Combined Immune Deficiencies in Children

Transcription

1 Lisa J. Kobrynski, MD, MPH Combined Immune Deficiencies in Children Abstract Combined immune deficiencies are a heterogeneous group of congenital disorders usually attributable to a single gene defect. The hallmark of these disorders is recurrent infections resulting from defects in both T- and -cell function. This article reviews the basic components of the immune system as well as the clinical presentation, laboratory findings, and treatment for 3 distinct combined immune deficiencies. Combined immune deficiencies (CIDs) are a heterogeneous group of congenital disorders. Although these disorders may vary in their clinical presentation and laboratory findings, they result in severe, often life-threatening infections because of the body s inability to mount protective immune response to infections involving bacteria, viruses, and fungi. Without prompt and aggressive therapy, these disorders generally are fatal in the first 2 years of life. Awareness of the signs and symptoms that accompany these disorders will lead to better detection and earlier treatment for children with CIDs. This article reviews the functions of 2 immune system components (the humoral and cellular immune systems), and describes the clinical signs and symptoms, laboratory testing, and treatment of 3 separate CIDs: severe CID, Wiskott-Aldrich syndrome, and DiGeorge syndrome. THE IMMUNE SYSTEM The immune system consists of 4 basic arms, or components, that act cooperatively and have some synergistic functions. These components can be broken down into humoral immunity involving antibodies that combat most bacterial infections and some viral infections; cellular immunity, which combats viral and fungal infections; neutrophils, which play a role in killing intracellular bacteria and some fungi; and complement, a serum protein that acts with immunoglobulin to facilitate the killing of certain microbes. lymphocytes are produced in the bone marrow. efore entering the bloodstream, cells are formed from blood stem cells and mature in Lisa J. Kobrynski is Assistant Professor of Pediatrics at Emory University, Atlanta, GA. Dr. Kobrynski is a pediatric immunologist at Emory Children s Center in Atlanta, Georgia. She is the clinical director of the pediatric immunology clinic, a regional center caring for children with primary immune deficiencies. She also is the clinical research director of the Southeastern Regional Center of Excellence for 22q. Her research interests focus on host immune responses to polysaccharide-coated bacteria, such as pneumococcus, and on new therapies for patients with primary immune deficiencies. Address correspondence to: Lisa Kobrynski, MD, MPH, Emory Children s Center, 2015 Uppergate Drive, Atlanta, GA ( lkobryn@emory.edu). 206 Journal of Infusion Nursing

2 the bone marrow. Once in the bloodstream, they migrate to other lymphoid organs such as the lymph nodes, spleen, and liver. Residing in the germinal centers of these lymphoid organs, cells come in contact with a variety of antigens, including both self-proteins and foreign proteins, circulating in the blood. The main function of cells is to produce immunoglobulins, or antibodies. Immunoglobulins are serum proteins composed of 2 heavy and 2 light chains (Figure 1). Immunoglobulins are produced by cells in response to stimulation by T cells, other cells, and cytokines. The variable regions of the heavy and light chains form an antigen-binding site, which selectively binds antigens. The immune system is capable of creating hundreds of thousands of different antigen-binding sites by rearranging a piece of the DNA segment encoding for the variable region. This process occurs to a limited extent before birth, then is continually modified throughout life as humans are exposed to different pathogens. The constant region of the immunoglobulin molecule determines its class. Recombination or rearrangement of the DNA in the constant region allows the cells to produce antigen-specific immunoglobulin (Ig) molecules of 4 different classes: IgM, IgG, IgA, or IgE. The Fc portion of the immunoglobulin molecule, composed of the 2 heavychain constant regions, can be bound to the cell membrane of cells, helping to initiate intracellular signaling, or it can be free in the bloodstream to bind bacteria with the corresponding variable region, which then bind to cells or macrophages. When bacteria are bound by the Fab end of the immunoglobulin molecule and complement is bound Sites for attachment to antigen Disulphide bonds Sites for attachment to complement Sites for attachment to phagocytic cells Heavy chain Light Chain FIGURE 1. The structure of an immunoglobulin (Ig) G1 molecule. The IgG molecule consists of 2 heavy and 2 light chains. Each chain has a variable region (gray) and a constant region (blue). The variable region determines the specificity of the antibody. The constant region determines the Ig class, and for IgG and IgM binds to complement proteins. by the Fc end, then direct killing of the bacteria can occur. acteria coated with immunoglobulin molecules are more easily recognized, ingested, and killed by white cells called phagocytes, a process called opsonization. 1 There are 4 classes of immunoglobulins, determined by the type of heavy chain, in the circulation. In response to infection, IgM is the first antibody produced. Later, during the immune response, IgG is produced, and this antibody can persist in the bloodstream for prolonged periods. The antibody IgA is found on mucosal surfaces, including the nasopharynx, the intestinal lining, and the urinary tract. The antibody IgE is formed as part of the allergic response to foreign proteins. Humoral immunity is the function of the immune system that responds to foreign cells that do not share the same major histocompatibility class (MHC) II profile as the host. When a bacteria or virus is present in the bloodstream, cells, dendritic cells, and macrophages can engulf these microbes and then digest them. Cells capable of this are called antigen-presenting cells (APCs). Once digested in the APC, small proteins or peptides are moved to the cell surface attached to the MHC molecule (Figure 2). T cells that recognize this peptide and the MHC molecule bind the APC through the T-cell receptor (TCR). When this binding accompanies the binding of costimulatory molecules, the T cells are activated and differentiate. The T cells also release cytokines, which help to recruit other T cells. When these T cells encounter cells in the lymph nodes, which already express this peptide on their cell surface, they can bind to these mature cells. This binding, along with the binding of another set of costimulatory molecules, CD40-CD40L, and the secretion of cytokines, activates the cells to proliferate and secrete antibody (IgG, IgM, or IgA) specific for that particular antigen. The cells may form plasma cells, which can secrete large amounts of specific immunoglobulins or antibodies. The cells that express specific immunoglobulins on their cell surface may bind to microbes in the circulation via the immunoglobulin molecule, thus helping to clear an infection. Immunoglobulin molecules in the bloodstream may bind bacteria or viruses and form an immune complex, which then may bind the complement protein and initiate a cascade, resulting in the death of the microbe. Thus, humoral immunity is important in protecting the body against bacterial organisms. Humoral immunity works in tandem with cellular immunity to control viral and fungal infections. The ability of the immune system to distinguish between self and nonself is critical for fighting infection and for avoiding the development of autoimmune diseases. Originating as blood stem cells in the bone marrow, T lymphocytes develop into mature T cells in the thymus, a glandular organ located in the chest. There, T cells develop into cells trained to recognize foreign antigens. Different subsets of T cells include T helper cells, T suppressor cells, T regulatory cells, and T cytotoxic cells. oth T helper cells and T regulatory cells express CD4 on Vol. 29, No. 4, July/August

3 Microbe APC IgG IgA PC MHC II APC TCR CD80 CD28 IgA T cell Cytokines Cytokines T cell their cell surface. The T suppressor cells and T cytotoxic cells express CD8. The T helper cells provide signals to cells to augment the production of antibodies, whereas the T suppressor cells help put the brakes on immune responses. The T cytotoxic cells are able to kill infected cells. 1 The thymus serves as the schoolhouse for T cells, educating them to recognize self and nonself. The T cells that cannot recognize self (through MHC I and II) undergo apoptosis, or cell death, as do the T cells that are too reactive to self-antigens, or autoreactive T cells. The genes encoding the T-cell receptors undergo rearrangement, creating T cells specific for a variety of antigens. They then develop into CD4 or CD8 cells before going out into the bloodstream as mature T cells. As the main component of cellular immunity, T cells are essential for combating viral and fungal infections. However, T cells also play an important role in humoral immunity, as described previously. Cytotoxic T cells (CD8 T cells) bind peptides on the surface of a virus-infected cell, then cause the death of that cell by releasing enzymes from granules inside the T cell through a pore in the cell surface. A deficiency in T-cell number or function leads to an increase in infection, whereas dysregulation of T-cell immunity can lead to autoimmune disease. Combined immune deficiencies are the result of an immune defect that affects both humoral and cellular immunity. Although certain disorders may appear to have a predominantly humoral or cellular immune defect, the underlying defect causes both arms of the immune system to function abnormally. CD40-CD40L FIGURE 2. Specific antibody response. Antigen-presenting cells (APC) ingest bacteria or viruses and express a portion of their protein in the cell surface. Recognition by the T cell leads to cytokine production and recruitment of additional T and cells. inding of antigen-specific T and cells with cosignals generated by binding CD40-CD40L causes class switching of the immunoglobulin (Ig) gene in cells. Mature cells secrete IgM initially, then IgG, IgA, or IgE after class switching. Plasma cells are longlived, antibody-secreting cells. MHC, major histocompatibility class; TCR, T-cell receptor. IgM IgG IgM CLINICAL PRESENTATION The hallmark of all primary immune deficiencies is an increase in the number and severity of infections. In CIDs, the onset of infections usually occurs early in life, often during the first 6 months. These infections may be typical infections, such as otitis media, but they occur more frequently and with more severity than usual. A variety of bacterial, viral, and fungal infections may occur. Opportunistic infections, with organisms such as Pneumocystis carinii (PCP) and cytomegalovirus (CMV) occur frequently in patients with CID. These types of infections do not occur in patients with normal immune systems. In addition, other signs of the disorder may manifest such as skin rashes, failure to thrive, chronic diarrhea, easy bruising or bleeding, and enlargement of the liver and spleen. The skin rashes can resemble eczema, but generally are more diffuse and severe, not responding well to topical therapy with corticosteroids or tacrolimus. 2 LAORATORY TESTING Figure 3 shows a diagnostic testing algorithm for CID. The algorithm encompasses testing of both humoral immunity and cellular immunity. Frequent bacterial infections suggest a defect in humoral immunity. The white blood cell count may be normal, but the differential may show a profound decrease in lymphocytes. Secondary causes of immune deficiency, such as HIV, must be ruled out. Evaluation of the humoral immune system proceeds with measurement of serum immunoglobulins and specific IgG antibodies to tetanus toxoid, diphtheria toxoid, Streptococcus pneumococcus, measles, and Haemophilus influenzae. If humoral immunity appears to be intact, then the investigations focus on the neutrophils and the complement system. If serum immunoglobulins are depressed or specific antibodies are not present, then a booster vaccine may be given, with retesting of the specific antibody titers 4 weeks later. 3 Recurrent or severe viral or fungal infections are suggestive of a defect in cellular immunity. Testing of the cellular immune system involves measurement of T-cell numbers, usually performed by flow cytometry, and measures of T-cell function. The measurement of T-cell function can be performed in vivo by placing 0.1 ml of an antigen such as tetanus toxoid or Candida albicans intradermally. This is performed in a manner similar to the placement of a purified protein derivative to test for tuberculosis exposure. If the patient has intact cellular immunity, a wheal and flare should be present at 48 hours. This is termed delayed-type hypersensitivity. A lack of response indi- 208 Journal of Infusion Nursing

4 FIGURE 3. Testing algorithm for combined immune deficiencies. The testing algorithm is used for patients with suspected immune defects. CC, complete blood count; DTH, delayed-type hypersensitivity; MA, bone marrow aspirate; Ab, antibody. Modified from Lindegren et al. 3 cates impaired T-cell function known as anergy. In vitro testing of T cells can be performed by stimulating T cells in culture with mitogens, which are plant proteins such as pokeweed, or with antigens such as tetanus toxoid or C. albicans. Normal T cells should proliferate in response to stimulation, and the amount of stimulation is measured either through incorporation of H 3 -thymidine or by flow cytometry. 3 ecause a majority of CIDs result from a mutation in a single gene, the diagnosis can be confirmed through identification of the genetic mutation in the patient. The genes to be tested are selected on the basis of the clinical presentation and the laboratory findings. Numerous syndromes are associated with CID, including SCID, Wiskott-Aldrich syndrome, DiGeorge syndrome, hyper-igm syndrome, chronic mucocutaneous candidiasis, immune dysfunctionpolyendocrinopathy-enteropathy-x-linked inheritance syndrome (IPEX), and hyper-ige (Job s) syndrome. The following sections discuss the first 3 of these disorders. SEVERE COMINED IMMUNE DEFICIENCY Severe combined immune deficiency (SCID) is one of the most devastating CIDs. The incidence is estimated to be 1 per 100,000 live births, although this is likely to be an underestimate. Affected infants rarely live beyond their first birthday without treatment. Although infants with SCID appear to have one disease, more than 15 separate singlegene defects have been described (Table 1). 4,5 However, the result is an arrest in T-cell development, which causes a profound decrease in T lymphocyte number. This T lymphocyte decrease, seen in nearly all infants with SCID, is pathognomonic for this disorder. Clinical Presentation Severe skin rash with red, peeling skin often develops in the first few weeks of an infant s life. This rash resembles eczema, but is more diffuse and usually does not respond to topical corticosteroids. Superinfection of the skin with Staphylococcus aureus occurs frequently. Recurrent, severe, and sometimes fatal infections occur with common viruses such as adenovirus, parainfluenza, and varicella. These infants have recurrent mucocutaneal infections with Candida. Candidal esophagitis can result in poor feeding and poor weight gain. acterial infections such as otitis media, pneumonia, and skin infections are seen frequently. Opportunistic infections (PCP, CMV) are the hallmark of a T-cell immune defect, and their presence should immediately prompt investigation for an underlying immune Vol. 29, No. 4, July/August

5 TALE 1 The Frequency of Specific Genetic Defects Resulting in SCID T-cell Defect Inheritance Proportion Affected, % Gamma chain deficiency X-linked 46 RAG 1/2 deficiency AR 20.4 Adenosine deaminase deficiency AR 16.1 IL-7 receptor alpha deficiency AR 10.3 Jak3 kinase deficiency AR 6.9 Artemis deficiency AR 1.1 CD3 delta deficiency AR 0.6 CD3 epsilon deficiency AR 0.6 Other AR defects AR 18 Unknown? 6.3 RAG, recombination-activating gene; IL, interleukin; AR, autosomal recessive. Data from uckley 4 and Notarangelo et al. 5 defect. In children with SCID, PCP infection is frequently fatal. Diarrhea may result from persistent infection, rotavirus, Giardia lamblia, or malabsorption. The use of an elemental formula may be helpful to reduce the diarrhea. If there is severe weight loss or failure to thrive, parenteral nutrition may be necessary. Infants with SCID may have severe, sometimes fatal reactions after vaccination with live vaccines (eg, for measles-mumps-rubella or varicella). These vaccines are contraindicated for all children with CID. The development of graft-versus-host disease has been described in infants with SCID after a blood transfusion. 6 Laboratory Testing Infants with SCID have profound T-cell lymphopenia, with less than 20% T cells, as compared with 55% to 75% for normal infants. Their proliferative responses after in vitro stimulation are absent or severely depressed. The -cell numbers may be low, normal, or increased. Hypogammaglobulinemia is common, although during the first few months of life, the persistence of maternal IgG may cause IgG levels to be normal. Infants with SCID are unable to produce specific antibodies for infection or after vaccination. 7 Treatment Early immune reconstitution offers the best chance of long-term survival. one marrow or stem cell transplantation can be performed within the first 3 months of life and offers a 95% survival rate. 8,9 Donors may be human leukocyte antigen identical siblings, cord blood units, or matched unrelated donors identified through the national registries or haploidentical parents. efore transplantation, supportive care includes prophylaxis against PCP pneumonia with trimethoprim-sulfamethoxazole, intravenous gammaglobulin, avoidance of all live vaccines, and the use of CMV-negative, leukodepleted, irradiated blood products. ecause more than half of SCID cases are caused by an X-linked defect, genetic counseling is important for parents and siblings to determine their carrier status. WISKOTT-ALDRICH SYNDROME Wiskott-Aldrich syndrome (WAS) presents with the classic triad of eczematous skin disease, thrombocytopenia (low platelets), and draining ears (recurrent infection). Occurring only in males, WAS is an X-linked disorder resulting from a defect of the WAS protein (WASP) on hematopoietic cells. Thus, it affects lymphocyte function and platelet function. The WAS protein is important for signal transduction in lymphocytes and for cytoskeletal reorganization. Cytoskeletal reorganization is necessary for the proper positioning of T cells during their contact with APC. 10,11 Clinical Presentation Thrombocytopenia is present from birth. Platelet counts usually range from 5,000 to 50,000. The hallmark of the thrombocytopenia in WAS is the presence of small platelets. 12 ruising, petechiae, and easy bleeding occur. The skin rash resembles classic eczema and may improve somewhat with topical steroids. Recurrent infections usually begin during the first year of life and include otitis media and pneumonia. Most patients die during the first or second decade of life. Later in life, malignancies, mainly lymphomas, occur with increased frequency Journal of Infusion Nursing

6 Laboratory Testing Lymphopenia may develop during the first decade of life. Thrombocytopenia, with a mean platelet volume less than 5 fl, is present in all patients. Levels of IgM typically are decreased, and IgE may be increased, whereas IgG and IgA levels are normal. Affected patients usually have poor specific antibody responses to polysaccharide antigens. Wiskott-Aldrich syndrome occurs as the result of gene mutations in Xp Treatment Supportive treatment includes platelet transfusions, intravenous gammaglobulin, and antibiotic prophylaxis to prevent otitis media or pneumonia and sometimes splenectomy for severe thrombocytopenia. Curative therapy with bone marrow or stem cell transplantation currently is the treatment of choice. The 5-year survival rates with transplantation approach 70% with all donors. 15 Transplantation frequently is complicated by rejection and graft-versus-host disease. DIGEORGE SYNDROME DiGeorge syndrome (DGS) is the name coined by Angelo DiGeorge to describe a group of disorders involving hypocalcemia and an absent thymus. Later, cardiac defects and facial dysmorphisms were added to the features of this syndrome. DiGeorge syndrome is also known as 22q11 deletion syndrome, velocardiofacial syndrome, Sphrintzen syndrome, and conotruncal anomaly face syndrome. This developmental field defect affects the development of the third and fourth branchial arches in the fetus. It results in characteristic facial features and other congenital birth defects. In 90% of affected patients, there is a microdeletion on the long arm of chromosome 22 (22q11.2). 16 The estimated prevalence of 22q11 deletion is about 1 per 3,000 to 5,000 live births. 17 In the state of Georgia, the prevalence was estimated to be 1 per 4,000 live births. 18 The phenotype of this DGS is extremely broad and includes multiple other congenital defects. Clinical Presentation The main features of DGS include a conotruncal cardiac defect (74%), hypoparathyroidism (50-60%), and a thymic defect (77%). Numerous other defects are associated with this disorder (Table 2). 19 Cleft palate with or without cleft lip, delayed speech, and velopharyngeal insufficiency is very common among patients with DGS. Various cardiac defects have been noted, but interrupted aortic arch, tetralogy of Fallot, truncus arteriosus, and pulmonary atresia TALE 2 Associated Abnormalities in DiGeorge Syndrome (22q11 Deletion Syndrome) Proportion Defect Affected, % Conotruncal heart defect 75 Hypoparathyroidism Thymic defects 77 Facial dysmorphisms 95+ Cleft palate ± lip 69 Velopharyngeal insufficiency 70 Speech delay (nonverbal at 4 years) 30 Hypernasal speech 80+ Renal abnormalities 37 Skeletal (vertebral) abnormalities 20 Feeding difficulties 35 Learning difficulties Short stature Data from McDonald-McGinn et al. 19 are the most common defects. The hypoparathyroidism may result in transient or persistent hypocalcemia. 20 The immune defects seen with DGS result primarily from defective development of the thymus. More than two thirds of DGS patients have decreased numbers of T cells. A small percentage has impaired T-cell function, and less than 1% have absent T cells (complete DGS). Other associated immune defects include IgA deficiency and polysaccharide antibody deficiency. Juvenile rheumatoid arthritis also develops at a higher frequency in patients with DGS than in the general population. 21,22 Laboratory Testing On the basis of the clinical findings, the DGS diagnosis can be confirmed using fluorescent in situ hybridization (FISH) for the 22q11 region. Affected patients have only one copy of this region. However, 10% of affected patients do not have this microdeletion, and the diagnosis rests on clinical suspicion. If the diagnosis of DGS is suspected, serum calcium, CC with differential diagnosis, lymphocyte enumeration, lymphocyte proliferation, and serum immunoglobulins should be performed to assess parathyroid and thymus function. In addition, an echocardiogram, renal ultrasound, x-rays of the spine, and assessment of the palate should be performed. Treatment For patients with cardiac defects, assessment and repair of the defect are indicated. Calcium and vitamin D replacement are needed for patients with hypocalcemia caused by Vol. 29, No. 4, July/August

7 hypoparathyroidism. Feeding therapy, gastrostomy tube feeding, and laxative therapy may be needed for children with difficulty swallowing because of velopharyngeal insufficiency and chronic constipation. In cases with a thymic defect, antibiotic prophylaxis may be necessary for the children with a CD4 count less than 400 cells/mm 3, and no live vaccines should be given unless T-cell numbers are normal. lood products should be CMV-negative, leukodepleted, and irradiated. For those patients with a profound thymic defect (complete absence of T cells), thymus transplantation is the recommended treatment. 23 GENETIC COUNSELING It is important to consider the ramifications of these diseases, not only for the patient, but also for the patient s parents, siblings, and other family members. oth WAS and X-linked SCID are inherited as defects on the X chromosome. Generally, the mother is a carrier, and 50% of the female siblings also will be carriers at risk for bearing affected children. There is a 50% risk that male siblings will be affected. In many cases the mutated X carried by the mother occurs as a result of a spontaneous mutation, so there are no other affected family members. However, the maternal grandmother should be tested for her carrier status, and if positive, other females should be offered carrier testing. DiGeorge syndrome is inherited as an autosomaldominant trait. About 10% of parents will have the deletion and be affected. There is a 50% risk that future offspring will be affected, and a 50% risk that the patient s offspring will be affected. With the other forms of SCID inherited as an autosomal-recessive disorder, there is a 25% chance of having another affected child, and 50% of the siblings may be carriers of the mutated gene. ecause the frequency of these mutated genes generally is very low, the likelihood of the siblings having an affected child is very low. Once the genetic defect is known, genetic counseling should be provided to the family. Prenatal diagnosis also is possible. GENERAL THERAPEUTIC CONSIDERATIONS Patients with CID are frequently ill with infections requiring hospitalization for intravenous antibiotics. They often require lifelong treatment, with monthly infusions of gamma globulin, and in some cases may need parenteral nutrition. Venous access becomes problematic for many patients. Indwelling catheters may be used to provide easy venous access, but they pose a significant risk for infection. Port-a-caths are generally preferred over broviacs for longterm use and appear to have a lower incidence of infection. In some cases, gamma globulin products can be administered subcutaneously, eliminating the need for long-term venous access. PROGNOSIS Combined immune deficiencies are a group of severe and usually fatal disorders. However, prompt recognition of the immune defect can lead to early diagnosis and initiation of treatment, improving the outcome for children with these disorders. The astute clinician should be able to recognize the signs of a CID and initiate appropriate laboratory investigations without delay. R E F E R E N C E S 1. Janeway C, Travers P, eds. Immunobiology: The Immune System in Health and Disease. 3rd ed. New York: Garland Publishing; onilla T. Combined immune deficiency. Available at: uptodate.com. Accessed Lindegren ML, Kobrynski L, Rasmussen SA, et al. Applying genetic and public health strategies to primary immunodeficiency diseases: a potential approach to other genetic disorders. MMWR: Recommend Rep. 2004;53:RR uckley R. The multiple causes of human SCID. J Clin Invest. 2004;114: Notarangelo L, Casanova JL, Fischer A, et al. Primary immunodeficiency diseases: an update. J Allergy Clin Immunol. 2004;114(3): Stiehm R, ed. Immunologic Disorders in Infants and Children. 5th ed. 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