• Selective IgA deficiency
  • For details, refer to the topics Immune Deficiency, Common Variable Immunodeficiency (CVID), and Immune A Deficiency.
• X-linked agammaglobulinemia (XLA) (Bruton agammaglobulinemia)
  • Intrinsic defect in B-cell maturation due to mutations in the gene on the X chromosome encoding a B-cell-associated tyrosine kinase. The protein is involved in cytoplasmic signal transduction.
  • All immunoglobulin isotypes are significantly decreased or absent.
  • Significant reduction or absence of B cells
  • Associated complications include arthritis of the large joints, chronic meningoencephalitis due to echoviruses, chronic diarrhea due to Giardia lamblia, neutropenia, autoimmune hemolytic anemia, dermatomyositis, and an increased incidence of lymphoreticular malignancies.
  • Patients are also susceptible to viral infections, particularly enteroviruses. Live viral vaccines are contraindicated in these patients because some patients have vaccine-associated poliomyelitis.
• Hyper-IgM syndrome
  • Predominantly an X-linked inheritance pattern. Affected females have been described.
  • Defect is caused by mutations in the gene encoding the CD40 ligand surface molecule on T cells. This leads to defective T-cell signaling for B-cell immunoglobulin class switching.
  • Normal to elevated IgM levels with low to absent IgG, IgA, and IgE
  • Associated complications include autoimmune hemolytic anemia/thrombocytopenia/neutropenia, opportunistic infections with Pneumocystis carinii, and lymphoproliferative disease.
• Transient hypogammaglobulinemia of infancy
  • It is difficult to differentiate this from the normal physiologic nadir of IgG that occurs between 3 and 6 months of age due to the loss of maternally derived immunoglobulin. This nadir is normally short lived.
  • Affected infants have abnormally prolonged delay in the onset of their own immunoglobulin production to compensate for this nadir.
  • The cause is unknown.
  • Self-limited, most infants recover by 18 to 36 months.
  • Clinical course is typically benign. Therapy with intravenous immunoglobulin (IVIG) should be considered only in infants with severe recurrent infections.
  • This syndrome is frequently seen in infants with a familial history of SCID or other immunodeficiencies.
• Selective IgG subclass deficiency (the four subclasses of IgG, in decreasing order of serum levels: IgG1, IgG2, IgG3, and IgG4)
  • Total serum IgG levels can be normal even when one subclass is low or absent.
  • Deficiency of IgG3 is most common in adults while deficiency of IgG2 is seen more frequently in children.
  • IgG2 deficiency has been associated with an inability to respond to polysaccharide antigens.
  • The clinical significance of IgG subclass deficiency has not been fully defined. Many patients have been described as having an increased frequency of upper and lower respiratory tract infections while others are asymptomatic.
  • There is no consensus on standard therapy for these patients in regards to replacement IVIG.
• X-linked hypogammaglobulinemia with growth hormone deficiency
  • Described in three families
  • Immunoglobulin heavy-chain deletion
  • Deletions on chromosome 14 in the area of the heavy-chain constant regions
  • Most homozygous individuals are asymptomatic. A small subgroup of patients have been noted to have recurrent pyogenic infections
• Kappa-chain deficiency
  • Absence of the kappa subtype of light chains in immunoglobulin molecules
  • Described in two families
  • Associated with variable defects in specific antibody formation
• Immunodeficiency with thymoma
  • Seen in adults, typically between 40 and 70 years old
  • Associated with significantly decreased to absent IgG, IgA, and IgM
• Secondary causes of hypogammaglobulinemia
  • Viruses: Epstein-Barr virus (EBV), cytomegalovirus (CMV), congenital rubella
  • The mechanism by which antibody responses and immunoglobulin production are altered in infected patients is not clearly defined.
  • Infectious mononucleosis has been associated with defective specific antibody responses to neoantigens and impaired in vitro B-cell function in normal individuals. These defects are transient and resolve within 6 to 8 weeks after the onset of the disease. A disastrous response to EBV infection is seen in X-linked lymphoproliferative syndrome. These patients develop fatal infectious mononucleosis, marrow aplasia, B-cell lymphoma, and agammaglobulinemia.
  • HIV, CMV, and rubella infections have been associated with abnormal specific antibody responses.

• Immunosuppressive/chemotherapeutic agents, phenytoin
• The associated defects in immune function and antibody production usually resolve after the therapy is discontinued.

• Protein-losing enteropathy
• Intestinal lymphangiectasia
• Nephrotic syndrome
• The hypogammaglobulinemia is due to direct loss through the gastrointestinal (GI) tract or kidneys.
• Lymphoreticular malignancies have been associated with various immune defects and decreased immunoglobulin production.

• Patients with humoral immunodeficiencies usually present with recurrent infections due to encapsulated bacteria, such as Haemophilus influenzae type B and Streptococcus pneumoniae.
• It is important to rule out hypogammaglobulinemia in patients with recurrent infections because replacement therapy with intravenous IgG is readily available.

Question: At what age did the recurrent infections start?
Significance: Patients with hypogammaglobulinemia usually present after 3 to 6 months of age. Late onset of infections may be more consistent with CVID.

Question: What type of infections have been diagnosed?
Significance: Hypogammaglobulinemia typically results in bacterial infections with encapsulated organisms.

Question: Have there been recurrent severe infections such as meningitis, sepsis, and osteomyelitis?
Significance: Some of the congenital immunodeficiency syndromes are signified by specific infections such as chronic meningoencephalitis with echoviruses, vaccine-associated poliomyelitis, and Pneumocystis carinii pneumonia.

Question: Is there a familial history of immunodeficiencies?
Significance: Previously affected males suggests an X-linked inheritance pattern.

Question: Early infant deaths?
Significance: Early infant deaths due to overwhelming infection may indicate a previously undiagnosed congenital immunodeficiency.

Question: Any other associated signs or symptoms?
Significance: Many of the congenital immunodeficiencies have associated arthritis, autoimmune disease, chronic lung disease, and GI manifestations.

Finding: Growth parameters
Significance: Children with significant, recurrent infections and GI disease related to immunodeficiency may present with failure to thrive.

Finding: Signs of chronic otitis media or conjunctal recurrent disease
Significance: Patients with XLA frequently have signs of chronic conjunctivitis.

Finding: Gingivitis and stomatitis
Significance: May occur with the neutropenia-associated hypogammaglobulinemia syndromes.

Finding: Lymphoid tissue
Significance: Absence of tonsillar tissue and palpable lymph nodes is suggestive of X-linked agammaglobulinemia.

Finding: Lymphadenopathy and tonsillar hypertrophy
Significance: Can be seen in hyper-IgM syndrome and CVID. Persistently enlarged nodes should be investigated.

Finding: Wheezes, rales
Significance: Acute pneumonia or chronic lung disease

Finding: Hepatosplenomegaly or masses
Significance: May be seen in hyper-IgM syndrome and CVID. Abdominal masses should be investigated promptly to rule out malignancy.

Finding: Arthritis, clubbing
Significance: Arthritis can be seen in patients with XLA and CVID. Clubbing can be seen in the presence of chronic lung disease/bronchiectasis.

Test: Complete blood count with differential
Significance: Autoimmune hemolytic anemia, neutropenia, and thrombocytopenia can be seen in XLA, hyper-IgM, and CVID.

Test: Quantitative immunoglobulin levels
Significance: Each isotype should be measured (IgG, IgA, IgM, IgE). A normal or elevated IgM level in face of low to absent IgG, IgA, is characteristic of hyper-IgM syndrome.

Test: Serial testing of immunoglobulins
Significance: Should be done in infants suspected of transient hypogammaglobulinemia to document subsequent normalization of immunoglobulin levels.

Test: Qualitative antibody levels
Significance: Isohemagglutinins are primarily IgM antibodies to the main blood groups. They should be present in normal patients. However, they will be absent in patients with AB blood type. In addition, their presence is inconstant in children under 1 year of age.

Test: Antibody titers to tetanus, diphtheria, and Haemophilus influenzae type B measured post-vaccination.
Significance: Pneumococcal antibody titers post-pneumococcal vaccine has been used by some groups as a measure of response to polysaccharide antigens. However, there is extreme variability from laboratory to laboratory in measurement of titers. In addition, responses to Pneumovax are unreliable in children under 2 years of age.

Test: B-cell enumeration
Significance: Numbers of peripheral B-cell will be decreased to absent in XLA and rare in CVID. They are usually normal in other hypogammaglobulinemia syndromes.

Test: Total lymphocyte count (derived from the CBC with differential)
Significance: Lymphocyte enumeration is done using monoclonal antibodies to cell-specific CD surface markers measured by flow cytometry.

Test: Chest and sinus radiography and CT scans
Significance: May be helpful in evaluating for acute and chronic disease. Bronchiectasis can be a long-term sequela of chronic pulmonary infection.

• Prompt and appropriate antibiotic therapy is an important part of routine treatment.
• There may be a role for prophylactic antibiotics in patients with persistent recurrent infections.
• Replacement therapy with IVIG is the primary therapeutic modality for XLA, hyper-IgM syndrome, and CVID. Usual initiating doses are 200 to 400 mg/kg every 3 to 4 weeks. Nadir IgG levels should be greater than 300 mg/dL.
• Patients receiving IVIG therapy should not receive routine vaccinations; they are passively immunized with the therapy.
• Therapy is usually lifelong in patients with documented humoral immunodeficiency.

Q: When should I make a referral?
A: Refer any patient suspected of having a primary humoral immunodeficiency to a specialist in allergy and immunology. These are patients with chronic disease who require prolonged follow-up and good communication between the referring physician and specialist.

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