SUMMARY

 

1.  X-linked agammaglobulinemia (XLA) is a humoral immunodeficiency caused by mutations in Bruton's tyrosine kinase (Btk) a key signal transduction molecule required for B-cell development.  

 

2.  Patients have low to absent B-cells (most patients have a small number of B-cells)  and reduced levels of all immunoglobulin classes.  A milder phenotype has also been described with some B-cell and antibody production.

 

3.  XLA is caused by mutations in Btk and accounts for 85% of patients who present with low B-cells and hypogammaglobulinemia (the remaining cases are caused by autosomal recessive forms of agammaglobulinemia).  

 

4.  Patients typically suffer from recurrent infections of the upper and lower respiratory tract by encapsulated bacteria (Strep pneumoniae, Haemophilus influenza type B, etc.).   Mycoplasma and ureaplasma infections can cause pneumonia and destructive septic arthritis.  Pseudomonal and Staphylococcal sepsis has been described in patients with XLA particularly in the setting of transient neutropenia.  

 

5.  There is an increased susceptibility to enterovirus infections (polio, coxsackie, echo virus), which can cause chronic diarrhea, meningitis, or fatal disseminated infection.   

 

6.  XLA patients are susceptible to infections with Helicobacter, Campylobacter, and Flexispira.  These organisms cause cellulitis and ulcers of the lower extremities.  Bacteremia, osteomyelitis, and septic arthritis can also occur.  

 

7.  Gastrointestinal infections with Giardia, Campylobacter, and Salmonella can be seen.  

 

8.  The diagnosis should be suspected in male patients with the above infectious history, low serum IgG, IgA, IgM, and low or absent CD19+ B-cells.  Molecular testing for Btk mutations confirms the diagnosis.      

 

9.  Immunoglobulin replacement therapy is the cornerstone of therapy for XLA patients.   

 

 

 

 

OVERVIEW

 

     X-linked agammaglobulinemia (XLA) or Bruton's agammaglobulinemia was one of the first primary immunodeficiencies for which a genetic cause was discovered.  It has an incidence of 1 in 100,000  200,000 live births.  Patients have low numbers of B-cells and thus have very low levels of all immunoglobulin classes (IgG, IgA, IgM).  On physical exam patients have significantly reduced size of lymph nodes and tonsils (these tissues are predominantly composed of B-cells).   XLA accounts for the vast majority (85%) of patients presenting with a phenotype of low B-cells and hypogammaglobulinemia.  The remaining patients have autosomal recessive (AR) agammaglobulinemia caused by mutations in the B-cell receptor components or the downstream signaling protein BLNK.  The clinical phenotype between X-linked and AR agammaglobulinemia is indentical.

 

     Patients typically do not present immediately after birth because they are initially protected by maternal IgG transferred across the placenta during the third trimester.  As maternal IgG is catabolized between 4-6 months of age, patients develop infectious complications.  As would be expected from an antibody deficiency syndrome, patients primarily present with recurrent sinopulmonary infections with encapsulated bacteria such as Steptococcus pneumoniae and Haemophilus influenzae.  Pseudomonas and Staphylococcal pneumonia and bacteremia has also been described.  While patients with XLA generally do not have difficulty with common respiratory virus infections, they do have an unusual susceptibility to enterovirus infections (poliovirus, echovirus, coxsackie virus).  Enterovirus infections can progress to meningoencephalitis and fatal disseminated disease (although these complications have decreased since immunoglobulin replacement therapy has become routine).  

 

    XLA patients can suffer from parasitic (Giardia) and bacterial (Campylobacter and Salmonella) gastrointestinal tract infections leading to chronic diarrhea and malabsorption.  Campylobacter, Flexispira, and Helicobacter can also cause a smoldering bacteremia or cellulitis/fasciitis in patients (these infections are difficult to treat and often require prolonged oral and IV antibiotic therapy).  Mycoplasma and ureaplasma are underappreciated causes of pulmonary infections as well as septic arthritis.   Rare case reports of Pneumocystis jiroveci pneumonia in patients have also been described.   

 

     While the majority of patients will have classic XLA, a milder phenotype with some B-cell and antibody production has been described as well.  Such patients are often misdiagnosed with other humoral immune deficiencies such as CVID or transient hypogammaglobulinemia.  

 

     Neutropenia is a finding in 10 % of patients at presentation and usually occurs with acute infection.  The neutropenia typically resolves after the infectious episode is properly treated.  

         

 

 

 

PATHOGENESIS

 

    XLA is caused by mutations in the gene for Bruton's tyrosine kinase (Btk) located at Xq21.3-22.  Pre-B cells express the pre BCR receptor complex which requires Btk mediated downstream signaling for the next step of B-cell maturation.  As a result, patients with XLA have arrest of B-cell development in the bone marrow at the pro-B to pre-B stage.


     Autosomal recessive agammaglobulinemias are caused by mutations in the B-cell receptor (µ Heavy-Chain, Lambda 5, Ig alpha, Ig beta) or downstream signaling molecules (BLNK).  As with XLA, B-cell development is severely impaired.  

 

         

 

 

DIFFERENTIAL DIAGNOSIS

 

 

While other forms of hypogammaglobulinemia must be excluded, the absence of B-cells makes this condition fairly distinctive.  The differential diagnosis for hypogammaglobulinemia includes the following conditions:

 

1. Common Variable Immune Deficiency (CVID)
2. Autosomal recessive agammaglobulinemia
3. Hyper IgM syndromes
4. WHIM syndrome
7. X-linked Lymphoproliferative Syndrome (XLP)
8. Goods syndrome (thymoma with immunodeficiency)
9. Transient Hypogammaglobulinemia of Infancy

 

 

 

EVALUATION

 

XLA should be suspected in male infants with bacterial sinopulmonary infections and absent tonsillar tissue.  A family history suggesting X-linked inheritance may be present but new mutations can also occur.  

 

Step 1:  Quantitative Humoral Evaluation

 

-Quantitative immunoglobulins (IgG, IgM, IgA) 
-Flow cytometry for B-cell, T-cell, and NK cell numbers 

-All immunoglobulin classes would be expected to be low.

 
-B-cells numbers will be very low while T-cell and NK cell numbers will be normal.      

 

 

Step 2:  Functional Humoral Evaluation

 

-Antibody titers to vaccine antigens   

 

-Protein and polysaccharide vaccine antibodies should be checked (ex.  Tetanus, Diphtheria, and Pneumococcus).  If serum antibody titers are low, patients can be vaccinated with repeat titers drawn 4-6 weeks later.  

 

 

Step 3:  Btk Protein expression and Genetic confirmation 

 

-Btk protein expression
-Btk mutation analysis

 

-Btk protein expression can be assessed by flow cytomery and is markedly reduced in XLA.   This assay is typically completed within a week and can provide a rapid diagnosis for a  suspected paient.  In contrast, gene sequencing typically takes 2 months and whole exome sequencing can take even longer.  

-If the mutation analysis is negative despite a suspicious clinical phenotype, autosomal recessive agammaglobulinemia should be considered (Mutations in the µ Heavy Chain, Lambda 5, Ig alpha, Ig beta, and BLNK have been described).  Testing for AR agammaglobulinemia can be achieved by sanger sequencing, whole exome sequencing or whole genome sequencing.

 

 

 

 

MANAGEMENT

 

 

   Replacement of serum IgG with monthly IVIG or weekly subcutaneous (SC) Ig is the cornerstone of therapy.  Typical replacement is started with 400-600mg/kg of IVIG every 4 weeks or 100-150mg/kg of SCIg every week.  Trough IgG levels should be checked after 5 IVIG doses.  It is clear that patients who maintain trough IgG levels above 700-900mg/dl have fewer infectious complications.   SCIg is ideal for patients who benefit from maintaining steady serum levels of immunoglobulins or who are unable to tolerate IVIG due to adverse side effects (headache, chills, nausea, thrombotic events).   


     The addition of prophylactic antibiotics can be considered in patients who continue to have infections despite appropriate immunoglobulin replacement.  Two sample prophylaxis regimens are listed below:

 

1.  Amoxicillin 20mg/kg divided twice daily.  Maximum of 500mg twice daily.
2.  Azithromycin 10mg/kg once weekly.  Maximum of 1 gram once weekly.

 

 

 

                                                                           

RESOURCES

 

Diagnostic Resources   

 

 

1.  Flow Cytometry for CD19 (B-cell) numbers (readily available at many academic centers and commercial laboratories including those listed below). 

Childrens Hospital of Philadelphia
ARUP Laboratories
Quest Diagnostics


2.  Quantitative Immunoglobulin levels and specific antibody responses to vaccines (readily available at many academic centers and commercial laboratories)

Childrens Hospital of Philadelphia
ARUP Laboratories
Quest Diagnostics


3.  Btk Genetic Testing

a. Correlagen Diagnostics:  Offers sequencing for Btk. 

b. Gene Dx:  Offers sequencing for Btk.   Testing typically takes 4-6 weeks.   

 

 

 

 

Literature Resources

 

 

1.  Ochs 2006

     XLA U.S. registry 201 patients

 

2.  Conley 2002

     XLA clinical findings

 

3.  Fried 2009

     Primary antibody deficiency and types of infections

 

4.  Cham 2002

     Neutropenia in antibody deficiency syndromes

 

5.  Alibrahim 1998

     Pneumocystis pneumonia in XLA

 

6.  Cuccherini 2000

     Flexispira & Helicobacter skin and bone infections in XLA

 

7.  Gerrard 2001

     Helicobacter cellulitis and bacteremia in XLA

 

8.  Arai 2007

     Campylobacter bacteremia in XLA

 

9.  Okada 2008

     A case of Campylobacter bacteremia in XLA

 

10. Holland 2007

      Persistent bacteremia infections in primary immune deficiency