Children with primary immunodeficiency diseases most commonly present with an increased susceptibility to infection. Respiratory tract infections and diarrhea are characteristic, but sepsis, meningitis, and osteomyelitis can occur as well. Individual infections may not be more severe than in a normal host, but the striking clinical feature of immunodeficiency is the chronic or recurrent nature of infections. It is difficult to provide specific guidelines about the number of infections that should prompt an evaluation for immunodeficiency, because a wide range of normal occurrence exists, and because the frequency of infections depends in part on the history of exposure. For example, first-born children whose care is provided by a parent who stays at home usually will have fewer infections than a child living with multiple other children in the household or one who is enrolled at a young age in a large day-care facility. Suggestions for when to consider an evaluation for immunodeficiency are provided in Box 427.1. Not all patients with immunodeficiency are diagnosed after a long series of recurrent infections. In some instances, the initial infection is so severe (e.g., pneumonia with empyema) or is caused by such an unusual organism (e.g., Pneumocystis jerovicii) that the diagnosis of immunodeficiency is made.

Because each functional compartment of the immune system plays a specialized role in host defense, infections with certain microorganisms characteristically are found in specific immunodeficiency diseases. For example, patients with abnormalities of cell-mediated immunity characteristically develop pneumocystic pneumonia, disseminated fungal infections, mucocutaneous candidiasis, overwhelming viral infections, and severe mycobacterial disease. Patients with defects of antibody or complement more often have infections with pyogenic encapsulated bacteria. Patients with phagocytic defects develop bacterial and fungal infections of the skin and reticuloendothelial system. These distinctions may be blurred, however, because the host’s defense against any given microorganism depends on the successful integration of all components of the immune system. Thus, a rare patient with an antibody deficiency develops pneumocystic pneumonia or chronic enteroviral meningitis, whereas patients with deficiencies of cell-mediated immunity can develop pyogenic bacterial infections. Recurrent infections at a single anatomic site always should prompt consideration of other predisposing conditions, such as ciliary dyskinesia, cystic fibrosis, or bronchial obstruction. Patterns of illness and screening tests for primary immunodeficiency disorders are outlined in Table 427.1.

Children with primary immunodeficiency diseases sometime present with clinical manifestations that do not appear to relate directly to their increased susceptibility to infection. Just as immunodeficiency can lead to defects in the protective functions of the immune system and an increased susceptibility to infection, immunodeficiency also can lead to abnormal immunoregulatory mechanisms, with the result being autoimmune or chronic inflammatory diseases. Thus, patients with primary immunodeficiency diseases sometime present with autoimmune hemolytic anemia or immune thrombocytopenia, autoimmune endocrinopathy, juvenile rheumatoid arthritis, a lupus-like illness, or inflammatory bowel disease. This type of presentation is seen most often in patients with common variable immunodeficiency, selective IgA deficiency, chronic mucocutaneous candidiasis, and deficiencies of the classical complement pathway. Occasionally, a disorder that appears to be autoimmune may be caused by an infectious agent (e.g., the dermatomyositis syndrome that is sometimes seen in patients
with X-linked agammaglobulinemia is really a manifestation of a chronic enteroviral infection and is not an autoimmune disease).

Immunodeficiency also can be seen as one part of a constellation of signs and symptoms in a syndrome complex (Table 427.2). Recognition that a patient has a syndrome in which immunodeficiency occurs allows a diagnosis of immunodeficiency to be made before any clinical manifestations of that immunodeficiency occur. For instance, children with the DiGeorge anomaly usually are identified initially because of the neonatal presentation of congenital heart disease or hypocalcemic tetany. This leads to the recognition that they have a T-lymphocyte defect before any infections occur that are attributable to that immunodeficiency. Similarly, a diagnosis of Wiskott-Aldrich syndrome can be made in young boys with eczema and thrombocytopenia, and they may be identified as immunodeficient before they develop infections attributable to their immunodeficiency. Recognition of any part of a syndrome complex should prompt a thorough investigation for other manifestations before they become symptomatic.