of the DiGeorge
Syndrome was usually made when at least three
of the characteristic findings described above were
present. Unfortunately, this caused many mild
cases to be missed. In recent years, the genetic
test has been more widely used. Over 90% of
patients with the clinical diagnosis of DiGeorge
Syndrome have a small deletion of a specific
portion of chromosome number 22 at position
22q11.2. This can be identified in a number
of ways, but the most common way is a FISH
analysis (for Fluorescent In Situ Hybridization). Use
of a FISH analysis test has made the diagnosis
of DiGeorge Syndrome more precise and more
common. Approximately 1 in 4000 babies have
DiGeorge Syndrome or chromosome 22q11.2
deletion syndrome. For patients who do not have
the deletion, the diagnosis continues to rely on the
characteristic combination of clinical features.

DiGeorge Syndrome
49
Therapy for DiGeorge Syndrome
Therapy for DiGeorge syndrome is aimed at
correcting the defects in the organs or tissues that
are affected. Therefore, therapy depends on the
nature of the different defects and their severity.
Treatment of the low calcium and
hypoparathyroidism may involve calcium
supplementation and replacement of the missing
parathyroid hormone. A heart (or cardiac) defect
may require medications or corrective surgery
to improve the function of the heart. If surgery is
required, the exact nature of the surgery depends
on the nature of the heart defect. Surgery can
be performed before any immune defects are
corrected. It is important that all the precautions
that are usually taken with children with T-cell
immunodeficiencies be observed, such as
irradiating all blood products to prevent
graft-vs.-host disease and ensuring the blood
products are free of potentially harmful viruses (see
chapter titled Specific Medical Therapy).
As mentioned above, the immunologic defect in
T-lymphocyte function varies from child to child.
Therefore, the need for therapy of the T-lymphocyte
defect also varies. Many children with the
DiGeorge Syndrome have perfectly normal
T-lymphocyte functions and require no therapy for
immunodeficiency. Other children initially have mild
defects in T- lymphocyte function which improve
as they grow older. In most cases of the DiGeorge
Syndrome, the small amount of thymus that is
present provides adequate T-lymphocyte function.
Rarely, the thymus is so small that adequate
numbers of T-cells do not develop. In these cases,
a special form of bone marrow transplantation or a
thymus transplant may be performed.
In some children with the DiGeorge Syndrome,
the T-lymphocyte defect is significant enough to
cause the B-lymphocytes to fail to make sufficient
antibodies. This occurs because antibodies are
produced by B-lymphocytes under the direction
of a specific subset of T-lymphocytes (see
chapter titled The Immune System and Primary
Immunodeficiency). When the B-cells are affected,
this most often results in a delay in the production
of antibodies. Rarely, children may require
immunoglobulin replacement therapy.
As described in the preceding paragraphs, not all
children with DiGeorge Syndrome require therapy
for their immunodeficiency. Approximately 80%
of the patients with the chromosome 22q11.2
deletion have diminished T-cell numbers. However,
less than 0.2% have an immunodeficiency that
requires a bone marrow transplant or a thymus
transplant. The majority of children with an
immunodeficiency have a mild to moderate deficit in
the number of T-cells. These patients usually do not
require transplantation; however, strategies aimed
at prevention of the bacterial infections can often be
quite helpful. This may include antibiotic prophylaxis
and adequate treatment of any allergies. Allergies
appear to be increased in patients with the
DiGeorge Syndrome. They may contribute to
the infections and are treated with the same
medications used in other patients with allergies.
Approximately 10% of patients with the
chromosome 22q11.2 deletion, and an unknown
number of patients with the DiGeorge Syndrome
without the deletion, have an autoimmune
disease. This occurs when the immune system
makes a mistake and tries to fight its own body.
It is not known why this happens in people with
T-lymphocyte problems. The most common
autoimmune diseases in the DiGeorge Syndrome
are idiopathic thrombocytopenia purpura
(antibodies against platelets), autoimmune
hemolytic anemia (antibodies against red blood
cells), juvenile/adult arthritis and autoimmune
disease of the thyroid gland.
Expectations for the DiGeorge Syndrome Patient
The outlook for a child with DiGeorge Syndrome
depends on the degree to which the child is
affected in all organ systems. The severity of heart
disease is usually the most important determining
factor. As mentioned above, most children have
a mild to moderate deficit in T-cell production
that often improves with age. Overall, the outlook
for the infection pattern is optimistic as most
patients do not suffer from recurrent infections in
adulthood. Nevertheless, approximately one third
of adults have minor recurrent infections.

chapter
10
IgG Subclass Deficiency
and Specific Antibody
Deficiency
There are five classes of immunoglobulins: IgG, IgA, IgM, IgD, and
IgE. The IgG class of immunoglobulins is itself composed of four
different subtypes of IgG molecules called the IgG subclasses.
Patients who lack, or have very low levels of, one or two IgG
subclasses, but whose other immunoglobulin levels are normal, are
said to have a selective IgG subclass deficiency.

IgG Subclass Deficiency and Specific Antibody Deficiency 51
Definition of Subclass Deficiency
Antibodies are made of proteins called
immunoglobulins. There are five types or classes
of immunoglobulin: IgG, IgA, IgM, IgD and IgE
(see chapter titled The Immune System and
Primary Immunodeficiency Diseases). Most of
the antibodies in the blood and the fluid that
bathes the tissues and cells of the body are of
the IgG class. The IgG class of antibodies is
itself composed of four different subtypes of IgG
molecules called the IgG subclasses. These are
designated IgG1, IgG2, IgG3 and IgG4. Patients
who suffer recurrent infections because they
lack, or have very low levels of, one or two IgG
subclasses, but whose other immunoglobulin
levels, including total IgG, are normal, are said to
have a selective IgG subclass deficiency.
While all the IgG subclasses contain antibodies,
each subclass serves somewhat different
functions in protecting the body against infection.
For example, the IgG1 and IgG3 subclasses
are rich in antibodies against proteins such
as the toxins produced by the diphtheria and
tetanus bacteria, as well as antibodies against
viral proteins. In contrast, antibodies against the
polysaccharide (complex sugar) coating (capsule)
of certain disease-producing bacteria (e.g. the
pneumococcus and Haemophilus influenzae) are
predominantly of the IgG2 type. Some of the IgG
subclasses can easily cross the placenta and enter
the unborn infant’s bloodstream, while others do
not. Antibodies of certain IgG subclasses interact
readily with the complement system, while others
interact poorly, if at all, with the complement proteins.
Thus, an inability to produce antibodies of a specific
subclass may render the individual susceptible to
certain kinds of infections but not others.
The IgG circulating in the bloodstream is 60-70%
IgG1, 20-30% IgG2, 5-8% IgG3 and 1-3% IgG4.
The amount of the different IgG subclasses
present in the bloodstream varies with age. For
example, IgG1 and IgG3 reach normal adult levels
by 5-7 years of age while IgG2 and IgG4 levels
rise more slowly, reaching adult levels at about
10 years of age. In young children, the ability to
make antibodies to the polysaccharide coatings
of bacteria, antibodies that are most commonly
of the IgG2 subclass, develops more slowly than
the ability to make antibodies to proteins. These
factors must be taken into account before an
individual is considered to be abnormal, either
by virtue of having a low IgG subclass level or an
inability to make a specific type of antibody.
Clinical Presentation of Subclass Deficiency
Recurrent ear infections, sinusitis, bronchitis and
pneumonia are the most frequently observed
illnesses in patients with IgG subclass deficiencies.
Both males and females may be affected. Some
patients will show an increased frequency of
infection beginning in their second year of life. In
other patients the onset of infections may occur
later. Often a child with IgG subclass deficiency
will first come to the physician’s attention because
of recurrent ear infections. Somewhat later in
life, recurrent or chronic sinusitis, bronchitis
and/or pneumonia may make their appearance.
In general, the infections suffered by patients
with selective IgG subclass deficiencies are not
as severe as those suffered by patients who
have combined deficiencies of IgG, IgA and IgM
(for example X-linked agammaglobulinemia or
common variable immunodeficiency). Very rarely,
IgG subclass deficient patients have suffered
recurrent episodes of meningitis or bacterial
infections of the bloodstream (e.g. sepsis).
Selective IgG1 subclass deficiency is very
rare. IgG2 subclass deficiency is the most
frequent subclass deficiency in children, while
IgG3 subclass deficiency is the most common
deficiency seen in adults. IgG4 deficiency most
often occurs in association with IgG2 deficiency.
The significance of isolated, or selective, IgG4
deficiency is unclear at this time. Since many
normal children under 10 years of age have
undetectable IgG4, IgG4 deficiency is generally
not accepted as a diagnosis in this age group.

52
IgG Subclass Deficiency and Specific Antibody Deficiency
Diagnosis of Subclass Deficiency
IgG subclass deficiency may be suspected in
children and adults who have a history of recurrent
infections of the ears, sinuses, bronchi and/or
lungs. An individual is considered to have a
selective IgG subclass deficiency if one or more
of the IgG subclass levels in their blood is below
the normal range for age and the levels of other
immunoglobulins (i.e. total IgG, IgA and IgM) are
normal or near normal.
An individual may have very low levels or absence
of one or more IgG subclasses and yet the total
amount of IgG in their blood may be normal or
near normal. Therefore, in order to make the
diagnosis of selective IgG subclass deficiency,
measurement of IgG subclasses is required along
with measurement of serum IgG, IgA, and IgM.
It is important to consider that the concentrations
of IgG subclasses vary up or down over time and
the normal ranges used in different laboratories
also vary. Normal values are usually “defined” as
those values between two standard deviations
below and above the average for that person’s
age. Unfortunately, that may give the impression
to some physicians and patients that individuals
below the second standard deviation are abnormal
when 2.5% of normal individuals fall below this
level. The finding of a mild IgG subclass deficiency
should prompt re-evaluation over a period of
months before calling that person abnormal.
Subclass deficiencies need to be interpreted by
taking into account the clinical status of the patient
as well as the ability to produce specific antibodies
in response to childhood vaccines.
IgG subclass deficiencies may accompany
IgA deficiency (see chapter titled Selective IgA
Deficiency). Combined deficiencies of IgA with
IgG2 and IgG4 deficiency are frequently observed.
IgG2 and IgG4 deficiency as well as IgA and
IgE deficiency also occur in association with
Ataxia Telangiectasia (see chapter titled Ataxia
Telangiectasia).
Many patients with selective IgG2 subclass
deficiency or IgA and IgG2 deficiency are unable
to produce protective levels of antibody when
immunized with unconjugated polysaccharide
vaccines against Streptococcus pneumoniae (the
pneumococcus) or Haemophilus influenzae bacteria.
Some patients may also be unable to produce
protective levels of antibody when immunized with
polysaccharides that are also conjugated to proteins.
Patients with IgG subclass deficiencies usually make
normal amounts of antibodies to protein vaccines
such as the diphtheria and tetanus toxoids in the
routine DPT immunizations.
Patients with IgG subclass deficiencies have
normal numbers of B and T-lymphocytes and their
T-lymphocytes function normally when tested.
An additional subset of patients have normal
immunoglobulin levels and normal IgG subclasses,
yet fail to produce protective antibody levels
in response to infections with Streptococcus
pneumoniae or to vaccines against this bacteria.
These patients are thought to have a Specific
Antibody Deficiency (SAD) and are usually grouped
along with patients with IgG subclass deficiency.
Natural History of Subclass Deficiency
The natural history of patients with selective IgG
subclass deficiency is not completely understood.
Selective IgG subclass deficiencies occur more
often in children than in adults and the type of
subclass deficiency in children (i.e. predominantly
IgG2) differs from that most commonly seen in
adults (i.e. IgG3). These findings suggested that at
least some children may “outgrow” their subclass
deficiencies. In fact, recent studies have shown
that many, but not all, children who were subclass
deficient during early childhood (i.e. under the age
of 5 years) develop normal subclass levels as well
as the ability to make antibodies to polysaccharide
vaccines as they get older. However, IgG subclass
deficiencies may persist in some children as well
as in adults and in some instances a selective
IgG subclass deficiency may evolve into common
variable immunodeficiency. At the present time,
it is not possible to determine which patients will
have the transient type of subclass deficiency
and in which patients the subclass deficiency
may be permanent or the forerunner of a more
wide-ranging immunodeficiency, such as common
variable immunodeficiency. For these reasons,
periodic reevaluation of immunoglobulin and IgG
subclass levels is necessary.

IgG Subclass Deficiency and Specific Antibody Deficiency
53
Inheritance of Subclass Deficiency
No clear-cut pattern of inheritance has been
observed in the IgG subclass deficiencies.
Occasionally, two individuals with IgG subclass
deficiency may be found in the same family. In
some families IgG subclass deficiencies have been
found in some family members while other family
members may have IgA deficiency or common
variable immunodeficiency.
Treatment of Subclass Deficiency
Patients with IgG subclass deficiency frequently
suffer recurrent or chronic infections of the ears,
sinuses, bronchi and lungs. Treatment of these
infections usually requires antibiotics. One goal of
treatment is to prevent permanent damage to the
ears and lungs that might result in hearing loss or
chronic lung disease. Another goal is to maintain
patients as symptom-free as possible so that they
may pursue the activities of daily living such as
school or work. Sometimes antibiotics may be
used for prevention (i.e. prophylaxis) of infections
in patients who are unusually susceptible to ear or
sinus infections.
For immunodeficiency diseases in which patients
are unable to produce adequate levels of the
major immunoglobulin classes (i.e. IgG, IgA and
IgM) and fail to make antibodies against proteins
as well as polysaccharide antigens (for example,
X-linked Agammaglobulinemia and Common
Variable Immunodeficiency), immunoglobulin
replacement therapy is clearly needed (see
chapter titled Specific Medical Therapy). The use
of immunoglobulin replacement therapy in patients
with IgG subclass deficiencies is not as clear cut
as it is for X-linked agammaglobulinemia and
Common Variable Immunodeficiency patients.
Patients with IgG subclass deficiency and/or
specific antibody deficiency have a more limited
antibody and immunoglobulin deficiency than
patients with X-linked Agammaglobulinemia
and Common Variable Immunodeficiency. For
patients in whom infections and symptoms can
be controlled with antibiotics, immunoglobulin
replacement therapy may not be necessary.
However, for patients whose infections cannot
be readily controlled with antibiotics, or have
abnormal antibody responses, immunoglobulin
replacement therapy may be considered.
Since many young children appear to outgrow their
IgG subclass deficiencies as they get older, it is
important to reevaluate the patient to determine if
the subclass deficiency is still present. Reevaluation
requires discontinuation of immunoglobulin
replacement and at least 4-6 months of
observation before IgG levels are re-tested. If the
subclass deficiency has resolved, immunoglobulin
replacement therapy may be discontinued and the
patient observed. If the deficiency has persisted,
immunoglobulin therapy may be re-instituted.
In teenagers and adults, disappearance of the
subclass deficiency is less likely.
Expectations for the Subclass Deficiency Patient
The outlook for patients with IgG subclass
deficiency is generally good. Many children appear
to outgrow their deficiency as they get older. For
those patients for whom the deficiency persists, the
use of antibiotics and, in certain circumstances, the
use of immunoglobulin replacement therapy may
prevent serious infections and the development
of impaired lung function, hearing loss or injury to
other organ systems.

chapter
11
Ataxia Telangiectasia
Ataxia Telangiectasia (A-T) is a primary immunodeficiency disease
which affects a number of different organs in the body. It is
characterized by: neurologic abnormalities resulting in an unsteady
gait (ataxia), dilated blood vessels (telangiectasia) of the eyes and
skin, a variable immunodeficiency involving both cellular
(T-lymphocyte) and humoral (B-lymphocytes) immune responses
and a predisposition to cancer.

Ataxia Telangiectasia
55
Definition of Ataxia Telangiectasia
Ataxia Telangiectasia (A-T) is a primary
immunodeficiency disease which affects a number
of different organs in the body. It is characterized
by: neurologic abnormalities resulting in an
unsteady gait (ataxia), dilated blood vessels
(telangiectasia) of the eyes and skin, a variable
immunodeficiency involving both cellular
(T-lymphocyte) and humoral (B-lymphocytes)
immune responses and a predisposition to cancer.
Clinical Presentation of Ataxia Telangiectasia
The first presenting symptom is generally ataxia,
a medical term used to describe an unsteady
gait. Children with Ataxia Telangiectasia (A-T) may
sway when they stand or sit and they wobble or
stagger when they walk. Ataxia usually results
from neurologic abnormalities affecting a part of
the brain (the cerebellum) that controls balance.
A-T first becomes apparent when the child begins
to walk, typically between 12 and 18 months of
age. At this early point in time, many children are
thought to have cerebral palsy or an undefined
neurologic disorder. The specific diagnosis of A-T
may be difficult to make when symptoms first
appear. Later, neurological symptoms include
abnormalities in eye movements, including rapidly
alternating twitches of the eyes (nystagmus) and
difficulty in initiating voluntary eye movements
(oculomotor apraxia). Patients with A-T also
develop difficulty using the muscles needed for
speech (dysarthria) and swallowing. Often, the
diagnosis of A-T is only suspected when the
neurologic problems start to become progressively
worse, typically at age 5-6 years.
Dilated blood vessels (telangiectasia) become
apparent after the onset of the ataxia, generally
between 2 and 8 years of age. Telangiectasia
usually occurs on the white portion of the eye
(bulbar conjunctiva) but may also be found on the
ears, neck and extremities. However, telangiectasia
does not develop in all people with A-T.
Another clinical feature of A-T is an increased
susceptibility to infections. This symptom is a
major feature in some individuals. Infections most
commonly involve the lungs and sinuses and
are usually caused by bacteria or viruses. The
infections are, at least in part, due to the variable
immunodeficiency seen in A-T. Another factor that
may contribute to lung infections is the swallowing
dysfunction that results in aspiration with solid
food and liquid going down the passageway to the
lungs (the trachea) instead of the passageway to
the stomach (the esophagus).
Patients with A-T may have defects in both their
T-lymphocyte system and B-lymphocyte system.
They may have reduced numbers of T-lymphocytes
in their blood. These abnormalities in T-lymphocytes
are usually associated with a small or immature
thymus gland. The low number of T-lymphocytes
generally does not increase the patient’s
susceptibility to infection. Most patients with A-T
produce some antibody responses against foreign
antigens, such as microorganisms, but some of
these responses may be impaired, particularly
those responses directed against the large sugar
molecules (polysaccharides) found on the outside
of bacteria that cause respiratory infections. These
disordered antibody responses may be associated
with low levels of immunoglobulins—especially
deficiencies of IgA, IgE and IgG subclasses
(see chapter titled IgG Subclass Deficiency and
Specific Antibody Deficiency). Finally, patients with
A-T have an increased risk for developing cancer,
particularly cancers of the immune system, such
as lymphoma and leukemia.

56
Ataxia Telangiectasia
Diagnosis of Ataxia Telangiectasia
The diagnosis of Ataxia Telangiectasia (A-T) is
usually based on characteristic clinical findings
and supported by laboratory tests. Once all of
the clinical signs and symptoms of A-T have
become obvious in an older child or young adult,
the diagnosis is relatively easy. The most difficult
time to diagnose A-T is during the period when
neurologic symptoms are first apparent (early
childhood) and the typical telangiectasia has
not yet appeared. During this period, a history
of recurrent infections and typical immunologic
findings can be suggestive of the diagnosis. One
of the most helpful laboratory tests used to assist
in the diagnosis of A-T is the measurement of
alpha-fetoprotein levels in the blood. This is a
protein that is usually produced only during fetal
development but may persist at high blood levels
in some conditions (such as A-T) after birth. The
vast majority of A-T patients (>95%) have elevated
levels of serum alpha-fetoprotein. When other
causes of elevations of alpha-fetoprotein are
eliminated, elevated alpha-fetoprotein in the blood,
in association with the characteristic signs and
symptoms, makes the diagnosis of A-T a virtual
certainty.
Other diagnostic tests include:
1. Detection of the protein (ATM) made by the A-T
gene using a western blot
2. Measurement of cellular damage (cell death or
chromosomal breakage) after exposure of cells
to x-rays in the laboratory
3. Sequencing (reading the spelling) of the A-T
gene (ATM)
Inheritance of Ataxia Telangiectasia
Ataxia Telangiectasia is inherited as an autosomal
recessive disorder (see chapter titled Inheritance).
The gene responsible for A-T has been identified
and is found on the long arm of chromosome
11 at 11q22-23. It controls the production of
a phosphatidylinositol-3-kinase-like enzyme
involved in cellular responses to stress, DNA
damage and cell cycle control. The identification
of the specific gene responsible for A-T has made
carrier detection and prenatal diagnosis possible,
though it can be done only in a few specialized
laboratories and is very expensive.
General Treatment for Ataxia Telangiectasia
There is no cure for any of the problems in
Ataxia Telangiectasia (A-T), and treatment is
largely supportive. Patients of all ages should be
encouraged to participate in as many activities
as possible. Children should be able to attend
school on a regular basis, but most will eventually
need full-time classroom aides. Progressive eye
movement abnormalities make reading difficult,
but listening skills do not deteriorate. As a result,
it is helpful to introduce books-on-tape at a young
age to foster development of listening skills.
Computers are also helpful learning aides that
can be easily adapted to the specific needs of an
individual who has problems with eye and hand
coordination. Physical and occupational therapists
should be included in the treatment team to
prevent the development of stiffness in muscles
and to maintain functional mobility.
A prompt diagnosis should be sought for all
suspected infections and specific therapy
instituted. For patients who have normal levels
of serum immunoglobulins and normal antibody
responses to vaccines, immunization with
influenza (flu) and pneumococcal vaccines may be
helpful. For patients with total IgG, or IgG subclass
deficiencies, and/or patients who have problems
making normal antibody responses to vaccines,
immunoglobulin replacement therapy may be
indicated. In an effort to decrease exposure to the
flu, all household members should receive the flu
vaccine every fall.

Ataxia Telangiectasia
57
General Treatment for Ataxia Telangiectasia continued
Special attention should be paid to the lungs.
A-T patients have difficulty taking deep breaths
and coughing to clear mucus from the airways.
They may benefit from daily chest physiotherapy
or use of a therapy vest. If chronic lung disease
develops, a lung specialist should be consulted
about the use of intermittent antibiotic prophylaxis,
inhaled medicines to decrease airway inflammation
or constriction and the need for supplemental
oxygen while sleeping. Many A-T patients develop
problems with chewing and swallowing. Those
who aspirate (have food and liquids entering their
windpipe and lungs) may improve when thin liquids
are eliminated from their diet. In some individuals,
a tube from the stomach to the outside of the
abdomen (gastrostomy tube) may be necessary to
eliminate the need for swallowing large volumes of
liquids and to decrease the risk of aspiration.
Diagnostic X-rays should be limited because of
the theoretical risk that the X-rays may cause
chromosomal damage. In general, X-rays should
only be done if the result will influence therapy and
there is no other way to obtain the information that
the X-ray will provide.
Specific Therapy for Ataxia Telangiectasia
Specific therapy for the neurologic problems
of A-T is not possible at the present time. The
use of thymic transplants, thymic hormones
and bone marrow transplantation has not led to
improvement. Similarly, there is no evidence that
any specific supplemental nutritional therapy is
beneficial. However, now that the gene has been
identified and the gene’s normal function is being
studied, hopefully new and specific therapy may
become available.
Expectations for the Ataxia Telangiectasia Patient
In general, Ataxia Telangiectasia (A-T) follows a
progressive course. It must be stressed that the
course of the disease can be quite variable and
it is difficult to predict the course in any given
individual. Even within families, where the specific
genetic defect is the same, there can be great
variability in the type and severity of different
neurologic problems and immunodeficiency.
The course of the disease in most patients
is characterized by progressive neurologic
deterioration. Many patients are confined to a
wheelchair in their teens. Infections of the lungs
(bronchitis or pneumonia) and sinuses (sinusitis)
are common and may damage the lungs even
if treated promptly. Malignancies or cancers are
also more common in patients with A-T. They can
be treated but require modifications of standard
chemotherapy protocols. For example, A-T patients
should never receive radiation therapy for cancer.
It should be emphasized, that although the above
course is the most typical, the course of A-T
varies considerably from patient to patient. Some
patients have been able to attend college and live
independently, and some have lived into the fifth
decade of life.

chapter
12
Hyper IgE Syndrome
Hyper-IgE syndrome (HIES) is a complex primary immunodeficiency
disorder characterized by a spectrum of abnormalities related to the
immune system, bones, connective tissue and teeth.

Hyper IgE Syndrome 59
Definition of Hyper IgE Syndrome
Hyper-IgE syndrome (HIES) is a complex primary
immunodeficiency disorder characterized by a
spectrum of abnormalities related to the immune
system, bones, connective tissue and teeth. The
cause of HIES is not known. The disease is also
known as Job Syndrome because skin boils, a
hallmark of the syndrome, are reminiscent of the
biblical character Job, who was smitten by Satan
“with sore boils from the sole of his foot unto his
crown.” HIES was initially defined as a triad of clinical
problems involving skin boils, severe episodes of
pneumonia and very high serum IgE levels.
History of Hyper IgE Syndrome
Davis, Schaller and Wedgewood (1966) first
reported two red-haired, fair-skinned girls with
many episodes of pneumonia, eczema-like
rashes and recurrent skin boils remarkable for
their lack of surrounding warmth, redness, or
tenderness. The syndrome was further defined
and clarified by Buckley et al. (1972), who noted
similar infectious problems in two boys who also
had distinctive facial appearances and extremely
elevated IgE levels. Following this report, elevated
IgE was found in the two girls from the initial
report, showing that Job syndrome and Buckley
syndrome represented the same condition.
Clinical Presentation of Hyper IgE Syndrome
Within the past decade, a large and comprehensive
study of the clinical features of HIES revealed a more
complete clinical picture of HIES involving the
immune system, the skeleton and dentition (teeth).
This study also showed that the severity of the
different clinical findings varied with age and from
individual to individual, even within the same family.
Immune System
There are a number of clinical features of HIES that
relate to underlying abnormalities in the immune
system. These include eczema, abscesses,
pneumonia, infections with a fungus called candida,
IgE values in the blood serum that are extremely
high and high numbers of a type of white blood
cell known as eosinophils. In the first month of life,
rashes are described in three quarters of HIES
cases. Most often, the rashes occur in the creases
behind the ears, the back, buttocks and scalp.
Staphylococcus aureus is the most common cause
of the abscesses or boils. Unlike boils in people
with normal immunity, those in HIES patients are
often not “hot”, red, or painful. Consequently, they
may not be recognized and treated promptly.
Upper respiratory infections—sinusitis, otitis media,
otitis externa and mastoiditis—are also frequent.
Fortunately, following institution of prophylactic
anti-staphylococcal antibiotics, abscesses, or
boils, occur less commonly and respiratory
infections decrease.
A clinical hallmark of HIES is recurrent pneumonia.
By early adulthood, more than 50% of patients
have had three or more X-ray proven pneumonias.
For reasons that are not understood, pneumonias
in HIES cause destruction of lung tissue, resulting in
cavities in the lung (pneumatoceles) or scarring and
thickening of the lower air passages (bronchiectasis).
Another chronic infectious problem in HIES are
chronic and recurrent candida fungal infections of
mucus membranes (such as the mouth and throat)
and the nail beds.
Skeleton and Connective Tissue
Skeletal abnormalities and a characteristic facial
appearance in HIES were recognized in the
original reports, but the fair skin and red hair in the
original cases turned out to be just a coincidence.
Patients often resemble each other, having a
prominent forehead and chin, broad nose and
thickened facial skin; these features evolve during
adolescence. Lax joints are also typical.

60
Hyper IgE Syndrome
Clinical Presentation of Hyper IgE Syndrome continued
Bone fractures occur with seemingly insignificant
trauma, and bone density may be reduced.
Curvature of the spine (scoliosis) is common and
needs to be monitored as children with HIES
grow so it can be treated if necessary. Fused skull
bones (craniosynostosis), and extra or abnormally
formed ribs or vertebrae are also found more often
than in the general population.
Teeth
Retention of primary (or baby) teeth in HIES
patients appears to be quite a consistent finding.
Reduced resorption of primary tooth roots
leads to failure to shed primary teeth, which in
turn prevents the appropriate eruption of the
permanent teeth. After an X-ray to make sure the
permanent teeth are present, children who have
had retained primary teeth extracted have had
normal eruption of their permanent teeth.
Other Clinical Findings
Patients with HIES are also at increased risk for
malignancies, especially lymphoma. Systemic
lupus erythematosus and other autoimmune
diseases have also been associated with HIES.
Diagnosis of Hyper IgE Syndrome
In the absence of a known gene or definitive
test for HIES, the diagnosis must be made on a
combination of clinical and laboratory findings. An
elevated level of serum IgE alone is not sufficient
to make the diagnosis since patients with certain
conditions such as severe allergic skin rashes
occasionally have IgE levels in the HIES range
without having HIES. An IgE of over 2,000 IU/ml
(normal adult value is less than 100 IU/ml) has
been used as a cutoff level for HIES when other
features including boils and pneumonia are present.
In infants, in whom normal IgE levels are very low,
an IgE of 10 times the age-appropriate level is a
reasonable guide for HIES. It should be noted that
in some adults with HIES, IgE may decrease and
even become normal. The presence of the other
clinical features involving the skeleton and teeth can
be very useful in supporting the clinical diagnosis.
Other than IgE level, laboratory tests are not helpful
in diagnosing HIES, and even high IgE levels are
not specific, since these can be found in other
conditions. Many studies have focused on the
immune aspects of HIES, such as the migration
of neutrophils toward damaged or infected tissue.
However, no specific immune defect has been
found consistently in all patients with HIES.
Inheritance of Hyper IgE Syndrome
Autosomal dominant HIES
HIES is very rare, with only around 200 published
cases. It occurs in males and females of all ethnic
groups with apparently equal frequency. Most
families with more than one affected person are
consistent with autosomal dominant inheritance. In
this form of inheritance, the presence of an abnormal
gene on only one of the patient’s two autosomes
(non-sex chromosomes) causes the disease (see
chapter titled Inheritance). The abnormal gene on
one chromosome “dominates” the normal gene
on the other chromosome and the disease occurs.
HIES in some, but not all of these families, have
been linked to markers on chromosome 4, a region
suggested by an abnormal chromosome in a single
patient with a sporadic HIES.
Autosomal recessive HIES
A small number of patients from consanguineous
families with severe pneumonia, abscesses,
eczema, high IgE and eosinophilia appear to
have an autosomal recessive form of HIES. In
addition to their bacterial infections, these patients

Hyper IgE Syndrome
61
Inheritance of Hyper IgE Syndrome continued
also have viral infections including Molluscum
contagiosum, Herpes simplex and recurrent
Varicella zoster. No lung cysts occurred in patients
with this form of HIES, although the incidence
of pneumonia was the same, and many died in
childhood with neurological complications.
Treatment of Hyper IgE Syndrome
Skin care and prompt treatment of infections
are the most important elements of HIES
management. Skin colonization precedes
infection. Topical antibacterials and oral antibiotic
treatment are often effective preventive measures.
When eczema is severe, topical moisturizing creams
and limited topical steroids can help achieve healing.
Antiseptic treatments of the skin greatly reduce
the bacterial burden in the skin without leading to
emergence of antibiotic resistant bacteria.
Skin abscesses may require incision and drainage,
but can largely be prevented with continuous oral
antibiotics. The role of prophylactic antibiotics
has not been rigorously investigated, but there is
general consensus in favor of use of antibiotics
against Staphylococcus aureus in HIES.
Candidiasis of the fingernails, mouth or vagina in
HIES rarely disseminates and responds to oral
triazole antifungals, which have been of great benefit
to patients with HIES. Although the over-use
of antibiotics and antifungals is discouraged in
general with “normal“ patients, due to concerns
about selection for resistant organisms, the
under-use in HIES leaves this group at risk for
infections that are debilitating and dangerous.
A remarkable feature of HIES is how well the
patient may feel (and appear) when they have an
infection. For example, even with evidence of a
significant infection on physical examination and
X-ray evidence of pneumonia, an HIES patient
may deny feeling sick and may not see the need
for invasive diagnostic testing or prolonged
therapy. Moreover, doctors unfamiliar with HIES
are hesitant to believe that patients who do not
appear very ill, and appear about the same as
usual, are really quite ill.
Finding the organisms causing an infection cannot
be overemphasized. Lung abscesses may require
drainage or resection, but surgery is difficult in
HIES because patients’ remaining lung tissue often
fails to expand to fill the chest cavity. Prolonged
chest tube drainage and intensive IV antibiotic
treatment may be needed. Therefore, pulmonary
surgery in HIES should not be undertaken lightly,
and ideally it should be performed at a medical
center with experience with the disease.
Following the resolution of acute pneumonias,
pulmonary cysts or cavities form what serve
as a focus for colonization with Pseudomonas
aeruginosa, Aspergillus and other fungal species.
These super infections can be a difficult aspect of
HIES. Potential management strategies include
continuous treatment with antifungal drugs and/or,
aerosolised antibiotics.
Although individual case reports have suggested
benefit from interferon, immunoglobulin
replacement therapy, G-CSF or other treatments,
a general role for immune reconstitution and/
or immune modulators in HIES is unproven.
It has been previously suggested that since
immunodeficiency is a central part of HIES,
bone marrow transplantation might be curative.
However, in the two instances in which it has
been performed, the results have not been
encouraging enough to recommend bone marrow
transplantation for most patients.
Expectations for Hyper IgE Syndrome Patients
Patients with HIES require constant vigilance with
regard to infections and chronic lung disease.
With early diagnosis and treatment of infections,
most patients with HIES lead full lives, becoming
productive adults.

chapter
13
Complement Deficiencies
Complement is the term used to describe a group of serum
proteins that are critically important in our defense against infection.
There are deficiencies of each of the individual components of
complement. Patients with complement deficiencies encounter
clinical problems that depend on the role of the specific
complement protein in normal function.

Complement Deficiencies
63
Definition of Complement Deficiencies
Complement is the term used to describe a group
of serum proteins that are critically important in our
defense against infection (see chapter titled The
Immune System and Primary Immunodeficiency
Diseases). The complement system includes at
least 30 proteins. The first nine of these proteins
were given numbers as their names, such as C1,
C2, C3, etc. As more proteins were discovered
they were named with letters, such as Factor B and
Factor D. Still, others were given more descriptive
names such as C1 Inhibitor.
These proteins act together to provide critical
help in our defense against infection in a number
of ways. One of the proteins, C3, acts to coat
bacteria so that the bacteria are more easily
ingested, or eaten, by white blood cells. Others,
C5, C6, C7, C8 and C9, assemble on the surface
of a certain kind of bacteria and punch holes in
the bacteria, causing them to rupture and die.
Finally, small fragments of two of the complement
proteins, C3 and C5, can cause an increase in
blood supply and the attraction of white blood
cells to local areas of infection, both of which are
needed to clear an infection.
The complement proteins act in a cascade,
one protein activating or stimulating the next in
a specific sequence of reactions, much like a
series of standing dominoes pushing each other
over. A protein that recognizes the invading
microorganism, such as immunoglobulin
(antibody) often starts the cascade of complement
proteins. There are 3 known major pathways of
complement activation. These are the classical
pathway, the lectin pathway, and the alternative
pathway. The classical pathway, the first to be
discovered, is triggered by the interaction of
antibodies (immunoglobulin) with microorganisms,
such as bacteria. In the lectin pathway, Mannose
Binding Lectin (MBL) binds to the sugars on a
bacterial surface and activates the complement
system. Like the lectin pathway, the alternative
pathway doesn’t need antibody or immunoglobulin
to be activated. These three complement
pathways all lead to the activation of the
components of complement, although each does
so in a slightly different way.
Some proteins of the complement system
regulate the degree to which the system is
activated and keep it under control so it doesn’t
activate excessively and overreact to invading
microorganisms. The control, or regulatory,
proteins such as C1 Inhibitor (C1INH) are also
critically important in stopping the complement
system from over reacting to trivial stimuli, such as
minor trauma.
There are deficiencies in each of the individual
components of complement. For example, there
are individuals deficient in C2, individuals deficient
in C3, individuals deficient in C5, individuals
deficient in C1 Inhibitor, etc.
Clinical Presentation of Complement Deficiencies
Deficiencies of the Third
Component of Complement
(C3) and those proteins of
the complement system that
activate C3
The third component of complement (C3) is
the protein that coats bacteria and makes
them more susceptible to being eaten by a
certain kind of white blood cell, phagocytic cells
(see chapter titled The Immune System and
Primary Immunodeficiency Diseases). Patients
who are deficient in C3 or the proteins that are
necessary to activate C3 (e.g. C1, C2 and C4)
are susceptible to a variety of bacterial infections.
Although patients with deficiencies of C3, C1 or
C4 are quite rare, patients with deficiencies of C2
are more common, occurring as frequently as 1 in
10,000 in the general population.
Interestingly, these patients also have a higher
than expected prevalence of some so-called
“autoimmune diseases” such as systemic lupus
erythematosis (SLE or Lupus) or rheumatoid
arthritis. Although the reasons for this association
of these autoimmune diseases with these
complement system deficiencies are unknown,
some complement deficient patients may have
more difficulty with autoimmune diseases than
they do with infection.

64
Complement Deficiencies
Clinical Presentation of Complement Deficiencies continued
Deficiencies of C5, C6,
C7, C8 or C9
Individuals who are deficient in any one of
these components of complement are only
susceptible to one family of bacteria. This
includes the organism that causes an important
form of meningitis, Neisseria meningitidis, and
the organism that causes gonorrhea, Neisseria
gonorrhoeae. These late acting complement
proteins are involved in forming holes in
membranes. It is thought that the hole-forming
complement proteins may be significant in
protecting against these organisms. Although
patients deficient in any of these components
possess the opsonic protein, C3, it does not
appear to be sufficient to provide protection
against these specific organisms.
Deficiency of C1 Inhibitor
There are individuals who are missing, or have
an abnormality of, the C1 inhibitor, a significant
regulator of the complement system. C1 inhibitor
has been shown to have inhibitory activity in the
complement system, the clotting system, the
kinin generating system (a system that generates
another inflammatory peptide, Bradykinin), and
the fibrinolytic system (the system that dissolves
blood clots). Patients with C1 inhibitor deficiency
often have the illness, Hereditary Angioedema.
Angioedema refers to swelling in tissues under
the skin or mucus membranes that are not itchy.
This swelling can affect the hands, feet, bowel,
mouth and airway. When the swelling affects the
skin, there is localized swelling, usually without any
redness or itching. If the swelling affects the wall of
the bowel, it causes extreme abdominal pain. The
swelling of the airways can be especially serious
since the swelling can compromise the patient’s
ability to breath. The swelling, or angioedema,
usually lasts up to three days.
Diagnosis of Complement Deficiencies
A variety of laboratory tests are used to diagnose
patients with deficiencies of individual complement
proteins or components. Initially, the ability of the
patient’s complement system to function as a
whole is examined by seeing if the whole cascade
is capable of punching a hole in red blood cells.
There are different ways to test the integrity
of the whole cascade, but the most common
is CH50 assay (see chapter titled Laboratory
Tests). If the integrity of the cascade is abnormal,
a search is made to determine which of the
components is not present or not functioning in
the proper fashion. Tests of individual components
are relatively sophisticated and not performed in
every laboratory. These tests check for either the
presence of the individual complement protein in
the patient’s blood serum or for the ability of the
individual complement proteins to function properly.
Inheritance of Complement Deficiencies
Most of the complement proteins and regulators
are inherited as autosomal recessive genes;
this means that there are two copies of each
gene present, one contributed by each parent
(see chapter titled Inheritance). There are two
exceptions:
1. A deficiency of Properdin, is inherited as an
X-linked recessive trait.
2. C1 Inhibitor Deficiency (or Hereditary
Angioedema) requires the presence of only
one abnormal gene out of the two genes for
this protein to produce the disease. When the
presence of one abnormal gene “dominates”
over the normal gene, it is called autosomal
dominant inheritance. In this case, the presence
of the one normal gene does not produce
sufficient C1 inhibitor to prevent patients from
having Hereditary Angioedema attacks.

Complement Deficiencies
65
Treatment of Complement Deficiencies
Deficiencies of the Third
Component of Complement
(C3) and those proteins of
the complement system that
activate C3 and Deficiencies of
C5, C6, C7, C8 or C9
At this time, it is not possible to replace the
missing components of the complement system.
In general, these proteins have rapid turnover
and often must be made by the body on a daily
basis. Therefore, long-term replacement therapy
is not an option since injections of highly purified
components would be required almost every day
and the proteins are difficult to purify. Patients
with abnormalities that are associated with a
high frequency of infection are usually helped by
immunization when available and, occasionally, are
treated with prophylactic antibiotics.
Deficiency of C1 Inhibitor
There has been extensive research in recent years
on the treatment of Hereditary Angioedema and
there are a number of companies developing
therapies for this illness. For several decades it
has been known that impeded androgens can be
highly effective in treating patients with Hereditary
Angioedema. Impeded androgens, such as
Danazol or Oxandrolone, are androgens in which
the masculinizing effect of the drug is minimized.
In Europe, the plasma protein that is deficient
in Hereditary Angioedema, C1 inhibitor, reliably
terminates attacks and is available for therapeutic
administration. It appears that it will become
available in North America as well.
Expectations for Complement Deficiency Patients
Most patients with complement deficiencies can
expect to become productive adults if they are
recognized as having the deficiency and treated
early and vigorously.

chapter
14
Other Important Primary
Immunodeficiency Diseases
In addition to the major primary immunodeficiencies described in
other chapters, there are other less common, but well-described,
immunodeficiencies. These less common disorders can be classified
into four categories:
Less common antibody deficiencies
Less common cellular deficiencies
Less common phagocytic cell deficiencies
Less common innate immune defects

Other Important Primary Immunodeficiency Diseases 67
Less Common Antibody Deficiencies
Similar to the patients described in the chapters
on X-linked Agammaglobulinemia (XLA), Hyper
IgM Syndrome, Selective IgA Deficiency, Common
Variable Immunodeficiency, IgG Subclass
Deficiency and Specific Antibody Deficiency,
individuals with less common antibody deficiencies
usually present with upper respiratory infections
or infections of the sinuses or lungs. Laboratory
studies show low immunoglobulins and/or
deficient antibody function. The patients often
improve with antibiotics but get sick again when
these are discontinued. These illnesses include the
following disorders:
Autosomal Recessive
Agammaglobulinemia
These patients resemble patients with XLA including
a profound deficiency of immune globulins,
antibodies and B-cells, but their BTK gene, the
gene defective in XLA, is normal. Several different
genetic abnormalities have been described. Each
of these abnormalities is inherited as an autosomal
recessive trait (see chapter titled Inheritance).
Therefore, both males and females can be affected
with these deficiencies. These patients should be
treated with immunoglobulin replacement therapy.
Antibody Deficiency
with Normal or Elevated
Immunoglobulins
These patients have severe infections similar to
patients with Common Variable Immunodeficiency,
but their immunoglobulin levels are normal or
elevated. They have decreased antibody levels
to most vaccine antigens, both protein and
polysaccharide, which differentiate them from
selective antibody deficiency patients.
Selective IgM Deficiency
These patients have low IgM (less than 30 mg/dl
in adults, less than 20 mg/dl in children) with
recurrent infections that are often severe. There
are variable antibody responses. Some patients
are asymptomatic. This disease may fit into the
group of disorders called Common Variable
Immunodeficiencies.
Selective IgE Deficiency
IgE is the allergy antibody. It is typically very low
(< 5 IU/ml) in up to 10 percent of the patients
attending an allergy clinic. Most of the patients
are not ill, but recurrent respiratory infections have
been described in some patients.
Immunodeficiency with
Thymoma (Good’s Syndrome)
This primary immunodeficiency is associated
with a benign thymic tumor. Good’s Syndrome
is usually first suspected when a thymic tumor
is seen on a chest X-ray. Most patients are
adults. Removal of the thymic tumor does not
cure the immunodeficiency although it may help
other symptoms.
Antibody Deficiency with
Transcobalamin II Deficiency
Transcobalamin 2 is a protein that transports
vitamin B12 to the tissues from the gastrointestinal
tract. A hereditary deficiency is associated with
anemia, failure to thrive, low white cell counts and
hypogammaglobulinemia. It can be treated with
B12 injections.
Warts, Hypogammaglobulinemia,
Infection, Myelokathexis
(WHIM) Syndrome
WHIM is an autosomal recessive disorder (see
chapter titled Inheritance) with severe warts,
recurrent bacterial and viral infections and low,
but not absent, immunoglobulins and neutropenia
(low granulocytes). The latter is due to failure of
the bone marrow to release granulocytes into the
blood stream (myelokathexis). WHIM is caused by a
defective gene for CXCR4, a chemokine protein that
regulates leukocyte movement. Treatment includes
immunoglobulin replacement therapy and G-CSF
(see chapter titled Specific Medical Therapy).

68
Other Important Primary Immunodeficiency Diseases
Less Common Primary Cellular Immunodeficencies
Drug-Induced Antibody
Deficiency
Several pharmaceuticals may depress
immunoglobulin and antibody levels, and this
may result in recurrent infections. The chief
drugs implicated include high-dose steroid
drugs (particularly when given intravenously),
anticonvulscent drugs (Dilantin and others),
anti-inflammatory drugs used for arthritis, and
the monoclonal antibody, Rituximab (Rituxan).
The latter drug targets B-cells, the precursor
of the antibody-producing plasma cells.
In rare instances, severe and permanent
hypogammaglobulinemia can occur with drug
therapy, but usually the hypogammaglobulinemia
reverses when the drug is discontinued.
Cellular immunodeficiencies discussed in
previous chapters included severe combined
immunodeficiency, ataxia telangiectasia,
Wiskott-Aldrich syndrome and the DiGeorge
syndrome. Some patients with less common
cellular immunodeficiencies also have severe
immunodeficiency with early onset and significant
morbidity and mortality while others have mild
problems. All have some defect of their T-cell
(cellular) immune system, recognized by
deep-seated infections, viral and fungal infections,
and tuberculosis and other mycobacterial
infections. Most of the other, less common T-cell
deficiencies described below are relatively rare.
Chronic Mucocutaneous
Candidiasis (CMC)
CMC is characterized by persistent Candida (fungus)
infections of the mucous membranes, scalp, skin
and nails, but not of the blood stream or internal
organs (i.e. not systemic candidiasis). CMC is usually
congenital and often hereditary, with onset in infancy
manifested by persistent oral Candida infections
(thrush). Later, the nails and skin become chronically
infected. These infections respond to anti-Candida
treatment but recur when the treatment stops.
CMC is associated with a selective T-cell
deficiency to Candida and a few related fungi, but
otherwise their immune system is fine. The most
common abnormal laboratory test is a negative
delayed hypersensitivity skin test to Candida
antigen despite widespread Candida infection.
One hereditary form of CMC is the
APECED Syndrome (autosomal recessive
polyendocrinopathy-candidiasis-ectodermal
dysplasia) associated with multiple endocrine
problems (eg hypothyroidism or Addison disease)
due to an AIRE gene defect on chromosome 21.
A few CMC patients develop severe hepatitis
or bronchiectasis. Treatment requires life-long
antifungal medicines.
Cartilage Hair Hypoplasia (CHH)
CHH is an autosomal recessive immunodeficiency
associated with dwarfism. It is particularly
common among the Amish because of family
intermarriage. Most patients have very fine
brittle hair and an unusual susceptibility to viral
infections. The immunodeficiency is variable
and usually involves both antibody and cellular
immunity. Some patients have been treated by
bone marrow transplantation, but this will not
correct their hereditary short stature.
X-linked Lymphoproliferative
(XLP) Syndrome
XLP is characterized by life-long vulnerability to
Epstein-Barr virus (EBV) infection, which can lead
to severe and fatal infectious mononucleosis,
lymph node cancers (lymphomas), combined
immunodeficiency and, less commonly, aplastic
anemia or vasculitis. XLP is associated with a
defect on the X chromosome termed SH2DIA.
This defect affects males. The mothers of the
affected males and possibly some of their sisters
are carriers (see chapter titled Inheritance).
Most XLP patients do well until they are exposed
to EBV. Then, they become seriously ill with fever,
swollen lymph nodes, enlarged liver and spleen,
and hepatitis. If they recover, they go on to
develop one of the above-named problems. Some
patients are misdiagnosed with common variable
immunodeficiency. Early recognition is crucial
since the disease can be cured by bone marrow
or cord blood transplantation. Immunoglobulin
replacement therapy is often used, but this will not
prevent the EBV infection.

Other Important Primary Immunodeficiency Diseases
69
Less Common Primary Cellular Immunodeficencies continued
X-linked Immune Dysregulation
with Polyendocrinopathy (IPEX)
Syndrome
IPEX is characterized by multiple autoimmune
endocrine diseases (particularly diabetes and
thyroid problems), chronic diarrhea and a rash
resembling eczema. IPEX is associated with
abnormalities of a gene on the X chromosome
termed FOXP3. These boys have activated T-cells
which stimulate autoimmune problems. Early
immunosuppressive medications (cyclosporin or
tacrolimus) followed by bone marrow transplantion
are commonly used as treatments.
Interferon-g/IL-12 Pathway
Deficiencies
These deficiencies are genetic disorders
characterized by a special susceptibility to
mycobacteria (the family of bacteria which cause
tuberculosis and related infections) and salmonella
infections. Many of the infants become ill as a
result of a live BCG tuberculosis vaccination, given
routinely at birth in many countries (not USA). Other
patients have skin infections, swollen lymph nodes
or blood stream infections with an enlarged liver and
spleen. The illness results from a genetic inability
to make interferon and/or IL-12, two proteins that
are especially important in helping to kill these
bacteria within the white blood cells. Several genetic
forms and several different molecular pathways are
responsible. Treatment includes antibiotics and bone
marrow transplantation.
Natural Killer Cell Deficiency
This is a rare disorder characterized by recurrent
herpes virus infection and a selective deficiency
of natural killer (NK) cells. Natural killer cells are
lymphocytes (about 10 percent of the circulating
lymphocytes) that are neither T- nor B-cells.
Natural killer cells kill tumors and viral-infected
cells and represent an early defense against
cancer and viral infection. These patients may
have recurrent or chronic herpes infections such
as cold sores, severe Epstein-Barr virus infection,
or varicella (chickenpox). Many of the patients
require continuous anti-viral medicines.
Less Common Phagocytic Cell Deficiencies
The chief phagocytic white blood cell is the
polymorphonuclear granulocyte (also known as
neutrophil). To be effective, the neutrophil must
move to a site of infection, ingest the organism
and then kill the organism (see chapter titled
The Immune System and Primary
Immunodeficiency Diseases).
Neutropenias
Neutropenias are disorders characterized by low
numbers of granulocytes, usually defined as a
neutrophil count of less than 500 cells/ul (normal is
more than 2000 cells/ul). Depending on its severity
and duration, neutropenia can lead to serious and
fatal infection or intermittent infection of the skin,
mucus membranes, bones, lymph nodes, liver,
spleen or blood stream (sepsis).
Neutropenia can occur at birth and can be
life-long. One form, termed severe congenital
neutropenia (Kostmann syndrome), is an
autosomal recessive disorder. This disorder is
associated with a gene abnormality of G-CSFR or
the receptor for G-CSF, a cytokine that stimulates
granulocyte growth. These infants require G-CSF
and may have bone marrow transplantation.
Another form of neutropenia is cyclic neutropenia
which is an autosomal dominant disorder in which
the neutropenia occurs every 2 to 4 weeks and
lasts about a week. It is associated with a gene
defect termed ELA-2.
A third form, benign chronic neutropenia, has
low but not life-threatening neutropenia and is
often asymptomatic. Treatment for all of these
disorders may include antibiotics for infections,
prophylactic antibiotics, G-CSF injections and
bone marrow transplantation.

70
Other Important Primary Immunodeficiency Diseases
Less Common Phagocytic Cell Deficiencies continued
Several primary immunodeficiencies have an
associated neutropenia. These immunodeficiecies
include X-linked hyper-IgM syndrome, X-linked
agammaglobulinemia, and WHIM syndrome.
Some of these patients acquire an autoimmune
antibody to their own neutrophils. This antibody
causes neutropenia due to accelerated destruction
of the neutrophils.
Phagocyte Killing Defects
Several rare phagocyte defects have an inability
to kill organisms similar to patients with chronic
granulomatous disease (CGD) (see chapter
titled Chronic Granulomatous Disease). They
should be suspected in patients who seem to
have CGD but tests for that disorder are normal.
These include enzyme defects or deficiencies
of glucose-6-phosphate dehydrogenase,
myeloperoxidase, glutathione reductase and
glutathione synthetase.
Specific Granule Deficiency
Specific granule deficiency is associated with
killing defects and decreased granules within their
neutrophils.
Glycogen Storage Disease
Type Ib
Glycogen storage disease type Ib is a disorder
with neutropenia, poor granulocyte killing, a large
liver and low blood sugar. It is due to a defect of
the enzyme glucose-6 phosphate transporter 1
with accumulation of glycogen in the liver.
b-actin Deficiency
b-actin Deficiency is associated with poor
granulocyte movement (chemotaxis) and
recurrent infection. b-actin is a structural protein
that allows cell movement. Some patients with
chemotactic disorders have severe periodontitis
and early tooth loss. Three of these syndromes are
termed Papillon-Lefebre syndrome, prepubertail
periodontitis, and juvenile periodontitis.
Less Common Innate Immune Defects
Innate immunity includes those body defenses that
are present at birth and do not increase following
microbial exposure or immunization.
Toll-like Receptor (TLRs)
Defects
Toll-like receptors are proteins present on the
surface of many leukocytes that react with proteins
present on many microbes. Upon contact with an
organism these TLRs send internal messages to
the nucleus of the cell to secrete cytokines, which
stimulate the immune system, and kill invading
microorganisms.
Several immunodeficiencies have been recently
described in which cellular proteins that should
transmit the message from the TLRs to the
nucleus are abnormal, resulting in failure of
cytokines to be produced in response to bacterial
infection. One of these is a disorder termed IRAK-4
deficiency. Another is ectodermal dysplasia with
immunodeficiency (EDA-ID), an X-linked disorder
associated with a defect of a gene termed NEMO
which encodes an enzyme (IKK-g) necessary
for nuclear signaling (see chapter titled Hyper
IgM Syndrome). Many of these latter patients
have defects of sweating, sparse hair, abnormal
dentition, and an antibody deficiency.
Mannose-binding Lectin (MBL)
Deficiency
MLB is a deficiency of a circulating protein that
allows microbes to activate the complement
system. A hereditary deficiency of MBL is
associated with recurrent severe infections.
A partial deficiency may aggravate other
problems such as cystic fibrosis, HIV or lupus
erythematosus.

Inheritance
chapter
15
Many diseases are genetic in origin and consequently, are passed
on in families. Most of the immunodeficiency diseases are inherited
in one of two different modes of inheritance: X-linked recessive or
autosomal recessive. Laboratory studies and family history can be
helpful in establishing the possible role of genes or chromosomes
in a particular primary immunodeficiency disease and may help to
identify a particular pattern of inheritance.

72
Inheritance
Inheritance of Primary Immunodeficiency Diseases
Most of our physical and chemical characteristics
are passed along from parents to children.
Examples of these include the color of our eyes,
our hair color, and the chemicals that determine
our blood type. In the same manner, many of the
primary immunodeficiency diseases are inherited,
or passed on, in families. The chemical structures
that are responsible for these characteristics, and
the tens of thousands of other characteristics that
make an individual unique are called genes. These
genes are packaged on long, string-like structures
called chromosomes. Every cell in the body
contains all the chromosomes and consequently,
all of the genes necessary for life.
Each of our cells contains 23 pairs of chromosomes,
hence, 23 sets of gene pairs. One of each pair of
chromosomes is inherited from our mother while
the other is inherited from our father. Since genes
are on these chromosomes, we also inherit one
gene (or message) for a certain characteristic (such
as eye color) from our mother and one gene for the
same characteristic from our father.
During egg and sperm production, the total number
of 46 parental chromosomes (23 pairs) is divided in
half. One chromosome of each pair, and only one,
is normally passed on in each egg or sperm. When
fertilization of the egg occurs, the 23 chromosomes
contained in the egg combine with the 23
chromosomes in the sperm to restore the total
number to 46. In this way each parent contributes
half of his/her genetic information to each offspring.
All of the chromosomes except the sex
chromosomes are called autosomes and are
numbered from 1-22 according to size. One
additional pair of chromosomes determines the
sex of the individual. These are called the sex
chromosomes and are of two types, X and Y
chromosomes. As shown in Figure 1, females
have two X chromosomes, and males have an X
and a Y chromosome. As a result of having two
X chromosomes, females can only produce eggs
that have an X chromosome. In contrast, since
men have both an X and Y chromosome, half of
the sperm produced will contain an X chromosome
and half will carry a Y chromosome. The sex of the
baby is determined by which type of sperm fertilizes
the egg. If the sperm that fertilizes (or combines
with) the egg carries an X chromosome, the child
that results will be a female. If the sperm carries a Y
chromosome, the child that results will be a male.
CHAPTER 15; FIGURE 1
The Sex Chromosomes

Inheritance
73
Types of Inheritance
Many diseases are genetic in origin and are
passed on in families. Most of the primary
immunodeficiency diseases are inherited in one
of two different modes of inheritance; X-linked
recessive or autosomal recessive. Rarely, the
inheritance is autosomal dominant. Laboratory
studies can be helpful in establishing the possible
role of genes or chromosomes in a particular
primary immunodeficiency disease. In addition,
family history information may help to identify
a particular pattern of inheritance, as can
comparisons to other families with similar problems.
Consult the appropriate handbook chapter or your
physician to learn whether a particular immune
deficiency disease is genetic, and if so, what form
of inheritance is involved.
X-linked Recessive Inheritance
One type of single gene disorder involves those
genes located on the X chromosome. Since women
have two X chromosomes, they usually do not have
problems when a gene on one X chromosome
does not work properly. This is because they have a
second X chromosome that usually carries a normal
gene and compensates for the abnormal gene
on the affected X chromosome. Men have only
one X chromosome, which is paired with their
male-determining Y chromosome. The Y
chromosome does not carry much active genetic
information. Therefore, if there is an abnormal gene
on the X chromosome, the paired Y chromosome
has no normal gene to compensate for the
abnormal gene on the affected X chromosome, and
the boy (man) has the disorder. This special type of
inheritance is called X-linked recessive.
In this form of inheritance, a family history of several
affected males may be found. The disease is
passed on from females (mothers) to males (sons).
While the males are affected with the disease, the
carrier females are generally asymptomatic and
healthy even though they carry the gene for the
disease because they carry a normal gene on the
other X chromosome. The diagram in Figure 2
illustrates how this kind of inheritance operates in
the usual situation.
X-linked agammaglobulinemia is used as the
specific example. Parents in the situation shown
in Figure 2 can have 4 different types of children
with respect to X-linked agammaglobulinemia.
CHAPTER 15; FIGURE 2
X-linked Recessive Inheritance—Carrier Mother

74
Inheritance
Types of Inheritance continued
The X chromosome is diagrammed as an “X.”
An X chromosome that carries the gene for
agammaglobulinemia is represented by an “AX.”
A normal X chromosome is represented by an “XN.”
A “Y” represents a Y chromosome.
The mother, who is a carrier, can produce two
kinds of eggs—one containing an X chromosome
carrying the agammaglobulinemia gene (AX), and
one containing an X chromosome with a normal
gene (XN). The father, who is unaffected, can
produce two kinds of sperm—one containing a
normal X chromosome (XN), and one containing a
Y chromosome.
If the egg containing the agammaglobulinemia X
chromosome (AX) combines with (or is fertilized by)
the sperm containing the normal X chromosome,
then a daughter who is a carrier (AX/XN) is
produced. The gene for agammaglobulinemia is
balanced out by the normal gene on the other X
chromosome.
If the egg containing the agammaglobulinemia
X chromosome (AX) combines with the sperm
containing the Y chromosome (Y), then a male
who is affected with agammaglobulinemia (AX/
Y) is produced. In this case, there is no gene
Examples of Primary Immunodeficiency
Diseases with X-linked Recessive
Inheritance:
X-Linked Agammaglobulinemia
Wiskott-Aldrich Syndrome
Severe Combined Immunodeficiency (one form)
Hyper IgM syndrome (two forms)
X-Linked Lymphoproliferative Disease
Chronic Granulomatous Disease (one form)
on the Y chromosome that corresponds to
the agammaglobulinemia gene, and only the
agammaglobulinemia gene is active in the child.
If the egg containing the normal X chromosome
(XN) combines with the sperm containing the
normal X chromosome (XN) then a normal female
(XN/XN) is produced. In this case the child does not
carry the agammaglobulinemia gene.
Finally if the egg containing the normal X
chromosome (XN) combines with the sperm
containing the Y chromosome (Y), then a normal
male (XN/Y) results.
CHAPTER 15; FIGURE 3
X-linked Recessive Inheritance—Affected Father

Inheritance
75
Types of Inheritance continued
The chances for a given egg combining with a
given sperm are completely random. According
to the laws of probability, the chance for any given
pregnancy of a carrier female to result in each of
these outcomes is as follows:
Carrier female—1 in 4 chance or 25%
Agammaglobulinemia male—1 in 4 chance or 25%
Normal female—1 in 4 chance or 25%
Normal male—1 in 4 chance or 25%
It should be noted that the outcome of one
pregnancy is not influenced by the outcome of a
previous pregnancy. Just as in coin flipping, the fact
that you get a “heads” on your first toss doesn’t
mean you will get a “tails” on the next. Similarly, if
you have a son with agammaglobulinemia with your
first pregnancy you are not guaranteed to have an
unaffected child with your second pregnancy; your
chances of having a son with agammaglobulinemia
are still 1 in 4 (25%) with each pregnancy.
In most of the X-linked primary immunodeficiency
diseases, carrier females can be identified by
laboratory tests if the mutation in a given family
has been determined. Consult with your physician
or genetic counselor to learn if carrier detection is
available in your specific situation.
With earlier diagnosis and improved therapy,
many young men with X-linked disorders, such
as agammaglobulinemia, are reaching adult
life and having children of their own. Figure 3
illustrates the kind of children that a man with
X-linked agammaglobulinemia would have if he
married a woman who did not carry the gene for
agammaglobulinemia. As can be seen in Figure 3, all
of the daughters of an affected male would be carrier
females and none of the sons would be affected.
Autosomal Recessive
Inheritance
If a primary immunodeficiency disease can only
occur if two abnormal genes (one from each parent)
are present in the patient, then the disorder is
inherited as an autosomal recessive disorder. If an
individual inherits only one gene for the disorder;
then he or she carries the gene for the disorder but
does not have the disorder itself.
CHAPTER 15; FIGURE 4
Autosomal Recessive Inheritance—SCID Example

76
Inheritance
Types of Inheritance continued
In this form of inheritance, males and females are
affected with equal frequency. Both parents carry
the gene for the disease although they themselves
are healthy. Figure 4 illustrates how this kind of
inheritance operates in the usual situation. One
form of severe combined immunodeficiency
disease (SCID) is used as the specific example.
As illustrated in Figure 4, these parents, each of
whom is a carrier, can have 3 different types of
children with respect to SCID. The chromosome
carrying the gene for SCID is diagrammed as a
vertical line with the initials SCID next to it. The
normal chromosome is diagrammed as a vertical
line with the initial “N” next to it. The mother can
produce two kinds of eggs—one containing the
chromosome carrying the SCID gene and one
containing a chromosome carrying the normal
gene. Similarly, the father can produce two kinds
of sperm—one kind containing the chromosome
carrying the SCID gene and the other containing
the chromosome carrying the normal gene. If an
egg containing the SCID chromosome combines
with a sperm containing the SCID chromosome,
then a child with SCID is produced; in this case
the child has two genes for SCID and no normal
genes to counteract them. If an egg containing the
chromosome carrying the SCID gene combines with
a sperm containing a normal chromosome then a
carrier child results; in this case the gene for SCID
is balanced by a normal gene and the child is well,
but still carries the gene for SCID. Similarly, if an
egg containing the normal chromosome combines
with a sperm containing the chromosome carrying
the SCID gene, a carrier child is also produced.
Examples of Autosomal Recessive
Inheritance:
Severe Combined Immunodeficiency
(several forms)
Chronic Granulomatous Disease (several forms)
Ataxia Telangiectasia
Finally, if an egg containing the normal chromosome
combines with a sperm containing the normal
chromosome, a normal child who is neither a carrier
nor has the disease is produced.
The chances for a given egg to combine with a
given sperm are completely random. According
to the laws of probability, the chance for any
pregnancy of carrier parents to result in each of the
following outcomes is as follows:
Affected child—1 in 4 chance or 25%
Carrier child—2 in 4 chance or 50%
Normal child—1 in 4 chance or 25%
Again, it should be noted that the outcome of one
pregnancy is not influenced by the outcome of a
previous pregnancy. Just as in coin flipping, the fact
that you get a “heads” on your first toss doesn’t
mean you will get a “tails” on your next. Similarly,
if you have a child with SCID with your first
pregnancy you are not guaranteed a normal child
or a carrier child with your second pregnancy; your
chances of having a child with SCID are still 25%
or 1 in 4 with each pregnancy.
Carrier Testing
In many primary immunodeficiency disorders,
carrier parents can be identified by laboratory
tests. Consult with your physician or genetic
counselor to learn if carrier detection is available
in your specific situation.

Inheritance
77
Reproductive Options
After the birth of a child with a special problem,
many families face complicated decisions about
future pregnancies. The risk of recurrence and the
burden of the disorder are two important factors
in those decisions. For instance, if a problem is
unlikely to occur again, the couple may proceed
with another pregnancy even if the first child’s
problem is serious. Or if the risk of recurrence
is high, but good treatment is available, the
couple may be willing to try again. On the other
hand, when both the risk and the burden are
high, the circumstances may seem unfavorable
to some families. It should be emphasized that
these decisions are personal. Although important
information can be gained from speaking to a
pediatrician, immunologist, obstetrician and/or
genetic counselor, ultimately the parents should
decide which option to choose.
There is a number of options available regarding
family planning for families with family members
with genetically determined (inherited) primary
immunodeficiency diseases. In some situations,
prenatal testing of a fetus in the uterus can
determine whether the infant will be affected
by the primary immunodeficiency disease.
Chorionic villus sampling (CVS) or amniocentesis
can be performed to obtain a fetal sample for
chromosome, gene or biochemical testing. CVS
is usually scheduled at 10-13 weeks of pregnancy
and involves the retrieval of a tiny sample
of the developing placenta from the womb.
Amniocentesis is typically performed at 16-17
weeks of pregnancy and involves the withdrawal
of fluid that surrounds the fetus. Both procedures
have a small risk of miscarriage that should be
balanced against the benefits of the testing.
Chromosome studies can be performed on
cells from CVS or amniocentesis. In addition
to determining the chromosome number and
structure, this study will identify the sex of
the fetus. For conditions that are X-linked,
identification of the sex will help determine
whether the fetus could be affected by the
disease (if male) or a possible carrier (if female).
The fetal sample can also be used to provide DNA
(deoxyribonucleic acid) for gene testing. There are
two main types of DNA studies: direct and indirect.
For some of the primary immunodeficiency
diseases, specific gene changes, or mutations,
can be identified in affected individuals. If the
specific change, or mutation, is known in the
affected family member who has the disorder,
the mutation can then be tested for in the DNA
from a fetal sample obtained during a subsequent
pregnancy. This direct testing of the DNA for a
specific mutation is the most accurate form of
DNA testing. If a specific mutation has not been
identified, or cannot be identified, a family linkage
study may be possible to follow the mutated
gene’s transmission through the family. Normal
DNA variations near the gene in question, called
polymorphisms or markers, can be identified in
some families. The inheritance of these markers
near the gene of concern can be used to
determine whether the gene has been passed on
to the fetus.
Finally, for some conditions, biochemical
measurement of a particular enzyme or protein in
the fetal cells may provide an alternative method of
testing for the disorder. Absence or severe deficiency
of the enzyme produced by the gene mutation
would indicate the presence of the disorder.
In certain situations, other prenatal testing
techniques may provide information about the
risk of an affected fetus. A detailed sonogram
at 16-18 weeks of pregnancy can often identify
the sex of the fetus. This information can be
helpful to families deciding whether to undergo
amniocentesis for an X-linked disorder. For some
families, testing chorionic villus or amniotic fluid
cells will not provide the proper information about
the fetus’s status, but testing of the fetus’s blood
will provide the proper information. This procedure
can be performed after 18 weeks of pregnancy
and involves the insertion of a needle into the
fetus’s umbilical cord or liver vein to withdraw a
small amount of blood for testing.
If an affected fetus is identified through prenatal
testing, the couple can then decide whether they
wish to continue the pregnancy.

78
Inheritance
Reproductive Options continued
Some couples at risk for autosomal recessive
disorders elect to use donor sperm through a
process called artificial insemination. Alternatively,
in both autosomal recessive and X-linked
recessive disorders, donor eggs can be used. The
risk for an affected child is reduced substantially
by using a donor, as the donor would be unlikely
to be a carrier of the same condition. Finally, for
certain conditions, testing of the early embryo
may be possible after in vitro fertilization
(conception outside the womb). This process,
called pre-implantation diagnosis, allows for those
embryos unaffected with the genetic condition to
be transferred to the woman’s uterus. Afterwards
the child is carried like any other until birth.
Although this type of procedure is not yet readily
available for any of the primary immunodeficiency
diseases, it may be accessible in the future.
Some couples may choose to adopt a child, if they
do not wish to attempt a pregnancy themselves.
Although this process can be frustrating and
lengthy, many couples are successful in locating
a baby or child to join their family. Finally, the
option of maintaining the current family size
may seem best to some couples. This may be
because the possibility of having an affected child
is unacceptable or because the demands of the
current family are high. Expansion of the family just
may not be desired.
Careful consideration of these options is important
before decisions can be reached. In addition,
periodic consultation with the medical staff can
be helpful in keeping current with recent medical
advances that could potentially provide more
information for your family. Once again, it should
be emphasized that these decisions are personal.
Although important information can be gained
from speaking to your pediatrician, immunologist,
obstetrician and/or genetic counselor, ultimately the
parents should decide which option they choose.

Laboratory Tests
chapter
16
Laboratory studies are essential to evaluate the immune system
to determine the presence of primary immunodeficiency disease.
This chapter will focus on basic approaches in using the laboratory,
limitations in using this data and a general concept of how to
interpret laboratory data.

80
Laboratory Tests
Laboratory Evaluation of the Immune System
Laboratory studies are essential to evaluate the
immune system to determine the presence of
primary immunodeficiency disease. The laboratory
evaluation of a person’s immune system is usually
prompted by an individual experiencing some
clinical problems such as a recurrent and/or
chronic infection. Information regarding the types of
organisms, the sites of infection and the therapies
required to effectively treat the individual’s infection
often help focus the laboratory studies. It is critical
to recognize that it is the patient’s medical history
and physical exam that direct the appropriate
choice of laboratory tests.
This chapter will focus on basic approaches
in using the laboratory, limitations in using this
data and a general concept of how to interpret
laboratory data.
Normal Versus Abnormal Laboratory Values
An important aspect of interpreting any laboratory
value, especially those relating to the immune
system, is what values are considered normal
and what values are considered abnormal. To
determine what is “normal,” samples are obtained
from a group of healthy individuals, who most
often are adults and equally divided between
males and females.
Once the test is given to these “normal”
individuals, the results can be used to determine
what the “normal” range is for these tests using
a variety of statistical approaches or tools. One
of the more common statistical measurements
is called a 95% confidence interval, which is a
calculated range that includes 95% of the “normal”
results. Other statistical approaches that can be
used include calculating a mean and standard
deviation for the results from the “normal”
individuals. In all of these calculations, the tested
“normal” group is viewed as representing the
general “normal” population. The range generated
from the “normal” group can be used to decide
if a result from a patient is “normal” or “not
normal.” It is important to note that by definition
when the “normal range” is set to include a 95%
confidence interval, 5% of the remaining samples
from “normal” individuals are outside this (normal)
range; 2.5% will have values above the range and
2.5% will have values below the range.
Using the measurement of height as an example,
normal individuals can be just above or just below
a normal range (or 95% confidence interval) and
still be normal. Someone 1 inch taller than the
95% confidence interval is not necessarily a giant
and someone 1 inch shorter is not necessarily
a dwarf. In fact, by definition, 2.5% of normal
individuals will fall below the 95% confidence limit
and 2.5% will fall above!
The fact that 5% of otherwise normal healthy
individuals will fall outside the normal range is
important when looking at laboratory results—
finding a value outside of the reference range
does not automatically represent an abnormality.
The clinical relevance of an “abnormal” laboratory
finding must be based on the clinical history as well
as the size of the difference from the normal range.
Another important issue to consider for the proper
interpretation of laboratory results is that the data
must be compared to the appropriate normal
group or reference range. This is a crucial issue for
tests of immune function related to age because
the immune system undergoes substantial
development during childhood. The range of test
values that are “normal” in infancy will probably
be quite different when the child is 2 or 20 years
old. Consequently, all studies in children must be
compared to age-related reference ranges. If the
laboratory reporting test results does not provide
age specific information, it is important to consult
with a specialist who can suggest appropriate
age-specific reference ranges. Optimally, this
should be provided by the laboratory performing
the tests, but if these are not available, it is
acceptable to interpret laboratory results using
published age-specific reference ranges.
The actual laboratory tests chosen should be based
on clinical history and physical examination. The
laboratory work-up can be broken up into approaches
used to evaluate immune disorders characterized
as antibody deficiencies, cellular (T-cell) defects,
neutrophil disorders and complement deficiencies.
These four major categories of tests for immune
deficiencies are described below. Information about
evaluative approaches, tests used to screen for
abnormalities and more sophisticated testing used
to better characterize the disorder are included.

Laboratory Tests
81
Major Categories of Tests
Laboratory Evaluation For
Antibody Deficiency
The standard screening tests for antibody
deficiency are measurement of quantitative
immunoglobulin levels in the blood serum. These
consist of IgG, IgA, and IgM levels. The results
must be compared to age-specific reference
ranges, taking into consideration the substantial
changes in immunoglobulin levels during infancy
and childhood.
There are also tests for specific antibody
production. These tests measure how well the
immunoglobulins that are present in the blood
serum function as antibodies aimed at specific
antigens such as bacteria and viruses. In this
approach, the fact that the patient has been
immunized with common vaccines, including
those that have antigens made of proteins (e.g.
tetanus toxoid, diphtheria toxoid) and those with
carbohydrate antigens (e.g. Pneumovax, Hib
vaccine) is used to see how well the patient is
able to form specific antibodies against these
various types of antigens. In some instances,
the patient may have already been immunized
with these vaccines as part of their normal care,
while in other instances the patient may need to
be immunized or re-immunized with the intent
of examining their response after a specific time
interval. The use of the two different types of
vaccines is necessary because certain patients
with recurrent infections (and normal or near
normal quantitative immunoglobulin levels) have
been identified with an abnormality in the response
to carbohydrate antigens, but a normal response
to protein antigens. It is worth noting that during
the maturing of the immune system, the response
to carbohydrate antigen vaccines lags behind
the response to protein antigen vaccines. The
interpretation of vaccine responses is best done
by a physician who deals with immunodeficient
patients on a regular basis.
The ability to evaluate the antibody response in a
patient receiving immunoglobulin replacement is
far more difficult. This is because immunoglobulin
is rich in most of the specific antibodies that
are generated following immunizations. When
immunized with common vaccines, it is difficult
to tell the difference between the antibody
provided by the immunoglobulin treatment and
any that might have been made by the patient.
The solution to this is to immunize with vaccines
that are not normally encountered by the general
population and therefore are unlikely to be present
in immunoglobulin preparations. Uncommon
vaccines, such as typhoid or rabies vaccine, can
provide these new antigens. It is important to
note that in a patient with a previously confirmed
defect in antibody production, stopping therapy
to recheck for antibody levels and immunization
response is unnecessary and may place the
patient at risk of acquiring an infection during the
period when the treatment is stopped.
Additional studies used to evaluate patients
with antibody deficiencies include measuring
the different types of lymphocytes in the blood
by staining those cells with chemicals that can
identify the different types of cells. A commonly
used test is called flow cytometry that can identify
B-cells present in the circulation (e.g. CD19 and
CD20 positive cells). The B-cell is the lymphocyte
that has the ability to become the antibody
factory. Certain immune disorders associated
with antibody deficiency have an absence of
B-cells (e.g. X-linked agammaglobulinemia) as a
characteristic feature.
In addition, analysis of DNA for mutations that are
associated with a particular disease can be used
to confirm a particular diagnosis (e.g. the gene
encoding Bruton tyrosine kinase [BTK] associated
with X-linked agammaglobulinemia). Finally, there
are studies done in specialized laboratories that
involve culture systems to assess immunoglobulin
production in response to a variety of different stimuli.
Evaluation of Cellular
(T-Cell) Immunity
The laboratory evaluation of cellular or T-cell
immunity focuses on determining the number of
T-cells and evaluating the function of these cells.
The simplest test to evaluate possible decreased
or absent T-cells is a complete blood count
(CBC) and differential to establish the total
blood (absolute) lymphocyte count. This is a
reasonable method to access for diminished T-cell
numbers, since normally about three-quarters
of the circulating lymphocytes are T-cells and a
reduction in T-lymphocytes will usually cause a
reduction in the total number of lymphocytes, or
total lymphocyte count. This can be confirmed by
using flow cytometry with reagents that identify
either the entire population of T-cells (e.g. CD3) or
subpopulations of T-cells (e.g. CD4 and CD8 cells).
The measurement of the number of T-cells is often
accompanied by cell culture studies that evaluate

82
Laboratory Tests
Major Categories of Tests continued
the functional capacity of T-cells. Most frequently
this is done by measuring the ability of the T-cells
to respond to different types of stimuli including
mitogens (e.g. phytohemaglutinin [PHA]) and
antigens (e.g. tetanus toxoid, candida antigen).
The T-cell response to stimuli can be measured
by observing whether the T-cells begin to divide
and grow (called proliferation) and/or whether
they produce various chemical mediators called
cytokines (e.g. gamma interferon). There are
an increasing variety of functional tests that are
available to evaluate T-cell function, all aimed at
providing data that allows quantitative assessment
of T-cell functional status. However, it remains
somewhat difficult to interpret the diagnostic
significance of T-cell functional data that falls in
between the extremes of markedly diminished and
entirely normal function.
Many of the primary cellular deficiencies are
associated with genetic defects. This is particularly
true with severe combined immune deficiency
(SCID) where more than 10 different genetic causes
for SCID have been identified. These can all be
evaluated using current technology for mutation
analysis and this approach provides the most
accurate means to establish the definitive diagnosis.
Evaluation of Neutrophil
Immunity
The laboratory evaluation of the neutrophil
begins by obtaining a series of white blood cell
counts (WBC) with differentials. The WBC and
differentials will determine if there is a decline in
the absolute neutrophil count (neutropenia). This
is the most common abnormal laboratory finding
with a clinical history that suggests defective
neutrophil immunity. More than one WBC is
necessary to rule out cyclic neutropenia.
A careful review of the blood smear is
important to rule out certain diseases that are
associated with abnormalities in the structure
of the neutrophil, or the way it looks under the
microscope. An elevated IgE level may also
suggest the diagnosis of Job’s (hyper IgE)
syndrome. If these initial screening tests of
neutrophil numbers are normal, testing would
then focus on two possible primary immune
disorders: chronic granulomatous disease (CGD)
and leukocyte adhesion deficiency (LAD). Both of
these disorders have normal or elevated numbers
of neutrophils and each of these disorders has
distinctive features that can help to direct the
appropriate evaluation.
Laboratory testing to diagnose CGD relies on
the evaluation of a critical function of neutrophils
that kills certain bacteria and fungi—the creation
of reactive oxygen. This leads to a process
called the oxidative burst that can be measured
using a number of different methods including
a simple dye reduction test called the Nitroblue
Tetrazolium (NBT) test. In addition, a more recent
testing approach uses flow cytometry to measure
the oxidative burst of activated neutrophils
that have been preloaded with a specific dye
(dihyrorhodamine 123 or DHR) referred to as the
DHR test. There is a third evaluation used by
some laboratories called a chemiluminescence
test. The DHR test has been used for more
than ten years, and it is extremely sensitive in
making the diagnosis. As a result of its excellent
performance, this test has become the standard
in most laboratories supporting clinics that see
CGD patients regularly. The best confirmation
of the specific type of CGD is suggested by the
results of the DHR test, but requires confirmation
by either specifically evaluating for protein
involved or its related gene mutation underlying
the disease.
Laboratory testing for the most common form
of LAD Type 1 involves flow cytometry testing to
determine the presence of a specific protein on
the surface of neutrophils (and other leukocytes).
This protein is part of a set of surface receptors
that form the Beta-2 integrins, proteins that
are necessary for normal neutrophil motility
or movement. When absent or significantly
decreased, the movement of neutrophils to
sites of infection is hampered and produces
a large increase in the number of these cells in
the circulation.
Laboratory Evaluation of
Complement
The finest screening test for deficiencies in
the complement system is the total hemolytic
complement assay or CH50. In situations with a
defect in one complement component, the CH50
will be almost completely absent. Specialized
complement laboratories can provide additional
testing that will identify the specific complement
component that is defective. There are some
extremely rare conditions in which there are
defects in another complement pathway. These
can be screened for by using a functional test
directed specifically at this pathway, the AP50 test.

Laboratory Tests
83
Summary
Laboratory testing plays a central role in the
evaluation of the immune system. All results must
be compared to appropriate reference ranges
to avoid misinterpretation. An accurate medical
history, family history and physical examination
are critical in developing the best strategy for
laboratory evaluation, and the orderly use of
laboratory testing is strongly recommended. This
typically begins with screening tests, followed
by more sophisticated (and costly) tests that
are chosen based on the initial test results. The
range of laboratory testing available to evaluate
the immune system continues to expand. This
has been driven in part by the recognition of new
clinical syndromes associated with recurrent and
or chronic infections. It is the direct link between
the clinical findings and laboratory testing that
has extended our understanding of immune
deficiency diseases. The continuation of this trend
and laboratory testing of the future will likely be
even more sophisticated and help provide further
answers to the underlying basis of the expanding
range of primary immunodeficiencies.

chapter
17
General Care
This chapter provides information pertinent to the general care
of the primary immunodeficient patient in the home, at school, at
work, and at play. General measures, both those that maximize
the body’s resistance to infection and those that reduce the risk
of acquiring an infection from the environment are included.
In addition, specific illnesses are discussed in terms of their
characteristic symptoms and supportive therapies.

General Care
85
General Health Measures
Nutrition
An adequate diet provides nutrients essential for
normal growth and development, body repair
and maintenance. While good dietary habits
are important for everyone, they are extremely
important for the primary immunodeficient
individual. Children, in particular, need a balanced
diet to grow and develop normally. Dietary
guidelines for Americans encourage eating a
variety of foods, maintaining an ideal body weight,
consuming adequate starch and fiber and limiting
the intake of fat, cholesterol, sugar, salt and alcohol.
There are a number of “fad” diets and other diet
recommendations that claim to boost immune
resistance or help fight disease. It is very important
to consider any unusual diet very carefully and to
partner with your physician in this decision. The only
truly proven dietary measure for increasing immunity
is to have a balanced diet with adequate nutrition.
CHAPTER 17; FIGURE 1
Digestive System
Special Medical Diets
In times of infection, illness, or food intolerance, the
normal diet may need to be modified. Talk to your
doctor to learn when these diets are indicated.
Clear Liquid Diet
A clear liquid diet may be used when there is
a severe intolerance to food during infection or
illness, or when nausea, vomiting and diarrhea
are present. Since it is nutritiously inadequate,
a clear liquid diet is usually only used for one
to two days. The main purpose of a clear liquid
diet is to replace lost fluids. Suggested fluids
include: electrolyte replacement solutions such as
Pedialyte and Gatorade , fat-free broth, strained
vegetable broth, strained citrus juices, plain
Jell-O , and fruit ices.
Full Liquid Diet
A full liquid diet may be ordered when there is
difficulty in chewing or swallowing solid foods,
as in pharyngitis, or when advancing from clear
liquids. When properly planned, this diet can be
nutritious and used for extended periods of time.
A full liquid diet includes all foods that are liquid at
room and body temperatures. Eggs (soft-cooked),
strained meats, fruits and vegetables, ice cream,
milkshakes and creamed soups are examples of
food which can be added to the diet.
Soft Diet
A soft or bland diet is the transitional step between
a liquid and a regular diet. Suggested foods
include those that are easily chewed, swallowed
and digested. Foods to be avoided include those
that have high fiber content, are rich and highly
flavored or are fried and greasy.
In some circumstances, if patients are not able
to eat or drink normally, or if they can eat but are
unable to absorb nutrients adequately from their
stomach and intestines, there are procedures to
assist them in maintaining adequate nutrition.

86 General Care
Special Dietary Procedures
Enteral Nutrition
Enteral nutrition is used when an individual with
a normally functioning gastrointestinal system
is unable, or refuses, to eat sufficient liquids to
maintain hydration and sufficient foods to meet
energy needs. Two common methods of providing
enteral nutrition are with the use of a nasogastric
tube or a gastrostomy tube. A nasogastric tube
involves placement of a small flexible plastic
tube through the nose, into the esophagus and
then to the stomach. A prescribed amount of
liquid feeding (containing essential nutrients) is
administered through the tube continuously or at
regular intervals. A gastrostomy tube involves the
placement of a feeding tube into the stomach or
small intestine.
Total Parenteral Nutrition
Total parenteral nutrition (TPN) (or intravenous
hyperalimentation) is a term used to describe
methods of delivering all essential nutrients,
fluids and calories directly into the blood stream.
Total parenteral nutrition is used to maintain the
nutritional status of an individual who is very ill,
malnourished, or whose gastrointestinal function
is inadequate. The TPN solution usually contains
protein, carbohydrates, electrolytes, vitamins,
water and trace minerals. Fats may be supplied in
a separate solution. Various types of intravenous
catheters are used to administer the solutions
through a large vein. Nutrients are introduced
directly into the blood stream, bypassing the
stomach and intestinal tract.
Nutritional Supplements
It is important to consider the large number
of nutritional supplements that are available.
These include a wide variety of vitamins, meal
replacements, herbal remedies, botanicals,
probiotics and naturopathic medicines. Many of
these are marketed with claims to improve various
aspects of your health. Since these items are not
considered “drugs” by the United States Food
and Drug Administration, the claims made by the
companies that produce these items do not need to
be based upon scientific data as medicines must.
For this reason, extreme caution is recommended
when adding these types of treatments to your
regimen. Importantly, some of these supplements
can even be harmful or interact directly with
prescription medicines you are taking. The use of
certain supplements, however, is supported by
scientific evidence under specific circumstances.
You should feel comfortable in discussing the use of
these treatments with your physician.
Hygiene
General principles of good hygiene are essential for
patients with immunodeficiency and their families.
Hand washing before meals, after outings, and
after using the toilet should become routine. It is
essential to remember that to be truly effective,
hands must be washed vigorously with soap
and water for at least 15 seconds (try timing this
sometime). When hands are not visually dirty,
alcohol-based hand gels are an effective alternative.
These have the advantage of being able to
neutralize germs, are portable and can be applied
rapidly. The regular use of hand gels has been
shown to reduce the occurrence of colds in healthy
people, and there is no reason to believe that this
would not apply to immunodeficient patients as
well. Individually wrapped and disposable hand
wipes are excellent for school lunches and for
outings. For younger children, periodic washing of
toys may be beneficial. Cuts and scrapes should be
cleansed, and a first-aid cream applied.
Some individuals with a primary immunodeficiency are
prone to tooth decay. Regular visits to the dentist and
proper brushing and flossing are to be encouraged.
Individuals with a primary immunodeficiency
should avoid exposure to people who are ill with
an infection. During periods of influenza outbreaks,
crowded areas such as shopping centers and
movie theaters should be avoided by patients with
severe combined immunodeficiency disease and
patients who already have developed significant
lung damage.

General Care 87
Exercise
Participation in age appropriate physical activities
should be encouraged. Hobbies and sports
promote physical fitness and provide an excellent
outlet for energy and stress. Swimming, biking,
running and walking promote lung function,
muscle development, strength and endurance.
In general, people who are physically fit and
participate in regular exercise get sick less than
people who do not exercise. In some studies,
people who exercise regularly were even found
to have stronger immune systems. Although
this has not been directly tested in primary
immunodeficiencies, exercise can be a fun,
rewarding and useful part of your routine.
Some patients with a primary immunodeficiency
may have problems controlling bleeding. In these
cases, the types of exercises in which the patients
can safely participate should be discussed with
their physician.
Sleep
Sleep is an essential requirement for good
health. An appropriate amount of sleep each
night that is consistent from day-to-day is highly
recommended. Although there have not been
specific studies of sleep habits in patients with
primary immunodeficiency, erratic sleep has been
shown to have negative effects on the immune
system in other types of patients. For this reason,
viewing sleep as a part of your therapeutic
program is very important. Some helpful guidelines
include: 1) trying to go to sleep and wake up
at roughly the same time each day; 2) trying to
avoid late nights; 3) avoiding consumption of
caffeine (such as caffeinated coffee, sodas or
tea) in the evening; 4) trying to minimize potential
disturbances during the night; 5) avoiding long
naps during the day that could interfere with your
regular sleep schedule; and 6) planning your
schedule around a night that will include an
age-appropriate amount of sleep. Children aged
three years and below also require naps during the
day that should be considered an essential part of
their sleep schedule (see table).
Age Appropriate Nightly Sleep
(adapted from Pediatrics. 2003. vol 111, page 302-307)
Age
Average nighttime
sleep duration
(hours)
Average daytime
sleep duration
(hours)
6mos 11 3 1/2
1yr 12 2
2yr 11 1/2 2
3yr 11 2
4yr 11 1
6yr 11 0
8yr 10 1/2 0
10yr 10 0
13yr 9 0
16yr+ 8 0
Stress
The common notion that people get sick more
often when they are under increased stress is
supported by scientific data. Some studies also
show that stress negatively affects the immune
system. There are also scientific studies that show
reducing stress can improve immune function.
Since some of these measures can be low-risk,
they may be worth considering. These include
massage therapy, biofeedback, meditation and
hobbies. These interventions have advantages
that may or may not apply to particular patients.
You should partner with your physician or
healthcare team in considering or choosing
specific interventions (some may actually be
covered by your medical insurance). However,
regular exercise and sleep are perhaps the most
important stress-reducing measures and should
be taken seriously.

88 General Care
General Care During Specific Illness
This section provides basic information about
some of the illnesses patients may experience
that may not require hospitalization. Medical terms
often used in association with these illnesses are
defined and their characteristic symptoms are
described. General supportive measures designed
to provide relief of symptoms and prevention of
complications are also provided.
These illnesses are grouped according to the body
“system” involved. These systems include the
visual (eyes), the auditory (ears), the respiratory
(nose, throat, lungs) and the gastrointestinal
(stomach, intestines). It is important to stress the
need for physician communication and supervision
for an individual with a primary immunodeficiency
during any illness. The frequency of even “minor”
illnesses should be reported because they can
influence the preventive therapy the physician feels
is necessary (i.e. immunoglobulin, antibiotics).
The goals of medical treatment and supportive
care of any primary immunodeficient individual
are to reduce the frequency of infections, prevent
complications and prevent an acute infection from
becoming chronic.
The patient, family and physician must work together
as a unit if these goals are to be accomplished.
Visual System
Conjunctivitis
Conjunctivitis (pink eye) is an inflammation or
infection of the lining of the eyelid and of the
membrane covering the outer layer of the eyeball
(conjunctiva). It can be caused by bacteria, viruses
or chemical irritants such as smoke or soap.
Conjunctivitis may occur by itself, or in association
with other illnesses, such as the common cold.
The symptoms commonly associated with
conjunctivitis are redness and swelling of the
eyelids, tearing, and discharge of pus. These
symptoms are usually accompanied by itching,
burning, and discomfort from light. In the morning,
it is not unusual to find the eyelids “stuck” together
from the discharge that has dried during the
night. These secretions are best loosened by
placing a wash cloth soaked in warm water on
each eye. After a few minutes, gently clean each
eye, working from the inner corner to the outer
corner of the eye. Meticulous hand washing is
necessary for anyone coming in contact with the
eye discharge in order to prevent the spread of
the infection. It may be necessary to be seen by
a physician to determine the type of conjunctivitis
involved, and the type of treatment required.
Auditory System
Otitis Media
Otitis Media is an infection of the middle ear
and is usually caused by bacteria or viruses. A
small tube called the Eustachian tube connects
the middle ear with the back of the throat and
nose. In the infant and small child, the tube is
shorter and straighter than in the adult, providing
a ready path for bacteria and viruses to gain
entrance into the middle ear. In some infections
and allergies, this tube may actually swell and
close, preventing drainage from the middle ear.
The characteristic symptom associated with otitis
media is pain, caused by irritation of the nerve
endings in the inflamed ear. A baby or young
child may indicate pain by crying, head rolling, or
pulling at the infected ear(s). The older child or
adult may describe the pain as being sharp and
piercing. Restlessness, irritability, fever, nausea,
and vomiting may also be present. Pressure in
the infected ear drum tends to increase when the
individual is in a flat position. This explains why
pain is often more severe at night, causing the
individual to wake up frequently. As fluid pressure
increases within the ear drum, pain becomes more
severe and the ear drum may actually rupture.
The appearance of pus or bloody drainage in the
ear canal is an indication of a possible ear drum
rupture. Although pain is usually relieved when
the ear drum ruptures, the infection still exists.
Whenever an ear infection is suspected, the
patient should be seen by a physician. Antibiotic
therapy is begun in order to stop the infection and
prevent hearing impairment. Decongestants may
also be prescribed to shrink mucous membranes,
promoting better drainage from the middle ear.
A follow-up examination may be performed
in approximately ten days to be sure that the
infection has cleared and that no residual fluid
remains behind the ear drum.

General Care 89
General Care During Specific Illness continued
Respiratory System
The following respiratory illnesses will be
discussed in terms of definitions and symptoms.
Because the general care of the patient during
these illnesses is similar, it will be handled as a
single discussion at the end of the section.
Rhinitis
Rhinitis is a term used to describe an inflammation
of the nose. It is usually caused by bacteria,
viruses, chemical irritants and/or allergens.
Symptoms may include sneezing, difficulty in
breathing through the nose, and nasal discharge.
The nasal discharge may vary from thin and
watery, to thick and yellow or green.
Pharyngitis
Pharyngitis is a term used to describe an
inflammation of the throat (sore throat). It is usually
caused by a bacterial or viral infection. Symptoms
include a raw or tickling sensation in the back of
the throat and difficulty swallowing. Temperature
may be normal or elevated. Sore throats caused by
streptococcus (strep throat) can, in rare incidences,
cause serious complications such as rheumatic
fever. Whenever you or your child complains of a
sore throat, your doctor should be contacted.
Temperature may be within normal limits or slightly
elevated. Repeated or prolonged episodes of
acute sinusitis may lead to chronic sinusitis.
Croup
Croup is a general term used to describe an
infection in children which causes narrowing of
the air passages leading to the lungs such as the
larynx, trachea and bronchi. Croup can be caused
by viruses or bacteria. The child’s temperature
may be normal or slightly elevated. The onset of
croup may be sudden or occur gradually. In some
instances, the onset occurs at night and the child
may awaken with a tight “barking” cough. Breathing
is difficult due to the narrowing of the trachea
(windpipe). Croup can be a frightening experience
for both the parents and child. Unfortunately, the
child’s anxiety may increase the severity of the
symptoms. It is important for the parents to remain
as calm and as reassuring as possible.
CHAPTER 17; FIGURE 2
Common Sites of Infection
Acute Sinusitis
Sinusitis is a term used to describe an
inflammation of one or more of the sinuses (see
Figure 2). The sinuses are small cavities, lined with
mucous membranes, located in the facial bones
surrounding the nasal cavities. The purpose of the
sinuses is thought to be to decrease the weight
of the skull and to give resonance and timbre
to the voice. The basic causes of sinusitis are
the blockage of normal routes of sinus drainage
and the spread of infections from the nasal
passages. Headache, aching in the forehead
and cheekbones and tenderness over the face in
these same areas are characteristic symptoms.
In addition, there may be pain in and around
the eyes and in the teeth of the upper jaw. The
pain and headache associated with sinusitis is
typically more pronounced in the morning due
to accumulated secretions in the sinuses during
sleep. Being in an upright position during the day
facilitates sinus drainage providing temporary
relief. Depending on the amount of post-nasal
drainage, cough, throat irritation, bad breath
and decreased appetite may also be present.

90 General Care
General Care During Specific Illness continued
Always notify your physician when you suspect your
child has croup. Your physician may recommend
that the child be seen immediately.
Acute Coryza (Common Cold)
Acute coryza (common cold) is an acute
inflammation of the upper respiratory tract (nose
and throat or nasopharynx). Early symptoms
include a dry tickling sensation in the throat,
followed by sneezing, coughing and increased
amounts of nasal discharge. There may also be
symptoms of fatigue, chills, fever and general
aches and discomfort.
Influenza (Flu)
Influenza (flu) is a term used to describe a highly
contagious respiratory infection which is caused
by three closely related viruses. Influenza may
occur sporadically or in epidemics. Usually
epidemics occur every two to four years and
develop rapidly because of the short incubation
period. The incubation period includes the time
a person is exposed to an infecting agent to the
time symptoms of the illness appear. Symptoms
of the flu include sudden onset of high fever;
chills, headache, weakness, fatigue, rhinitis, and
muscular soreness. Vomiting and diarrhea may
also be present with one type of influenza.
Acute Bronchitis
Acute Bronchitis is an inflammation of the bronchi
(the major branches off the trachea or windpipe).
It often accompanies or follows an upper
respiratory tract infection, such as the common
cold. Symptoms include fever and cough. At the
onset, the cough is dry, but gradually becomes
productive (producing mucus).
Pneumonia
Pneumonia is an acute infection of the lungs and
can be caused by bacteria, viruses, and fungi.
Symptoms include chills, high fever, cough,
and chest pain associated with breathing and
coughing. In some cases nausea, vomiting, and
diarrhea may also occur. Patients who develop
pneumonia must be treated by a physician since
permanent lung damage may develop if it is not
treated aggressively.
General Care of the Individual with
Respiratory Illness
The treatment of respiratory infections is directed
toward the relief of symptoms and the prevention
of complications. Your doctor may prescribe
a medication to relieve fever and general body
aches. Antibiotics may be prescribed to control
infections of bacterial origin and/or to prevent
complications. Expectorants may be prescribed
to liquefy (water down) mucus secretions.
Decongestants to shrink swollen mucous
membranes may also be ordered. Fluids should be
encouraged, and drinking a variety of beverages is
important. Beverages served with crushed ice can
be soothing to a sore throat. Warm beverages,
such as tea, may promote nasal drainage and
relieve chest tightness.
During the acute phase of any illness, there may
be an initial loss of appetite. You or your child
should not be forced to eat, and large meals
should not be offered. It is often better to offer
small frequent feedings of liquid and soft foods.
Once the appetite returns, a high-caloric, high
protein diet, to replace the proteins lost during the
acute phase of the illness, should be offered (see
section in this chapter titled Nutrition).
General comfort measures also include rinsing
the mouth with plain water at regular intervals.
This will relieve the dryness and “bad taste” that
often accompanies illness and mouth breathing.
A vaporizer is helpful in increasing room humidity.
If you use a vaporizer; it must be kept clean, to
prevent contamination with molds and bacteria.
A petroleum jelly coating can provide relief
and protection to irritated lips and nose. Body
temperature fluctuations may be associated with
periods of perspiration. Bed linens and clothing
should be changed as often as necessary,
and your child should be protected from drafts
and chills. Finally, adequate rest is important.
If persistent coughing or post nasal drip interferes
with rest, elevation of the head and shoulders
with extra pillows during periods of sleep should
be attempted.
The individual should be encouraged to cover the
mouth and nose when sneezing and coughing.
Soiled tissues should be promptly discarded.
Frequent hand washing is essential to prevent
the spread of the infection. In some cases of
bronchitis and pneumonia (depending on the
age and level of understanding) coughing and
breathing deeply at regular intervals should be
encouraged. Coughing protects the lungs by
removing mucus and foreign particles from the
air passages. Deep breathing promotes full
expansion of the lungs, reducing the risk of further
complications. In some situations, a physician
may order chest postural drainage, chest
physiotherapy, or sinus postural drainage.

General Care 91
General Care During Specific Illness continued
Gastrointestinal System
Diarrhea
Diarrhea is characterized by frequent, loose, watery
bowel movements (stools). Diarrhea may be caused
by viral, bacterial, or parasitic infections. Certain
medications may also cause diarrhea. Diarrhea
may be mild to severe in nature. Whether it is mild
or severe depends on the frequency of stools,
their volume, how loose they are, the presence
or absence of fever and how much fluid the
child or adult can take and retain by mouth. The
significance of diarrhea is related to the amount
of body fluids lost and the severity of dehydration
which develops. Infants and young children are
at a greater risk for dehydration than older children
and adults.
Symptoms of dehydration include:
Poor skin turgor (loss of elasticity)
Dry, parched lips, mouth and tongue
Thirst
Decreased urinary output
In infants, depressed (sunken) fontanelles (soft
spots) when the child is lying down
A sunken appearance to the eyes
Behavioral changes ranging from increased
restlessness to extreme weakness.
The general care of diarrhea focuses on the
replacement of lost body fluids and the prevention
of dehydration. When diarrhea is mild, changes in
the diet and increased fluid intake may compensate
for fluid losses. The doctor may suggest giving the
infant or young child clear liquids. If clear liquids
are tolerated (no vomiting) and the frequency and
volume of stools decrease, you may be instructed
to offer diluted formula or milk.
An infant may find comfort in a pacifier. Sucking
may help relieve abdominal cramping. Burping
is still necessary to expel any swallowed air. The
older child and adult may be encouraged to drink
fluids such as weak tea, Gatorade , bouillon and
“flattened” soft drinks. If nausea and vomiting are
present, offer the older child and adult ice chips
and popsicles. Fluids taken too quickly, or in too
large of an amount, may precipitate vomiting. If
these fluids are tolerated, gradually offer small sips
of other fluids. Bland foods, such as rice cereal,
yogurt, and low fat cottage cheese can slowly be
added to the diet (see section titled Nutrition).
General comfort measures include coating the
rectal area with a petroleum jelly preparation.
This will help protect the skin and reduce irritation
from frequent diarrheal stools. Soiled diapers and
clothing should be changed immediately. The
older child and adult may be encouraged to rinse
his mouth with water regularly. This helps to relieve
mouth dryness and “bad taste” associated with
illness and is especially important after vomiting.
In infectious diarrhea, several measures are used
to reduce the chances of spreading the illness to
other family members. Frequent hand washing
is essential for everyone. It may be easier for the
infected person to use disposable cups, dishes,
and utensils. Soiled diapers, clothing and linens
should be kept separate and washed separately
from other family laundry. Bathrooms should
be cleaned with a disinfectant solution as often
as necessary.
Use of the Internet
As many patients and their families have access
to the internet, it is very important to carefully
consider the source of any information available.
Although there are many valuable resources on
the internet, including nearly all of the scientific
data that helps guide expert care of primary
immunodeficient patients, there are also just as
many personal opinions and unproven testimonials.
Talk to your physician and healthcare team
partners about finding good sources of information
on the internet and in interpreting other information
you may have found.

chapter
18
Specific Medical Therapy
There are several specific medical therapies available for patients
with primary immunodeficiency diseases. Effective therapies for
these disorders are a reality for most patients, improving their
productivity and allowing most of them to lead active lives, pursue
careers and have families.

Specific Medical Therapy
93
Introduction
There are several specific medical therapies
available for patients with primary immunodeficiency
diseases. Effective therapies for these disorders are
a reality for most patients, improving their quality
of life and allowing them to become productive
members of society. In this chapter, five established
therapies (immunoglobulin replacement, stem cell
transplantation, granulocyte-colony stimulating
factor, gamma interferon and adenosine deaminase
replacement) and an experimental type of therapy
(gene therapy) will be considered. Their specific
indications, dose and treatment regimens, and
risk/benefit ratios should be discussed with your
physician.
Immunoglobulin Therapy
The term, immunoglobulin, refers to the fraction
of blood plasma that contains “immunoglobulins”
or “antibodies.” Individuals who are unable to
produce adequate amounts of immunoglobulins
or antibodies, such as patients with X-linked
agammaglobulinemia, common variable
immunodeficiency, hyper-IgM syndromes or other
forms of hypogammaglobulinemia, may benefit
from replacement therapy with immunoglobulin. It
is important to understand that the immunoglobulin
that is given partly replaces what the body should
be making, but it does not help the patient’s own
immune system make more. Unfortunately, the
immunoglobulin only provides temporary protection.
Most antibodies, whether produced by the patient’s
own immune system or given in the form of
immunoglobulin, are used up or “metabolized” by the
body. Approximately 1/2 of the infused antibodies
are metabolized over 3 to 4 weeks, so repeat doses
are required at regular intervals. Depending on the
route of administration, this may be done by giving
small infusions under the skin as often as every 2 or
3 days, or larger intravenous infusions once every 3
or 4 weeks. Since it only replaces the missing end
product, but does not correct the defect in antibody
production, immunoglobulin replacement is usually
necessary for the patient’s whole life.
As explained in other chapters of this handbook
(see chapter titled The Immune System and
Primary Immunodeficiency Disease), B-lymphocytes
mature into plasma cells, which manufacture
antibodies and release them into the bloodstream.
There are literally millions of different antibodies
in every normal person, but because there are so
many different germs, no one person has made
antibodies to every germ. The best way to ensure
that the immunoglobulin will contain a wide variety
of antibodies is to combine, or “pool”, blood from
many individuals.
To commercially prepare immunoglobulin
that can be given to patients with a primary
immunodeficiency, the immunoglobulin must first
be purified (extracted) from the plasma, or liquid
part, of the blood of normal healthy individuals.
Each donor must be acceptable as a blood
donor according to the strict rules enforced by
the American Association of Blood Banks and
the U.S. Food and Drug Administration (FDA).
Donors are screened for travel or behavior that
might increase the risk of acquiring an infectious
disease. All immunoglobulin licensed in the U.S.
is made from plasma collected in America. The
blood or plasma from each donor is carefully
tested for evidence of transmissible diseases,
such as AIDS or hepatitis, and any sample that is
even suspected of having one of those diseases
is discarded. Plasma is collected from tens of
thousands of donors, and then pooled together.
The first step in immunoglobulin production is to
remove all the red and white blood cells. This is
frequently done right as it comes out of the donor’s
arm by a process called plasmapheresis, which
returns the red and white cells directly back to the
donor. Then, the immunoglobulins are chemically
purified from the liquid plasma in a series of steps
usually involving treatment with alcohol. This
process results in the purification of antibodies
of the immunoglobulin G (IgG) class; only trace
amounts of IgA and IgM remain in the final product
(see chapter titled The Immune System and Primary
Immunodeficiency Disease). The purification
process removes blood proteins other than IgG
and is also very effective at killing viruses and other
germs that may be in the blood.
Immunoglobulin was first used to prevent
infectious diseases in World War II and it was first
given for primary immune deficiency in 1952. Until
the early 1980’s, the only form that was available

94 Specific Medical Therapy
Immunoglobulin Therapy continued
was usually given by deep injection into muscle
(intramuscular or IM). Immunoglobulin products
for intramuscular injection continue to be used to
give normal individuals a boost of antibodies after
exposure to some specific diseases such
as measles or hepatitis, or before they travel to
areas where those diseases are prevalent. The
amount of immunoglobulin needed to prevent
these diseases is small, only about five ml
(one tsp.). Unfortunately, patients with a primary
immunodeficiency require frequent injections with
much larger doses of immunoglobulin. These
intramuscular injections were very painful, and
only modest amounts of immunoglobulin could
be given in this way. There simply wasn’t enough
room inside the muscle for more.
In the early 1980’s, new manufacturing processes
were developed to make immunoglobulin
preparations that could be safely injected
intravenously, or directly into the vein. There are
now several immunoglobulin preparations licensed
in the U.S. for intravenous (IV) use. For the most
part, the products are equivalent in antibody
activity. However, there are some minor differences,
which may make one particular preparation
more suitable for a given individual. Most of the
products that can be given intravenously contain
some type of sugar or amino acids which help
preserve the IgG molecules and prevent them
from sticking together to form aggregates, which
can cause severe side effects. Although these
additives are harmless for most people, some of
them may cause problems for specific individuals.
Your doctor is your best source of information
about which product is best for you. IV infusions
are usually given once every three or four weeks.
This results in a very high “peak” IgG level in the
blood right after the dose is given and may leave a
relatively low IgG level in the blood at the “trough”
just before the next dose is due.
Another route for giving immunoglobulin is to inject
it relatively slowly, directly under the skin. This is
known as subcutaneous infusion, and is done with
a much smaller needle than is used for IV, and a
small pump that can be worn on the belt. It is an
alternative for those patients who have difficulty
getting venous access and for some who have
adverse reactions to intravenous immunoglobulin.
Typically, subcutaneous infusions are given once
or twice a week by the patient (or by a parent or
partner) at home. Since small doses are given
more frequently than is usually done with IV
therapy, the “peaks” and “troughs” tend to level
out. Subcutaneous therapy may be preferred by
patients who have side effects from the high peaks
or feel “washed-out” or weak before their next IV
dose would be due. Subcutaneous infusions might
also be preferred by patients who have trouble
getting IVs started, and by those who prefer treating
themselves at home on their own schedule.
Purified immunoglobulin has been used for nearly
50 years and has an excellent safety record. There
has never been a case of AIDS due to the use
of immunoglobulin. However, in 1993, before we
had good tests for the presence of the Hepatitis
C virus, there was an outbreak of hepatitis C
associated with one of the immunoglobulin
preparations. Since that time, all immunoglobulin
preparations are treated with special steps which
are included to specifically kill viruses such as
the AIDS virus and the hepatitis viruses. Some
processes treat the immunoglobulin with solvent
and detergent to dissolve the envelopes of the
viruses. Others pasteurize with heat or use acid
treatment to kill them. These methods have been
shown by FDA tests to destroy all AIDS and
hepatitis viruses, and most manufacturers now
perform several of these steps on every batch to
make the chance of any virus getting through as
low as possible.
Most patients usually tolerate the intravenous
immunoglobulin products very well. They can be
administered either in an outpatient clinic or in the
patient’s own home. A typical infusion will take two
to four hours from start to finish. Some patients
may tolerate certain preparations more quickly,
while others may take longer to receive their
dose of IgG. Use of intravenous products allows
physicians to give larger doses of immunoglobulin
than could be given intramuscularly. In fact, doses
can be given that are large enough to keep the
IgG levels in the patient’s serum in the normal
range, even just before the next infusion when the
level would be lowest. Most patients have no side
effects from the IV infusions, but sometimes
low-grade fever or headaches occur. These
symptoms can usually be alleviated or eliminated
by infusing the immunoglobulin at a slower
rate and/or by giving acetaminophen, aspirin
or other common medications an hour or so
before infusion. Less often, patients experience
hives, chest tightness or wheezing. These
symptoms usually respond to antihistamines
such as diphenhydramine (Benadryl ) and/or
asthma medications like albuterol. Headaches
may occasionally be severe, especially in patients
with a history of migraine. These headaches may
occur during the infusion or as long as three to five

Specific Medical Therapy 95
General Care During Specific Illness continued
days later. Some patients with the more severe
and persistent headaches have been found to
have an increase in the number of white blood
cells in the cerebral-spinal fluid, which surrounds
the brain. This is known as aseptic meningitis.
The cause of this apparent inflammation is not
known, but it is not an infection and patients
have not had permanent injury. It is bothersome,
and usually requires treatment. In some patients
merely changing brands of IVIG will eliminate the
problem. In some cases, it is necessary to treat
with a steroid, before, during, or after the infusion.
You should notify your doctor if you experience
headaches that do not respond to standard
medications such as acetaminophen.
The dose of immunoglobulin varies from patient
to patient. In part, the dose is determined by
the patient’s condition and weight. It is also
determined by measuring the level of IgG in the
patient’s blood at some interval after infusion,
and by determining how well a given dose of
immunoglobulin treats or prevents symptoms in
an individual patient. Studies have shown that
patients with chronic sinusitis and chronic lung
diseases such as bronchitis do better when given
higher doses of immunoglobulin. Some patients,
who lose IgG molecules from their digestive tracts
or kidneys, may require more frequent doses.
It is important to remember that although our
current immunoglobulin products are very good,
they do not duplicate exactly what nature normally
provides. The manufactured immunoglobulin is
almost pure IgG, so essentially no IgA or IgM is
transferred to the patient. The specific protective
functions of these immunoglobulins are therefore
not replaced. The IgA on the mucosal surfaces of
the respiratory tract is not being replaced, which
may be part of the reason that antibody deficient
patients remain somewhat more susceptible
to respiratory infections, even though they are
receiving enough immunoglobulin to maintain
normal or near-normal blood levels of IgG.
Hematopoietic Stem Cell Transplantation
Transplantation of stem cells from a normal donor
to a recipient with a primary immunodeficiency is
a highly specialized procedure that can be used
to treat some primary immunodeficiency diseases.
A “stem cell” is a type of cell that can produce
descendants that branch into different types of
cells, such as Blymphocytes and Tlymphocytes. It
can also make more stem cells and continuously
regenerate the pool of stem cells. Traditionally,
stem cells for the immune system were obtained
from bone marrow. This process was called
“bone marrow transplantation.” Now, purification
techniques allow separation of stem cells from
peripheral blood, and blood obtained from the
placenta at birth (“cord blood”). Cord blood, in
particular, has been shown to provide an excellent
alternative source of stem cells for the immune
and blood systems. The stem cells that give rise
to the lymphocytes and other cells of the immune
system also make blood cells. They are called
“Hematopoietic” stem cells (HSC). The process
of taking stem cells from one person and putting
them into another is therefore called “HSCT”
or hematopoietic stem cell transplantation. The
primary immunodeficiency diseases for which
HSCT is most commonly performed include
those diseases that are characterized by deficient
T-lymphocytes or combined deficiencies of
T-lymphocytes and B-lymphocytes. HSCT
is most often used to treat severe combined
immune deficiency (SCID). HSCT has also been
used in some patients to treat other primary
immunodeficiency diseases such as the
Wiskott-Aldrich syndrome, hyper-IgM syndromes,
and chronic granulomatous disease.
As mentioned in the chapter titled The Immune
System and Primary Immunodeficiency Diseases,
bone marrow is the organ in which immature cells
of the immune system, the stem cells, divide and
begin the developmental journey on the road to
becoming mature T-lymphocytes, B-lymphocytes,
and macrophages and neutrophils. In the normal
fetus, there are so many stem cells that they
spill out of the bone marrow which makes fetal
blood and umbilical cord blood rich sources of
stem cells. The transplantation of HSCs from a
“normal” individual to an individual with a primary
immunodeficiency has the potential to replace the
deficient immune system of the patient with
a normal immune system.

96 Specific Medical Therapy
Hematopoietic Stem Cell Transplantation continued
There are two potential obstacles that must
be overcome for this to succeed. The first
obstacle is that, except for the children with
the most complete form of severe combined
immunodeficiency, the patient (the recipient or
host) will have enough immune function remaining
to recognize the transplanted marrow as foreign,
react against it and reject it. This first problem
is called graft rejection. Thus, most patients
other than those with SCID must be treated with
chemotherapy and/or radiation therapy, even
if they do not have cancer, in order to further
weaken their own residual immune system to
prevent it from rejecting the transplanted HSCs.
Another similar situation occurs when the
recipient’s bone marrow is full of its own, defective
stem cells. In that case, the grafted cells may
not find any place to establish themselves and
there may be a “failure of engraftment.” In this
situation, chemotherapy and/or radiation must
also be given to reduce the number of defective
stem cells in the recipient’s bone marrow to “make
room” for the new stem cells to engraft. Although
the chemotherapy and/or radiation therapy
prevents the patient (recipient) from rejecting the
transplanted HSCs, it may cause serious side
effects. These include loss of all of the cells of the
bone marrow, including the red cells that carry
oxygen, the white cells that help fight infection,
and the platelets that help the blood clot. There is
a very high risk of contracting a serious infection
during the weeks immediately after a transplant.
The chemotherapy also may cause severe
blistering of the mouth or other mucus membranes
that makes eating and drinking impossible. It
is because of these serious complications that
transplantation is reserved for those patients with
the most severe immune defects.
The second obstacle arises from the fact that the
transplanted stem cells (or graft) carry the immune
system of the donor. Mature T-cells may be carried
along with the stem cells and/or may develop
from the graft and may recognize the recipient
(host) patient’s tissues as foreign. The grafted
immune system can react against and attack
tissues in the recipient (or “host”). This problem
is called “graft vs. host disease (GvHD).” Often,
medicines such as steroids and cyclosporine,
which suppress inflammation and T-cell activation,
are given to prevent and/or treat GvHD. In order to
overcome the dual problems of graft rejection by
the host and, more importantly, graft versus host
disease, doctors try to find a “match” in which
certain proteins called “transplantation,” “HLA,” or
“histocompatibility” antigens are the same on the
cells of the donor and recipient (see paragraph
below). Alternatively, the bone marrow or other
HSC preparation can be treated to remove most
of the mature T-lymphocytes, which are the ones
that cause most GvHD. Unfortunately, depletion
of T-cells may cause delays in the development
of the new immune system or incomplete
engraftment.
Selection of the Donor
A “matched” HSCT is one that uses a donor
whose tissue (or transplantation) antigens are very
similar or identical to those of the recipient. These
transplantation antigens are called histocompatibility
antigens because they determine whether the
transplanted tissue is “compatible” with the donor.
In humans, these histocompatibility antigens are
referred to as HLA antigens.
Each of us has our own collection of these
histocompatibility antigens on most of our cells
including the cells of our immune system and
bone marrow, as well as on cells in most other
tissues including skin, liver and lungs. The exact
structure of these HLA antigens is determined
by a series of genes clustered on the sixth
(6th) human chromosome. Since the genes for
histocompatibility antigens are closely clustered
on the chromosome they are usually inherited as a
single unit called a haplotype. There are so many
different forms of these histocompatibility antigens
that each person’s haplotype (or collection of
HLA antigens) is relatively unique. Since people
who are closely related (like brothers and sisters)
share many genes, they may also share their gene
clusters (their haplotypes) which determine their
histocompatibility antigens.
Since all of us have two number 6 chromosomes,
we each have two haplotypes encoding the
HLA antigens. Within each haplotype the
histocompatibility gene cluster contains four major
groups (or loci) designated HLA-A, HLA-B, HLA-C
and HLA-D, with many different specificities
possible in each of these four different groups or
loci. There are so many different specific antigens
possible for each of the four different HLA groups
the chance that two unrelated individuals would
have identical haplotypes is low. However, since
haplotypes tend to be inherited as a unit, the
chance that an individual’s brother or sister would
have the same haplotype is relatively high.

Specific Medical Therapy 97
Hematopoietic Stem Cell Transplantation continued
The four loci in each haplotype are clustered together
on each of the 6th chromosomes (see Figure 1
below). The ways that parents could pass them
on to their children are also shown in the diagram.
In almost all cases, the four genes making up the
haplotype on one chromosome stay together when
the paired chromosomes are separated and one
member of each pair goes into one individual egg or
sperm cell. Like any other genetic characteristic, the
choice of which of the two number 6 chromosomes
goes into any given sperm or egg cell occurs in a
random fashion. Whichever one of each parent’s
chromosomes is passed on to a child determines
each of the two haplotypes the child will have.
As with any other genetic characteristic, each
parent passes on only one chromosome and only
one set of transplantation genes (haplotype) to each
child. There are only four possible combinations
of haplotypes in the children. Each of the four
combinations is represented in Figure 1.
In the usual situation, a brother or sister of the patient
is selected as the donor. Each sibling has a 25%
chance of having the same transplantation genes
and being a perfect match for the patient since there
are only four possible combinations of genes. Due to
the laws of probability and the fact that most families
have limited numbers of children, fewer than 25% of
patients have a sibling which is a “match.” There has
been a major effort to develop alternative methods
for giving transplants to patients who do not have a
matched donor in their own family.
CHAPTER 18; FIGURE 1
Selection of the Donor
Matched Unrelated Donors
If an HLA identical matched sibling donor is not
available, one alternative is to try to find a suitable
“matched” donor through one of the worldwide
computer-based registries of individuals who
have volunteered to serve as bone marrow
donors. The National Marrow Donor Program
in the United States has listings of hundreds of
thousands of individuals who have provided a
blood sample to have their HLA type measured.
Successful transplants for patients with a primary
immunodeficiency using donors found through
this and other registries have saved the lives of
many patients over the past 20 years with results
using a fully matched unrelated donor (MUD
donor) now approaching the success rate for
transplants using sibling matches. There have
also been many patients successfully transplanted
using donors that were not fully matched. The
success rate for such transplants has not been
as high as with those full matches and diminishes
with the greater the degree of mismatch between
donor and patient. With mismatched transplants,
other measures must be added to the transplant
procedure in effort to protect the patient from
graft versus host disease or GvHD that may occur
when the T-cells in the graft recognize the new
host as foreign and begin to attack.
Another source of HSC that may be used
for transplantation in patients with primary
immunodeficiency is umbilical cord blood. In the
growing fetus, the HSC frequently leaves the
marrow and are found circulating in high numbers
in the blood. At the time of birth, the placenta is
recovered, the blood that is remaining is removed
and the HSC isolated and banked. These cord
blood HSC may then be HLA typed and used
for transplantation. Since cord blood contains
fewer mature T-lymphocytes than the marrow
or blood of adult donors, sometimes cord blood
transplants have been successful even though
the degree of match between donor and patient
was not very good. A limitation of cord blood HSC
transplantation is if only a small amount of cord
blood is obtained, there may not be a sufficient
number of HSC to treat a larger child or adult.
T-cell Depletion
Another alternative approach for the transplantation
of a patient who does not have a matched sibling
donor is to remove the mature T-lymphocytes
from the stem cells before infusing them into the
patient. In this way, the infused cells are less able

98 Specific Medical Therapy
Hematopoietic Stem Cell Transplantation continued
to recognize the patient (host) as foreign, and the
graft versus host reaction is markedly reduced and
sometimes eliminated. Although the mature
T-lymphocytes have been removed from the grafted
stem cells, T-lymphocytes of donor origin can still
develop from those stem cells and reconstitute the
patient’s T-lymphocyte immunity. The risk of graft
versus host disease from these T-lymphocytes is
markedly reduced because these cells develop
inside the new host from immature precursor cells
in the grafted marrow. Like a person’s own T-cells,
they are “educated” during their maturation to
ignore or “tolerate” the histocompatibility antigens
on the cells of the recipient (host). Since it takes
longer for new T-cells to mature and learns to
work with other cells in the recipient, engraftment
from T-cell depleted HSCTs is usually slower than
with matched HSCTs, and complete immunologic
reconstitution may not occur. Occasionally, more
than one transplant has to be performed to help
create a fully functioning new immune system in
the recipient. Unmatched donors for this kind of
transplant will usually be one of the recipient’s
parents (called haploidentical transplants), since
they share one half of the transplantation antigens
of their child (see Figure 1). Some centers use
this approach frequently for treatment of SCID
babies while other centers believe that the search
for a matched unrelated donor is the first choice
option. It is also possible to do T-cell depletion in
situations where less than fully matched unrelated
donors are used.
The Procedure of Bone Marrow
Transplantation
Bone marrow transplantation is accomplished by
removing bone marrow from the pelvic bones.
Bone marrow is removed by drawing the marrow
up through a needle which is about 1/8 of an
inch in diameter. Only two teaspoons are taken
from each puncture site because, if more is
taken, the sample is diluted with the blood which
flows through the bone marrow space. Bringing
blood with the bone marrow increases the risk
of carrying over the mature T-cells which cause
GvHD. Usually, two teaspoons are taken for each
two pounds of the recipient’s body weight. The
average donor might have only a few punctures
performed to get enough stem cells for a baby,
but over 100 punctures may be required to
get enough stem cells for a teen or full sized
adult. The procedure may be performed under
general anesthesia or under spinal anesthesia.
The discomfort after the procedure varies from
donor to donor. Nearly everyone will require some
type of pain control medication for two to three
days, but most are not required to stay in the
hospital overnight, and are able to return to full
activity shortly. Due to the ability of stem cells to
regenerate them, being a donor does not deplete
or damage one’s immune system.
After removal from the donor, the bone marrow is
passed through a fine sieve to remove any small
particles of bone and then placed in a sterile
plastic bag. The cells are given to the patient with
a primary immunodeficiency through a needle into
a vein in the same manner as a blood transfusion.
Results of Bone Marrow
Transplantation
Bone marrow transplantation between HLA
matched siblings has been successfully employed
in the treatment of immunodeficiency since 1968.
The first child to receive a transplant, a patient
with SCID, is still alive, healthy and has a family
of his own. This case suggests that, as best as
can be determined, the graft is very long lasting
and appears to be permanent. In the usual
patient with a primary immunodeficiency, bone
marrow transplantation involving a “matched”
marrow has minimal graft versus host disease
and is associated with an overall success rate of
as high as 90%. Many of these recipients can be
considered cured and will be free from any signs
of their primary immunodeficiency. However, a
great deal depends on the health of the patient
at the time of the transplant. If the patient is in
relatively good health, free from infection at the
time of the transplantation and does not have lung
damage from previous infections, the outlook is
very good. The chances of a successful transplant
in SCID with full recovery by the recipient will be
best if the transplant is done within the first month
of life. Many patients who have diseases such as
Wiskott-Aldrich syndrome, chronic granulomatous
disease, or hyper IgM syndromes who require
chemotherapy before the transplant to allow
engraftment of the new bone marrow can also be
cured by HSCT. Here again, the initial health of the
patient is extremely important and the best survival
is in children transplanted under the age of five
who are relatively free of infections and who do not
have pre-existing lung or liver damage.

Specific Medical Therapy 99
Granulocyte-Colony Stimulating Factor (G-CSF)
Cells that are derived from stem cells in the
bone marrow can take several different paths or
“lineages” as they develop into mature cells in
the blood. The particular pathway any given cell
will follow is partly determined by its exposure to
“growth factors” or chemical signals from other
cells that tell the bone marrow what is needed. For
example, a growth factor called “erythropoietin”
is necessary for production of the red blood cells
that carry oxygen in the blood.
The types of white blood cells that eat and kill
bacteria are called granulocytes. The most
important type of granulocyte is the neutrophil
or poly. If a patient does not make enough
of this kind of white blood cell, or if they are
destroyed in the blood stream or the spleen,
the condition is called neutropenia. The most
important growth factor which helps stem cells
in the bone marrow produce neutrophils is called
granulocyte-colony stimulating factor (G-CSF).
It got this name because it was first discovered
as a protein which caused stem cells to develop
into colonies of granulocytes in laboratory culture
experiments. The gene for G-CSF has been
isolated, replicated and put into cells in test tubes,
which then produce the human protein. This is
purified and can be injected into patients to raise
their white blood cell counts. G-CSF is available
as Neupogen ® and in a slightly modified form
called Neulasta ® . These growth factors are most
commonly used for cancer patients whose bone
marrow has been suppressed by chemotherapy.
They are also used in patients with a primary
immunodeficiency that have had bone marrow
transplants, in order to get the new marrow
to produce white blood cells faster. G-CSF is
also used in patients who do not make enough
granulocytes because of defects in their own bone
marrow or autoimmune diseases. Neupogen ®
is usually kept in the refrigerator and is given by
subcutaneous injection at home, several times a
week, or everyday in some cases. The dose must
be adjusted according to the resulting rise in the
white blood cell count. Side effects may include
local reactions at the injection sites, pain in the
bones, and potentially, serious allergic reactions.
Gamma-Interferon
Phagocytic cells (neutrophils, monocytes,
macrophages and eosinophils) of patients with
chronic granulomatous disease (CGD) are not
able to kill certain types of bacteria and fungi (see
chapter titled Chronic Granulomatous Disease).
Gamma Interferon is a protein the immune system
uses to stimulate the phagocytes to kill bacteria
more efficiently, amongst other effects (see next
paragraph). CGD patients who are given gamma
interferon three times weekly by subcutaneous
injection have approximately 70% fewer serious
infections than patients not receiving gamma
interferon. When patients taking gamma interferon
do have infections, they require less time in the
hospital. Benefit from gamma interferon is most
evident in children under ten years of age, but all
age groups benefit to some degree.
Interferon is a substance that is found naturally
in the body. It is called “interferon” because it
was originally discovered to interfere with virus
growth. Several different types of interferon have
been identified and it has been shown that they
exert numerous effects on the immune system.
The types of interferons are named alpha, beta
and gamma. Gamma interferon is related to alpha
and beta interferon for its antiviral activities. In
addition, gamma interferon is a potent stimulus for
phagocytic cells and can help make up for the fact
that CGD cells do not make hydrogen peroxide
properly. Gamma interferon improves the bacterial
killing by the phagocytic cells.
Gamma interferon is supplied in a single dose vial
of 0.5 ml. The dose for each patient is determined
by body surface area, which means that both
height and weight are considered. For small
children, the surface area is not a reliable method,
so their dose is based only on their weight. The
vials must be kept refrigerated, but not frozen, and
should not be shaken. There is no preservative
in the gamma interferon preparation, so opened
vials should be discarded after twelve hours at
room temperature. Expired vials should not be
used. Gamma interferon is given at home as a
subcutaneous (under the skin) injection three
times a week (such as Monday, Wednesday, and
Friday). The preferred sites for injection are in the
thighs and arms. These injections are similar to
giving insulin to diabetics. Used syringes should

100 Specific Medical Therapy
Gamma-Interferon continued
be disposed of in an approved needle waste box
and the full box returned to the physician or local
emergency room for proper disposal. Needles
and syringes should not be discarded in your
household trash.
Common side effects of gamma interferon
include fever, muscle aches, headaches, and
occasionally chills. Taking the interferon at bedtime
can minimize side effects. If headaches persist
the next morning, the drug should be given
earlier in the evening. If the severity of the side
effects is unacceptable, it may be appropriate to
reduce the dose, but this should be determined
by the physician. If no other side effects are
seen but fevers suddenly follow the gamma
interferon injection, this should be reported to
the physician. In some instances fevers following
gamma interferon can be a sign of a sub-clinical
(or hidden) infection. A few patients experience
symptoms of depression from gamma interferon,
and if depression occurs, consult your physician.
Patients with a history of seizures should not take
gamma interferon.
PEG-ADA
Deficiency of the enzyme adenosine deaminase
(ADA) causes a rare, life threatening form of severe
combined immunodeficiency disease (SCID) (see
chapter titled Severe Combined Immunodeficiency).
About one in a million children are born with
ADA deficiency. Cells of the immune system
(lymphocytes) are more dependent on ADA for
their development and proper functioning than are
most other types of cells. When ADA is missing, a
substance called deoxyadenosine builds up. This is
toxic to the developing immune system, but it does
not hurt other types of cells as much. Most ADA
deficient infants lack both T- and B-lymphocytes
and begin to get repeated, serious infections of
the skin, respiratory and digestive tracts soon after
birth. However, there are milder cases, in which the
onset of serious illness may be delayed for months
or even a few years. The complete deficiency of
ADA results in SCID. Although antibiotics and
regular treatment with intravenous gamma globulin
are helpful, ADA-deficiency SCID that is not treated
specifically is usually fatal by two years of age if
immune function is not restored. Like other forms
of SCID, ADA deficiency can be cured by HSCT
from a matched donor with the same tissue type
as the patient (usually a brother or sister). Although
some experts may differ, most now recommend
that ADA SCID patients receive chemotherapy
“conditioning” prior to their transplant. This
is because in many cases there is significant
resistance to the transplanted HSC from engrafting
in this form of SCID that may be overcome by the
“conditioning” treatment.
There are three approaches to treating ADA
deficient SCID patients who do not have
a “matched” donor: “partially matched” or
haploidentical HSCT, enzyme replacement, and
experimental gene therapy. The various methods
of carrying out bone marrow transplantation and
some experimental approaches to gene therapy
are discussed earlier in this chapter. This section
will deal with enzyme replacement therapy. The
rapid elimination of purified enzymes by the body
made enzyme replacement for ADA deficiency
impractical until it was discovered that linking
a large molecule called polyethylene glycol, or
PEG, to the enzyme could greatly prolong its life
and therefore its effectiveness after injection. A
clinical trial of PEG-ADA (ADAGEN ® ), using ADA
purified from cows, was begun in April 1986 in
a critically ill child who had failed to benefit from
two haploidentical marrow transplants. Based
on the results with this patient and others treated
subsequently, PEG-ADA was approved for
treatment of ADA deficiency by the US Food and
Drug Administration in March 1990. A teaspoon
of PEG-ADA has as much ADA activity as a billion
normal T-lymphocytes. Intramuscular injection
of this amount or less of PEG-ADA once or
twice a week maintains enough ADA activity in
the bloodstream of patients to largely eliminate
the toxic effects of deoxyadenosine that cause
the immune deficiency. This gives the immune
system a chance to recover over a period of
several weeks to a few months. Continued weekly
injections of PEG-ADA are then necessary to
maintain clinical improvement.

Specific Medical Therapy 101
PEG-ADA continued
Immune function (as measured in the laboratory)
improves in nearly all patients, but the degree of
improvement varies, ranging from very little to
nearly normal. However, clinical benefit is more
uniform and is evident within a few weeks of
treatment even in the 20% of patients whose
lymphocyte counts remain most depressed.
Pneumonia, diarrhea and other serious infections
present at the start of therapy usually resolve,
and growth, which may be severely impaired
initially, resumes. Over the longer term, most
treated children have responded well to ordinary
childhood infections, allowing them to have normal
contact with other children. Older patients are
attending school. Thus far, IGIV has been able to
be discontinued in about half the children receiving
PEG-ADA. Those who have caught chicken pox
and other viral infections, which can be fatal to
untreated patients with SCID, have recovered
uneventfully and developed long-lasting, normal
levels of antibody to the virus.
Aside from the discomfort of the intramuscular
injections, PEG-ADA has had few side effects.
Initially there was concern that, because a
nonhuman source of ADA was being used, patients
might develop antibodies that could neutralize the
enzyme or cause allergic reactions. Antibodies to
bovine ADA can be detected by sensitive tests
in most patients, but there have been no serious
allergic reactions, and in only a few cases has
the development of antibody against the ADA
necessitated an increase in the dose of PEG-
ADA. Since ADA deficiency is so rare, and the first
patients to be treated with ADAGEN are just now
surviving into young adulthood, we are still learning
about this disease and PEG-ADA treatment.
Recently it has been recognized that the improved
laboratory tests of immune function seen early
after PEG-ADA is instituted usually decline over
time and may return to levels comparable to what
they were before PEG-ADA treatment was begun.
Despite these disturbing laboratory observations,
most patients continue to have a clinical course that
remains improved.
It is clear that PEG-ADA can be a lifesaving
treatment that is effective at preventing infections
and their complications in ADA deficient patients.
Its use has reversed the dire clinical outlook
associated with SCID due to ADA deficiency
for many of those patients not given an HLA
identical sibling donor marrow transplant. If the
diagnosis of ADA deficiency is delayed and the
child develops serious lung disease, PEG-ADA
may not be able to reverse that damage nor
prevent its progression. Early diagnosis and, if
a suitable HSC donor cannot be found quickly,
institution of PEG-ADA therapy is extremely
important. There are some ADA SCID patients
with a milder delayed onset form of the disease
where PEG-ADA therapy alone may be sufficient.
Unfortunately, the high cost of this drug may
deplete that individual’s lifetime cap for insurance
payments before they reach adulthood and leave
them uninsurable thereafter. It can be a difficult
decision in these cases where the balance lies
between the potential risks and benefits of stem
cell transplantation combined with conditioning
treatment and the unknown continued future
success of PEG-ADA treatment. For the ADA
deficient infant with classic early onset SCID, there
is little disagreement that HSC transplantation
from a matched donor is the treatment of choice
since it can provide a cure for this disease. In
addition, the use of gene therapy for ADA SCID
has improved to the degree that it should also be
seriously considered in a patient where a matched
donor cannot be found. If gene therapy is under
consideration, it may be important not to begin
PEG-ADA treatment since this may interfere with
the successful use of gene therapy.

102 Specific Medical Therapy
Gene Therapy
Most of the primary immunodeficiency diseases
are caused by “spelling” defects (mutations) in
specific genes. It has long been the dream of
physicians that one day it would be possible to
cure these diseases by fixing the mutation that
causes the disease and restore the patient to
normal health. As a result of the human genome
project and similar efforts to map all of the
genes present in human beings, we now know
the identities of the specific genes involved in
many diseases, including the majority of primary
immunodeficiency disorders, with more genes
being identified nearly every week. Finally, we have
reached the stage where that long held dream is
becoming reality with the cure of a few patients
with primary immunodeficiency diseases leading
the way, just as these diseases were the first
disorders cured by bone marrow transplantation
when it was introduced in the late 1960s.
Not every genetic disorder will eventually be
correctable by gene therapy and this is also
probably true for some primary immunodeficiencies,
but primary immunodeficiency diseases as a
general rule are better suited for this therapy
than almost any other class of genetic disease.
Transplantation of bone marrow taken from a
normal donor has been successful in curing
many of these disorders, so it should also be
possible to take the patient’s own bone marrow
and correct the genetic defect in those cells by
adding a normal copy of the gene that is causing
the disease. We should always have the patient’s
own bone marrow so the absence of a suitable
matched marrow donor will not be a problem
for the gene therapy approach. Similarly, GvHD
should not be a problem when the patient’s own
HSC are used for the transplant. Also, since bone
marrow cells are readily removed from the body
and worked on in the laboratory, it is much easier
to deliver the corrective gene to these cells in the
test tube than it would be if we needed to deliver
the genes to cells still remaining in the body like
the liver, heart, lungs or muscles.
Although it is beyond the scope of this chapter
to describe the technology of gene transfer in
detail, in the first cases successfully treated by
gene therapy, the corrective genes were packaged
inside a modified virus (called a vector). These
modified viruses were then used to deliver the
disease fighting gene to the patient’s lymphocytes
or HSC in laboratory culture. After two to four
days, to allow the viruses to insert the genes,
these cultured cells were washed and then given
to the patients just as if they were receiving a
blood or bone marrow transfusion. The particular
viruses used were from a class of viruses
(retroviruses) that normally insert their own genetic
material directly into the chromosomes of the cells
that they infect. The viral genetic material becomes
part of the genetic inheritance of the cells that
they infect including the characteristic that the viral
genes then get transmitted to the cell’s daughters
when cell division occurs. For use in gene therapy,
the viruses own genes are discarded and replaced
with the genes that we want delivered, but by
using the machinery of the virus—now the disease
correcting gene becomes part of the inheritance
of the vector treated cells and this results in cure
that is transmissible to all of the daughter cells that
normally develop from the originally treated cell.
As we know, relatively few HSC can give rise to all
of the blood and immune system cells in the body
for life and because these stem cells divide and
reproduce, the genetic correction added to the
stem cells will spread widely to many different blood
and immune system cells and also last for life.
The first clinical trial of gene therapy was in
1990 and treated a four-year-old girl with ADA
deficiency. In this first use of gene transfer the
ADA gene was inserted into T-lymphocytes grown
from the girl’s blood using a combination of T-cell
growth factor and T-cell receptor stimulation.
After the cells were treated with the ADA vector
and expanded in culture by several dozen fold
they were infused into her vein periodically for
a total of twelve infusions over two years. Now,
this girl is clinically well and still has about 25% of
her circulating T-cells carrying the corrective ADA
gene. The design of this first trial did not attempt
to correct the defective HSC and therefore gene
correction has been limited to the T-cells.

Specific Medical Therapy 103
Gene Therapy continued
The next primary immunodeficiency to be treated
by gene therapy did target the HSC using a
retrovirus to deliver the gene for the gamma chain of
the major cytokine receptor family, the gene defect
in X-SCID. Beginning with a groundbreaking study
in France, there now have been nearly 20 X-SCID
babies around the world cured using this strategy
for gene therapy of X-SCID, but a major
complication also developed in three infants
treated by this technique. About three years after
the treatment was completed and the immune
system had shown complete recovery, these
three children developed an unusual type of
leukemia that appeared to be caused by where
the inserted gene happened to splice itself into
the chromosomes of the treated HSC. This
complication is called “insertional mutagenesis”
and it is still not clear why these three infants
developed the problem while the others are
healthy and appear cured. Two of these children
are in remission after treatment for the leukemia,
but the leukemia treatment was unsuccessful
in the third. After an evaluation period when no
additional patients were treated by gene therapy,
clinical trials have now cautiously resumed using
modified vector designs and preparations and
there is optimism that this curative treatment will
soon become the standard of care for X-SCID.
Attempts to treat ADA SCID using a similar
approach targeting the HSC were disappointing
with very low rates of engraftment of the genecorrected
cells and no sustained cures. In another
important breakthrough, a trial was undertaken
in Milan which in addition to the gene therapy
using ADA gene treated HSC, PEG-ADA was
discontinued and the patients were also given
chemotherapy conditioning, although less
intensive conditioning than is used if allogeneic
bone marrow transplantation was been performed.
Now, these ADA SCID children also have shown
full recovery of both T-and B-cell function and
appear to be cured as well. In another clinical
trial, a small group of patients with the X-linked
form of CGD have received HSC gene therapy
combined with chemotherapy conditioning and
also have shown remarkable improvement with
clearing of deep seated infections and restoration
of granulocyte function. These trials are too recent
to tell us if this will result in cure for CGD, but the
data is clearly very encouraging that gene therapy
may be effective treatment for yet another of the
primary immunodeficiency diseases.
There is great potential as well as many risks
involved in gene therapy, which must still be
regarded as an experimental therapy whose
“kinks” have not been completely worked out.
Some diseases, such as SCID, are close to
the point where gene therapy may become the
treatment of choice. Other diseases are more
complex and the perfection of gene therapy will
be farther off. Among the factors complicating the
development of gene therapy for other diseases
include the need to use genes that require tight
physiologic regulation, genes that are needed
only very early during embryonic development
before a critical window of opportunity closes,
dominant gene defects where the presence of a
single normal gene copy is already known not to
reverse the disease process or genes that must
be expressed in the majority of immune system
cells and do not by themselves give a selective
advantage to the corrected cell population.
Despite these problems, we are hopeful that one
day, gene therapy will be the procedure of choice
for the majority of immunodeficiency diseases.

chapter
19
Infants and Children with
Primary Immunodeficiency
Diseases
Most children with primary immunodeficiency diseases continue to
play, go to school and socialize normally.

Infants and Children with Primary Immunodeficiency Diseases
105
Introduction
If your child has received the diagnosis of a
primary immunodeficiency disorder, it is important
to understand the role you will play in the child’s
future. It would be nice to think you could adjust
to this new role slowly, however, unless there is a
family history, you are presented with a number of
new challenges with little preparation. One of your
first challenges is to minimize the impact of chronic
illness upon the child’s life without compromising
their care.
Once the diagnosis of a primary immunodeficiency
has been made, children must learn how to live
with this diagnosis on a daily basis. Although having
a primary immunodeficiency disease is a chronic
disorder, the symptoms and their impact on the child
will vary considerably. The diagnosis of a primary
immunodeficiency does not mean that the child
will be sick every day. Most diagnosed children will
continue to play, go to school and socialize normally.
Understanding the diagnosis, using preventive
measures, and communicating with medical
professionals will help you, your child, and your
family live with this chronic health condition.
The family as a whole is affected by any chronic
illness and should be encouraged to participate
in decision-making events that affect the family
unit. Family stresses on top of those encountered
while managing chronic illnesses can be minimized
if recognized early and addressed immediately.
Communication with all parties is essential.
Dealing with a chronic illness in an infant or child
can be very emotional. Fear of the unknown can
be one of the most prevalent emotions, but can be
easily controlled with education. If you want your
child to grow up and be able to handle their own
care, lead by example. Don’t feel ashamed to seek
help from medical professionals or others in your
situation, and look for credible information sources.
Coordinating Your Child’s Care
When your child is diagnosed with a primary
immunodeficiency disease, you become part of
your child’s health management team and his or
her primary advocate. Your role in monitoring your
child’s symptoms and responses to treatments and
communicating your observations and concerns
is vital to the medical team’s assessment and
treatment of your child. In many cases, more than
one physician will be involved in caring for your child;
therefore, coordinating communication and keeping
comprehensive and accurate records of your child’s
medical course is essential. Many parents suggest
that a diary is an invaluable tool to document events
affecting your child’s medical care.
Recommendations for items to be kept in the
diary include:
• A brief history leading to the diagnosis that can
be written by the parent or a physician
• Copies of laboratory evaluations confirming
the diagnosis
• A current list of physicians caring for the child
with up-to-date addresses and phone numbers
• A chronology of important events, specifically
noting types of treatment and therapy, changes
in therapy and subsequent responses to
that therapy
• A current up to date list of the child’s medications
• Allergies to medications
• An immunization record or lack of immunization
• Current insurance information
• Explanation of benefits records can be kept in
the diary or separately, but should be
periodically reviewed for accuracy
Insurance concerns that arise are more easily
resolved through the use of the diary. The diary may
be especially useful if the child should need to see
a new physician, especially in an emergency. This
form of accurate information shortens the lengthy,
often repeated history-taking sessions by new
physicians, allowing for more time to focus on the
immediate issue at hand. It is wise for more than
one person in the family to be aware of the child’s
medical routine. A well-documented diary can be
extremely helpful for those times when the child is in
the care of caregivers other than parents.

106 Infants and Children with Primary Immunodeficiency Diseases
Coordinating Your Child’s Care continued
In addition to bringing the diary to each medical
visit, additional suggestions when visiting a
medical professional include:
• Have a list of questions prepared in writing.
Doctors cannot spend as much time as they
would like with each patient, so be ready with
your list of questions.
• Remember to take notes. When possible,
take another family member or friend along on
the visit. It is always wise to have more than
one person familiar with the patient’s medical
routine. This will allow you time to visit with the
doctor individually, if necessary, as well.
Designate a special tote bag just for these medical
visits. The tote should contain:
• A couple of toys or age-appropriate activities.
It may not be wise to share toys at the doctor’s
office; you don’t want to go home with more
germs.
• Favorite books or a new book can help your
child stay occupied and calm during long
waiting periods.
• A notebook for taking notes
• A contact list with names and phone numbers
of family, friends, and school personnel
Sometimes you and your child will go for tests
immediately after the visit or the visit could be
extended for other reasons. Be prepared for a
change in plans or long office visits. For instance,
you may need to make other arrangements for
your other children.
Encourage the medical professional to
communicate directly to your child when possible.
Although your child may be young, it is always
appropriate for him or her to build a relationship
with involved healthcare providers.
Ask for written instructions concerning medicines
and treatments. This will help avoid mistakes by all
parties, as well as give you written instructions to
be placed in your medical diary.
Normalizing Your Child’s Life
When a child has a chronic health condition,
everyone in the family is affected. Parents may
be tempted to be overprotective, which is a very
natural response as it reflects the concern of
keeping the child as healthy as possible. It is also
common for parents to want to compensate for
the additional challenges their child with a primary
immunodeficiency faces.
Such challenges may include:
• coping with symptoms that may be
uncomfortable or hinder regular activities
• daily treatments or medicines
• trips to the physician’s office
• uncomfortable procedures
It may be a natural inclination to compensate for
challenges by loosening rules and expectations
or by providing rewards. However, the loosening
of rules, or provision of extra rewards, may result
in some undesired consequences. For instance,
children may recognize when parents change what
is expected of them and worry about why this
has changed or what the change means. Some
children may even wonder if it means their illness
is getting worse. Changes in expectations, or
expectations that are different from their siblings,
may also serve to confirm the child’s concerns
about being different and he or she may perceive
that difference negatively. In addition, children
may expect this special treatment to continue
even when parents or other caregivers begin to
transition to more typical behavioral expectations,
creating a potential cause of friction in the family.
Finally, brothers and sisters are also likely to
sense a difference in behavioral expectations
and may become jealous and/or resentful of
the attention and rewards the child with primary
immunodeficiency receives.
It is helpful to remember that children need limits
and consistent expectations and responses to
their behavior. This provides security to children
by increasing the predictability of their world.
Developing and maintaining expectations, or
“family rules” for all children in the family helps

Infants and Children with Primary Immunodeficiency Diseases 107
Normalizing Your Child’s Life continued
them understand their role in the family and what to
expect as well as what is expected of them. If your
child with primary immunodeficiency is unable to
do his chores, reevaluate the expectations and find
something else that he or she can do to contribute
to the family. If he or she is able but not willing, or
chooses not to follow through on an expectation,
the consequences should be clearly stated,
age-appropriate and similar to siblings, and carried
out. This process of limit-setting and discipline
should be the same for all children in the family.
Similar to the pitfalls of relaxing family rules and
expectations, providing children with rewards
requires some careful consideration. As parents
find, because there are so many trips to the
physician’s office, it becomes clear that they
cannot reward the child with every needle stick
or test. Such procedures or treatments may
indeed be challenging for your child. Planning and
practicing ways of coping can help you and your
child better manage difficult events. For those
times when a reward is appropriate, provide your
child with a few choices that blend into his or her
everyday world. For example, on treatment days,
allow your child to select a much loved activity or a
favorite meal for dinner.
Providing knowledge of your child’s condition to
their friends and their friends’ parents at an early
age helps to foster acceptance. They will grow up
together knowing the special circumstances that
surround them. Your child will know he or she is
not so different after all.
Preparing for School or
Other Care Outside the Home
In addition to their role with the health care team,
parents also act as the link with their child’s other
caregivers, such as those adults who interact
with and supervise their children in childcare
or school. The transition from infant/toddler to
school-aged child is particularly challenging. Often
this is the first occasion the child and parent are
separated for an extended length of time. Also,
the addition of new care providers can create
anxiety for children and parents alike. Conversely,
this opportunity to grow intellectually and
emotionally should be greeted with enthusiasm as
it represents a great milestone in life.
Children are very perceptive and will often share
their parents’ emotions during this change in life.
An optimistic outlook beginning weeks, even
months, before the first day away eases the
transition to school or care outside the home.
Many parents recommend advance preparation
to feel more comfortable with any specific
concerns related to their child’s health needs.
Preparation includes a refresher course on your
child’s particular primary immunodeficiency and
his or her current therapy. By reviewing your
child’s medical diary with school officials and
personnel, you will aid in educating them about
your child’s condition and potentially facilitate
the prediction of illness patterns in this new
environment. Timing and early warning signs of
illness should be discussed with key personnel
(i.e., school nurses, teachers, counselors, and
principals). Your child’s physician and other health
care providers may also be called upon to answer
any specific questions. Other items to consider
include transportation on normal and sick days, as
well as a phone “call down” list in case of illness.
Appropriate letters from the physician about
physical limitations, if any, medications to be given
at school, and immunization recommendations,
should be obtained in advance to allow resolution
of specific concerns prior to the beginning of
school. In addition, plan in advance with your
child’s teachers for specific needs that may
impact school routine. Special arrangements
may be necessary for children who need frequent
meals or restroom privileges due to intestinal
malabsorption, hall passes or scheduled nursing
visits for medication administration, and/or
assignment of classes to minimize the effects of
absences due to regularly scheduled treatments or
doctor’s visits. Yearly review of these items should
allow a safe and smooth transition throughout the
school experience.
Some parents have reported two types of
misunderstandings that may arise among
other people with little knowledge of primary

108 Infants and Children with Primary Immunodeficiency Diseases
Preparing for School or Other Care Outside the Home continued
immunodeficiency diseases. One is the
perception that parents of children with primary
immunodeficiency diseases are overprotective.
Often, a child looks healthy to others, but the
child’s parents are aware that a simple cold can
lead to other complications. Due to their keen
awareness of their child’s history, these parents
are often in the physician’s office before symptoms
are apparent to others. As a parent, you know
your child best of all and will often pick up the
early signs of potential trouble. Another situation
resulting from the misunderstanding of primary
immunodeficiency diseases is the fear that a
child with a primary immunodeficiency disease
will spread illness to others when, in fact, the
opposite is true. Families of a child with primary
immunodeficiency may fear going to public
places or having their child attend school due
to a perceived risk of illness exposure. It should
be emphasized that most children with primary
immunodeficiency diseases are able to attend
school safely. In some very special instances,
home schooling, homebound and even dualenrollment
options can be viable alternatives.
Your child’s physician can help in making this
decision, but as a general rule, if your child has no
restrictions on being in public spaces (i.e., movies,
malls, airplanes), they may safely attend school. It
is important to prepare yourself and your child for
handling such misunderstandings. Planning what
to say in a situation where someone expresses
worry that your child will spread illness to others,
for instance, can be beneficial and minimize the
tension of the situation.
Hospitalizations
Everyone in the family is affected when a child
is admitted to the hospital. Parents worry about
the well-being of their child in the hospital, who
will take care of siblings at home, and about
missing work. The child in the hospital is likely
to experience stress related to procedures,
separation from family and friends, and/or
disappointment related to missing out on regular
activities such as field trips or other school events.
Brothers and sisters may worry about the child
in the hospital and about how their own lives will
be affected (e.g. who will take care of them while
their parents are at the hospital, how their lives will
change). Siblings may also feel jealous or resentful
of the attention that the hospitalized child receives.
Following are some relatively simple strategies
that may help minimize the stressful effect of
hospitalizations on the child and family:
For the hospitalized child, bring favorite items
and activities such as stuffed animals, a
special blanket, books, videos, toys or games
from home. These all help make the hospital
environment more familiar and comfortable.
If the hospitalization will be longer than a few
days, ask if pictures and get well cards can be
taped to the walls. Become familiar with what
procedures will be conducted and when you
may accompany your child. When possible,
prepare your child for procedures or events
by helping him or her know what to expect
(different parts of a procedure, what it may
feel like, sound like, look like) and by planning
how to cope or get through it (utilize Child Life
specialists, nurses, and procedure technicians).
Maintain regular limits and routines.
For siblings, maintain routines as much as
possible. Try to keep siblings at home if
possible, rather than sending them to stay
elsewhere; consider bringing alternative
caregivers to stay with them in the home if
necessary. Communicate honestly and openly
about the situation and provide updates as
needed. Support the continued connection
between children at home and the hospitalized
child through phone calls, notes or cards, and
visits, if possible (check with your child’s nurses
about visiting policies). Maintain regular limits.
For parents, utilize the support and resources
available in your community and at the hospital.
Continue to take care of yourself, try to eat
nourishing meals and get enough sleep. Be
sure to take short breaks to get outside or at
least out of the hospital room. This may help
you gain energy and perspective at times.

Infants and Children with Primary Immunodeficiency Diseases 109
A Child’s Understanding of Illness
Very young children can sound like experts
regarding their illness when they repeat the words
and explanations they have heard adults use.
However, the ability to repeat such statements
does not indicate that children truly understand the
meaning of the words they have just used. Asking a
child, “What does that mean to you?” can help you
evaluate his or her individual level of understanding.
As children continue to grow and develop, they will
need to revisit questions related to their primary
immunodeficiency disease (e.g. “What is this
illness?”; “How come I have it?”; “How did I get it?”;
“What’s the medicine for and why do I need it?”).
Sometimes changes in your child’s behavior can be
a clue to initiate these conversations.
School-age Child
The child begins to develop an understanding of
the interior body and an understanding of illness.
This age-group benefits from employing their
natural curiosity to facilitate understanding about
the body systems and their specific symptoms
and treatments. Books and/or videos, such
as children’s anatomy books (resources listed
in the Resources section) and even science
“experiments” can encourage more advanced
discussion and understanding.
Preschool Child
The child may perceive treatment, procedures,
or hospitalization as punishment because of their
immature understanding. What these children
need to know is that they did not cause the illness
and that the treatments are not punishment—
instead it is the best way the doctors and nurses
know for helping them stay well or get better. If it’s
a particularly challenging treatment or procedure,
it may help to say, “we wish there was an easier
way, but this is the best way.”
Learning from Your Children
Children are resilient. However, there may be
times when you are not sure how well your child is
coping. You may have noticed some changes in
your child’s behavior that occur more commonly
than the occasional tough day that all children have.
Watch for continuing patterns of:
• eating or sleep disturbances
• changes in school performance
• an increase or appearance of fears
• changes in social behavior
• regression in developmental milestones
• withdrawing from others
These actions may alert you that your child needs
some extra support. Often, talking and giving your
child the opportunity to share concerns with you
and together planning ways to cope in the future is
all that’s needed.
Other times, children and parents may benefit from
additional support from extended family and friends,
and caring adults in the child’s school or community
(such as guidance counselors, religious youth group
leaders, and mental health providers).

110 Infants and Children with Primary Immunodeficiency Diseases
How to Ask Questions That Get Children Talking
Open-ended Questions
“What kind of questions do you have?” is very
different than “Do you have any questions?”
“What do you think will happen?”
“What do you think is the best (or worst) thing that
could happen?”
“What are you wondering about?”
Multiple Choice
“I’ve read (or heard) that lots of kids whose brother
or sister is in the hospital worry that...” then offer
several likely possibilities (such as, it could happen
to them, they won’t be able to do things their
friends are doing like the school trip). Ask “What
has this been like for you?”
When You’re Concerned About
A Specific Behavior
“I’ve noticed that you’re not eating much lately,
and that’s not like you. I think there’s something on
your mind.”
“Lately, you’ve been getting angry about things
that don’t usually bother you. Why do you think
that is?”
Playing and Learning from Your Children
Pretend Play/Dramatic Play
By using dolls, animals, action figures, even cars
and trucks, children play out their experiences.
Adults can learn what is on children’s minds by
watching and by participating. Play with cars can
become play about the mommy car, the daddy
car, the baby car, the big brother car. To learn the
most from your children, guide the play gently—
perhaps setting the characters (“You be the
mommy and daddy dolls, and I’ll be the baby and
sister dolls”) and setting the scene (“The mommy
and baby dolls are at the hospital. What do you
think is happening there?”). Using questions such
as “What does he say?” or “What is she thinking/
feeling now?” can further extend the play. Usually
children take over the play and begin to direct all
of the characters. If you sense that your child is
reluctant or wants to do different play, give him or
her the freedom and control to move on.
Drawing
Children often use drawing and other forms of art
for emotional expression. Encouraging children
to talk about their drawings or artwork can be
eye-opening for adults. Open-ended questions
such as, “What is happening in this picture?; What
is this person thinking or feeling?” or “Tell me the
story of this picture.” can help you learn about
your child’s inner world.
Learn from your children by observing their
behaviors and playing and talking with them. These
connections will help you identify and change
potentially problematic stress reactions before they
interfere with your child’s normal activities.

Adolescents with Primary
Immunodeficiency Diseases
chapter
20
Differences in the coping styles of family members and variations
in maturity through the adolescent years can all influence how
well adolescents and their families will deal with a primary
immunodeficiency disease.

112 Adolescents with Primary Immunodeficiency Diseases
Introduction
Adolescents diagnosed with a primary
immunodeficiency disease, and their families,
face not only the day-to-day challenges of any
family, but also the challenges of learning how to
manage the effects of that disease while nurturing
growth towards adulthood. Today’s families have
busy lives, with each member of the family dealing
with demands of time and energy in their home,
work, education, and social lives. With the variety
of primary immunodeficiency diseases, there is a
wide range of how adolescents may be impacted
by these diseases. Differences in the coping
styles of family members and variations in maturity
through the adolescent years can all influence how
well adolescents and their families will deal with a
primary immunodeficiency disease.
Having a Balanced Approach
Family life during the adolescent years has many ups
and downs, as the adolescent grows physically and
develops the maturity needed for establishing social
and family relationships, and an educational path
toward an occupation. Through these years, both
adolescents and family members experience some
ongoing tensions between the adolescent’s desire
for independence and autonomy and the increasing
personal responsibilities that go with that desire.
They typically go through a series of steps in this
maturing process, commonly having both successes
and setbacks in navigating into adulthood.
Each of these ups and downs can be shaped
by the adolescent’s primary immunodeficiency
disease, as it can impact overall health, friendships,
family, and career plans. For some, the primary
immunodeficiency disease will only minimally affect
their personal growth. For others, the disease will
substantially affect them in two quite distinctive
ways. On one hand, the disease and related health
problems can directly challenge adolescent desires
for independence and autonomy, as they have
to increase their dependence on family members
and healthcare providers to meet significant
health challenges. At the same time, these health
challenges can provide significant opportunities for
developing coping skills and maturity beyond their
years. Families, then, need to develop flexibility
and the support needed to help their adolescents
through these challenges.
Families experiencing ongoing health challenges
will, at times, tend to struggle with finding a
balanced approach to maintaining their family
life while addressing these health issues. A
lengthy infection, hospitalization, or major change
in treatment can be quite disruptive to their
lives. Time and energy become so focused on
responding to the illness and treatments that other
aspects of life become neglected, such as school,
work, leisure activity, and social relationships.
While this kind of attention may be necessary at
the time of a health crisis, over time, it can lead to
isolation from activities and relationships that help
the adolescent and family cope in the long run.
There will also be times when the primary
immunodeficiency disease and the related health
issues may fade into the background for an
extended period. A treatment routine becomes
successful, symptoms and health complications
are absent, and the family experiences an extended
period of routine life. Time and energy become
invested in pursuing new leisure interests, planning
for the future with new interest in school and
career, and cultivating relationships. It is at this
point that there may be some tendency to ignore
subtle health symptoms, neglect basic preventative
health care, and be less consistent in maintaining
a relationship with healthcare professionals. It is
understandable that adolescents would want a
break from focusing on the disease, yet ongoing
neglect of symptoms or treatment routines can lead
to a serious health setback.
Adolescents who best manage their primary
immunodeficiency disease are those who find a
balanced approach to the disease and to life. An
emphasis should be placed on both the disease
compromising overall health (the signs, symptoms,
and treatments of the primary immunodeficiency
disease) and overall health itself (the activities
and relationships that promote a healthy lifestyle).
However, enough attention must also be placed
on addressing the primary immunodeficiency
disease without the disease absorbing and defining
the adolescent and family life. The family should
help adolescents learn the coping skills needed
to manage day-to-day issues of the primary
immunodeficiency. This gives adolescents a greater
sense of control, and helps them develop an
identity based on personal strengths and healthy
choices rather than on symptoms of disease.

Adolescents with Primary Immunodeficiency Diseases 113
Your Family
Adolescents and their families who cope best with
an ongoing health problem typically follow several
guidelines during the maturing process. In young
adolescents, parents are often more active in
taking the lead in learning and setting an example.
Later, parents encourage increasing involvement
of the adolescent in management of their
disease, with parents monitoring the adolescent’s
increasing responsibility of self care. Finally,
as the adolescent moves toward adulthood,
parents encourage the adolescent to take main
responsibility for managing the disease, with family
members as more distant supporters.
Ideas for Successful
Family Coping
Learn all you can about primary
immunodeficiency disease and help cultivate
this learning and curiosity in your adolescent.
Use trusted written and online resources, and
resources suggested by your adolescent’s
physician and healthcare team. Bring your
information and questions to physician visits
to learn how to best apply the information.
Encourage your adolescent to seek
information about successful ways of dealing
with their primary immunodeficiency disease.
This learning might be incorporated into their
science or health classes. Encourage your
adolescent to become an active consumer of
health information and have them practice asking
questions of their healthcare providers. This will
prepare your adolescent to stay informed when he
or she leaves home for college or a career.
Notice all you can about your adolescent’s
personal body pattern and help cultivate
personal awareness and communication
skills in your adolescent.
What are the personal signs of a new infection, or
successful response to medication and treatment?
When energy is low, what are the personal signals
of the body that help your adolescent know if it
is time to push through the weariness to build
their strength, or a time to take a needed rest to
refresh and heal? This gives adolescents a greater
sense of being in charge and helps make the shift
in managing their health from parent awareness
and reminding to adolescent awareness and
self-reminding. Vacations with extended family,
stays at summer camp, and trips with school
or youth organizations give the opportunity
for the adolescent to begin to practice greater
responsibility in being aware of their body’s needs.
Use these times to prepare your adolescents for
their future when they will live more independently,
pursuing college or career goals.
In conversation with your adolescent and
healthcare providers, develop a personalized
list of successful approaches to managing
your adolescent’s health.
What health and wellness habits have been
most successful in keeping your adolescent
happy? What routines for diet, rest, and leisure
have been the most refreshing? What activities
have promoted the most success with physical
fitness? What medications and treatments have
been most reliable in managing the symptoms of
the adolescent’s disease? Having a personalized
understanding of your adolescent’s primary
immunodeficiency, medications and treatment,
and strategies for health and wellness will help
encourage good habits.
Parents who model good health and wellness
habits in their own lives will provide a positive
example for their adolescent to follow. Along with
modeling, make sure that your adolescent has
a full understanding of specific health concerns
and treatments, and how preventative care and
an emphasis on wellness can help. Reinforce
their efforts in taking responsibility for their health,
and emphasize how this is important sign of
maturity. With opportunity for responsibility and
encouragement, your adolescent can develop
lifetime habits of positive coping skills for their
health challenges.
Create and maintain supportive relationships
for your adolescent with other family
members, friends, and members of the
community in school and such organizations
such as scouts, music groups, sports teams,
and spiritually based groups.
Sometimes, having a primary immunodeficiency
can make an individual feel very different
than other people and isolated from their
peers. Depending on the particular primary
immunodeficiency, and its impact, some
adolescents may do well playing on a sports
team with very high physical demands, stringent
practice requirements, and lengthy traveling
games. Others may do better with a sport with
varying physical demands, some flexibility with
participation, and leaders who are responsive

114 Adolescents with Primary Immunodeficiency Diseases
Your Family continued
to the skills and needs of each person on the
team. With younger adolescents, parents may
play a greater role in helping them discover
these activities and interests, and negotiate their
participation. As adolescents grow older, parents
can put more emphasis on them exploring
their interests, making contact with others, and
developing their place in groups and on teams.
Feeling like they belong and are successful may
be very challenging when an adolescent has a
primary immunodeficiency disease. Not everyone
will be understanding or helpful in supporting
your adolescent in finding his or her strengths
and social supports. Be prepared to help them
deal with the ups and downs of their successes
and disappointments. While most relationships
in adolescents may not carry through a lifetime,
the skills and experiences in relationships during
adolescence will shape how that adolescent
relates to others as an adult.
Share your experience of having a family
member with a primary immunodeficiency
disease with others—at the right time and
with the right people.
This may be limited to immediate family and
friends, or it may include sharing with other
families in the same situation through a support
network. For some adolescents, it may include
broader and more public sharing, such as giving
a primary immunodeficiency disease presentation
in a health class, doing a science fair or project
in competition. Sharing can break the social
isolation, improve supportive relationships, and
give the adolescent a way to show their strengths
and successes in dealing with a condition that
can be very challenging. However, not everyone in
your adolescent’s life will have a positive reaction.
As with almost any kind of difference that can
be noticed between people, the differences
caused by a primary immunodeficiency disease
can sometimes make the adolescent a target
for teasing and isolation. Guide your adolescent
in regards to the appropriate people, times and
places to relay personal situations.
Your Adolescent
The adolescent years have many dramatic
changes: bodies that grow from child to adult,
responsibilities that shift from the role of the
parents to the role of maturing adolescent,
childhood friendships that transform into young
adult relationships and schoolwork that takes on
new meaning as the adolescent moves towards
college and career. Each of these changes
can be impacted by the adolescent’s primary
immunodeficiency disease. Parents, healthcare
providers, and other concerned adults in the
adolescent’s life need to help cultivate open and
supportive communication about these issues.
These adolescents may still have a lot to learn
about growing up, but they also deserve to be
respectfully heard as they share their thoughts
and feelings that come from the wealth of their
experience dealing with day-to-day issues. One
of the best ways to show this respect is to lead
off any discussion by asking about their feelings,
views, and experiences first. This approach
helps to establish a respectful discussion in both
directions, and there will be times when you learn
that the adolescent’s viewpoint and concerns,
while said a little differently, may be very close
to the concerns that you, as a concerned adult,
may be having.
Here are some common questions that may
be helpful in starting a conversation with
your adolescent:
So, am I sick or am I well?
Have a discussion about the balance needed to
cope with a primary immunodeficiency disease.
Your adolescent’s healthcare providers may be
helpful in advising on how to focus energies on
both managing the disease and living life more
fully. Help your adolescent identify enjoyable
interests and activities that may be less impacted
by days when the adolescent is not feeling well.
Music, arts, crafts, and other creative activities can
be enjoyed alone and with groups. These creative
outlets also can provide needed distraction and
relaxation when an adolescent is experiencing
health challenges.

Adolescents with Primary Immunodeficiency Diseases 115
Your Adolescent continued
I hate being treated differently! Why can’t I be
just like everybody else?
Adolescents will vary in how much they wish
to express their uniqueness or blend in with
the crowd. Helping your adolescent find their
own unique qualities and talents will help build
confidence and reduce the likelihood that they see
their uniqueness mainly as being the person in
their group that has an uncommon disease.
What do I tell my friends about primary
immunodeficiency disease?
This may be related to the question about
being treated differently. It also involves learning
relationship skills of trust building and sharing.
Your adolescent can benefit from a trusted peer
who can understand and offer personal support
when a primary immunodeficiency can disrupt
a regular routine. Your adolescent can also be
hurt by less mature peers who use personal
information as a way to bully or tease. Help your
adolescent make wise choices in their friendships
and personal sharing.
How do I handle this at school?
When your adolescent asks this, it might be
more about the friendship aspect of school. Your
adolescent may also be asking about how to
deal with teachers, coaches, assignments, and
team requirements. While a long-term goal is
self-responsibility, some school issues may require
parents to be more active in helping establish
positive relationships with school personnel and
in establishing realistic expectations for balancing
health and school performance.
Why do I have to go see my physician/take
my medications/continue my treatments?
As adolescents learn new levels of responsibility,
there will be times that they will want to do things
differently. Begin by hearing out the adolescent’s
concerns and responding with the details of
treatment decisions previously made, realizing that
some of these decisions and routines may have
been originally made when the adolescent was
much younger and not involved in the information
gathering or decision making process. Some of
the questions about care may relate to a healthy
need to have a greater sense of control over
their life. This may be a good time to review the
adolescent’s current responsibilities throughout
their life, not only with their healthcare, but also
with their home responsibilities, schoolwork, and
leisure activities. Having a greater sense of control
in other areas often helps balance the sense of
lacking control that can come with some of the
symptoms of a primary immunodeficiency disease.
Am I going to be dealing with this
disease forever?
Younger adolescents may ask this when they
realize that their primary immunodeficiency will
not be like other health problems they may have
experienced, like a sprained ankle or broken bone,
which has healed and is now forgotten. This may
be about that balance of addressing the illness
and health aspects of their disease, and realizing
how health and wellness habits will help them.
Older adolescents may ask this when they are
thinking about their future—career plans, college
plans, or developing relationships. Discuss how
they can apply their earlier learning experience
to these new challenges of young adulthood,
and suggest talking with their physician or other
healthcare professionals.
Why do I have to have this disease? It’s not fair!
This is a very tough question. It is one often asked
by parents as well as their adolescents. This may
be a question about their particular disease and
how the immune system works. Often, though,
this question is looking beyond scientific answers
and looking more toward personal beliefs and
values about life. Families need to reach out to
the people and resources they have for finding
meaning in life.

116 Adolescents with Primary Immunodeficiency Diseases
Your Adolescent’s Healthcare Providers
Some adolescents may experience few medical
problems that are related to their primary
immunodeficiency disease while others may
have very complex medical concerns that involve
a number of physicians and other healthcare
providers. Maintaining good communication
with, and among, these providers is important to
effectively manage a primary immunodeficiency
disease. Clear and accurate information about both
the history and current status of your adolescent’s
health condition is needed by all who will be
providing care. Healthcare providers need to know
exactly what your adolescent is experiencing and
how each of the providers is contributing to your
adolescent’s care.
To maintain clear communication and good
teamwork with healthcare providers, keep a diary
or notebook outlining your adolescent’s symptoms
and treatments. Prior to a visit or phone call with
your healthcare provider), use these notes to
summarize your adolescent’s current condition
and plan any specific questions that you may
have. Ask all healthcare providers to provide you
with copies of all major treatment summaries,
laboratory and diagnostic test results, and
correspondence. When requested by healthcare
providers, help make sure that they are also
copied with reports from other providers. Keep
these organized in your adolescent’s healthcare
notebook as a reference for new providers.
Including adolescents in helping with this
communication process will help then be ready for
their adult role of managing their own healthcare.
Transitioning from late adolescence into young
adulthood may involve changing healthcare
providers. This may occur as they move away
from home to attend college or begin a career. For
others, the transition occurs as older adolescents
are shifted from pediatric care providers to adult
care providers. Discuss this with current physician
and healthcare providers for the best way to
manage these care transitions.
There may be times that are particularly stressful
in family life. This may be from significant
changes in family life, such as a change in parent
employment, financial changes, a move, divorce
or death. Or, the stress may be more directly
related to coping with a primary immunodeficiency
disease. Whatever the source of these high levels
of stress, it can impact any healthcare problem, so
do not hesitate to address the sources of family
stress. Your adolescent’s physician should be
kept updated on these matters, so that general
guidance can be offered or a referral can be
made to a family counseling professional for more
specific help.

Adolescents with Primary Immunodeficiency Diseases 117
Your Adolescent’s School
Some adolescents with a primary
immunodeficiency disease will not experience
any difficulties at school due to their particular
condition. Other adolescents, with more
substantial health concerns will need significant
assistance in the educational setting. For
adolescents with a number of concerns, you will
be wise to make advance contact with school
personnel to discuss your adolescent’s healthcare
condition and how it may impact school. School
personnel should be included in advance of
problems with adequate information. They can
often develop plans that will work to address
concerns of reducing exposure to infection,
coordinating schoolwork during absences, and
providing certain modifications of schoolwork
when needed.
Federal and state educational regulations
include requirements and guidelines for how
schools should respond to a student’s health
and its impact on their learning. Parents, school
personnel, and the adolescent’s physicians and
other healthcare providers can coordinate specific
plans through mandated programs such as the
Section 504 Plan or Individualized Education
Plan (IEP). Additional information about these
regulations and guidelines for modifying your
adolescent’s educational setting are available
through your local school district, Web sites
of your state education department, student
advocacy Web sites and in the Immune
Deficiency Foundation’s publication, A Guide
for School Personnel.
Include your adolescent as much as possible in
these planning meetings and discussions with
school personnel. Just as adolescents need to
develop skills in managing healthcare decisions,
they need to develop skills in managing education
decisions that lay the foundation for their future
with college or career plans. For your older
adolescent with college plans, be aware that there
are also federal guidelines for higher education
institutions. Many student service departments
of colleges include resources for health, career,
counseling, and other campus-based services
that can help. When your adolescent begins to
explore college choices, it may be useful to include
visits with these services when touring campus or
examining literature or Web sites.
Adolescent Insurance Concerns
Most young adults in this country are covered
under a group insurance plan offered by one of
their parent’s employers. Many of these employer
sponsored plans end dependent coverage when
the dependent child turns 19, if not attending
college, or to age 23 or 25, if enrolled in school
full-time. When dependent children are no longer
eligible for group insurance under a parent’s
plan, they are entitled for up to 36 months of
COBRA coverage (if the employer has 20 or more
employees). Some plans continue to cover totally
disabled dependents as “adult disabled children”
beyond the usual end date for dependent children.
To know how dependents are covered under
the employer sponsored health plan, the parents
should ask their human resources department for
a copy of the Summary Plan Description (SPD).
A SPD is a requirement of the law (ERISA) that
sets the terms of each employee benefit plan in a
written plan document.
Medicaid, usually available through the state’s
Children’s Health Insurance Plan (CHIP), is another
form of insurance that usually ends when the
dependent child turns 19. Medicaid for disabled
Supplemental Security Income (SSI) can end if the
young adult is no longer designated as disabled
or if income or assets exceed the allowable limits.
Some states offer incentive programs to Disabled
Medicaid individuals who work and make over a
certain amount of money.

118 Adolescents with Primary Immunodeficiency Diseases
Adolescent Insurance Concerns continued
If an adolescent’s insurance is about to end, it
is important to understand what is available well
in advance. Here are some important questions
to research to provide a better picture of what
insurance options are available:
• How long am I entitled to insurance under my
parent’s plan?
• Will COBRA be available to me after I graduate?
If yes, how will the premiums be paid?
• Will my Medicaid end when I turn 19?
• If I get a job, how long is the waiting period
before benefits begin?
• Does my state have a high risk pool? What are
the premiums?
• Does my state Medicaid plan offer incentives to
work despite my disability?
Coordinated Support
As you, your family members, and your adolescent
with a primary immunodeficiency disease handle
the challenges that may accompany that disease,
remember to keep your support system close at
hand. Particularly stressful times, when support is
most needed, may also be the times when it is the
most difficult to maintain those connections with
family, friends, and the professionals that are in
your support network. Stay current through your
adolescent’s healthcare providers, your reading,
and networking. Keep your circle of support
informed and involved. Show your adolescent how
to both be realistic about the challenges as well as
encouraged by the choices in life.

Adults with Primary
Immunodeficiency Diseases
chapter
21
Adults with primary immunodeficiency diseases live full lives in the
real world. They work, play, marry and have families.

120 Adults with Primary Immunodeficiency Diseases
Introduction
Although the first primary immunodeficiency
diseases were identified in children, there has
been a growing awareness that adults, too, may
have a number of primary immunodeficiency
diseases. Advances in medicine and earlier
diagnosis and treatment of the childhood
immunodeficiency diseases have allowed many
patients born with primary immunodeficiencies to
grow into adulthood. In other cases, many children
born with apparently normal immune systems go
on to develop a primary immunodeficiency later in
adolescence or adulthood.
There are several features of primary
immunodeficiency diseases of which a newly
diagnosed adult should be aware. In most
cases, the well-informed patient, working with
attentive medical staff should be able to pursue
a career and live a full, active and productive life.
This chapter reviews the types of problems that
adults with primary immunodeficiencies may
develop, discusses how you and your physician
can coordinate care, and outlines some of the
psychosocial aspects of living as an adult with
these disorders.
Common Symptoms
Recurrent infections are the most common
problem that patients with primary
immunodeficiencies experience. Typically,
patients will have recurrent infections in the
sinuses (sinusitis) and in the chest (i.e., bronchitis
and pneumonia). Early recognition of illness
is important to allow timely treatment before
infections become severe. Early signs may be
as obvious as changes in color or consistency
of drainage from the nose or changes in sputum
coughed up from the chest, or as subtle as easier
fatigability or a shortened temper.
In addition to recurrent respiratory infections,
diarrhea is a common symptom that antibody
deficient patients may experience. The diarrhea
may be caused by a variety of infections or even
by an overgrowth of the “normal bacteria” that
live in the gastrointestinal tract. Either of the
above events results in decreased absorption
of important nutrients required for normal body
function. Giardia is one of the more common
protozoal intestinal infections that can cause
diarrhea. Patients with compromised immune
systems are uniquely susceptible to Giardia which
can be treated easily with oral medication.
Also, it is not unusual for adults with a primary
immunodeficiency to have chronically red eyes,
a condition known as “conjunctivitis.” In many
patients, if the immunodeficiency can be treated
with immunoglobulin, the conjunctivitis often
improves, although additional antibiotics are
sometimes needed.
Some patients also experience arthritis-like
symptoms or other symptoms seen in patients
with “autoimmune” diseases. These conditions
are covered in specific chapters in this handbook
(see chapters titled Selective IgA Deficiency and
Common Variable Immunodeficiency).
It is important that patients be familiar with
the common symptoms that accompany their
particular diagnosis, so that appropriate care
can be sought. Most physicians who provide
care to patients with primary immunodeficiencies
know that these patients may require frequent
antibiotics. Also, these antibiotics often need to
be given earlier in the course of an illness and for
longer periods of time than in people with intact
immune systems.

Adults with Primary Immunodeficiency Diseases 121
General Care
It is important for any patient with a primary
immunodeficiency to understand as much as he
or she can about the workings of the immune
system. Knowing when to involve medical
professionals may mean staying healthier longer.
To help maintain good health, there are things
that patients can do in their everyday lives. In
particular; good nutrition is of great importance.
A balanced diet is essential for normal growth,
development, body repair and maintenance, and
especially important in preventing and fighting off
disease. The general principles of good hygiene
are also critical. Simple things like washing hands
before meals and after using the restroom go a
long way to prevent illness and should become
routine habits. Most viruses, including the ones
responsible for the common cold, are spread
by unwashed hands. Any cuts or scrapes on
the skin should be cleansed completely and any
unusual redness or drainage should be reported
to a physician so further treatment can be initiated
promptly. Dental hygiene and regular dental
check-ups are essential since some patients are
more prone to tooth decay and gum diseases.
Regular exercise helps to maintain optimal function
of the body and is also a good means of stress
relief for the mind.
Specific treatment for the primary immunodeficiency
disease should be coordinated between the
patient and the healthcare team members. Each
adult should do everything possible to foster good
communication between themselves and their
healthcare providers. Patients are the only people
who can honestly inform their physician about how
they feel. They are the ones who have experienced
and know which treatments have truly been of
benefit and which had not.
The Newly Diagnosed Adult Patient
Some people who have been recently diagnosed
have felt unwell for years, without any answer as to
what was causing their illnesses and problems. In
some cases, a diagnosis can actually be a relief for
the patient by finally providing that answer. However,
at the same time, the newly diagnosed adult patient
must face questions and problems that have already
been faced by children who have grown up with
these disorders. Feelings of self-pity and fear are
quite normal, but must be identified and addressed
promptly. Above all, it is important to realize that you
are still the same person, only now you must come
to terms with your diagnosis and treatment decisions
to create a normal life for yourself.
Self Education
Self education is the key to caring for one’s own
health. The more an individual understands about
his or her primary immunodeficiency disorder, the
more confident that person will feel, thus, making
treatment decisions easier. Whether they grew
up with the disorder or were recently diagnosed
as adults, patients must ask questions, obtain
educational materials and understand the realities
of their deficiency. Most importantly, patients should
read about their disorder and become informed,
getting involved with their own care. This can help
produce a feeling of independence and control over
their life. One way to begin this process is to seek
out healthcare professionals who specialize in these
disorders. Physicians who have little interaction
with patients with primary immunodeficiency
diseases may either overestimate the difficulties or
underestimate the need for complete evaluation. It
is important to ask as many questions as you can
of a specialist. No question about your disorder is
too trivial. New methods of investigating and treating
these illnesses are being developed each year, and
it is in the patient’s best interest, regardless of age,
to find out what these are. Another way to gather
knowledge is through contact with other individuals
who live with primary immunodeficiency diseases.
Immune Deficiency Foundation can put you in
touch with another patient through its peer contact
program. Talking to other patients and families is
often helpful, and any feelings of isolation you may
be experiencing can be dispelled.

122 Adults with Primary Immunodeficiency Diseases
Advanced Education
A major goal of adults is to be self-sufficient
and the importance of receiving an education
to achieve this is hard to overestimate. It is
important for an individual with a chronic illness
or medical condition to obtain a job with good
health insurance and a position with enough
flexibility to allow appropriate medical attention
when necessary. Advanced training and education
provide a greater range of choices and flexibility
for anyone, and particularly for a person with a
preexisting health condition. For young adults
who leave home to go to college or other training
facility and are on their own, a potential problem
is the tendency to “downplay their illness” or fail
to disclose their medical history to the school. It
is hard for a college or school infirmary to care
appropriately for a student who has not informed
the school of his/her specific diagnosis. A primary
immunodeficient individual may need antibiotics
more often, or sooner in an illness, than another
student. For a student with a more serious
deficiency, school infirmaries may not be an ideal
place to receive care. One way to manage this
problem is for the parent or student to find out
in advance a local physician with experience in
treating patients with a primary immunodeficiency
before school starts. Copying records including
the patient diary can be of tremendous help
in maintaining continuity of care. Should more
complicated problems arise, appropriate
arrangements can be made. A referral from your
current physician may help.
Employment
Adult patients, in choosing a job or career,
must think in terms of ones that are suitable
for their condition. Depending on the nature of
your condition, you may or may not be limited
physically. However, there may be complications
that need to be fully considered. Factors like time
and stress and how they affect your condition
and treatment, cannot be ignored. In seeking
employment, be aware that there are laws against
discriminating against an applicant based on a
chronic health condition. However, that does not
mean that the laws are easy to enforce. You may
want to familiarize yourself with the wording of
the laws. For many patients, the health insurance
coverage associated with employment is the
most problematic. Small employers, for instance,
may not be able to cover you, so perhaps larger
corporations and government jobs should be
considered while considering careers. New
Health Insurance Portability and Accountability
Act of 1996 (HIPAA) legislation has improved the
ability to transfer insurance coverage from job
to job once you are insured (see chapter titled
Health Insurance). Most patients with primary
immunodeficiency disorders work in a variety of
jobs. The Family Medical Leave Act (FMLA) also
ensures continued employment in the face of
prolonged work absences due to illness. Disability
in this population is uncommon and usually results
from complications of illness and not the primary
immunodeficiency itself.

Adults with Primary Immunodeficiency Diseases 123
Home Care
Adult patients must learn to fit their treatment
into their school and working lives. No longer are
patients limited to long cumbersome treatments.
Choices mentioned previously including homecare
for intravenous immunoglobulin and subcutaneous
immunoglobulin administration allow flexibility,
minimizing the impact on normal daily living. Home
healthcare services permit treatment in your own
home environment. This is particularly useful in
avoiding missed time from work. You will want
to discuss with your physician these treatment
options and ensure that your insurance will cover
home healthcare. In many cases, your physician
can provide you with the names of a number of
home healthcare agencies in your area. Some
adult patients who need infusions of intravenous
immunoglobulin can learn to give their own
infusions. This can be less expensive and more
convenient for the working person. In other cases,
a nurse who is employed by a home healthcare
company can deliver all of the home care.
Health Insurance
Health insurance is an issue that all people with
a primary immunodeficiency disorder must face
(see chapter titled Health Insurance). Decisions
regarding school or employment may be affected
by insurance coverage. This cannot be taken
lightly by anyone with a pre-existing condition.
If you allow your insurance to lapse or do not
look into the options that exist before coverage
terminates, your ability to qualify for insurance
may be seriously jeopardized. It is important for an
engaged or married couple to also face the issue
of health insurance realistically and understand its
importance in career decisions.
Dating, Marriage and Children
Some people may find it difficult to discuss their
disorders with their regular friends, and particularly
with significant others. It often depends on an
individual’s own personality as to how much they
want to explain, and when they feel comfortable
discussing their medical condition. When you
do discuss your disorder with your partner,
be sure that you make it clear that you have a
primary immunodeficiency disease, and that it is
not contagious. Often when a patient becomes
seriously involved with another person, it may be
helpful to have that person accompany them on a
visit to the immunologist to better understand the
disorder. When a couple is considering marriage,
it is important for both to understand the genetic
implications of the disorder, and whether it could
be passed onto children or grandchildren. Your
immunologist or genetic counselors can accurately
answer these questions. You may wish to refer to
the chapter titled Inheritance in this handbook.
Emotional Strains
An adult with a primary immunodeficiency disease
has all of the medical problems that a child would
have, and yet by the definition of adulthood, is
supposed to be responsible for his or her life,
career, financial planning, and the future of his or
her children. Obviously, this can bring enormous
stress into a family. For the adult who has
recently been diagnosed, there may be feelings
of confusion, self pity and, above all, fear. These
thoughts and feelings are normal. The positive side
of having a diagnosis is that the uncertainty is over,
and you can be on your way to understanding
your illness. However, emotional difficulties
may arise. It is difficult to have a chronic illness
and to be susceptible to repeated or recurring
infections in addition to other medical ailments.

124 Adults with Primary Immunodeficiency Diseases
Dating, Marriage and Children continued
One of the difficulties associated with primary
immunodeficiency disease is the unpredictability
of manifestations such as infections. This can
place pressures on oneself, family and friends. In
addition, the possibility of unexpected absences
from work, last minute changes of social activities,
or even hospitalizations may cause added tension.
Emotional and social problems caused by primary
immunodeficiencies are just as important as
physical problems and should be discussed with
your physician. Sometimes just airing your fears
can have a therapeutic effect. This is where an
informed friend can be invaluable. True adult
friends know when to help and when to motivate
you to help yourself.
Another often unspoken stress in families in which
the primary immunodeficiency is inherited, may be
feelings of guilt on the part of the parent who has
passed the defect onto a child. Again, the best
way to deal with these feelings is to discuss them
with your family, your physician and your genetic
counselor. Remember that this is out of your control,
and you have also passed on a number of extremely
good qualities. Children with a parent diagnosed with
a primary immunodeficiency may themselves have
a fear of becoming ill when they are older. In most
cases the fear is unfounded and can be dispelled
with the proper information and testing.
There are a variety of ways to help keep your
frustrations and anxieties to a minimum. You
may simply require some time to discuss these
feelings with a spouse, understanding friend,
clergy or healthcare professional. A number
of patients are helped by meeting with others
in a support group setting. For many patients,
learning as much as possible about an illness is
the best way to guard against confusion about
the illness itself. Understanding one’s own primary
immunodeficiency can lead to taking control of
one’s own life.
Summary
Adults with primary immunodeficiency live in
the real world. They work, play, marry and have
families like other people. There is no reason why
their primary immunodeficiencies should alter this.
However, they must be aware of their condition,
and use common sense in recognizing symptoms
and treating infections. These adult patients must
make sure they have access to trained specialists
who understand their disorders and are aware of
the most recent developments in treatment. They
must be careful and informed about obtaining and
keeping health insurance coverage and about
the laws and regulations that govern insurance.
Education and awareness are keys to helping
adults with a primary immunodeficiency make
good choices and realize their potential.

Health Insurance
chapter
22
Having the diagnosis of a chronic condition, like a primary
immunodeficiency, can be financially taxing. If diagnostic services
are limited and therapy is not administered on a regular basis,
the cost of complications and subsequent hospitalizations is
burdensome.

126 Health Insurance
Health Insurance for Primary Immunodeficiency
Having the diagnosis of a chronic condition, like
a primary immunodeficiency, can be financially
taxing. If diagnostic services are limited and
therapy is not administered on a regular basis,
the cost of complications and subsequent
hospitalizations is burdensome.
Most individuals with primary immunodeficiency
rely on private third party payers to assist them
with these expenses. Unfortunately, people are
often frustrated when faced with the overwhelming
task of paperwork, phone calls and other issues
simply to justify the use of a diagnostic procedure
or therapy prescribed by their physician.
Looking for health insurance and understanding the
maze of issues involved can be an overwhelming
process that often leads to feelings of isolation and
helplessness. While not designed to solve each and
every health insurance problem, this chapter will
provide you with some of the information to prepare
you to be your own best advocate.
Most of the information is practical. First, there
is a description of the various payers, what
they cover and whom they serve. Next, there is
information about what to look for when changing
insurance coverage, a very important issue
when a chronic condition is involved. The Health
Insurance Portability and Accountability Act of
1996 (HIPAA). HIPAA is then reviewed. It is one
of the most important federal laws enacted within
the past decade regarding protection for you and
your family’s health insurance coverage when
faced with life events. Other features that you
should have a general working knowledge of are
explained, such as COBRA, a name for extended
benefits.
Other hands-on information follows with how to
prepare yourself to face your insurer confidently
with questions about your coverage. And last,
but not least, as in every profession these days,
health insurance has its own “language.” There is
a glossary of insurance terms so that you will feel
confidently “bilingual.”
When it comes to your health coverage, never
hesitate to ask lots of questions and search for as
many resources as possible. Your well-being and
that of your family relies on it.
Who Are the “Payer Players”?
To best prepare for working with your health
insurer, you must understand who the various
“payer players” are in the scheme of things.
Group Health Insurance
Group health insurance coverage is a policy that
is purchased by an employer and is offered to
eligible employees of the company (and often
to the employees’ family members) as a benefit
of working for that company. The majority of
Americans have group health insurance coverage
through their employer or the employer of a family
member. Many people don’t realize that health
insurance is issued differently for different types
of employers, and that, because insurance is
regulated at the state level of government, the
laws regarding health insurance offered by the
different types of employers can vary significantly
from state to state. Millions of Americans work
for small employers, which for health insurance
purposes are generally those with 50 employees
or less. Millions of other Americans get their health
insurance coverage through large employers.
Generally, those are business with more than 50
employees. The laws about how coverage can
be issued to large groups are different than those
for small groups, and premium rates are also
determined differently. Federal law mandates that
no matter what pre-existing health conditions
small employer group members may have, no
small employer or an individual employee can
be turned down by an insurance company for
group coverage. This requirement is known in the
insurance industry as “guaranteed issue.”
COBRA
Most people who are able to continue their group
health insurance benefits are eligible to do so
according to federal law called the Consolidated
Omnibus Budget Reconciliation Act of 1985
(COBRA). However, COBRA does not apply to
all employers; so many states have developed
other continuation-of-coverage options for people
who are not covered by COBRA. Also, many

Health Insurance 127
Who Are the “Payer Players”? continued
people leaving group insurance to buy individual
health insurance privately have portability benefits
required by another federal law.
You are responsible for paying the premium,
which is usually kept at 102% of what your
employer was paying on your behalf. (The 2% is
for administrative fees). For job termination or a
reduction in hours, COBRA’s duration is normally
18 months. In the case of a divorce, separation
or death of a spouse, COBRA may be available
for up to 36 months. In the case of a dependent
child ceasing to be a dependent child under the
parent’s employer plan, may be entitled up to 36
months. If you are deemed disabled by Social
Security within 60 days of your termination of
employment or reduction in hours of employment,
you are able to extend the COBRA continuation
period from 18 months to 29 months. This
extension is granted under the HIPAA federal
legislation discussed earlier. The extended period
of time offered is designed to protect you until
you become eligible for Medicare, since there is a
29 month waiting period before you can receive
Medicare benefits.
When these situations, known as “qualifying
events” occur, it is your responsibility, as the
employee, to notify the human resources
department of your employer (that person or
group responsible for medical insurance) within 60
days or you lose the option.
For further information on COBRA coverage and
your rights under COBRA law, you should contact
the human resource department or the benefits
manager within your organization or call your local
Department of Labor.
Individual Health Insurance
Individual health insurance is coverage that a
person buys independently. It can be for an
individual, a parent and dependent children, or a
family. The majority of Americans get their health
insurance coverage through an employer or
through a government program, but five percent of
the population purchases private health coverage
on an individual basis. Each state separately
regulates how individual policies may be marketed
and sold.
Individual health insurance is very different than
group health insurance, which is the type of
insurance that is offered through an employer.
Since laws mandating what types of services
must be included in individual policies are often
different than those dictating what must be
included in group policies, benefits are generally
less extensive than what most people would
receive through coverage they have through
work. Individual consumers may be surprised to
learn that some benefits that may be considered
“standard” in a group policy, may not be included
in an individual plan.
Individual health insurance companies are much
more limited than group insurance companies in
their ability to spread risk, so the laws concerning
individual health insurance are different in most
states. This means that applicants for individual
insurance will need to complete a medical
questionnaire when applying for benefits and,
unlike a group insurance policy, in most states
a company can decide not to cover people with
very serious medical conditions (e.g., primary
immunodeficiency), deeming them “uninsurable.”
The Uninsurable
In most states you can be turned down
for individual coverage if you have a very
serious medical condition (e.g., primary
immunodeficiency). Most states have developed
some way to provide uninsurable people with
access to individual health insurance coverage.
Thirty-three states provide coverage to medically
uninsurable people through high-risk pools. Twelve
states use other means of providing uninsurable
people with access to individual coverage (e.g.,
requiring that all individual health insurance
companies issue individual policies regardless
of health status, coverage through a designated
health insurance company of last resort, etc.)
There are five states that still have no means of
providing individual health insurance access to
people with catastrophic medical conditions. To
find out what your state’s options are for medically
uninsurable individuals, check with your local
Insurance Commissioner’s Office.
High Risk Pools
At the time of the writing of this handbook,
thirty-three states provide coverage to medically
uninsurable people through high-risk pools.
High-risk pools are private, self-funded health
insurance plans organized by states to serve
high-risk individuals who meet enrollment criteria
and do not have access to group insurance.
In most states, they are independent entities
governed by their own boards and administrators,
but in other states, they function as part of the

128 Health Insurance
Who Are the “Payer Players”? continued
state’s department of insurance. You generally
have a choice of health plan options and will
receive enrollment cards and other information
just like any other health plan. High-risk pools
normally contract with a health insurance carrier or
third-party administrator to administer paperwork
and claims, so your enrollment card and other
paperwork may not even appear to be produced
by the high-risk pool. Once enrolled, you use your
benefits just like any other consumer of private
insurance coverage.
Coverage options are very similar to traditional
individual health insurance offerings. It is generally
a comprehensive major medical plan with a range
of deductible options. The most common riskpool
option is a PPO plan, but many states also
offer indemnity coverage and some states have
HMO and/or HSA options available to consumers.
Risk pool health insurance is more expensive than
traditional individual insurance.
Medicare
Medicare is a federal health insurance program
which provides coverage for people over the age
of 65, blind, disabled individuals, and people
with permanent kidney failure or end-stage renal
disease. The Medicare program is administered
by the Centers for Medicare and Medicaid
Services (CMS) and pays only for medical services
and procedures that have been determined as
“reasonable and necessary.” Medicare is divided
into three parts—Parts A, B, and D.
Part A covers inpatient hospital services and
certain follow-up care. This includes the cost of lab
tests, x-rays, nursing services, meals, semi-private
rooms, medical supplies, medications, necessary
appliances, and operating and recovery rooms.
Part B covers physician’s services and other
medical expenses. Medicare Part B will cover both
the IVIG product and administration when provided
in a physician’s office or in the hospital outpatient
setting. The coverage determination for IVIG is
reviewed by each Medicare regional carrier through
their medical policy department. Each carrier will
issue their own local coverage determination (LCD),
which outlines the specific coverage guidelines
for the use of IVIG therapy. Since January 1,
2004, the Medicare Part B program only allows
coverage in the home setting. It is important to
note that the home coverage provision is ONLY for
primary immunodeficiencies, and the coverage and
reimbursement is only intended for the IVIG drug
itself. Ancillary charges that may accompany the
IVIG infusion are not covered under this provision.
Beneficiaries must pay a monthly premium and a
small deductible each year for all approved services
covered under Part B.
Part D The new Medicare Prescription Coverage
program (Medicare Part D) went into effect on
January 1, 2006. Anyone who has Medicare
coverage can choose the new prescription
coverage benefit. The new prescription
benefit coverage was passed by Congress to
give Medicare beneficiaries more options for
prescription drug coverage that had never before
been covered under the Medicare program. As
it relates to coverage of IVIG, the new Medicare
Part D program DOES NOT cover IVIG in the
home setting for those who have a primary
immunodeficiency. However, Medicare Part D may
cover IVIG in the home for other disease states.
CMS administers the Part D program through
contracts with commercial and private payers
referred to as Medicare Prescription Drug Plans
(PDPs). To learn more about the new prescription
drug coverage go to www.medicare.gov, or call
1-800-MEDICARE.
For most of these services, Medicare pays 80%
of the bill and the beneficiary pays the 20%
coinsurance. You must first have Part A before
receiving Part B. If you apply for Social Security
disability, you will receive Medicare benefits after
being on disability for two years.
In many states, people covered under Medicare
have the option of choosing between managed
care and fee-for-service plans.
Individuals may also consider purchasing a
Medigap (supplemental insurance) policy. Medigap
policies help pay some of the health care costs
that your original Medicare plan will not cover.
For instance, there are 12 different standardized
Medigap policies (Plans A through L). Some of
these plans will help pay for the 20% coinsurance
under the Medicare Part B program. To learn
more about the various plans and coverage
guidelines go to www.medicare.gov/medigap,
or call 1-800-MEDICARE.
Medicaid
Medicaid is a welfare program sponsored by
both the federal and state governments, which is
administered by the individual states. Coverage
varies from state to state although each of the state
programs adheres to certain federal guidelines.

Health Insurance 129
Who Are the “Payer Players”? continued
Medicaid enrollment criteria also varies from state
to state, but coverage is usually available only to
those who are not eligible for any other type of
health insurance and meet poverty guidelines.
Each state has a predetermined income level that
an individual or family must meet to qualify for
Medicaid benefits. The local office of the State
Department of Social Services is responsible for
reviewing applications and managing eligibility
requirements. Some states require Medicaid
beneficiaries to join managed care plans.
Medicaid programs may require prior authorization
for certain forms of treatment or prescription drugs.
This means that your physician must contact
Medicaid to obtain approval for reimbursement of
the treatment before you receive it.
State Assistance Programs
Your state may have a special assistance program
for particular chronic conditions. Most of these
programs are funded by state and local budgets
and are designed to meet the needs of adults
and/or children who are not eligible for any other
medical coverage.
They may also serve as a secondary or
supplemental coverage to Medicaid. The level of
coverage available will change according to such
variables as state needs and available funding.
These programs may be identified under such
names as Children with Special Health Care
Needs, Crippled Children’s Services, or Children’s
Medical Services.
Coverage for children with primary
immunodeficiencies may be severely restricted
or not available at all. It is best to check with
your local sources of information for eligibility
information before considering this as a coverage
option. SSI, or Supplemental Security Income,
makes monthly payments to aged, disabled, and
blind people with limited income and resources.
Disabled children, as well as adults, may qualify
for SSI payments. Eligibility and benefits vary by
state, but more information can be obtained by
contacting your local Social Security Office listed
in the White Pages of the phone book.
State Children’s Health
Insurance Program (Schip)
As part of the Balanced Budget Act of 1997,
Title XXI (or SCHIP) of the Social Security Act
was passed in late 1997. The State Children’s
Health Insurance Program gives grants to states
to provide health insurance coverage to uninsured
children up to 200% of the federal poverty level
(FPL). States may provide this coverage by
expanding Medicaid or by expanding and creating
a separate state children’s health insurance
program. The program’s primary purpose is to
help children in working families with incomes too
high to qualify for Medicaid but too low to afford
private family coverage. Although benefits vary
from state to state, children generally are eligible
for regular check-ups, immunizations, eyeglasses,
doctor visits, prescription drug coverage, and
hospital care. Based on income levels, states
can impose premiums, deductibles, or fees for
some services. Since coverage and benefits do
vary, it is important that families investigate the
options available in their respective state. For more
information regarding eligibility and coverage, call
1-877-Kids-NOW (1-877-543-7669).
The Abc’s of Health Plans
Most health insurance companies offer several
types of programs with many variations in
deductibles, copayments and covered services.
Review the details of any specific plan very
carefully before purchasing to ensure it will meet
you and your family’s specific needs. Below is a
description of the different types of plans offered
through insurance companies, starting with the
most restrictive, least expensive plan.
HMO is a Health Maintenance Organization. As
a member of an HMO, you select a primary care
physician from a list of doctors in that HMO’s
network. Your primary care physician will be the
first medical provider you call or see for a medical
condition. He or she will make any needed
referrals to a medical specialist. Typically, these
specialists will be part of the HMO network. If you
obtain care without your primary care physician’s
referral or obtain care from a non-network
member, you will be responsible for paying the
entire bill (with exceptions for emergency care).
Normally HMOs have a copayment for the visit or
service. This is the most restrictive type of plan.

130 Health Insurance
Who Are the “Payer Players”? continued
POS is a Point-of-Service Plan. It is a type of
managed care plan that is an HMO with an outof-network
option. You can decide whether to go
to a network provider and pay a flat dollar or to
an out-of-network provider and pay a deductible
and/or a coinsurance charge.
PPO is a Preferred Provider Organization. As a
member of a PPO, you can use the doctors and
hospitals within the PPO network or go outside of
the network for care. You do not need a referral to
see a specialist. If you obtain care from a medical
provider outside of the PPO network, you will
pay more for the service. For example, a PPO
might pay 90 percent of the cost for a visit with
an in-network doctor but only 70 percent of the
cost for a visit to a non-network doctor. You will
typically pay a copayment for each office visit. You
will usually be responsible for paying an annual
deductible.
Indemnity plan is commonly known as a fee
for service or traditional plan. If you select an
Indemnity plan you have the freedom to visit any
medical provider. You do not need referrals or
authorizations; however, some plans may require
you to precertify for certain procedures. Most
indemnity plans require you to pay a deductible.
After you have paid your deductible, indemnity
policies typically pay a percentage of “usual and
customary” charges for covered services; often
the insurance company pays 80% and you pay
20%. Most plans have an annual out of pocket
maximum and once you’ve reached this they will
pay 100% of all “usual and customary” charges
for covered services. Many health insurance
companies have moved away from indemnity
plans. This is the least restrictive, therefore the
most expensive type of health plan.
Health Insurance Portability
And Accountability Act of 1996
(hipaa)
Probably one of the most important and
encompassing federal laws affecting the health
insurance industry was the passage of HIPAA.
We all are susceptible to a variety of events in
life, which may affect health insurance coverage.
Situations such as the onset of a chronic illness
or disabling disease, changing jobs or a business
closing can have adverse consequences when
locating or attempting to keep your health
insurance coverage. HIPAA protects health
insurance coverage for workers’ families when
they change or lose their jobs. Due to the fact that
the HIPAA law is very complex and contains many
more provisions than indicated in this writing, we
recommend that you contact your employer’s
benefits administrator or your State Insurance
Commissioners office for further information on
how HIPAA can affect you or your family.
Key Provisions
Group Health Insurance—Employees can credit
time spent under their previous employer’s plan
satisfying a preexisting exclusion towards the new
employer’s plan, as long as they do not have more
than a 63 day break between coverage.
Moving from Group Health to an Individual
Health Plan—If you are no longer eligible for Group
coverage, you are able to obtain coverage with an
Individual health plan, which includes HMO’s if:
• You have an aggregate 18 months or more
of previous coverage under a group health,
government or church plan.
• You have had no lapse in coverage longer than
63 days.
• You are not eligible under another group plan,
Medicare or Medicaid.
• You do not have any other health insurance
coverage.
• You have elected and exhausted any eligible
COBRA coverage.
• You were not terminated from your most
recent prior coverage due to non-payment of
premiums or fraud.
Be aware that your state law may provide for
greater protection than HIPAA, but not less than the
minimum requirement mandated by the HIPAA law.
Comparing Plans
It is important to consider specific issues when
deciding on a health insurance policy. You should
compare: the cost of premium, coinsurance,
copayments, deductibles, lifetime maximums, and
the prescription coverage.
Your lifetime maximum (LTM) will differ according
to your health coverage plan. Most LTMs will
range from $250,000 to $1 million. Once you
have exhausted your LTM, you no longer have
health coverage, so it is wise to keep a running
total of the major expenses that affect it such as

Health Insurance 131
Who Are the “Payer Players”? continued
hospitalizations, surgeries, annual cost of drug
therapy, etc. Also, know the difference between
elective and required procedures and plan
accordingly, as these costs most likely will go
against your lifetime maximum.
Ask such questions as: How are chronic
conditions like primary immunodeficiency
covered within the plan? What about referrals to
specialists? What are the procedures? Do they
have restrictions on prescription drugs?
Words to the Wise
It cannot be emphasized enough that it is critical
for you to be your own best advocate when
dealing with your health plan. First, read your
policy and then ask your personnel department,
the Immune Deficiency Foundation (IDF), and any
other resource you can find, lots of questions. Try
to keep current information concerning the new
rules affecting your policy.
Review your medical bills to check for mistakes;
billing errors occur more often than you might
think. Keep important information such as your
policy number, your ID number, insurer’s address
and phone number, and doctor’s address and
phone number in one place to refer to whenever
you communicate with your insurer. If there’s a
possibility you might reach your lifetime maximum,
please explore the alternatives before your
maximum runs out.
Many employers offer open enrollment once a year
when you may change your coverage to another
plan offered by your employer. Ask your employer
if and when an open enrollment period is offered.
If you have difficulty getting benefits through your
employer, consider coverage through associations,
schools, professional groups, farm groups, or
local chambers of commerce. You may qualify for
individual or group benefits. Document each time
you contact your insurer. Get the full name and title
of each person you talk with whenever you contact
your insurer. This information will be important if you
experience difficulties with your coverage and need
to document your situation in writing.
If your problem becomes more complicated, don’t
panic. You, and/or your physician, may appeal to
the medical director of the insurance company
and may need to work with the provider to submit
additional justification of your claim. Often, in the
case of primary immunodeficiencies, insurers need
to be educated as to what the condition is and
what the approved forms of treatment are. Most of
the manufacturers of intravenous immune globulin
(IVIG) offer reimbursement support services for
their products and should be an excellent source
of information.
The IDF can refer you to these sources. There
may come a time when an insurance company
terminates your policy. If it does so for any other
reason than bankruptcy, they are required by
state and federal law to find you new coverage.
Enforcing this law is up to the State Insurance
Commissioner. You should contact them especially
if you feel your cancellation is due to a pre-existing
condition. Arbitrary cancellation is illegal.
Conclusion
You could spend a major portion of every waking
day working on insurance issues for yourself or
your family. Some of you are fortunate enough
to never experience problems. Others of you are
in an endless search for insurance coverage or
adequate reimbursement. Never hesitate to seek
assistance from resources. There is no such thing
as a stupid question when it comes to you or your
family’s well being.

132 Health Insurance
Glossary of Insurance Terms
ACCESS: Right to enter or use healthcare services.
ANCILLARY SERVICES: Healthcare services conducted
by providers other than physicians and surgeons.
These will usually include such services as physical
therapy and home healthcare.
ANNUAL BENEFIT CAP: Maximum amount paid for
specific medical services or total medical services.
ASSIGNMENT OF BENEFITS: A written authorization by
the patient/insured to make payment to the provider
of services (hospital, physician, home care company,
etc.) directly.
BALANCE BILLING: The practice of participating
providers (such as doctors, hospital, or other medical
practitioner) billing the insured for the difference of
the billed amount minus the contracted rate. Many
plans prohibit the use of balance billing and may use
sanctions against providers who balance the bill.
BASIC BENEFITS: Refers to the portion of the insurance
policy which generally provides coverage for inpatient
services: room and board, surgery, drug therapy,
physician services, etc.
BENEFICIARY: The person entitled to receive benefits
under a plan, including the covered employee and his
or her dependents.
CASE MANAGEMENT: Planned approach to manage
service or treatment to an individual with a serious
medical problem. Its dual goal is to contain costs
and promote more effective intervention to meet
patient needs. This is often referred to as large case
management.
Centers for Medicare and Medicaid
Services (CMS): A branch of the federal
government’s health and human services that govern
the Medicare and Medicaid programs.
CHARGE-BASED: Reimbursement based upon billed
fees for physician’s services.
CLAIM FORM: Requests for payment are submitted
to insurers on claim forms. Claim forms include
spaces for showing the patient’s name and address,
diagnosis, documentation of medical necessity and
kinds of services received.
COBRA: Consolidated Omnibus Budget Reconciliation
Act (COBRA) provides continuation of group health
coverage that otherwise might be terminated. It was
passed by Congress in 1986. COBRA provides certain
former employees, retirees, spouses, former spouses,
and dependent children the right to temporary
continuation of health coverage at group rates. This
coverage, however, is only available when coverage is
lost due to certain specific events.
CODING: Several coding systems are used to describe
patients and the services they receive in the healthcare
system. These are used on medical records and
billing forms.
COINSURANCE: An agreement between the insured and
the insurance company where payment is shared for all
claims by the policy. A typical arrangement is 80%/20%
up to $5,000. The insurance company pays 80% of
the first $5,000 and the insured pays 20%. Usually
after 80% of $5,000, the insurance company then pays
100% of covered expenses during the remainder of the
calendar year up to any limits of the policy.
COORDINATION OF BENEFITS (COB): A contractual
provision to prevent an insured from receiving benefits
under more than one health insurance plan so that
the insured’s benefits from all sources do not exceed
allowable medical expenses or eliminate appropriate
patient incentives to contain cost.
COPAYMENT: A flat fee paid at the time a medical
service is received. It does not accumulate towards a
plan’s deductible or out-of-pocket maximum.
COST-BASED: Reimbursement methodology typically
used to pay institutions on the basis of accounting
cost audits. The books of the provider are examined in
an effort to avoid paying profits and unallowed items.
COVERAGE: The products and services your health plan
is willing to pay for.
DEDUCTIBLE: A flat amount that the patient is
automatically responsible for paying before the
insurance plan begins to pay benefits.
EFFECTIVE DATE: The date that coverage begins for
the insured.
ELIGIBLE EXPENSE(S): The portion of the medical care
provider’s services that are covered for payment under
the terms of the health plan or insurance contract.
ELIGIBILITY: The screening method used by an
insurance company or government program to
determine whether the patient qualifies for benefits.
EXCLUSIONS: Illnesses, injuries, devices, procedures, or
conditions for which the policy will not pay.
EXPLANATION OF BENEFITS (EOB): A document sent
to an insured when the plan or insurance company
handles a claim. The document explains how
reimbursement was made, or why the claim was not
paid, and if any additional information is needed. The
appeals procedure should be outlined to advise the
insured of his/her rights if there is dissatisfaction with
the decision.
FEE-FOR-SERVICE: Payment for services based on
each visit or service rendered. Under this arrangement
plans or insurers have not established contracted or
capitated rates of payments with providers prior to the
insured claim occurrence.
FEE SCHEDULE: Maximum dollar or unit allowances for
health services that apply under a specific contract.
INSURED/POLICYHOLDER: The person for whom the
insurance policy is registered under.

Health Insurance 133
LIFETIME MAXIMUM: The maximum amount that the
insurance company will pay for medical expenses.
This amount may be listed as the maximum amount
for each illness or condition. Or it may be listed as total
costs paid from a portion of a policy; e.g. inpatient
expenses vs. outpatient.
MAJOR MEDICAL: Refers to the portion of the insurance
policy which usually provides coverage for outpatient
services: doctor’s office visit, outpatient pharmacy
services, home therapy, etc.
MEDICAL NECESSITY: In order to be financed by an
insurer, a service must be medically necessary.
OPEN ENROLLMENT: A time period when a person
can obtain insurance coverage or change insurance
carriers without penalty for a pre-existing condition.
This opportunity may be available from some
employers on an annual basis.
OUT-OF-NETWORK: Medical services obtained by
managed care plan members from unaffiliated or
non-contracted healthcare providers. In many plans,
such care will not be reimbursed unless previous
authorization is obtained.
OUT-OF-POCKET EXPENSES: Those medical
expenses that an insured must pay that are not
covered under the group contract.
OUT-OF-POCKET MAXIMUM: The maximum amount
that an insured is required to pay under a plan or
insurance contract.
PARTICIPATING PROVIDER: A provider who has
agreed to contract with a managed care program to
provide eligible services to covered persons.
PRE-AUTHORIZATION: Previous approval required
for referral to a specialist or non-emergency
healthcare services.
PRE-CERTIFICATION: Utilization management program
that requires the individual or provider to notify the
insurer before hospitalization or surgical procedure.
Notification allows the insurer to authorize payment
and to recommend alternate courses of action.
PRE-EXISTING CONDITION: A condition or diagnosis
which existed (or for which treatment was received)
before coverage began under a current plan or
insurance contract, and for which benefits are not
available or are limited.
PREMIUM: The payment a subscriber must pay in order
to maintain medical benefits.
PRIMARY CARE PHYSICIAN (PCP): The network
physician designated by an employee (and each of
his or her dependents) to serve as that employee’s
entry into the healthcare system. The PCP often is
reimbursed through a different mechanism (such
as capitation) than are other network providers.
This physician sometimes is referred to as the
“gatekeeper.”
PRIMARY COVERAGE: The insurance plan that is
required to pay benefits first based on state and
federal insurance regulations.
QUALITY ASSURANCE: Set of activities that measures
the characteristics of healthcare services and may
include corrective measures.
REASONABLE & CUSTOMARY: The maximum amount
a plan or insurance contract will consider eligible
for reimbursement, based upon prevailing fees in a
geographic area.
REIMBURSEMENT: The amount the plan pays for a
particular product or service. Your plan may reimburse
the full amount charged by your doctor, pharmacy,
or hospital; or it may reimburse a percentage or set
amount.
SECONDARY COVERAGE: An insurance plan that is
required to pay benefits after the primary plan has paid
or denied payment for medical expenses.
SUPPLEMENTARY COVERAGE: Insurance to help
cover those parts of Medicare Part B that are
non-reimbursable.
THIRD PARTY ADMINISTRATOR (TPA): Method
by which an outside person or firm, not a party to
a contract, provides specific administrative duties
(including premium accounting, claims review and
payment, arranges for utilization review and
stop-loss coverage) for a self-funded plan. Entity
may also handle payment of claims.
USUAL, CUSTOMARY, AND REASONABLE (UCR)
Fees: Charges of healthcare providers that are
consistent with charges from similar providers for
identical or similar services in a given locale.
UTILIZATION REVIEW: The process of evaluating the
appropriateness, necessity and quality at medical care
for purposes of insurance coverage.
References:
National Association of Health Underwriters (NAHU): http://www.nahu.org
Consumer Guides for Getting and Keeping Health Insurance: http://www.healthinsuranceinfo.net/

134 Glossary
Glossary
Acquired immune deficiency syndrome
(AIDS): A secondary immunodeficiency caused by
the HIV Virus.
Acute: A descriptive term used to describe an illness
which is usually short in duration and of recent onset.
Adenosine Deaminase (ADA): An enzyme essential
for the development of the immune system.
Agammaglobulinemia: An almost total lack of
immunoglobulin or antibodies.
Amniocentesis: The withdraw of amniotic fluid
surrounding a fetus in order to perform prenatal
genetic testing.
Androgen: A male sex hormone.
Anemia: A condition in which the blood is deficient in red
blood cells, in hemoglobin, or in total volume.
Antibodies: Protein molecules that are produced
and secreted by certain types of white cells
(B-lymphocytes, plasma cells) in response to
stimulation by an antigen; their primary function is to
fight bacteria, viruses, toxins, and other substances
foreign to the body.
Aspergillus: A kind of fungi which includes many
common molds.
Antigen: Any foreign substance that provokes an
immune response when introduced into the body; the
immune response usually involves both T-lymphocytes
and B-lymphocytes.
Ataxia: An unsteady gait caused by neurological
abnormalities.
Autoimmune disease: A disease that results when
the body’s immune system reacts against a person’s
own tissue.
Autosomal recessive inheritance: A form
of inheritance where the characteristic, or disease,
is inherited from both parents.
Autosomes: Any chromosome other than the
sex chromosome.
Bacteria: Single cell organisms (microorganisms)
that can be seen only under a microscope. While
bacteria can be useful, many bacteria can cause
disease in humans.
B-lymphocytes (B-cells): White blood cells of
the immune system derived from bone marrow and
involved in the production of antibodies.
Bone marrow: Soft tissue located in the hollow
centers of most bones that contain developing red
blood cells, white cells, platelets and cells of the
immune system.
Bronchiectasis: A dilation of the tubes (bronchi)
leading to the air sacs of the lung; usually the
consequence of recurrent infection.
Carrier detection: The detection of a genetic
characteristic in a person who carries the
characteristic (or disease) in their genes but shows
no clinical evidence.
CD 40 ligand: A protein found on the surface of
T-lymphocytes; individuals with X-linked hyper IgM
syndrome have a deficiency in this protein.
Cellular immunity: Immune protection provided by
the direct action of the immune cells.
Chromosomes: Physical structures in the cell’s
nucleus that carry genes; each human cells has 23
pairs of chromosomes.
Chronic: Descriptive term used to describe an illness
or infection that may be recurrent or last a long time.
Chorionic villus sampling (CVS): Involves the
retrieval of a sample of the developing placenta from
the womb in order to perform prenatal genetic testing.
Combined immunodeficiency: Immunodeficiency
when both T- and B-lymphocytes cells are inadequate
or lacking.
Complement: A complex series of blood proteins that
act in a definite sequence to affect the destruction of
bacteria, viruses and fungi.
Complete blood count: A blood count that
includes separate counts for red and white blood cells.
Congenital: Present at birth.
Consanguineous: Descended from the same family
or ancestors.
Cord blood: Blood obtained from the placenta
at birth.
Cryptosporidium: An organism that can cause
gastrointestinal symptoms and liver disease; may be
present in drinking water.
Cytokines: A protein secreted by cells of the lymph
system that affects the activity of other cells and
is important in controlling inflammatory responses.
Interleukins and interferons are cytokines.
DNA (deoxyribonucleic acid): The carrier of
genetic information found in the cell nucleus.
Eczema: Skin inflammation with redness, itching,
encrustations, and scaling.
Endocrine system: A series of glands in the body
that produce hormones.
Eosinophilia: An increase in the number of granular
white blood cells that stain with the dye eosin,
occurring in some allergies and parasitic diseases.
Fungus: Member of a class of relatively primitive
microorganisms including mushrooms, yeast,
and molds.

Glossary 135
Gamma globulins: The protein fraction of blood that
contains immunoglobulins or antibodies.
Gamma interferon: A cytokine primarily produced
by T-lymphocytes that improves bacterial killing
by phagocytes; used as treatment for chronic
granulomatous disease.
Gene: A unit of genetic material (DNA).
Gene (or genetic) testing: Testing performed to
determine if an individual possesses a specific gene or
genetic trait.
Gene therapy: Treatment of genetic diseases by
providing the correct or normal form of the abnormal
gene causing the disease.
Graft-versus-host disease: A reaction in which
transplanted immunocompetent cells attack the tissue
of the recipient.
Graft rejection: The immunologic response of the
recipient to the transplanted organ or tissue resulting
in rejection of the transplanted organ or tissue.
Granulocyte: A white cell of the immune system
characterized by the ability to ingest (phagocytize)
foreign material; neutrophils, eosinophils, and
basophils are examples of granulocytes.
Haplotype: A series of gene clusters on the
sixth human chromosome that determines
histocompatibility antigens.
Helper lymphocytes (Helper T-cells):
A subset of T-lymphocytes that help B-lymphocytes
and T-lymphocytes to function more optimally.
Histocompatibility antigens: Chemicals on the
surface of many cells of the body, including the cells
of the immune system, which are relatively unique to
each individual and are responsible for our tissue type.
Humoral immunity: Immune protection provided by
soluble factors, such as antibodies, which circulate in
the body’s fluids.
Hypogammaglobulinemia: Lower than normal
levels of gamma globulins or immunoglobulins (or
antibodies) in the blood.
Hypoplasia: The failure of an organ or body part to
grow or develop fully.
IgA: An immunoglobulin found in blood and secreted
into tears, saliva, and on the mucous membranes of
respiratory and intestinal tracks.
IgD: An immunoglobulin whose function is poorly
understood at this time.
IgE: An immunoglobulin found in trace amounts in the
blood and responsible for allergic reactions.
IgG: The most abundant and common of the
immunoglobulins. IgG functions mainly against
bacteria and some viruses. It is the only antibody
that can cross the placenta from the mother to the
developing fetus.
IgM: An immunoglobulin found in the blood. IgM functions
in much the same way as IgG but is formed earlier
in the immune response. It is also very efficient in
activating complement.
Immune response: The response of the immune
system against foreign substances.
Immunocompetent: Capable of developing an
immune response.
Immunodeficiency: A state of either a congenital
(present at birth) or an acquired abnormality of the
immune system that prevents adequate immune
responsiveness.
Immunoglobulin replacement therapy:
The intravenous or subcutaneous injection of
immunoglobulin.
Immunoglobulins (Ig): Another name for antibody;
there are five classes: IgA, IgD, IgG, IgM, and IgE.
Incubation period: The period between the infection
of an individual by a pathogen and the manifestation of
the disease it causes.
In vitro: Outside of a living environment; refers to a
process or study taking place in test tubes, etc.
In vivo: Inside a living environment; refers to a process
or study taking place in the body.
Intravenous immunoglobulin infusion:
Immunoglobulin (gamma globulin) therapy injected
directly into the vein.
Killer lymphocytes: T-lymphocytes that
directly kill microorganisms or cells that are infected
with microorganisms.
Leukemia: Type of cancer affecting the cells of the
immune system.
Leukocyte (white blood cell): Group of
small colorless blood cells that play a major role
in the body’s immune system. There are five basic
leukocytes: monocytes, lymphocytes, neutrophils,
eosinophils, and basophils.
Live vaccines: Live viruses are used in the vaccine;
live vaccines (particularly oral polio) can transmit
the disease they were designed to prevent in
immunocompromised individuals.
Lymph: Fluid made up of various components of the
immune system that flows throughout tissues of the
body via the lymph nodes and lymphatic vessels.

136 Glossary
Glossary
Lymph nodes: Small bean-sized organs of the
immune system, distributed widely throughout
the body. Each lymph node contains a variety of
specialized compartments that house B-lymphocytes,
T-lymphocytes, and macrophages. Lymph nodes unite
in one location the several factors needed to produce
an immune response.
Lymphocytes: Small white cells, normally present
in the blood and in lymphoid tissue, that bear the
major responsibility for carrying out the functions of
the immune system. There are two major forms of
lymphocytes, B-lymphocytes, and T-lymphocytes,
which have distinct but related functions in generating
an immune response.
Lymphoma: Type of cancer of the lymphocytes of the
immune system.
Macrophages: A phagocytic tissue cell of the immune
system that functions in the destruction of foreign
antigens (as bacteria and viruses), and serves as an
antigen-presenting cell.
Major histocompatibility complex: A series
of genes on chromosome 6 that direct the synthesis
of the chemicals on the surface of many cells of the
body, including the cells of the immune system, which
are relatively unique to each individual and provide our
tissue type.
Malignancy: Cancer.
Metabolism: A general term which summarizes the
chemical changes within a single cell, and the body
as a whole, which results in either the building up or
breaking down of living material.
Microorganisms: Minute living organisms, usually
one-cell organisms, which include bacteria, protozoa,
and fungi.
Molecules: The smallest unit of matter of an element
or compound.
Monocyte: Phagocytic cell found in the blood that
acts as a scavenger, capable of destroying invading
bacteria or other foreign material; these cells develop
into macrophages in tissues.
Monokines: Chemical messengers produced and
secreted by monocytes and macrophages.
Mucosal surfaces: Surfaces that come in close
contact with the environment, such as the mucus
membranes of the mouth, nose, gastrointestinal tract,
eyes, etc; IgA antibodies protect these surfaces, or
mucus membranes, from infection.
Neurology: A branch of medicine concerned
especially with the structure, functions, and diseases
of the nervous system.
Neutropenia: A lower than normal amount of
neutrophils in the blood.
Neutrophils: A type of granulocyte, found in the
blood and tissues that can ingest microorganisms.
Nystagmus: Involuntary usually rapid movement
of the eyeballs.
Opportunistic infection: An infection that
occurs only under certain conditions, such as in
immunodeficient individuals.
Organism: An individual living thing.
Osteomyelitis: Infection of the bone.
Parasite: A plant or animal that lives, grows, and feeds
on or within another living organism.
Parathyroid gland: Small glands found in the neck
near the thyroid that control the normal metabolism
and blood levels of calcium.
Petechiae: Pinhead-sized red spots resulting from
bleeding into the skin.
Phagocyte: A general class of white blood cells that
ingest microbes and other cells and foreign particles;
monocytes, macrophages, and neutrophils are types
of phagocytes.
Plasma cells: Antibody-producing cells descended
from B-lymphocytes.
Plasmapheresis: A process in which blood taken
from a patient is treated to extract the cells and
corpuscles, which are then added to another fluid and
returned to the patient’s body.
Platelets: Smallest and most fragile of the blood cells;
primary function is associated with the process of
blood clotting.
Polymorphism: The quality or state of existing in or
assuming different forms.
Polysaccharides: Complex sugars.
Primary immunodeficiency: Immunodeficiency
that is intrinsic to the cells and tissues of the immune
system, not due to another illness, medication or
outside agent damaging the immune system.
Prophylactic: Medical therapy initiated to prevent
or guard against disease or infection.
Protein: A class of chemicals found in the body
made up of chains of amino acids (building blocks);
immunoglobulins (antibodies) are proteins.
Recurrent infections: Infections, such
as otitis, sinusitis, pneumonia, deep-seated
abscess, osteomyelitis, bacteremia or meningitis
that occur repeatedly.
Secondary immunodeficiency:
Immunodeficiency due to another illness or agent,
such as human immunodeficiency virus (HIV),
cancer, or chemotherapy.

Glossary 137
Sepsis: An infection of the blood.
Spleen: An organ in the abdominal cavity; it is
directly connected to the blood stream and like
lymph nodes contains B-lymphocytes, T-lymphocytes,
and macrophages.
Stem cells: Cells from which all blood cells and
immune cells are derived, bone marrow is rich in
stem cells.
Subcutaneous infusion: Administration of gamma
globulin in which it is infused slowly directly under the
skin with a small pump.
Telangiectasia: Dilation of the blood vessels.
Thrombocytopenia: Low platelet count.
Thrush: A fungal disease on mucous membranes of
the mouth caused by Candida infections.
Thymus gland: A lymphoid organ located behind
the upper portion of the sternum (breastbone). The
thymus is the chief educator of T-lymphocytes. This
organ increases in size from infancy to adolescence
and then begins to shrink.
T-lymphocytes (or T-cells): Lymphocytes that are
processed in the thymus; they are responsible in part
for carrying out the immune response.
Unusual infectious agents: These are normally
non-pathogenic agents or those not generally found
in humans which can cause serious disease in
immunocompromised patients.
Vaccine: A substance that contains components from
an infectious organism which stimulates an immune
response in order to protect against subsequent
infection by that organism.
Vacuole: A cavity or vesicle in the cytoplasm of a cell
containing fluid.
Vectors: Modified viruses containing normal genes;
used in gene therapy to insert normal genes in cells.
Virus: A submicroscopic microbe causing infectious
disease; can reproduce only in living cells.
White blood cells: See leukocyte.
X-linked recessive inheritance: A form of
inheritance where the characteristic, or disease, is
inherited on the X-chromosome.

138 Reference
Reference
Information About Primary
Immunodeficiencies
Immune Deficiency Foundation
www.primaryimmune.org
(800) 296-4433
The Immune Deficiency Foundation, founded in 1980, is
the national non-profit patient organization dedicated to
improving the diagnosis and treatment of patients with
primary immunodeficiency diseases through research,
education and advocacy.
A-T Children’s Project
www.atcp.org
The A-T Children’s Project is a non-profit organization
that raises funds to support and coordinate biomedical
research projects, scientific conferences and a clinical
center aimed at finding a cure for ataxia-telangiectasia,
a lethal genetic disease that attacks children, causing
progressive loss of muscle control, cancer and immune
system problems.
CGD Café
cgd.cultivatecommunity.com
This is a community supported site that provides a place
for family, friends and patients with chronic granulatomous
disease to share information, stories and ideas.
The Jeffrey Modell Foundation
www.jmfworld.org
(866) INFO-4-PI
The Jeffrey Modell Foundation is dedicated to early and
precise diagnosis, meaningful treatments, and ultimately
cures of primary immunodeficiencies.
Severe Combined Immunodeficiency (SCID) Homepage
www.scid.net
This site contains information about SCID with links
to journal articles, latest research developments, and
patient support.
Understanding XLP
www.xlp.ca
This site provides families and patients with
X-linked Lymphoproliferative Disorder (XLP) a means
of communication.
National Institute Of Health
U.S. Department Of Health And Human Services:
National Institute Of Health (NIH)
www.nih.gov
(301) 496-4000
NIH provides information on advances in health, science
and medical issues.
National Cancer Institute (NCI)
www.cancer.gov
(800) 422-6237
NCI is a division of the NIH that provides the following
information about cancer: topics, trials, statistics
and research.
National Heart, Lung and Blood Institute (NHLBI)
www.nhlbi.nih.gov
(301) 592-8573
NHLBI provides leadership for a national program in
diseases of the heart, blood vessels, lung, and blood;
blood resources; and sleep disorders.
National Human Genome Research Institute (NHGRI)
www.genome.gov
(301) 402-0911
NHGRI is a division of the National Institutes of Health,
marking a decade that saw genomics emerge as a
powerful research tool and looking ahead to an era in
which genomics will transform medical care.
National Institute of Allergy and Infectious
Diseases (NIAID)
www.niaid.nih.gov
Office of Communications: (301) 496-5717
NIAID is a division of NIH that provides information
on allergy and infectious diseases, but also primary
immunodeficiencies.
National Institute of Child Health and Human
Development (NICHD)
www.nichd.nih.gov
(800) 370-2943
NICHD is a division of the NIH that provides general
information on children’s health issues, including an
in-depth booklet on primary immunodeficiencies.
National Library of Medicine (NLM)
www.nlm.nih.gov
(888) 346-3656
NLM is the world’s largest medical library. The library
collects materials and provides information and research
services in all areas of biomedicine and health care.

Reference 139
NIH Clinical Trials
www.clinicaltrials.gov
(800) 411-1222
The NIH Clinical Trials Web site contains current
information on clinical trials being conducted, some of
which may be pertinent to primary immunodeficiencies.
NIH Health Information
www.health.nih.gov
A-Z index of NIH health resources, clinical trials,
MedlinePlus, health hotlines.
NIH News & Events
www.nih.gov/news
News releases, press room, RSS, Podcasts, calendars,
radio & video, media contacts, News in Health newsletter,
NIH Research Matters eColumn.
NIH Office of Rare Diseases (ORD)
www.rarediseases.info.nih.gov
(301) 402-4336
The goals of ORD are to stimulate and coordinate
research on rare diseases and to support research to
respond to the needs of patients who have any one of the
more than 6,000 rare diseases known today.
NIH Research Training & Scientific Resources
www.nih.gov/science
Intramural research, Human Embryonic Stem Cell
Registry, scientific interest groups, library catalogs,
journals, training, labs, scientific computing.
Federal Organizations
and Assistance Programs
Center for Biologics Evaluation and Research—
Food and Drug Administration (FDA)
www.fda.gov/cber/index.html
(800) 835-4709
The Center for Biologics Evaluation and Research, a
division of the FDA, whose mission is to protect and
enhance public health through regulation of biological
products to ensure their safety, effectiveness and timely
delivery to patients. This agency provides information on
biological products, such as blood and plasma, including
new product approvals, adverse events, product recalls
and withdrawals.
Centers for Disease Control and Prevention (CDC)—
Vaccine and Immunization
www.cdc.gov/node.do/id/0900f3ec8000e2f3
(800) 232-4636
The Vaccine and Immunization division of the CDC
provides information on general vaccinations and
specific precautions for individuals affected with
primary immunodeficiencies.
Centers for Medicare & Medicaid Services (CMS)
www.cms.hhs.gov
(800) 633-4227
CMS provides information for individuals receiving services
from Medicare, Medicaid or SCHIP.
Equal Employment Opportunity Commission (EEOC)
www.eeoc.gov
(800) 669-4000
EEOC is the federal agency whose mission is to promote
equal opportunity in employment through administrative
and judicial enforcement of the federal civil rights laws and
through education and technical assistance. The Web site
contains information on the agency, its current activities
and legislative documents such as “The Americans with
Disabilities Act.”
Healthfinder
www.healthfinder.gov
Healthfinder.gov is a Federal Web site for consumers,
developed by the U.S. Department of Health and Human
Services together with other Federal agencies. It is a key
resource for finding government and nonprofit health and
human services information on the Internet.
Job Accommodation Network (JAN)
www.jan.wvu.edu
(800) 526-7234
JAN is a free consulting service through the Office of
Disability Employment Policy within the U.S. Department
of Labor. It is designed to increase the employability of
people with disabilities.
National Office of Public Health Genomics
www.cdc.gov/genomics
(770) 488-8510
This site provides updated information on how human
genomic discoveries can be used to improve health
and prevent disease. It also provides links to CDC wide
activities in public health genomics.
U.S. Department of Education
www.ed.gov/parents/landing.jhtml
This site contains information for parents about education
for children of all ages and abilities.
U.S. Department of Health and Human Services (HHS)
www.hhs.gov
(877) 696-6775
HHS is the U.S. government’s principal agency for protecting
the health of all Americans and providing essential human
services. The Web site contains information on the
department’s numerous federal programs.

140 Reference
Reference
U.S. Department of Justice Civil Rights Division:
Americans with Disabilities Act (ADA)
www.usdoj.gov/crt/ada/adahom1.htm
(800) 514-0301
This division of the government provides information to
assist persons with disabilities and to help communities
better serve these individuals.
U.S. Department of Labor: Continuation of Health
Coverage (COBRA)
www.dol.gov/dol/topic/health-plans/cobra.htm
COBRA gives workers and their families who lose their
health benefits the right to choose to continue group
health benefits provided by their group health plan for
limited periods of time under certain circumstances such
as voluntary or involuntary job loss, reduction in the hours
worked, transition between jobs, death, divorce, and other
life events.
U.S. Health Care Financing Administration (HCFA)
www.hcfa.gov
HCFA is the federal agency that administers Medicare,
Medicaid and the State Children’s Health Insurance
Program (SCHIP). The Web site provides information on
these programs and initiatives put out by the Department
of Health and Human Services, such as the “Health
Insurance Portability and Accountability Act.” It also lists
the state health insurance commissioners.
U.S. Social Security Administration
www.ssa.gov
This Web site contains complete information about
Social Security.
National Organizations
American Academy of Allergy, Asthma, and
Immunology (AAAAI)
www.aaaai.org
(313) 371-8600
Physician Referral Service: (800) 822-2762
AAAAI is a professional organization for physicians who
treat patients with allergies, asthma and immunologic
disorders. The organization provides a worldwide referral
system for physicians in various geographical regions.
American Academy of Pediatrics (AAP)
www.aap.org
(847) 434-4000
AAP is a professional organization for pediatricians. It is
committed to the attainment of optimal physical, mental,
and social health and well-being for all infants, children,
adolescents, and young adults.
Clinical Immunology Society
www.clinimmsoc.org
(414) 224-8095
The mission of the Clinical Immunology Society is to
facilitate education, translational research and novel
approaches to therapy in clinical immunology to promote
excellence in the care of patients with immunologic/
inflammatory disorders.
Federation of Clinical Immunology Societies (FOCIS)
www.focisnet.org
FOCIS exists to improve human health through
immunology by fostering interdisciplinary approaches to
both understand and treat immune-based diseases.
Infusion Nurses Society (INS)
www.ins1.org
INS is dedicated to exceeding the public’s expectations of
excellence by setting the standard for infusion care.
National Marrow Donor Program (NMDP)
www.marrow.org
(800) 627-7692
NMDP is a non-profit organization that facilitates unrelated
marrow and blood stem cell transplants for patients with
life-threatening diseases who do not have matching
donors in their families.
International Organizations
European Society for Immunodeficiencies (ESID)
www.esid.org
ESID is a non-profit medical organization. The purpose
of ESID is to foster excellence in research and medical
practice and to promote interaction with nurses and
patient associations, so as to increase exchange of
information among patients, parents of patients, nurses,
doctors and researchers.
International Nursing Group for
Immunodeficiencies (INGID)
www.ingid.org
The purpose of INGID is to improve and extend
the quality of nursing care of patients with primary
immunodeficiencies, and to increase the awareness
and understanding of primary immunodeficiencies
amongst nurses.

Reference 141
International Patient Organization for Primary
Immunodeficiencies (IPOPI)
www.ipopi.org
IPOPI is an international organization whose members
are national patient organizations for the primary
immunodeficiencies. The Web site provides general
information on PIDD and resource contacts for patients
and professionals worldwide. The following countries have
a patient support organization:
Argentina www.aapidp.com.ar
Australia www.idfaustralia.org
Canada www.cipo.net
Denmark www.idf.dk
Estonia
janne.rimmel@mail.ee
Finland
anna-riitta.satama@luukku.com
France
www.associationiris.org
Germany www.dsai.de
www.immundefekte.de
Hungary meerdos@yahoo.com
Iceland
onaemisgalli@onaemisgallar.is
India
rubbyipspi@rediffmail.com
Iran
www.iranianpia.org
Ireland
crone@eircom.net
Italy
www.aip-it.org
Morocco www.associationhajar.org
New Zealand www.idfnz.org.nz
Norway evabrox@online.no
Poland
immuno@czd.vaw.pl
South Africa www.pinsa.org.za
Spain
www.aedip.com
Sweden www.pio.nu
Switzerland s.vassalli@bluewin.ch
The Netherlands www.stichtingvoorstoornissen.nl
United Kingdom www.pia.org.uk
United States www.primaryimmune.org
www.info4pi.org
Yugoslavia koruga@sezampro.yu
Education Issues
HEATH Resource Center
http://www.heath.gwu.edu
(800) 544-3284
The HEATH Resource Center is the national clearinghouse
on postsecondary education for individuals with
disabilities. It provides information about educational
support services, policies, procedures, adaptations and
opportunities at American campuses, vocational-technical
schools and other postsecondary training sites.
National Information Center for Handicapped Children
and Youth (NICHY)
www.nichcy.org
(800) 695-0285
NICHY is a national information and referral center that
provides information on disabilities and disability-related
issues for families, educators and other professionals.
Specific information on early intervention programs,
special education, individualized education programs,
education rights and transition to adult life can be found
through this organization.
Wrightslaw
www.wrightslaw.com
This Web site is dedicated to helping individuals advocate
for children with disabilities with regard to the education
system and legal issues.
Latin American Group for Primary
Immunodeficiencies (LAGID)
www.lagid.lsuhsc.edu
LAGID is a professional organization comprised of
physicians from various Latino countries who are
dedicated to promoting the awareness, diagnosis
and treatment of primary immunodeficiency diseases
in these countries.

142 Reference
Reference
Patient Advocacy and
Support Organizations
Advocating for Chronic Conditions, Entitlements and
Social Services (ACCESS)
(888) 700-7010
ACCESS helps families navigate the often complex maze
of state and federal entitlement programs, as well as
eligibility for health insurance through state high-risk pools
and other alternatives and through group health insurance
continuation under federal law (COBRA and HIPAA).
Children’s Defense Fund
www.childrensdefense.org
(800) 233-1200
The Children’s Defense Fund is a non-profit organization
devoted to children’s issues, including the Children’s
Health Insurance Program. The Web site provides
information on these topics.
Families USA
www.familiesusa.org
(202) 628-3030
Families USA is a non-profit organization dedicated to
the achievement of high-quality, affordable health and
long-term care for all Americans. The Web site contains
state and national resources.
Family Voices
www.familyvoices.org
(888) 835-5669
Family Voices is a national organization that provides
information and education concerning the health care of
children with special health needs.
ImmunoDeficiency Resource (IDR)
http://bioinf.uta.fi/idr/index.shtml
IDR is a Web accessible compendium of information on the
immunodeficiencies. This resource includes tools for clinical,
biochemical, genetic, structural and computational analyses
as well as links to related information maintained by others.
National Committee for Quality Assurance (NCQA)
www.ncqa.org
NCQA is a private, not-for-profit organization dedicated to
assessing and reporting on the quality of managed care plans.
National Disabilities Rights Network (NDRN)
www.ndrn.org
NDRN is a non-profit membership organization for the
federally mandated Protection and Advocacy (P&A)
Systems and Client Assistance Programs (CAP) for
individuals with disabilities.
National Organization for Rare Disorders (NORD)
www.rarediseases.org
(800) 999-NORD
NORD is a non-profit organization which provides
information, programs and services for thousands of rare
medical conditions, including primary immune deficiencies.
National Patient Travel Center
www.patienttravel.org
(800) 296-3797
This non-profit organization provides a variety of services to
individuals and families seeking ways to travel long-distances
for specialized medical evaluation, diagnosis and treatment.
Patient Advocate Foundation
www.patientadvocate.org
(800) 846-4066
The Patient Advocate Foundation is a national non-profit
organization that seeks to safeguard patients through
effective mediation assuring access to care, maintenance
of employment and preservation of their financial stability.
Patient Notification System
www.patientnotificationsystem.org
(888) UPDATE-U
This is a program developed by the Plasma Protein
Therapeutics Association (PPTA) to notify patients who
receive plasma products, such as IVIG, about product recalls.
Patient Services Incorporated (PSI)
www.uneedpsi.org
(800) 366-7741
PSI is a non-profit charitable organization dedicated to
subsidizing the high cost of health insurance premiums
and co-payments for persons with specific chronic
illnesses, including primary immunodeficiencies.
Especially for Youth
Band-aids and Blackboards
www.lehman.cuny.edu/faculty/jfleitas/bandaides.
Band-aids and Blackboards is a Web site about growing up
with medical problems. The site helps people understand
what it is like, from the perspective of children and teens.
There are separate areas for kids, teens and adults.
KidsHealth
www.kidshealth.org
KidsHealth is a Web site that provides health information
to kids, teens and parents. The site contains articles,
animations, games and resources.
National Family Caregivers Association (NCFA)
www.nfcacares.org
(800) 896-3650
NCFA is a grass roots organization created to educate,
support, empower and speak up for millions of Americans
who care for chronically ill, aged, or disabled loved ones.

Reference 143
Manufacturing Companies and
Product Related Organizations
Baxter Healthcare Corporation
www.baxter.com & www.immunedisease.com
Reimbursement Hotline: (800) 548-4448
This company manufactures Gammagard S/D
and Gammagard Liquid. The Web site provides
information about the company, their products, general
information about primary immunodeficiency diseases and
reimbursement assistance.
CSL Behring
www.cslbehring.com
Reimbursement Services Hotline: (800) 676-4266
This company manufactures Carimune NF and Vivaglobin.
The Web site provides information about the company,
their products, general immunology and reimbursement
assistance.
Grifols USA, Inc.
www.grifolsusa.com
Customer Service: (888) 474-3657
This company manufactures Flebogamma. The Web site
provides information about the company, Flebogamma
and customer service.
InterMune Pharmaceuticals, Inc.
www.intermune.com
Access Hotline: (877) 305-7704
This company produces ACTIMMUNE (interferon gamma-1b)
Injection for the treatment of chronic granulomatous
disease (CGD). The company has a reimbursement hotline
and patient assistance program to help patients with
insurance and reimbursement issues.
Octapharma USA, Inc.
www.octapharma.com
(866) 766-4860
This company produces Octagam. The Web site provides
information about the company and Octogam.
Plasma Protein Therapeutics Association (PPTA)
www.plasmatherapeutics.org
(410) 263-8296
This organization is the primary advocate for the
leading producers of plasma-based and related
recombinant biological therapeutics. The Web site
provides specific information on the quality, safety and
efficacy of plasma products.
General Health Issues
American Dietetic Association (ADA)
www.eatright.org
ADA serves the public by promoting optimal nutrition,
health and well-being.
HealthWeb
www.healthweb.org
HealthWeb is a collaborative project of the health sciences
libraries of the Greater Midwest Region (GMR) of the
National Network of Libraries of Medicine (NN/LM) and
those of the Committee for Institutional Cooperation.
MayoClinic.com
www.mayoclinic.com
The Web site is a service of the renowned Mayo Clinic
health care system and provides a wealth of information
on health and medical topics. New material is added every
workday and is reviewed by Mayo Clinic experts.
Medline Plus
www.medlineplus.gov
MedlinePlus will direct you to information to help answer
health questions. MedlinePlus brings together authoritative
information from NLM, the National Institutes of Health
(NIH), and other government agencies and health-related
organizations. Pre-formulated MEDLINE searches are
included in MedlinePlus and give easy access to medical
journal articles. MedlinePlus also has extensive information
about drugs, an illustrated medical encyclopedia,
interactive patient tutorials, and latest health news.
PubMed Central
www.pubmed.com
PubMed Central is a free digital archive of biomedical and
life sciences journal literature at the U.S. National Institutes
of Health (NIH) developed and managed by NIH’s National
Center for Biotechnology Information (NCBI) in the
National Library of Medicine (NLM).
USDA Food and Nutrition Information Center
www.nal.usda.gov
This Web site provides general information and tips on
maintaining a healthy lifestyle through good nutritional habits.
WebMD
www.webmd.com
WebMD is a commercial Web site containing information
on general health, medical and fitness issues.
Talecris Biotherapeutics
www.talecris.com
Reimbursement Helpline: (800) 288-8374
This company manufactures Gamunex. The Web site
provides information about the company, their products,
links to information about primary immunodeficiency
diseases and reimbursement assistance.

144 Reference
Reference
Genetic Issues
Genetic Alliance
www.geneticalliance.org
(800) 336-GENE
The Genetic Alliance is an international coalition of families,
health professionals, and genetic support organizations that
provide information, support and advocacy to those affected
by genetic conditions, including primary immune deficiencies.
Gene Tests
www.geneclinics.org
At this site one can enter a diagnosis and pull up scholarly
articles about many primary immunodeficiency diseases
including CVID.
Human Genome Project: Ethical, Legal, and
Social Issues (ELSI)
www.ornl.gov/hgmis/elsi/elsi.html
The ELSI division of the Human Genome Project is the
world’s largest bioethics program devoted to studying these
issues related to the availability of genetic information. The
Web site contains information on genetic testing with regard
to privacy and legislation, gene patenting, gene therapy and
genetics used in the courtroom.
Publications
Immune Deficiency Foundation
Immune Deficiency Foundation. Patient and Family
Handbook for Primary Immunodeficiency Diseases,
4th edition, 2007.
3rd edition available in Spanish.
Immune Deficiency Foundation. LeBien, Sara. Our
Immune System. 1990.
Also available in Spanish.
Immune Deficiency Foundation. A Guide for School
Personnel on Primary Immune Deficiency Diseases, 2005.
Immune Deficiency Foundation. Diagnostic and Clinical
Care Guidelines for Primary Immunodeficiency
Diseases, 2006.
Immune Deficiency Foundation. IDF Guide for
Nurses on Immunoglobulin Therapy for Primary
Immunodeficiency Diseases, 2007.
Other Publications and Resources
General Information on Immunology and Primary
Immune Deficiencies
AAAAI. IVIG Toolkit. www.aaaai.org/members/resources/
initiatives/ivig.stm
National Institutes of Health, National Institute of Allergy
and Infectious Diseases. Primary Immune Deficiency
Diseases: Discovering Causes; Improving Lives;
Working Toward A Cure. 1998.
U.S. Department of Health and Human Services.
Understanding the Immune System. 1990. NIH
Publication No. 90-529.
National Institute of Child Health and Human
Development. When the Body’s Defenses are Missing:
Primary Immunodeficiency. 1999.
U.S. National Institute of Allergy and Infectious Diseases.
The Immune System: How it Works. NIH Publication
No. 92-3229.
Health Care Information
Cafferky, Michael E. Managed Care and You: The
Consumer Guide to Managing Your Health Care.
Practice Management Information. 1995.
Foote, Patricia. How are You? Manage Your Own Medical
Journey. Medical Journeys Network. 1998.
Kongstvedt, Peter R. Managed Care: What it is & How it
Works. Jones & Bartlett Publishers, Inc. 2003.
Marckinko, David E., Hetico, Hope R. Dictionary of Health
Insurance and Managed Care. Springer Publishing
Co., Inc. 2006.
Patient Advocate Foundation. The Managed Care Answer
Guide. 1997.

Reference 145
Books For Youth
Balkwil, Fran. Cell Wars. Lerner Publishing Group. 1992.
(Ages 12 and up)
Balkwill, Frances R. Amazing Schemes within Your Genes.
Lerner Publishing Group. 1993. (Ages 8–11)
Balkwill, Frances R. DNA Is Here to Stay. Carolrhoda
Books. 1994. (Ages 9–12)
Baxter Healthcare Corporation. My IVIG Book Kit.
(Ages 3–10)
Berger, Melvin. Germs Make Me Sick! Harper Trophy.
1995. (Ages 4–8)
Birch, Beverly. Pasteur’s Fight Against Microbes.
Barron’s Educational Series, Inc., New York, NY. 1996.
(Ages 9–12)
Bostrom, Kathleen Long. When Pete’s Dad Got Sick:
A Book about Chronic Illness. Zonderkidz Publishing.
2004. (Ages 4–8)
Cole, Joanna. The Magic School Bus: Inside the
Human Body. Scholastic, Inc., New York, NY. 1989.
(Ages 6–9)
Duncan, Debbie. When Molly Was in the Hospital: A Book
for Brothers and Sisters of Hospitalized Children.
Rayne Productions, Inc. 1995. (Ages 4–7)
Gelman, Rita Golden. Body Battles. Scholastic, Inc. 1992.
(Ages 8–12)
Howard Hughes Medical Institutes, Office of
Communications. Arousing the Fury of the Immune
System. www.hhmi.org. 1998. (Young Adult)
Huegel, Kelly. Young People and Chronic Illness. Free
Spirit Publishing, Inc. 1998. (Young Adult)
Libal, Autumn. Chained: Youth with Chronic Illness. Mason
Crest Publishers. 2004. (Ages 9–12)
McGrath, Tom. When You’re Sick or in the Hospital:
Healing Help for Kids. Abbey Press. 2002. (Ages 3–11)
Mills, Joyce C. Little Tree: A Story for Children with
Serious Medical Problems. American Psychological
Associates. 2003. (Ages 5–8)
Nadler, Beth. The Magic School Bus: Inside Ralphie: A
Book About Germs. Scholastic, Inc. 1995. (Ages 6–9)
Romanek, Trudee. Achoo!: The Most Interesting Book
You’ll Ever Read About Germs. Kids Can Press, Ltd.
2003. (Ages 12 and up)
Zoehfeld, Kathleen Weidner. Pooh Plays Doctor. Disney
Press. 1999. (Preschool)
Books For Parents
Barrett-Singer, Alesia T. Coping with Your Child’s Chronic
Illness. Robert D. Reed Publishers. 2004.
Berends, Polly Berrien, Peck, M. Scott. Whole Child/
Whole Parent. Harper Collins.1997.
Bluebond-Langner, Myra. In the Shadow of Illness:
Parents and Siblings of the Chronically Ill Child.
Princeton University Press. 2000.
Leff, Patricia Taner, Walizer, Elaine H. Building the Healing
Partnership: Parents, Professionals and Children with
Chronic Illness and Disabilities. Brookline Books. 1992.
McCollum, Audrey. The Chronically Ill Child: A Guide for
Parents and Professionals. Yale University Press. 2001.
Stein, Ruth E. K. Caring for Children with Chronic Illness:
Issues and Strategies. Springer Publishing Company. 1989.
Books For Adults With Chronic Illness
Donoghue, Paul J., Siegel, Mary E. Sick and Tired of
Feeling Sick and Tired: Living with Invisible Chronic
Illness. 2nd ed. W.W. Norton & Company. 2000.
Pitzele, Sefra Kobrin. We are Not Alone: Learning to Live
with Chronic Illness. Workman Publishing Co. 1986.
Pitzele, Sefra Kobrin. Finding Joy in Today: Practical
Readings for Living with Chronic Illness. Hazelden
Information Education. 1999.
Selak, Joy H., Overman, Steven S. You Don’t Look Sick!
Living Well with Invisible Chronic Illness. The Haworth
Press. 2005.
Sveilich, Carol. Just Fine: Unmasking Concealed Chronic
Illness and Pain. Avid Reader Press. 2004.
Wells, Susan Milstrey. A Delicate Balance: Living
Successfully with Chronic Illness. Perseus Books. 2000.
Medical Textbook and Articles
Buckley, R. Primary Immunodeficiency Diseases Due to
Defects in Lymphocytes. New England Journal of
Medicine, Nov. 2, 2000, Vol. 343, No. 18, pp. 1313-1324.
Kirkwood, Evelyn and Lewis, Catriona. Understanding Medical
Immunology. 2nd ed., John Wiley and Sons. 1991.
Ochs HD., Smith CI, Puck JM. Primary Immunodeficiency
Diseases: A Molecular and Genetic Approach. Oxford
University Press. 2006.
Stiehm ER, Ochs HD, Winkelstein JA. Immunologic
Disorders in Infants and Children. W.B. Saunders, 2004.

146

This publication has been made possible
through a generous grant from
Baxter Healthcare Corporation
40 West Chesapeake Avenue, Suite 308
Towson, Maryland 21204
800-296-4433
www.primaryimmune.org
idf@primaryimmune.org