Approach to the Child with Primary Immunodeficiency

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21 Approach to the Child with Primary Immunodeficiency

Lisa Forbes, Terri Brown-Whitehorn

Primary immunodeficiencies are a diverse group of inherited disorders with defects in one or more components of the immune system. Persistent, recurrent, or hard to treat infections are hallmark features of primary immunodeficiency diseases (PIDs). Early diagnosis and referral to a pediatric allergist/immunologist is essential. Treatments such as prophylactic antibiotics or antifungals; immunoglobulin replacement; early recognition of infection; and at times, hematopoietic stem cell transplant can save lives, help prevent infections and end organ damage, and improve long-term outcomes and quality of life.

Primary immunodeficiency disorders are rare, with the exception of IgA deficiency (prevalence of 1 : 500–700 whites). Overall, the incidence of primary immunodeficiency is one in 10,000, with a range of one in 10,000 to one in 200,000. The prevalence differs among ethnic groups and countries of origin. There are approximately 400 new cases of primary immunodeficiency diagnosed in the United States each year. Approximately 80% are diagnosed before 5 years of age. The male-to-female ratio is roughly 2 : 1. According to recent registry data, antibody defects account for 65% of primary immune deficiency, combined defects account for 15%, phagocyte defects account for 10%, complement defects account for 5%, and cellular defects without antibody dysfunction account for 5%. Although immunodeficiency may be secondary to many disease processes, including infection, metabolic disorders, protein-losing states, medications, and oncologic and rheumatologic disorders, this chapter focuses on the approach to the PIDs.

Etiology and Pathogenesis

The pathogenesis of primary immune defects is related to the underlying cellular defect, which may be further divided into problems with the innate and adaptive immune system. Immune defects are distinguished by the cellular mechanism involved, including B cells and humoral or antibody defects, T cells and cell-mediated defects, combined B and T cell defects, phagocytic defects, complement defects, and newly described defects in pattern recognition molecules (Toll-like receptors [TLRs] and signaling molecules). The innate immune system is composed of phagocytes (dendritic cells, macrophages, and neutrophils), complement components, natural killer (NK) cells, TLRs, and signaling molecules. These cells are the first line of defense and respond to pathogens in a nonspecific manner. The adaptive immune system includes B cells, T cells, and combined defects. These cells recognize and respond to pathogens in a specific manner, leading to long-lasting immunity. There are also genetic disorders of immune regulation that cross both arms of the immune system. Specific disorders are often associated with particular infectious organisms (Table 21-1).

Table 21-1 Infectious Organisms Associated with Immunodeficiency

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Disorders of the Innate Immune System

Phagocytes

Phagocytes are responsible for detecting and migrating to the site of intruder by recognition of microbial products, antibody-mediated detection, or complement. In turn, these cells produce cytokines and signal the adaptive immune system to fight an infection or react to the danger signal. Abnormalities lead to severe and unusual infections. Representative disorders include congenital neutropenia, chronic granulomatous disease, and hyper immunoglobulin E (IgE) syndrome. Four specific genetic defects in phagocyte NADPH oxidase have been described in chronic granulomatous disease. A neutrophil defect should be considered in children who have recurrent abscesses, Staphylococcus infections, granulomas, and an unusual sensitivity to Aspergillus or atypical mycobacterium.

Natural Killer Cells

NK cells confer immunity against viruses, intracellular bacteria, and parasites and provide cytotoxicity against tumor cells. The three disorders that affect NK cells and related interferon gamma (INF-γ)/interleukin-12 (IL-12) pathway are NK cell deficiency (e.g., CD16 deficiency), IFN-γ receptor 1 and 2 defects, and Griscelli syndrome (albinism with immunodeficiency). Patients with defects in the IFN-γ/IL-12 pathway typically present with atypical mycobacterium infection. Patients with isolated NK cell defects are susceptible to herpes viral infections.

Complement

The complement system shares responsibility in host defense, induction of the adaptive immune system, inflammation, and clearance of apoptotic cells and immune complexes. The clinical manifestations of deficiencies early in the complement cascade are susceptibility to infections with Streptococcus pneumoniae and Haemophilus influenzae and rheumatologic abnormalities, such as systemic lupus erythematosus (see Chapter 29). Neisseria infections are more common with defects in later components of the complement cascade. Hereditary angioedema results from a defect in C1 esterase inhibitor enzyme function.

Toll-like Receptors

TLRs are a recently discovered component of the innate immune system. They are a family of pattern recognition receptors whose sole job is immunologic surveillance. TLRs recognize microbial products and danger signals and activate pathways that produce cytokines to recruit the appropriate immune response. Most defects in the TLRs or signaling molecules downstream affect children early in life until the adaptive immune system can mature and contribute to immune regulation. IRAK-4 (interleukin-1 receptor-associated kinase 4) deficiency is an example of a specific defect of the TLR pathway.

Disorders of the Adaptive Immune System

Humoral Immune System

The humoral immune system defects, including B cell and antibody defects, make up the most common PIDs. These defects include selective IgA deficiency, transient hypogammaglobulinemia of infancy, X-linked agammaglobulinemia (XLA, or Bruton agammaglobulinemia), hyper IgM syndrome (CD40 ligand deficiency), IgG subclass deficiency, selective antibody deficiency, and common variable immune deficiency (CVID). Patients with humoral defects are typically older than 6 months; they may be diagnosed in the toddler or school-age group. Although CVID can be diagnosed at an earlier age, it is typically diagnosed in adolescents and adults. Children with transient hypogammaglobulinemia of infancy have low quantitative IgG levels with normal IgG function, as noted by protective titers to immunization. Over time, the quantity of IgG normalizes. Children with other humoral defects are unable to respond normally to bacterial infections. Specific defects have been described for some disorders. In XLA, the absence of the Btk gene leads to impairment in B cell development, maturation, function, and receptor signaling. Diagnosis is made by absence of mature B cells. Patients with hyper IgM most commonly have a defect in CD40 ligand (on T cells). Without CD40 ligand binding to CD40 on B cells, the normal switch from IgM to IgG or IgA does not occur. In CVID, patients may have normal mature B cells. However, they have defects in differentiation to immunoglobulin-secreting plasma cells. Characteristic infections seen in humoral defects include severe enteroviral infections in patients with XLA, Pneumocystis carinii pneumonia or Cryptosporidium parvum (associated with sclerosing cholangitis) in patients with hyper IgM, and Giardia infections in patients with XLA or CVID. In addition to infection, some of these patients are more at risk for autoimmune disease and malignancy.

Cell-Mediated Immune System

Defects in the cell-mediated immune system are often quite severe. T cell disorders often begin in early infancy and childhood. These defects affect T cell development or function with varying degrees of defects in the other lymphocytes (i.e., B cells and NK cells). Severe combined immunodeficiency (SCID) is the most serious immune defect and is considered a “medical emergency.” These patients present in infancy with severe viral infections, opportunistic infections, bronchiolitis, and failure to thrive. They typically have absolute lymphocyte counts of less than 2800 cell/microliter and nonfunctioning lymphocytes. Without a bone marrow transplant, these children generally die by 2 years of age. Prompt diagnosis and treatment with transplant increases the survival rate to upward of 90%. One must also consider complete DiGeorge syndrome or secondary immune defects (e.g., HIV) in these very ill infants. Patients with SCID may have a single gene defect or may be a part of an immunodeficiency syndrome such as 22q11.2 deletion syndrome, cartilage hair hypoplasia, or CHARGE (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth or development, genital or urinary abnormalities, and ear abnormalities and deafness) syndrome.

Other T cell immunodeficiencies include chronic mucocutaneous candidiasis, CD4 lymphopenia, and OKT4 epitope deficiency. People with Wiskott-Aldrich syndrome (WAS) present with eczema, thrombocytopenia (small platelets), and T cell defects. Children with ataxia telangiectasia also have T cell defects presenting with ataxia and recurrent infections. These children are also at increased risk for lymphoma.

Other Defects of the Adaptive Immune System

Many other immune defects have been described. If a child presents with insulin-dependent diabetes mellitus, autoimmune disease, noninfectious diarrhea, lymphadenopathy, food allergy and recurrent infections, and a defect in the FoxP3 gene, a diagnosis of IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X linked) is likely.

Clinical Presentation

History

Children with primary immune deficiencies can present in a variety of ways (Table 21-2). Classically, the most severe defects occur early on with recurrent or persistent viral illnesses, failure to thrive, or chronic diarrhea. Older toddlers and school-aged children may present with recurrent ear infections, sinus infections, pneumonias, or poor growth. When obtaining the history, one must pay particular attention to patient’s age at time of infection, type(s) of infection, site of infection, and ability to treat infection with oral or intravenous (IV) antimicrobials, as well as the number of hospitalizations. The overall health, growth, and development of the patient are important. The birth history and maternal prenatal history must be obtained. Prior miscarriages may be an indication of a genetic problem. The presence of maternal infection during pregnancy may lead to an immunodeficiency in a newborn. The immunization history is crucial when evaluating for an antibody defect or a T cell abnormality. The child’s response to immunizations is a way to look at the function of the immune system. Also, it is important to recognize that children with suspected or known severe immune defects should not receive live viral vaccines. Included in the history should be a comprehensive family history. Many of the primary immunodeficiencies are X-linked or associated with known genetic mutations. At times, there is a family history of autoimmune disease. A list of medications should be obtained, including any that may have been given in the past such as chemotherapeutics or antiepileptics. Finally, a detailed review of systems may be helpful detailing concomitant medical or development concerns and phenotypes leading to the diagnosis of a genetic syndrome.

Table 21-2 Clinical Presentation of the Primary Immunodeficiencies

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Physical Exam

The physical examination can sometimes give clues as to the possible immune defect and guide laboratory evaluation. Assessing the child’s growth and evaluating the growth curves are important. Some children have failure to thrive or they “fall off the growth chart.” Characteristic facial abnormalities have been seen in some of the genetic and syndromic deficiencies, such as hyper IgE syndrome. The absence of tonsils and palpable lymph nodes may indicate a B or T cell abnormality, such as XLA or SCID. Lymphadenopathy and splenomegaly may be associated with autoimmune lymphoproliferative disorder (ALPS). Erythroderma and lymphopenia in the newborn period can be indicative of a form of SCID called Ommen syndrome. Nail and hair abnormalities can be seen in some of the rare immune defects. Telangiectasias and photosensitivity, along with ataxia, are associated with ataxia telangiectasia. Patients with cartilage hair hypoplasia classically present with short limb dwarfism. Patients with X-linked anhydrotic ectodermal dysplasia with immunodeficiency (also known as NEMO or NF-κB essential modulator defect) have conical teeth with delayed eruption and osteopetrosis. Developmental delays have also been described in some of the immune defects.

Differential Diagnosis

When a child presents with recurrent infections, one must keep in mind that there are other causes that should be considered. The differential diagnosis includes cystic fibrosis; ciliary dyskinesia; and secondary immune defects from treatment of malignancies or underlying infections, such as HIV or cytomegalovirus (CMV).

Evaluation and Management

Laboratory Studies

If one is concerned about an underlying immunodeficiency, screening blood tests are necessary. For most patients, this includes obtaining a complete blood count (CBC) with differential, quantitative immunoglobulins (IgG, IgA, IgM, and IgE), and antibody titers to immunizations (diphtheria, tetanus, pneumococcal serotypes, and H. influenzae B) or naturally occurring antibodies (isohemagglutinin titers). When obtaining a CBC with differential, calculating the absolute lymphocyte count and the absolute neutrophil count is important. “Normal” lymphocyte values change with the age of the child, and thus appropriate references should be consulted for normal values when obtaining these tests. If there are further concerns or abnormalities in this screening laboratory evaluation, additional testing can be performed, and referral to a specialist is warranted (Table 21-3). For T cell defects, lymphocyte subsets along with functional assays, including mitogens or antigens, are important. In children where a neutrophil defect is suspected, absolute neutrophil number, morphology, and functional assays should be performed. A dihydrorodamine reduction (DHR) assay or nitrotetrazolium blue (NBT) assay is available to assess oxidative burst, the abnormality in chronic granulomatous disease (CGD). Complement deficiencies can be screened with a CH50 and C4 levels. Some assays look at absolute numbers and function of NK cells. DNA mutation analysis is available for some of the immune deficiencies with known genetic mutations. If a child has an abnormal immune evaluation or if there is a suspected defect or concern, immediate referral to an immunologist may be necessary.

Table 21-3 Laboratory Evaluation of Immunodeficiencies

Laboratory Test Abnormality Seen Possible Immune Defect
CBC    
Absolute lymphocyte count Changes as patient ages; <2800 cells/microliter in an infant is concerning SCID
Absolute neutrophil count Decreased Congenital neutropenia
Platelet count Decreased WAS (small platelets, eczema, and T cell immunodeficiency)
DHR assay Assesses neutrophil oxidative burst; absent burst is diagnostic Chronic granulomatous disease
CH50 assay If negative Complement deficiency
T cell markers (CD3, CD4, CD8) Low Multiple immunodeficiencies, including SCID, CVID, selective deficiency
B cell markers (CD19, CD20) Absent mature B cells only XLA
  Absent mature B cells with decreased or absent T cells or NK cells SCID
IgG Low or absent
XLA
Hyper Ig M
CVID
SCID
Transient hypogammaglobulinemia of infancy

IgA Absent
Selective IgA deficiency
CVID

IgM Elevated IgM in the absence of IgG, IgA, and IgE
Hyper IgM
IgE Elevation
Hyper IgE syndrome (Job’s syndrome)
Severe atopy
Antibody titer assessment: diphtheria, tetanus, pneumococcal Normal response with protective titers; less likely to be primary immune defect
Less likely to be primary immune defect
IgA deficiency
Transient hypogammaglobulinemia of infancy
Antibody titer assessment: diphtheria, tetanus, pneumococcal Nonprotective titers
May need booster and reassess titers 4 weeks later
Abnormalities seen in all B cell abnormalities, selective pneumococcal deficiency, and common variable immune defect
Lymphocyte stimulation by mitogens (PHA, PWM, and Con A) Absent
SCID
Complete DiGeorge syndrome

CBC, complete blood count; Con A, concanavalin A; CVID, common variable immune deficiency; DHR, dihydrorodamine reduction; Ig, immunoglobulin; NK, natural killer; PHA, phytohaemagglutinin; PWM, Pokweed mitogen; SCID, severe combined immunodeficiency; WAS, Wiskott-Aldrich syndrome; XLA, X-linked agammaglobulinemia.

Radiographic Studies

Although radiographic studies have minimal role in specific diagnosis, they can be useful in detecting clinical manifestations of the immunodeficiency. Chest radiographs are often obtained in infants and children with suspected pneumonia. In infants, an absence of the thymus may indicate SCID. Patients with adenosine deaminase (ADA) deficiency (a type of SCID) may also present with anterior cupping of the ribs. To evaluate for abscesses and granulomatous disease of the gastrointestinal tract, imaging studies are useful.

Management

Genetic counseling is essential for families of patients with primary immunodeficiency. Some infants can be diagnosed in utero. There has even been a reported case of an in utero bone marrow transplant for SCID. Otherwise, in the neonatal period, newborns with known or suspected combined defects should be placed in protective isolation. All blood products must be irradiated and CMV negative. Some of these children are placed on antibiotic and/or antifungal prophylaxis pending laboratory results and diagnosis.

In children with SCID, stem cell transplants are lifesaving. Human leukocyte antigen– (HLA-) matched siblings are preferred and have a lower incidence of graft-versus-host disease. When an HLA-matched sibling is not available for a patient with SCID, haploidentical or matched urelated donor transplants are performed. Bone marrow transplantation has been performed in patients with other immune defects, WAS, chronic granulomatous disease, leukocyte adhesion defects, and complete DiGeorge syndrome.

For children with more severe humoral immune defects, replacement IV immunoglobulin is standard of care administered either intravenously or subcutaneously. These patients do not need immunizations except for the yearly influenza vaccine because they have passive immunity through the infusion. Live virus vaccines should be avoided in children with primary immunodeficiency, especially in patients with severe T cell defects or severe agammaglobulinemia.

Antimicrobial prophylaxis is recommended for patients with CGD and WAS. Prophylactic antibiotics have been used in patients with humoral immunodeficiencies as an adjuvant to IV immunoglobulin. Antifungal prophylaxis is also recommended for patients with CGD.

Patients with underlying immune defects remain at risk for infections. Unnecessary exposure to individuals with infection must be avoided. These children can become quite sick very quickly. Aggressive management of any infection is imperative. Up-to-date knowledge of these disorders is important. Often, these children present with a fever, and the cause needs to be elucidated. In the event of infection, identification of the organism is helpful and strongly recommended. Some of these children may also be at risk for autoimmune disease or cancer.

Future Directions

As described in this chapter, early diagnosis of underlying primary immune disorders will help save lives, prevent infections, treat infections, and improve long-term outcome and quality of life. With specific genetic mutations known and others being pursued, gene therapy may become the therapy of choice in the future. At this time, improvements and strides in awareness, diagnosis, and overall care of these patients are of great importance.

Suggested Readings

Ballow M. Approach to the patient with recurrent infections. Clin Rev Allergy Immunol. 2008;34:129-140.

Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(suppl):S1-S63.

Carneiro-Sampaio M, Coutnho A. Immunity to microbes: lessons from primary immunodeficiencies. Infect Immun. 2007;75(4):1545-1555.

Slatter MA, Gennery AR. Recurrent infections in childhood. Clin Exp Immunol. 2008;152:389-396.

Stiehm ER, Ochs HD, Winkelstein JA. Immunodeficiency Disorders in Infants and Children, ed 5. Philadelphia: Elsevier Saunders; 2004.

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