Approach to the Child with Primary Immunodeficiency

21 Approach to the Child with Primary Immunodeficiency



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).




Disorders of the Innate Immune System







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.

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Jun 19, 2016 | Posted by in PEDIATRICS | Comments Off on Approach to the Child with Primary Immunodeficiency

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