Chapter 82

Primary immune deficiency diseases (PIDDs) are characterized by increased susceptibility to infections, often associated with autoimmunity and inflammation and an increased risk of malignancies because of impaired immune homeostasis and surveillance. Depending on the nature of the immune defect, the clinical presentation of PIDD may vary and may include recurrence of upper and lower respiratory tract infections, invasive bacterial infections, purulent lymphadenitis, skin or deep abscesses, infections sustained by poorly virulent or opportunistic pathogens (Pneumocystis jiroveci, cytomegalovirus, environmental mycobacteria, Cryptosporidium, Giardia lamblia), persistent or recurrent candidiasis, autoimmunity, increased susceptibility to malignancies, and association with typical signs of specific immunodeficiency syndromes.

With the exception of immunoglobulin (Ig) A deficiency, PIDDs are generally rare, with a prevalence of approximately 1:10,000 to 1:50,000. However, prompt recognition of PIDD is of importance, because diagnostic delay is associated with increased risk of death and of irreversible complications. Most forms of PIDD follow mendelian inheritance; however, some, for example, common variable immunodeficiency (CVID), have a multifactorial origin. In most cases, PIDDs present in childhood, but late presentations may occur or even predominate in some forms, such as CVID.

The diagnostic approach to PIDD is based on a detailed family and clinical history, physical examination and appropriate laboratory tests. Lymphopenia is characteristic of severe combined immune deficiency. Abnormalities of the neutrophil count can be observed in patients with disorders of neutrophil production (e.g., congenital neutropenia) or function (e.g., chronic granulomatous disease), respectively. Evaluation of serum immunoglobulin levels and of antibody responses to immunization antigens is important for patients with a history of recurrent infections. The clinical presentation and the results of these preliminary evaluations may prompt additional laboratory testing. For instance, patients with a profound hypogammaglobulinemia and a history of recurrent infections should be tested for the presence of circulating B lymphocytes (CD19+ or CD20+ cells), which are absent or markedly reduced in X-linked agammaglobulinemia. On the other hand, early presentation with severe and/or opportunistic infections, especially if associated with lymphopenia, should prompt enumeration of lymphocyte subsets. A severe reduction of circulating CD3+ T cells is typically observed in severe combined immune deficiency, and may be associated with defects of B and/or natural killer cells. Deep bacterial infections, or infections sustained by Aspergillus, require evaluation of neutrophil count and function, to identify patients with congenital neutropenia and chronic granulomatous disease, respectively. Invasive recurrent infections sustained by Neisseria species are an indication for assessing complement levels and function. On the other hand, complement component deficiencies may also lead to systemic lupus erythematosus-like features or to autoimmune disorders. Laboratory results should be compared to age-matched control values, as white blood cell counts, lymphocyte subsets, complement components and immunoglobulin levels, and antibody production (especially to polysaccharide antigens) undergo significant changes and progressive maturation in the first years of life. It is important to rule out secondary forms of immunodeficiency, such as human immunodeficiency virus infection, protein loss, immunodeficiency secondary to use of immunosuppressive drugs, ...

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