Continuing Education Activity

X-linked agammaglobulinemia or XLA is a primary immunodeficiency disorder that prevents affected individuals from making antibodies and requires them to rely on lifelong immunoglobulin replacement therapy for survival. Without immunoglobulins (or antibodies), XLA patients are rendered vulnerable to invasive infections. Hospitalization for bacterial pneumonia, requiring intravenous antibiotics for resolution, is usually what prompts the diagnostic work-up for primary immunodeficiency. This activity reviews the pathophysiology of XLA and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of X-linked agammaglobulinemia.

• Review the evaluation process for X-linked agammaglobulinemia.

• Outline the treatment and management options available for X-linked agammaglobulinemia.

• Summarize interprofessional team strategies for improving care coordination and communication to advance X-linked agammaglobulinemia and improve outcomes.

Introduction

X-linked agammaglobulinemia or XLA is one of the most common pediatric primary immunodeficiencies that prevent affected individuals from making antibodies and requires lifelong immunoglobulin replacement therapy for survival.[1]

The molecular basis for XLA is a disruption in B cell development due to mutation in Bruton's tyrosine kinase (Btk). Affected individuals inherit a defect that prevents precursor B cells in the bone marrow from forming mature, circulating B-lymphocytes that would otherwise be capable of proliferating and differentiating into antibody-producing plasma cells in secondary lymphoid organs like the tonsils and lymph nodes. This dysfunction results in dangerously low, clinically undetectable levels of all immunoglobulin isotypes in the serum.[2][3][4]

Without immunoglobulins (or antibodies), XLA patients are rendered vulnerable to invasive infections from encapsulated bacteria (such as Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae), have an increased incidence of enterovirus infections (e.g., poliovirus, coxsackievirus, echovirus), and chronic diarrhea (from Giardia lamblia).[5][6][7]

XLA patients commonly present with a history of recurrent upper respiratory tract infections, including sinusitis and otitis media, beginning after 6 to 9 months when most of the maternal antibodies have been exhausted.  However, hospitalization for bacterial pneumonia, requiring intravenous antibiotics for resolution, is usually what prompts the diagnostic work-up for immune deficiency disease. The average age of diagnosis is 2.5 years, and almost all cases of XLA get diagnosed before 5 years of age. Notably, late-onset forms of XLA also exist.[8]

There is currently no cure for XLA; however, early management with immunoglobulin replacement therapy and antibiotics to prevent and treat infections. Although this lifelong avenue is costly, it has been the mainstay of treatment for the past fifty years. Any significant delay in diagnosis poses the danger of developing chronic, treatment-resistant infections, and end-organ damage that cannot be corrected.[9][3]

Etiology

XLA results from mutation of the Bruton's tyrosine kinase gene (Btk) located on the long arm (q) of the X chromosome (Xq21.3-Xq22), affecting males almost exclusively. Hundreds of different mutations have been reported to cause XLA, including missense, frameshift, deletion, insertion, premature stop codon, and point mutations. The molecular location of these mutations encompasses base pairs 101349447 to 101390796 on the X chromosome. However, no single mutation correlates with more than 3% of the known cases.[10][11]

The gene for Btk codes for a cytoplasmic tyrosine kinase protein, BTK, which acts as a signal transducer driving the final stages of B cell maturation. The inheritance of disease-causing mutation of the Btk gene interferes with BTK protein expression, resulting in the arrest of differentiation at the pre-B-cell stage in the bone marrow, causing a profound lack of mature B lymphocytes in the peripheral circulation and a corresponding absence or severe reduction in all immunoglobulin isotypes from the serum.[12]

While the majority of agammaglobulinemia cases result from X-linked inheritance of Btk gene mutations, approximately 10% of the cases are the result of autosomal gene mutations. The resulting condition is known as autosomal recessive agammaglobulinemia(ARA) and describes the clinical phenotype seen in females with congenital agammaglobulinemia, which is comparable to XLA in males. The molecular defects responsible for ARA include mutations to the following genes: mu heavy chain (UGHN); gamma 5 (IGLL1); Igalpha (CD79A); Igbeta (CD79B); and BLNK. The wild-type proteins encoded by these genes have been shown to operate in collaboration with BTK, to promote the transition from pro-B-cells to pre-B-cells in the bone marrow, during B cell maturation.[13][14][10]

Epidemiology

XLA exclusively affects males. The reported incidence and prevalence of XLA vary considerably. Some sources report that XLA occurs at a rate of 1 in 190000 live births with a frequency of 1 per 100000 newborn males, and an estimated prevalence of 1 to 9 per 1000000.[10]  There is no known ethnic predisposition, but the reported incidence is highest in individuals of the White race.[15][16]

Common aliases for X-linked agammaglobulinemia include Bruton agammaglobulinemia, Btk agammaglobulinemia, Bruton tyrosine kinase agammaglobulinemia, agammaglobulinemia of Bruton, and congenital agammaglobulinemia.

Pathophysiology

When the disease-causing mutation affects a gene on the X chromosome, one copy of the mutant gene is sufficient to cause the condition. In theory, this means that XLA will affect 50% of males born to mothers who are carriers. When the disease-causing mutations occur on genes within autosomes, either gender may be affected, e.g., females with autosomal recessive agammaglobulinemia.

Individuals with XLA have one of several inherited defects in the Btk gene that interferes with the production of mature B-lymphocytes in circulation. T lymphocytes are unaffected.[3]

B cell development is a process that occurs in the bone marrow, where pro-B cells develop into pre-B cells before fully mature B cells enter the peripheral circulation. Normally, pre-B cells express the pre-BCR complex, which undergoes activation by BTK to initiate downstream signaling events involved in the maturation process. This process becomes blocked at the pre-B cell stage in individuals with inherited mutations that prevent BTK expression (figure 1). Western blotting or flow cytometry analysis of BTK protein expression in the monocytes or platelets of individuals with XLA demonstrates that it cannot be detected.[8][6]

Figure 1. Precursor B Cell  ->  Pro-B Cell -l X l-  Pre-B Cell -> Immature B Cell

B cell differentiation becomes arrested at the Pre-B cell stage with an associated failure of immunoglobulin heavy chain rearrangement; this abrogates the production of immunoglobulins and prevents secondary lymphoid organs from developing fully. 

Histopathology

Underdevelopment of lymphoid tissues, including the spleen, lymph nodes, tonsils, and Peyer's patches are visible on histology of tissue samples from patients with XLA. These findings, however, are not diagnostic of XLA.

History and Physical

A thorough medical history and physical exam is a requirement for all individuals suspected of having XLA.

In the case of infants or very young children, history is elicited through a careful interview of the parents or caretakers. Obtaining information about the general health status, past infections, hospitalizations, surgeries, vaccinations, vaccination reactions, allergies, and current and past medications is crucial. Knowledge of the patient’s diet, home environment, social history, and travel activities may also be contributory. 

A history of frequent, chronic, or recurrent infections, such as conjunctivitis, upper respiratory tract infections (e.g., pharyngitis; sinusitis; bronchitis; pneumonia), deep-seated skin infections (e.g., empyema), purulent otitis media, and diarrhea should raise suspicion. Patient records containing documented information of cultures found positive for encapsulated bacteria may help guide the diagnosis. Bacterial pneumonia, for example, is rare in infants and immunocompetent young children. Other important clues that can be used to direct the work-up include a history indicating the need for IV antibiotics to resolve infections, multiple hospitalizations before the age of 3 years, or developmental delay.[17][18]

A careful review of systems should be completed, with special attention paid to the upper and lower respiratory, lymphatic, gastrointestinal, and integumentary systems.

XLA infants are born healthy, with no outward signs of impending illness, and do not develop recurrent infections until 6-8 months of age when maternal antibodies are no longer active.  Although a history of recurrent infections beginning after 6 months of age is very characteristic of this disease, a physical exam is also important.  Lymphoid tissues are typically hypoplastic in XLA patients. The tonsils may be difficult to visualize, and the cervical/inguinal lymph nodes may not be palpable. The otoscopic exam may be used to detect signs of chronic damage, i.e., purulent otitis media, perforation of the tympanic membrane, or nasal discharge. Chest auscultation is performed to check for prolongation of expiration or inspiration, cough, any increase in respiratory effort, or stridor. Audible rhonchi, crackles, wheezing, and/or inspiratory squeaks suggest lung pathology and warrant further testing (e.g., lung function tests, CT scan, or biopsy) to rule out bronchiectasis. Similarly, the presence of abdominal distention justifies the need to perform an abdominal ultrasound to exclude hepatosplenomegaly.[1]

Finally, it is important not to overlook the family medical history, including information about past infections, hospitalizations, surgeries, previous diagnoses or symptoms of immunodeficiency, the ages and health status of living relatives, or causes of death.

Evaluation

The definitive laboratory evaluation of XLA involves quantitating serum immunoglobulin levels, enumerating lymphocyte subsets, performing provocative antibody response tests, and conducting molecular and genetic analyses.[19][20]

A typical diagnostic test sequence would evaluate serum levels of IgG, IgM, and IgA, the number of CD19-positive or CD20-positive B cells in circulation, humoral vaccine responses, BTK protein expression in peripheral monocytes, and Btk gene sequencing.

Test results consistent with a diagnosis of XLA in a male patient with a history of recurrent bacterial infections would include finding:

• Serum levels of IgG, IgM, and IgA that are more than two standard deviations below age-matched controls
• Absence of mature B lymphocytes in the peripheral circulation (i.e., fewer than 1-2%)
• Little or no increase in antibody titers 3-4 weeks after protein- or polysaccharide antigen vaccines (e.g., immunizing against pneumococcal pneumonia or diphtheria-tetanus)
• Low or absent BTK protein or mRNA expression levels
• Detection of disease-causing mutations in the Btk gene

Researchers have isolated several different mutations in the Btk gene. The finding of Btk gene mutations alone does not constitute a diagnosis.[10][11]

Findings which suggest a diagnosis of XLA in males whose B cell levels are below the 1 to 2% threshold include all or most of the following:

• A history of recurrent bacterial infections requiring one or more hospitalizations before the age of 5 years
• Poor humoral responses to vaccines
• No palpable tonsils or cervical lymph nodes

Tests with abnormal results should be repeated by independent testing for confirmation before beginning treatment or seeking referrals.

Treatment / Management

There is no curative treatment for XLA. However, management is by preventing, reducing, and treating infections.[3][1]

The optimal management of patients with XLA includes[21][22][23][24][23][22]:

• Regular immunoglobulin replacement therapy, using intravenous or subcutaneous infusions
• Therapeutic and prophylactic use of antibiotics to treat and prevent bacterial infections
• Careful monitoring to manage reactions arising from immunoglobulin infusions, complications of infections, or the emergence of clinical disease (e.g., autoimmune, inflammatory, malignant)
• Support (nutritional, social, psychological, and educational)
• Counseling about the importance of receiving all available immunizations except for those containing live bacteria or viruses, e.g., polio (OPV, oral polio vaccine), measles/mumps/rubella (MMR), chickenpox (Varivax), BCG, yellow fever, and rotavirus (Rota-Teq)

Intravenous immunoglobulin (IVIG) or subcutaneous immunoglobulin (SCIG) therapy requires several considerations:

• A dose of 400 to 800 mg/kg every 3 to 4 weeks has been established to maintain an IgG trough greater than 5g/L.[25] Dose adjustments may be necessary for XLA patients with bronchiectasis and/or refractory infections such as meningoencephalitis.[17][26]
• Both IVIG and SCIG are appropriate first-line therapies. IVIG may be preferred if a larger infusion volume due to a higher dose requirement is needed. SCIG has been reported to have a lower incidence of adverse reactions and allows for a more stable IgG trough following injection.[27] 
• Most adverse reactions are transient and pose no serious threat to the patient. These include immediate effects such as headache, fever, myalgia, hypo/hypertension, nausea, and chest pain. Reactions that resemble anaphylaxis are associated with higher transfusion rates and occur during the infusion. Although IgA deficiency is associated with a risk of anaphylaxis during IVIG infusion, antibodies against IgA are unlikely in XLA patients due to agammaglobulinemia. Reactions may temporarily require cessation of the infusion until symptomatically managed with agents such as NSAIDs (for flushing, pain, and headache), diphenhydramine (for pruritus, rashes, and flushing), ondansetron (for nausea or vomiting) or muscle relaxants (for muscular spasm).
• Delayed reactions are of greater concern, though less common, and include thromboembolism due to hyperviscosity, renal failure secondary to osmotic injury associated with sucrose-containing preparations, pseudohyponatremia, autoimmune hemolytic anemia, aseptic meningitis, and neutropenia.[28]   
• To avoid adverse reactions, it is appropriate to adhere to a regimen with appropriate premedications and rate of infusion that has been previously well-tolerated by the patient.

Differential Diagnosis

The differential diagnosis for XLA is:

• Autosomal recessive agammaglobulinemia (ARA)
• Common variable immunodeficiency disease (CVID)
• Transient hypogammaglobulinemia of infancy (THI)
• X-linked hyper IgM syndrome (Hyper-IgM)
• X-linked lymphoproliferative disease (X-LPD)
• Severe combined immunodeficiency disease (SCID)

Pertinent Studies and Ongoing Trials

Immunoglobulin replacement therapy has been used for decades and continues to be the core treatment modality for patients with XLA. Although there are isolated reports of successful immune reconstitution using stem cell transplants from HLA-identical donors as well as attempts at gene replacement therapy, these approaches are not currently standard of care due to risks outweighing benefits.[3][15][16][29]

Prognosis

Before regular immunoglobulin replacement therapy, most XLA died before the age of 10 from complications of lung disease, sepsis, or meningitis. Although chronic lung disease persists as an important factor in the mortality in patients with XLA, life expectancy extends into adulthood.[23] Affected individuals who get diagnosed early (i.e., before five years of age) receive regular immunoglobulin replacement therapy and are prescribed antibiotics treat or prevent infections can be expected to have a normal quality of life and live beyond the age of 40.[30]

Complications

XLA patients are at risk for complications of the disease itself as well as secondary to treatment.

Complications associated with XLA usually arise from infections, especially those that have become recurrent. Susceptible individuals can become chronically ill and suffer organ damage.  For example, repeated episodes of acute pneumonia may culminate in chronic lung disease and lead to bronchiectasis, which has the potential to reduce life expectancy. The likelihood that chronic infections will evolve into serious, life-threatening conditions increases with the length of delay in diagnosis. The later treatment begins, the more difficult it is to eradicate the causative organisms and prevent the systemic spread of infection to joints and vital organs.[7]

Complications associated with chronic infections are, by far, the most common problem confronted by patients with XLA.  Other, less common complications include the increased risk of developing malignancy, inflammatory conditions, or autoimmune disease.

Complications associated with treatment are mainly those which arise from immunoglobulin replacement therapy. The replacement of immunoglobulin is a lifelong requirement for individuals with XLA.  Indeed, regular immunoglobulin replacement therapy is known to increase life expectancy, lower the rate and severity of infections, decrease the number of hospitalizations, and reduce the need for antibiotics. Unfortunately, it also correlates with side effects and must, therefore, have careful monitoring. Clinicians can overcome complications associated with immunoglobulin replacement therapy by changing (1) the time interval between immunoglobulin infusions, (2) the route of administration, (3) the rate of administration, or (4) the product used for replacement.[31]  

Immunoglobulins used in therapy derive from the pooled serum of thousands of healthy donors who have had screening for transmissible diseases. The donor serum is processed to retain maximal amounts of IgG and only trace amounts of IgA and IgM, thus reducing the likelihood of triggering anaphylactic reactions to IgA or developing kidney damage from complex formation induced by IgM.

The length of time between infusions varies according to the route of administration. The two most common routes of administering immunoglobulins are intravenous (IVIG) and subcutaneous (SCIG).  The interval between IVIG infusions can be as long as a month, while the maximum interval between SCIG infusions is usually no more than a week.[32][33]

The rate of delivery and hence, the final immunoglobulin concentration obtained is another important factor. The higher the rate of delivery, the greater the likelihood of complications. In situations where higher immunoglobulin levels are needed to combat a recalcitrant infection, the clinician must balance the decision to increase the infusion rate against the side effect profile. 

Differences in the exact composition of the product used for immunoglobulin replacement also contributes to tolerability. The purity and constituents (i.e., additives used to reduce the aggregate formation and enhance delivery) vary according to the manufacturer, and the reactions elicited vary in different individuals.

Reactions to immunoglobulin infusion therapy can be immediate or latent. The most common immediate side effect is a headache. Headache occurs within minutes and is managed using over-the-counter medications, although it can often be avoided altogether by simply slowing the rate of infusion.

Other common infusion reactions include nausea, malaise, fever/chills, chest tightness, and migraines. Infusion reactions can also categorize according to the system affected. Cardiovascular reactions include tachycardia, palpitations, flushing, and hypotension; neurologic reactions include anxiety, nervousness, irritability, tremor, fainting and seizures; respiratory system reactions include cough, chest tightness, dyspnea, wheezing, and bronchospasm; dermatologic reactions include erythema, urticaria, and eczema; musculoskeletal reactions include low backache, arthralgia, and myalgia; and gastrointestinal reactions include abdominal pain, distention, and liver dysfunction.

More serious complications can also arise. These are much less common and occur after a period of latency. Examples include aseptic meningitis, anaphylactic reactions, Stevens-Johnson syndrome, erythema multiforme, acute renal failure, acute respiratory distress syndrome, transfusion-associated lung injury, deep vein thrombosis, pulmonary edema, pulmonary embolism, cardiac arrest, shock, coma.[34]

Deterrence and Patient Education

Patients and their families should be provided resources and educational materials informing them about vaccines, immunoglobulin replacement therapy, prophylactic and therapeutic use of antibiotics, routine and emergency medical care, the importance of keeping follow-up appointments, healthcare team specialists, preparation for traveling, the importance of record-keeping, support, and how to become a good patient advocate.

Reasons for avoiding live virus vaccines, such as oral polio, mumps, measles, rubella, rotavirus, yellow fever, chickenpox, should be explained thoroughly.

Patients and families should be given the following advice when planning a trip:

Carry a portable water filtration system, prophylactic antibiotics, and other medications;

Know the vaccination requirements for traveling to foreign countries; be prepared to comply or obtain formal exemptions;

Carry an approved list of resources, including the locations, contact information, hours of operation, for:

• infusion centers (to avoid interruption in the regular immunoglobulin replacement regimen)
• physicians and pharmacists (to obtain antibiotics needed to combat new infections)
• hospitals, medical specialists, emergency centers, therapists, and other support personnel

Record keeping should be encouraged. All aspects of patient care, management, and follow-up should be included, as well as a list of contacts and resources that are helpful to the patient.

Information regarding the patient's vaccination record, infection history, doctor/emergency department visits, hospitalizations, illnesses, days missed from school, therapist- and in-home care provider visits, lab test results, growth record, allergies, sensitivities, dietary preferences, medications, supplements; travel record, and social contacts and activities should be recorded.

Pearls and Other Issues

• Early diagnosis is key in decreasing morbidity and mortality of patients with XLA
• Characterized by mutation of Btk, which prevents maturation of B-lymphocytes and subsequently the production of circulating immunoglobulin, resulting in severely impaired humoral immunity
• Look for a male infant or toddler (who no longer has protection from maternal IgG) with recurrent encapsulated organism infections requiring frequent hospitalizations and intravenous antibiotics
• Recurrent sinusitis, otitis, pneumonia, gastroenteritis
• Laboratory investigation reveals absent or very low levels of mature B-lymphocytes and circulating immunoglobulin
• The current mainstay of treatment is with intravenous immunoglobulin
• Avoid live vaccines

Enhancing Healthcare Team Outcomes

XLA is one of the most common primary immunodeficiencies occurring in the pediatric population. Males over the age of 6 months present with recurrent infections due to encapsulated organisms because they lack the ability to produce mature B-lymphocytes and subsequently circulating immunoglobulin.  This disease does not present at birth because maternal IgG provides immune defense during the earliest months of life. The initial presentations of XLA occur most commonly in the pediatric primary care and inpatient hospitalist settings. The involvement of multiple disciplines is vital to improving the outcomes of patients with XLA so that diagnosis can take place as early as possible, with streamlined treatment.

Appropriate care team members for a patient with XLA would most likely include a pediatrician, immunologist, and pulmonologist, as well as other specialists who can contribute to the care of complications and comorbidities associated with XLA. Pathologists and radiologists can aid in the early diagnosis of XLA, while pharmacists can help clinicians select appropriate treatment regimens and perform medication reconciliation. Nursing should be able to counsel the family, answer questions, and assess the progress of treatment. This interprofessional team approach will lead to better outcomes, and give the family/patient more resources form which to access care and information about XLA. [Level V]

Family members or caretakers should be encouraged to take part in the patient’s care and learn how to become effective patient advocates, with the goal of transferring advocacy skills to the patient.

Records should also include a useful contact list regarding healthcare team members, for physicians, staff, physician assistants, therapists, nurses, specialists, specialty centers (e.g., for immunoglobulin replacement therapy), hospitals, pharmacies, support groups, and insurance providers.

The patient needs to understand the necessity for regular follow-up visits. Patients should receive advance information regarding the specialists that they need to see, the tests that are necessary (e.g. routine blood tests, determination of lymphocyte subsets and immunoglobulin levels; liver function tests; hepatitis screening; pulmonary function tests; CT scans) and the role that the resulting information will play in monitoring treatment responses and stemming disease progression.

Randomized-controlled trials (RCTs) supporting the best treatment methods are very limited due to the rare nature of XLA.  Additionally, the poor prognosis associated with a lack of treatment ethically prevents such studies. Current recommendations are made based on an exhaustive review of current case reports and case series of XLA cases from peer-reviewed journals, as well as small RCTs regarding the treatment of primary immunodeficiencies in general.  Expert opinion from an interprofessional team may be necessary when current evidence fails to provide a definitive recommendation for treatment modalities. 

Overall, an interprofessional team approach to the treatment of patients with XLA is the proper management methodology.