Immune deficiencies that present in childhood comprise rare disorders that have been characterized by a combination of clinical patterns, immunologic laboratory tests, and often molecular identification of the mutant gene. Children with primary immunodeficiency (PID) commonly present with recurrent and/or severe bacterial infections, failure to thrive, and/or developmental delay as a result of infection. Immunodeficiency should be considered when infections are recurrent, severe, persistent, resistant to standard treatment, or caused by opportunistic organisms. Because delayed diagnosis of PIDs is common, heightened diagnostic suspicion is warranted.
The human immune system consists of the phylogenetically more primitive innate immune system and the adaptive immune system. For the purpose of clinical categorization, PIDs are commonly divided into four main groups: antibody deficiencies, combined T- and B-cell immunodeficiencies, phagocyte disorders, and complement deficiencies. Understanding the role each part of the immune system plays in host defense allows critical evaluation for possible immunodeficiency as the cause of recurrent infections.
IMMUNODEFICIENCY EVALUATION: PRIMARY CONSIDERATIONS
When evaluating for a possible PID, other conditions that increase susceptibility to infections have to be considered, such as allergic rhinitis, asthma, cystic fibrosis, foreign body aspiration, and conditions that interfere with skin barrier function. Common causes of secondary or acquired immunodeficiency need to be excluded. These include malnutrition, aging, certain drugs (chemotherapy, immunosuppressive medications, glucocorticoids, disease-modifying antirheumatic drugs, rituximab), protein loss via gastroenteropathy or kidney disease, and other diseases associated with impaired immunity (bone marrow and blood cell malignancies, and certain chronic infections, including AIDS). If a single site is involved, anatomic defects and foreign bodies may be present. Figure 33–1 outlines when PIDs should be considered.
General approach to primary immunodeficiencies.
Key clinical patterns can indicate the presence of a PID and the category of immune impairment. Frequency, severity, and age of onset of infections are important clues. The Modell Foundation warning signs for PID are shown in Figure 33–2. Children who meet two or more of these signs should be screened for PID. The type of infections should guide initial investigation, as antibody, complement, and phagocyte defects predispose mainly to bacterial infections, but diarrhea, superficial candidiasis, opportunistic infections, and severe herpesvirus infections are more characteristic of T-lymphocyte immunodeficiency. Combined immunodeficiency syndromes will present with a combination of infections typical for B- and T-lymphocyte deficiencies. Table 33–1 classifies PID into four main host immunity categories based on age of onset, infections with specific pathogens, affected organs, and other special features. Finally, male gender increases the likelihood of an X-linked (XL) PID, while consanguinity increases the likelihood of an autosomal recessive (AR) form of PID.
Warning signs of primary immunodeficiency. (Data from the Jeffrey Modell Foundation.)