Patient & Family Handbook. For Primary Immunodeficiency Diseases

Transcription

1 Patient & Family Handbook For Primary Immunodeficiency Diseases

2 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

3 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 idf@primaryimmune.org

4 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

5 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

6 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

7 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 ( ) 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

8 iv Patient and Family Handbook Contents Chapter 1 The Immune System and Primary Immunodeficiency Diseases Chapter 2 Common Variable Immune Deficiency Chapter 3 X-Linked Agammaglobulinemia Chapter 4 Selective IgA Deficiency Chapter 5 Severe Combined Immune Deficiency Chapter 6 Chronic Granulomatous Disease Chapter 7 Wiskott-Aldrich Syndrome Chapter 8 Hyper IgM Syndromes Chapter 9 DiGeorge Syndrome Chapter 10 IgG Subclass Deficiency and Specific Antibody Deficiency Chapter 11 Ataxia Telangiectasia Chapter 12 Hyper IgE Syndrome Chapter 13 Complement Deficiencies Chapter 14 Other Important Primary Immunodeficiency Diseases Chapter 15 Inheritance Chapter 16 Laboratory Tests Chapter 17 General Care Chapter 18 Specific Medical Therapy Chapter 19 Infants and Children with Primary Immunodeficiency Diseases Chapter 20 Adolescents with Primary Immunodeficiency Diseases Chapter 21 Adults with Primary Immunodeficiency Diseases Chapter 22 Health Insurance Glossary Resources

9 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.

10 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.

11 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.

12 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.

13 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

14 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.

15 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

16 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.

17 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

18 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.

19 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.

20 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.

21 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.

22 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.

23 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.

24 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.

25 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.

26 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.

27 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.

28 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.

29 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).

30 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.

31 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.

32 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.

33 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.

34 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.

35 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.

36 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.

37 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 That patient is alive and well today.

38 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.

39 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.

40 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.

41 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.

42 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.

43 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.

44 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.

45 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 (<15,000) wear a helmet to protect them from head injuries until treatment is able to raise their platelet count.

46 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.

47 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.

48 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.

49 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.

50 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.

51 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

52 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.

53 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.

54 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.

55 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.

56 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.

57 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.

58 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.

59 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.

60 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.

61 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.

62 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.

63 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.

64 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 11q 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.

65 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.

66 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.

67 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.

68 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

69 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.

70 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.

71 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.

72 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.

73 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.

74 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

75 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).

76 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.

77 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.

78 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.

79 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.

80 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

81 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

82 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

83 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

84 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.

85 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 weeks of pregnancy and involves the retrieval of a tiny sample of the developing placenta from the womb. Amniocentesis is typically performed at 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 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.

86 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.

87 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.

88 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.

89 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

90 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.

91 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.

92 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.

93 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.

94 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.

95 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 vol 111, page ) Age Average nighttime sleep duration (hours) Average daytime sleep duration (hours) 6mos /2 1yr yr 11 1/2 2 3yr yr yr yr 10 1/2 0 10yr yr yr+ 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.

96 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.

97 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.

98 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.

99 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.

100 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.

101 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 Until the early 1980 s, the only form that was available

102 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

103 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.

104 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.

105 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

106 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 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.

107 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

108 100 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 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.

109 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.

110 102 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.

111 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.

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

113 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.

114 106 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

115 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

116 108 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.

117 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).

118 110 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.

119 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.

120 112 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.

121 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

122 114 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.

123 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.

124 116 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.

125 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.

126 118 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.

127 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.

128 120 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.

129 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.

130 122 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.

131 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.

132 124 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.

133 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.