Continuing Education Activity

Agammaglobulinemia or hypogammaglobulinemia is a rare inherited immunodeficiency disorder, characterized by low or absent B cells with absent immunoglobulins. X-linked agammaglobulinemia being the most common type. Mainly presents after 6 to 9 months of age when maternal antibodies wear off. This can lead to life-threatening recurrent sinopulmonary and gastrointestinal infections. To avoid the high morbidity and mortality associated with this condition, it must be promptly diagnosed and treated. This activity reviews the evaluation and treatment of agammaglobulinemia and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Describe the etiology of agammaglobulinemia.
• Summarize the typical blood test findings associated with agammaglobulinemia.
• Outline the various management consideration for agammaglobulinemia.
• Review the importance of improving care coordination amongst an interprofessional team members to improve outcomes for patients affected by X-linked agammaglobulinemia.

Introduction

Agammaglobulinemia or hypogammaglobulinemia is a rare inherited immunodeficiency disorder. It is characterized by low or absent mature B cells, which can result in severe antibody deficiency and recurrent infections.[1] It can manifest in an infant as soon as the protective effect of maternal immunoglobulins wanes at around six months of age.

Agammaglobulinemia is comprised of the following types:

• X-linked agammaglobulinemia (XLA), discovered in 1952 by Dr. Ogden Bruton.[2]
• X-linked agammaglobulinemia with growth hormone deficiency
• Autosomal recessive agammaglobulinemia (ARAG)

Etiology

X- linked agammaglobulinemia is caused by a mutation in the Bruton tyrosine kinase (BTK) gene, located on the long arm of the X-chromosome. BTK is a member of the Tec family and encodes for cytoplasmic non-receptor tyrosine kinases, which are signal transduction molecules. BTK is critical in the maturation of pre-B cells to mature B cells, a process that occurs in the bone marrow.[3] The disease has been associated with 544 mutations that include mainly missense mutations, insertions, deletions, and splice-site mutations.[4]

Autosomal recessive agammaglobulinemia has been reported to be caused by genes that affect B cell development. Up to 15% are presumed to be autosomal recessive. The genetic cause of ARAG is much more complex as it involves other genes, mapped to loci on different chromosomes, 22q11.21 (IGLL1), 14q32.33 (IGHM), and 9q34.13 (LCRR8).

Beyond the primary hypogammaglobulinemia, a secondary immunodeficiency may be caused by drugs or other viral infections that affect the function of both T and B lymphocytes. Those drugs include steroids, azathioprine, cyclosporin, cyclophosphamide, leflunomide, methotrexate, mycophenolate, rapamycin, and tacrolimus. One such example of a viral infection that causes immunodeficiency, HIV (AIDS), mainly affects CD4+T cells, which in turn hampers cellular immune responses, resulting in opportunistic infections and cancers.[5] 

It has been reported that 85% of patients with chronic lymphocytic leukemia (CLL) were found to have developed hypogammaglobulinemia along the disease course. Its incidence rate increases with the duration and advancing stages of the disease. It is, therefore, more important to monitor patients for the development of any antibody deficiencies.[6]

Congenital rubella infections also have a profound effect on immune system development. Defects observed may be transient, and can include complete immune paralysis, and other immunoglobulin abnormalities.[7]

Epidemiology

X-linked agammaglobulinemia is inherited in an X-linked manner. Most mutations in the BTK gene are familial; in those cases, the mothers of the affected individuals are healthy carriers. Approximately 50% of patients have a history of previously affected family members, while 15% to 20% of mutations occur de novo.

XLA a very rare disorder with an occurrence rate of approximately 1 in 200,000 live births and a frequency of about 1 in 100,000 male newborns.[8]

Only about 10 cases of X-linked agammaglobulinemia with growth hormone deficiency have been reported. The boys in these families have reduced or undetectable numbers of B-lymphocytes. Speculation among clinicians and geneticists is that a second mutation in the BTK gene, very close to the mutation that causes XLA, is responsible for the combination of agammaglobulinemia and very short stature.

Pathophysiology

BTK plays a major role in promoting the maturation of pro B cells to pre-B cells. The mutation in the BTK gene results in the failure of B cell development, leading to significantly low levels of mature B lymphocytes in peripheral blood circulation. As a result, B cells fail to generate plasma cells, leading to significantly reduced levels (hypogammaglobulinemia) or absence (agammaglobulinemia) of all classes of immunoglobulins.[9]

These immunoglobulins (antibodies) fight against extracellular organisms, particularly encapsulated pyogenic bacteria, which commonly include Streptococcus pneumoniae, Haemophilus influenzae type B, Streptococcus pyogenes and the Pseudomonas species. Lack of humoral immunity leads to recurrent sinopulmonary infections.[10]

Histopathology

B cells undergo maturation, differentiation, and storage in tonsils, adenoids, intestinal Peyer’s patches, and lymph nodes. Due to mutations in B cells, these structures remain underdeveloped. However, lymph nodes can appear normal due to T cell hypertrophy.

History and Physical

During the early stages of life, passively transferred maternal IgG provides protection against various infections. From 6 to 12 months of age, these antibodies start depleting, causing children with XLA to present with recurrent sino-pulmonary infections such as otitis media, sinusitis, bronchitis, and pneumonia. More than 50% of children with X-linked agammaglobulinemia have had serious infections within their first two years of life.

Pyogenic encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, are the most commonly isolated pathogens in patients with XLA. Other commonly encountered infectious organisms include Staphylococcus aureus, Pseudomonas, and Mycoplasma species. Less commonly, some patients can acquire opportunistic infections from the Pneumocystis jirovecii and other fungi.

Patients with XLA are also at higher risk of developing bloodborne bacterial infections. About 3% to 4% of patients with XLA have been reported to develop bacterial meningitis, caused predominantly by Streptococcus pneumoniae and Haemophilus influenzae type B. Other less commonly reported causative bacteria were Pseudomonas, Neisseria meningitidis, Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes. Septic arthritis and osteomyelitis are other common associations reported among patients with XLA.[11]

Patients with XLA have frequent gastrointestinal infections, and Giardia lamblia is a frequently isolated pathogen from the stool samples of these patients; it can sometimes be difficult to eradicate. Persistent infection can result in chronic diarrhea and malabsorption. Another unusual pathogen, Campylobacter jejuni, is known for causing gastrointestinal manifestations, bacteremia, and skin lesions.[12]

The physical evaluation may reveal signs of recurrent and chronic sinopulmonary infections, which include postnasal discharge, tympanic membrane perforation, digital clubbing, and bronchiectasis. One of the greatest clinical clues in the diagnosis of XLA is absent or atrophied tonsils and lymph nodes. Some patients may also show signs of growth failure.

Evaluation

X-linked agammaglobulinemia (XLA) is an inborn error of immune function that can cause life-threatening infections and chronic lung disease such as bronchiectasis. Delays in diagnosis are detrimental to the prognosis and quality of life of patients.

The diagnosis relies on clinical suspicion by history, especially family history, and physical examination followed by laboratory and genetic tests.[13][14]

Initial laboratory tests include:

• Complete blood count with differentials
• Quantitative serum immunoglobulin levels (IgG, IgA, and IgM)
• Serum specific antibody titers response to immunization such as against tetanus or diphtheria

In patients with XLA, serum levels of all immunoglobulins are either low or nearly undetectable, and there will be an absent antibody response to vaccinations. If initial test results are positive, the diagnosis of XLA can be further aided by lymphocyte phenotyping using flow cytometry. The test will document an absent or reduced B-cell count and normal T-cell count. Definitive diagnosis can be made by detecting BTK gene mutation, using the Western blot technique.

Newborn screening tests have been developed for the diagnosis of XLA & other B cell defects. According to studies, immunoglobulin kappa-deleting recombination excision circles (KRECs assay), are a useful screening tool for early B cell maturation defects. Polymerase chain reactions are performed on dried blood spots to detect KRECs. KRECs are normally formed during allelic exclusion in the process of B cell maturation in normal individuals. An absence of KRECs indicates defects in B cell maturation, as in cases of XLA.[15]

These patients have repeated sinopulmonary infections, and a variety of screening methods are used to diagnose and monitor the patient’s condition such as FEV1 (forced expiratory volume at 1 sec), FEV (forced vital capacity), and TLCO (transfer factor for carbon monoxide), as well as basic exercise tests. Imaging techniques employed include MRI and HRCT (high-resolution computerized tomography). Other tests involve sampling cultures of induced sputum and blood gas analysis. Since there is no local or national guideline for screening or treatment, the process lacks standardization, which creates a lot of variation in treatment methodologies.[16]

In pediatric patients, clinical and laboratory tests are typically done with less frequency and are more complicated when compared to adults. For instance, infants may require sedation or general anesthetic for imaging. And lung function testing tends to be less reliable in children under 6 years.[17]

Due to the high risk for pulmonary infectious and non-infectious complications, these patients are often treated with broad-spectrum antibiotics before a definitive diagnosis has been made. In these situations, fiberoptic bronchoscopy (FOB) and bronchoalveolar lavage (BAL) can provide a definitive diagnosis.[18] In addition, audiological evaluation, including audiometry, acoustic immittance assessment, and auditory brainstem-evoked response, should be an integral part of the clinical care/management of these patients.[19]

As mentioned earlier, a variant of XLA is associated with a growth hormone deficiency; however, no current guidelines are available regarding routine monitoring of growth hormone levels in patients with XLA.

Treatment / Management

The primary precautionary measure against infections for these patients is hygiene-focused, such as handwashing and avoidance of respiratory droplets. If possible, these patients should avoid the ingestion of untreated drinking water.

Replacement of IV immunoglobulins (IVIG) has altered the outcome & quality of life in patients with X-linked agammaglobulinemia. Being the cornerstone of treatment, immunoglobulins are replaced every 3-4 weeks intravenously or every 1-2 weeks subcutaneously. Patients might require a loading dose (e.g., 1 dose of 1 g/kg body weight or divided into separate doses), followed by maintenance therapy (400 to 600 mg/kg/month). These doses and intervals are adjusted to maintain serum trough level at least above 500 mg/dl and may vary on a case by case basis. For instance, patients with chronic refractory sinusitis or chronic lung disease may require higher trough levels (>800 mg/dl).[20]

Though IVIG is the main treatment option for these patients, it has its drawbacks such as;

• It protects against most of the pathogens, but protection against uncommon pathogens is limited if the donor pool has not been exposed to them.
• During treatment, only IgG is replaced while the rest of the immunoglobulins are not; these include IgA, and IgM, which have their unique functions, particularly protecting mucosal surfaces.
• Replacement IVIG therapy is very costly and not sustainable – especially in areas with limited resources.

Subcutaneous administration of IgG is an alternative to IVIG in case of difficult IV access or adverse reaction to IVIG. Just as safe as IVIG, with fewer systemic adverse effects, and smaller fluctuations in serum concentrations, the ability to self-administer IgG at home brings added convenience to this method. Overall this method will improve the patient’s quality of life. In very rare cases with subcutaneous IgG, local side effects like swelling, erythema, and tenderness may occur. These side effects tend to resolve within 24 hours.[21]

Hematopoietic stem cell transplantation (HSCT) is an alternate treatment for these patients. It is a tedious procedure with difficulty in matching suitable donors, making this treatment less popular. Additionally, there are heightened risks of allogeneic HSCT, including rejection and graft-versus-host disease. Often people in developing countries opt for HSCT because of lack of resources and high costs, making IVIG less suitable.

A potential therapy for XLA is stem cell gene therapy, which has the potential to cure XLA. However, this technology is still in its developing stages and is associated with severe complications because of the random integration of the vector into chromosomes; this can lead to an increased risk of cancer, and in some cases, even death. While adenovirus vectors have been under investigation as a method to repair the BTK gene, the long-term success of this treatment is still unknown.[22]

In addition to IVIG, these patients will require aggressive antibiotic therapy for any suspected or documented infections. The prolonged use of antibiotic therapy may be indicated in some patients for ongoing pulmonary infections or chronic sinusitis. As prophylactic therapy, many antibiotics options exist, but with little reliable data available, the effectiveness of a specific regimen for patients with XLA is lacking. It is typically initiated with amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin. If these are deemed non-effective, others such as amoxicillin-clavulanate or clarithromycin may be used. Some practitioners opt between full therapeutic doses or half-doses, some rotate preventative antibiotics every 1 to 6 months, and others stick with one agent.

The goal of the regimen is to ensure coverage over the following organisms: Enterococcus faecalis, Staphylococcus species, Streptococcus species, Streptococcus pneumoniae, and also some gram-negative bacteria like Escherichia coli, Hemophilus influenzae, Proteus mirabilis, and Neisseria gonorrhoeae.

Patients that develop bronchiectasis may benefit from bronchopulmonary hygiene, regular macrolide, and inhaled corticosteroids. The need for short- and long-acting inhaled B2 agonists, in bronchiectasis, is debatable.[23]

Differential Diagnosis

It is often challenging to differentiate X-linked agammaglobulinemia from other conditions clinically; thus, a careful investigation should be performed to rule them out. These other conditions include common variable immunodeficiency (CVID), transient hypogammaglobulinemia of infancy (THI), autosomal-recessive agammaglobulinemia (ARA), and severe combined immunodeficiency (SCID). All of these conditions have low/absent B cells and their associated antibody response. However, further lab testing provides clues that support the diagnosis of XLA, such as:

• A patient with SCID has a low T cell count as compared to XLA with a normal T cell count.
• Generally, observations show that patients with XLA have fewer B cells than those with CVID; however, these differences are not absolute.
• In THI, there is low serum IgG with or without decreased IgA and IgM levels. Children usually grow out of this, with normal immunoglobulin levels by age four. One of the proposed causes for THI is the suppressive effect of maternal antibodies (IgG) that affect fetal immunoglobulin production.

Eventually, genetic testing for the BTK gene mutation will differentiate XLA from other conditions.

Prognosis

In the last two decades, children with X-linked agammaglobulinemia from developed countries have shown significant improvement in their overall prognosis and survival rate. This can be attributed to early diagnosis, prompt and judicious use of antibiotics, along with regular administration of immunoglobulins. With these modalities, patients with XLA are now surviving beyond adolescence into adulthood. The adults and children with XLA mostly live productive and fulfilling lives, despite the fact that they have more absences from school/work and are hospitalized more often than males in the general population.[24][25]

Despite the monthly immunoglobulin replacement, approximately 10% of patients with XLA suffer from severe infections or chronic lung disease. The bronchiectasis is a leading cause of mortality and morbidity.

Unfortunately, in developing countries, the fate of patients with XLA is still poor. A significant percentage of children die before the diagnosis has been established while the remainder has permanent lung damage at the time of diagnosis.

Complications

The most frequent long-term complication in patients with X-linked agammaglobulinemia is a chronic lung disease, with bronchiectasis being the most common condition. According to a study, 46% of patients with XLA were suffering from chronic lung disease. And its prevalence was age-related, being higher in patients above 20 years of age.[26] The recognition of underlying etiology may be delayed. 

Patients with XLA can handle childhood viral infections due to preserved T cell function, but they are still more prone to certain enteroviruses, namely Polio, Coxsackie, and Echo viruses. These viruses can cause chronic meningoencephalitis leading to slowly progressive neurological impairments such as ataxia, paresthesia, loss of cognitive skills, developmental regression, and sensorineural hearing loss. In other cases, it presents with fever, headaches, seizures, and/or paralysis. Enteroviral infections involving muscles and skin may cause dermatomyositis like syndrome, presenting as an erythematous rash with peripheral edema.[27][28]

Patients with XLA have a lower risk of inflammatory and autoimmune diseases in comparison to other primary immune deficiency disorders. They present with symptoms of inflammatory bowel disease, arthritis, etc. Long term survivors also have an increased rate of malignancy with a 30 times higher incidence of colorectal cancer.[29]

There is also a risk of malignancy, such as lymphoproliferative disorders, gastric cancer, and colorectal cancer.

Deterrence and Patient Education

Patients with genetic immunodeficiencies should be informed about the possibility of having children with similar medical conditions. They should also be educated about the various therapies and treatments for these disorders and the importance of pregnancy monitoring and therapeutic abortion. Additionally, patients should be aware of the importance of avoiding consanguineous marriage.

Pearls and Other Issues

Agammaglobulinemia is a rare disorder, and its diagnosis is often overlooked. Regardless of age, all males with hypogammaglobulinemia and low circulating B cells must be assessed for XLA by investigating the BTK gene. Certain varieties of XLA mimic other disorders, like CVID. The disease, which is characterized by a low count of B cells and reduced antibody production, is less severe in childhood and increases in intensity during adulthood.

These patients should not receive live vaccines such as oral polio or MMR. Because of the deficient immunoglobulins, they are not capable of mounting the appropriate immunological response to these vaccines. There are reported cases of patients with XLA that developed vaccine-related poliomyelitis after vaccination with live attenuated poliovirus. The condition carries a high rate of mortality, and those who survived had severe neurological complications, such as permanent paralysis. Hence, special emphasis is given to avoiding the oral live attenuated SABIN-type polio vaccine. Furthermore, it is not proven that active vaccines, in general, have any beneficial effect on patients with XLA, as they lack the normal ability to maintain immune memory.

Inactive or conjugate vaccines like inactive polio vaccine can be administered safely. Additionally, these patients should not be given any medicines that suppress the immune system, such as immunosuppressive drugs or corticosteroids.

Previous guidelines advised to aim for an IgG level of at least 5 g/L, but recent studies recommend a higher IgG level of 8 g/L, in an effort to effectively prevent infections and promote respiratory health. Additionally, some studies also recommend that treatments should be individualized, and the target trough IgG levels should be adequate to prevent infection for an individual.[30][31]

Enhancing Healthcare Team Outcomes

While the diagnosis of X-linked agammaglobulinemia may seem simple enough, managing patients with this disease are complex. Treatment of XLA can be expensive and requires the commitment of the patient’s parents, as well as treating physicians. This can require an interprofessional team that includes a hematologist, pediatrician, oncologist, geneticist, and primary care provider. The primary goal remains the prevention of infections, which can be achieved with methods such as frequent handwashing and good respiratory hygiene.

Immunoglobulin replacement therapy has altered the paradigm of XLA and greatly improved the quality of life for patients. However, there are still issues with this treatment method. One of the emerging problems is that replacement therapy fails to restore the IgA and IgM in commercial immunoglobulins; this can cause recurrent respiratory and gastrointestinal infections. There is little evidence available regarding the benefits of IgA and IgG rich immunoglobulins; hence this treatment cannot generally be offered to patients with XLA due to safety concerns. HSCT is an alternative treatment, but it is not routinely offered due to its tedious procedure and complications such as rejection, graft vs. host disease, and mortality. However, in under-developed countries, the cost and availability of IVIG lead patients to opt away from this treatment method.

The advent of newborn screening can allow pre-symptomatic treatment, thus reducing the risk of disease-related complications. New advances in the treatment of XLA, such as gene therapy, may show promising results in these patients, but this treatment modality is still in the developmental stages.

As with all chronic diseases, the patient’s quality of life going forward is of utmost concern. An assessment must be made of the burden on a patient’s health physically, mentally, and socially. This aspect of the disease needs to be addressed further for the improved outcome of these patients.

Despite early diagnosis and treatment with immunoglobulins, the prognosis for patients with XLA is guarded. The major cause of morbidity and mortality is from pulmonary complications such as bronchiectasis and cor pulmonale. These patients will also require constant medical treatment, and consequently, their quality of life may remain poor.[32] [Level 5]