A 13-month-old boy is hospitalized with high fever, cough, and decreased oral intake. Diagnostic work up reveals pneumococcal pneumonia (Figure 218-1). He responds well to intravenous and oral antibiotic treatment with complete resolution of symptoms. His birth history is unremarkable with a normal full-term delivery and birth weight (3.3kg). At 4 months of age, he developed otitis media successfully treated with oral antibiotics. Since then he has had numerous upper respiratory and ear infections. At 8 months of age, he was hospitalized for treatment of Staphylococcus aureus cellulitis. Each infection responded well to short courses of antibiotic therapy. He has received all scheduled immunizations up to 12 months. Physical exam reveals a pale, thin child who is below the 3rd percentile for height and weight. He has normal features and developmental milestones. Further family history reveals a maternal uncle with similar symptoms in childhood. Immunologic work up is notable for severe hypogammaglobulinemia and low antibody vaccine titers. Genetic testing for BTK mutation confirms the diagnosis of X-Linked Agammaglobulinemia (XLA). Treatment with intravenous immunoglobulin replacement is started for management of antibody deficiency. Over the next 12 months, the boy has a significant decrease in infections and is noted to have improved growth.

Disorders of primary B cell immunodeficiency comprise approximately half of all primary immunodeficiencies. They are a group of heterogeneous disorders resulting from disruption of B cell maturation and function at various stages of development. The main role of B lymphocytes is production of antibodies for recognition and destruction of foreign antigens. Dysfunction of B lymphocytes results in impaired antibody production leading to illness characterized by unusual susceptibility to recurrent infections, particularly by encapsulated bacterial pathogens.

B cell immunodeficiencies are distinguished phenotypically by clinical severity, mode of inheritance, and age of onset. As a group, they share common clinical features and strategies for evaluation and management that will be discussed in this chapter.

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  Humoral immune deficiency.

  
  
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  Antibody deficiency syndrome.

  
  
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  X-Linked Agammaglobulinemia (XLA)/Bruton’s Agammaglobulinemia.

  
  
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  Common Variable Immunodeficiency (CVID).

  
  
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  Acquired Hypogammaglobulinemia.

  
  
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  Transient Hypogammaglobulinemia of Infancy.

  
  
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  Hyper IgM Syndrome.

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  B cell immunodeficiencies make up approximately 50 percent of primary immune deficiencies.¹

  
  
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  IgA deficiency is the most common B cell disorder (estimated incidence of 1 in 700 persons of European ancestry).²

  
  
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  The second most common B cell disorder is CVID (estimated incidence of 1 in 30,000 ro 50,000 persons).³

  
  
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  Early B cell defects such as X-linked Agammaglobulinemia (XLA) are rare (estimated incidence of XLA is 1 per 200,000 male births).²

  
  
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  XLA accounts for approximately 85 percent of individuals with profound hypogammaglobulinemia and markedly reduced or absent B cells.¹

  
  
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  Age of onset is variable among primary B cell immunodeficiencies.

  
  
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  The degree of immunoglobulin deficiency is a key determinant of disease severity and time of presentation. Individuals with more severe hypogammaglobulinemia or agammaglobulinemia have clinical presentation earlier in life.

  
  
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  Disorders with severe hypogammaglobulinemia present most commonly between 6 and 18 months of age. Their first infections can present as early as 4 months as protection from passive maternal IgG wanes.

  
  
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  CVID can present as early as 4 years of age but is more commonly diagnosed as an adult with onset between the 2nd and 4th decade of life.

  
  
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  Transient Hypogammaglobulinemia of infancy occurs in patients with low IgG, with or without low IgA or IgM, whose immunoglobulin levels are low but increase over time.

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  B cells originate in the bone marrow and undergo maturation in peripheral lymphoid organs including the lymph nodes, spleen, and mucosa-associated lymphoid tissue (MALT).

  
  
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  B cell immunodeficiencies are caused by molecular defects leading to disruption of B cell development or the interactions between B and T cells required for B cell function.

  
  
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  The etiologies of these defects are variable including genetic inheritance and spontaneous mutation.

  
  
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  Table 218-1 summarizes the modes of inheritance and known genetic mutations of the major disorders of B cell immunodeficiency.⁴

Clinical Features

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  Recurrent fever.

  
  
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  Recurrent bacterial infections with encapsulated pyogenic organisms (i.e., Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitides).

  
  
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  Chronic gastrointestinal infections (i.e., Giardia lamblia, Campylobacter jejuni)

  
  
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  Enterovirus infections (i.e., Coxsackievirus, ECHOvirus, wild-type and vaccine-associated polio virus).

  
  
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  Opportunistic viral infections are rare in pure B cell disorders but can be seen in subset of CVID involving T cell dysfunction (Figure 218-2).

  
  
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  Poor growth, failure to thrive.

  
  
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  Chronic diarrhea.

  
  
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  Concomitant autoimmune conditions (i.e., diabetes mellitus, autoimmune hepatitis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatoid arthritis, interstitial lung disease, inflammatory bowel disease, or uveitis).

  
  
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  Family history of immunodeficiency or frequent infections.