Basics
Description
- A disorder of the humoral immune system characterized by deficient or absent immunoglobulins and the inability to produce specific antibody
- Subtypes include primary immunodeficiency and secondary deficiency due to other extrinsic disease (i.e., malignancy).
Epidemiology
Incidence and prevalence depends on underlying defect or cause. Antibody deficiency syndromes represent ~70% of primary immune deficiencies. á
Risk Factors
Genetic defects have been identified in many cases, which are identified in the "Differential Diagnosis."Ł á
Diagnosis
History
- Recurrent upper and lower respiratory tract infections (otitis media, pneumonia, and sinusitis)
- Infections with encapsulated bacteria such as Streptococcus pneumoniae, Haemophilus influenzae
- May have diarrhea, infections with Giardia
- Chronic cough and chronic rhinitis may be present.
Physical Exam
- May be normal if an infection is not present
- Evaluate for growth delay and failure to thrive.
- Patients with X-linked agammaglobulinemia (XLA) may have absent or minimal tonsillar tissue.
- Digital clubbing may be present in cases with history of severe infections.
Diagnostic Tests & Interpretation
Lab
- CBC with differential
- Can rule out associated anemia, thrombocytopenia, and neutropenia
- Quantitative immunoglobulins: IgG, IgM, IgA, and IgE
- Look for low or absent isotypes.
- Qualitative antibody titers specifically to tetanus, H. influenzae type B, S. pneumoniae postvaccination
- Absent response after vaccination can identify specific antibody deficiencies.
- Evaluate for presence of isohemagglutinins (primary IgM antibodies to the main blood groups) in unvaccinated children.
- Flow cytometry to evaluate B cell numbers
Alert
- Normal immunoglobulin levels vary by age.
Imaging
- Chest radiography, CT chest and/or sinus
- To evaluate for acute disease and if with history of multiple infections, to look for chronic parenchymal changes such as bronchiectasis
Differential Diagnosis
Primary Defects in Antibody Production
- Selective IgA deficiency
- Most common cause of hypogammaglobulinemia
- Low to undetectable levels of IgA with normal other immunoglobulin classes
- Prevalence of 1/300-1/800 in Caucasians
- Most are asymptomatic, a proportion may have recurrent infections (upper and lower respiratory infections), risk of giardiasis, and GI infections
- May develop anaphylactic reactions to blood products due to presence of antibodies to IgA
- Common variable immunodeficiency
- The second most common cause of hypogammaglobulinemia
- Peaks in 1st and 3rd decades of life
- Affects both sexes equally; incidence of 1/20,000-1/100,000
- Characterized by decreased IgG (2 SD below the age-adjusted mean) and impaired humoral response to polysaccharide antigens
- Risk of development of malignancy such as non-Hodgkin lymphoma, gastric cancer
- Can be associated with autoimmunity in up to 25% (i.e., rheumatoid arthritis, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia)
- Genetic defects have been identified in TACI, ICOS, BAFF-R, and CD19, although only 10% have a family history of disease.
- XLA
- X-linked mutation in Bruton tyrosine kinase (Btk) gene leading to a defect in B cell maturation
- Reported in 1/379,000 U.S. births
- Patients often present with infections after waning of maternal IgG after 3 months of age.
- Labs reveal low serum immunoglobulin levels and <2% circulating B cells.
- Patients are susceptible to viral infections such as enterovirus.
- Autosomal recessive agammaglobulinemia occurs in ~15% without Btk mutations and can occur in females; has a similar phenotype.
- Transient hypogammaglobulinemia of infancy
- Prolongation of the "physiologic"Ł hypogammaglobulinemia of infancy, which is normally observed during the first 3-6 months of life
- IgG levels should be at least 2 SD below the mean age-matched controls.
- Typically recover by 9-15 months of age and have normal Ig levels by 2-4 years
- Must be diagnosed in retrospect after immune recovery and patients should be followed with serial immunoglobulin levels.
- Etiology remains unknown.
- Antibiotic prophylaxis and/or immunoglobulin replacement should be considered in those with severe recurrent infections.
- Disorders of immunoglobulin class-switch recombination (Ig-CSR)
- CD40L mutation: X-linked hyper IgM syndrome (HIGM)
- Also known as HIGM1
- Estimated frequency of 1 in 500,000 live male births
- Due to a mutation in the CD40 ligand gene
- IgM may be elevated or normal. IgG, IgA, and IgE levels are low to absent.
- Affects T cell priming and antigen-specific T cell responses, in addition to defective antibody production
- Chronic diarrhea and failure to thrive are present.
- In addition, can have opportunistic infections, particularly with Pneumocystis, Cryptosporidium, and Histoplasma organisms
- May have lymphadenopathy and hepatosplenomegaly on exam
- Treatment includes allogeneic hematopoietic cell transplantation.
- Autosomal recessive hyper IgM syndromes (AR-HIGM)
- Includes mutations in the following:
- CD40 (HIGM3)
- Activation-induced cytidine deaminase (AID) (HIGM2): the most common AR-HIGM, AD mutations in AID are also described
- Uracyl-N-glycosylase (UNG) (HIGM5)
- CD40 mutations present similarly to X-linked HIGM.
- AID and UNG mutations have less incidence of opportunistic infections and neutropenia and are associated with lymph node hyperplasia.
Secondary Defects in Antibody Production
- Increased loss: Loss of protein can occur via the kidneys, intestinal tract, lymphatic system, or skin.
- Protein-losing enteropathy
- Intestinal lymphangiectasia can be congenital.
- Post-Fontan procedures with resultant hypogammaglobulinemia
- Nephrotic syndrome
- Decreased production
- Malignancy
- Chronic lymphocytic leukemia
- Lymphoma
- Multiple myeloma
- Medications
- Sulfasalazine
- Systemic steroids
- Phenytoin
- Carbamazepine
- Androgen replacement
Treatment
Medication
- Appropriate antimicrobial therapy at first sign of infection. Prompt initiation of therapy is recommended.
- Select patients may benefit from prophylactic antibiotics.
- Regular replacement therapy with gammaglobulin in either IV or SC forms. Usually 300-600 mg/kg every 3-4 weeks IV or every 1-2 weeks SC.
- Trough levels of 700-800 mg/dL are now preferred compared to previous recommendations of >300 mg/dL.
Ongoing Care
Patient Monitoring
Patients on immunoglobulin replacement should have trough IgG levels followed regularly as well as CBCs with differential and metabolic panels to look for hemolytic processes and side effects of replacement. á
Prognosis
In most cases (except transient hypogammaglobulinemia of infancy), it requires lifelong therapy. á
Additional Reading
- Conley áME. Genetics of hypogammaglobulinemia: what do we really know? Curr Opin Immunol. 2009;21(5):466-471. á[View Abstract]
- Qamar áN, Fuleihan áRL. The hyper IgM syndromes. Clin Rev Allergy Immunol. 2014; 46(2):120-130. á[View Abstract]
- Rose áME, Land áDM. Evaluating and managing hypogammaglobulinemia. Cleve Clin Med. 2006;73(2):133-144. á[View Abstract]
- van der Burg áM, van Zelm áMC, Driessen áGJA, et al. New frontiers of primary antibody deficiencies. Cell Mol Life Sci. 2012;69(1):59-73. á[View Abstract]
- Yong áPFK, Chee áR, Grimbacher áB. Hypogammaglobulinaemia. Immunol Allergy Clin North Am. 2008;28(4):691-713. á[View Abstract]
Codes
ICD09
- 279.00 Hypogammaglobulinemia, unspecified
- 279.04 Congenital hypogammaglobulinemia
- 279.01 Selective IgA immunodeficiency
- 279.02 Selective IgM immunodeficiency
- 279.03 Other selective immunoglobulin deficiencies
ICD10
- D80.1 Nonfamilial hypogammaglobulinemia
- D80.0 Hereditary hypogammaglobulinemia
- D80.2 Selective deficiency of immunoglobulin A [IgA]
- D80.4 Selective deficiency of immunoglobulin M [IgM]
- D80.8 Other immunodeficiencies with predominantly antibody defects
- D80.7 Transient hypogammaglobulinemia of infancy
- D83 Common variable immunodeficiency
SNOMED
- 119250001 Hypogammaglobulinemia (finding)
- 267460002 Congenital hypogammaglobulinemia
- 190979003 Selective immunoglobulin A deficiency
- 190980000 Selective immunoglobulin M deficiency
FAQ
- Q: When should I check immunoglobulin levels?
- A: Immunoglobulins and antibody responses to vaccinations may be considered in any patient with a history of recurrent sinopulmonary infections.
- Q: I have a 2-month-old male patient with a family history of XLA. His IgG level is normal. Do I need to recheck it in the future?
- A: At 2 months of age, most infants still have maternal IgG present. Levels tend to wane and the infant will start to produce his or her own IgG in the 3-4-month range. Rechecking after this time is recommended.