Agammaglobulinemia Disease

Agammaglobulinemia: An Evolving Update on Diagnosis and Treatment

The low concentration of antibodies in the blood caused by specific lymphocytes being absent from the blood and lymph is the characteristic of a group of inherited immune deficiencies known as agammaglobulinemia (hypogammaglobulinemia).

According to NIH agammaglobulinemia associated with X is inherited in an X-linked fashion. The majority of BTK gene mutations run in families; in those instances, the affected people's moms are healthy carriers of the mutation. While 15% to 20% of mutations occur de novo, about 50% of patients have a history of family members who have previously been affected.

XLA is an extremely rare condition that affects roughly 1 in 200,000 live births and 1 in 100,000 male babies on average.

There are reportedly only roughly ten examples of X-linked agammaglobulinemia combined with growth hormone insufficiency. These families' males have either negligible or low B-lymphocyte counts. Clinicians and geneticists speculate that the combination of agammaglobulinemia and very short height is caused by a second mutation in the BTK gene, which is located very close to the mutation that causes XLA.

The essential and fundamental elements of the immune system are proteins known as antibodies, such as immunoglobulins (IgM), (IgG), and so on. To effectively combat bacteria, viruses, and other foreign substances that pose a threat to the body, the immune system needs them. B cells, which are mature lymphocyte cells, are insufficient because the specialized precursor cells that produce gamma globulins do not develop or function correctly. Congenital agammaglobulinemia is a category of primary antibody deficiencies that are characterized by extremely low blood immunoglobulin concentrations, missing peripheral B cells, and early-stage B cell growth stops.

Agammaglobulinemia is classified into three types: Autosomal Recessive Agammaglobulinemia (ARAG), Bruton or X-linked agammaglobulinemia (XLA), and the much rarer X-linked agammaglobulinemia with growth hormone deficiency. Lung infections (pneumonia and bronchitis), ear infections (otitis), pink eye (conjunctivitis), and sinus infections (sinusitis) are the most frequent bacterial diseases in individuals with XLA. Chronic diarrhea-causing infections are also frequent.

A genetic mutation is the cause of X-linked agammaglobulinemia. The disease prevents affected individuals from producing antibodies that fight infection. A family member with the illness affects about 40% of those affected by it.

Sign and symptoms -

The main signs of agammaglobulinemia are recurrent bacterial infections, which are caused by deficiencies in B-lymphocytes, which prevent certain immune responses from working as intended. These lymphocytes are in charge of controlling antibody synthesis. Usually, males with X-linked primary agammaglobulinemia don't exhibit symptoms of these infections until much later in the first year of life, when their mother's IgG antibodies have been exhausted. Children with agammaglobulinemia experience unusually severe illness as a result of infections by virtually any member of the enterovirus family and the poliomyelitis virus.

Children with primary agammaglobulinemia who have mycoplasma bacterial infections experience severe arthritis, including joint swelling and pain. The most frequent mucous-producing (pyogenic) infection that affects individuals with X-linked agammaglobulinemia is Hemophilus influenzae.

X-linked agammaglobulinemia in males is characterized by extremely low blood levels of IgA, IgG, and IgM antibodies. The capacity of specialized white blood cells (neutrophils) to eliminate bacteria, viruses, or other invasive organisms (microbes) is compromised. This happens because neutrophils need the immune system's antibodies for them to start opsonizing—destroying invasive bacteria.

Children with agammaglobulinemia have consistently low circulating neutrophil counts, or they experience waxing and waning (cyclic, transient neutropenia) in those affected by these disorders.

Diagnostic Analysis -

Blood Test- 

• Flow cytometry- To assess infectious diseases, autoimmune disorders, or immunodeficiencies, flow cytometry is used to count and characterize different types of white blood cells.
• Immunoelectrophoresis- Serum immunoelectrophoresis is a laboratory test used to quantify immunoglobulins, which are proteins present in the blood.
• Quantitative Nephelometry test- A lab test called quantitative nephelometry is used to quickly and precisely determine the blood's concentration of specific proteins known as immunoglobulins. Antibodies called immunoglobulins aid in the fight against infection. Particularly, the immunoglobulins IgM, IgG, and IgA are measured by this test.

Genetic Test

Genetic testing examines for variations in genes, chromosomes, or proteins. A genetic test's findings are used to confirm, rule out, or estimate a person's risk of acquiring or passing on a suspected genetic disorder.

Diagnostic Market Players and Products -

Treatment Analysis-

Medications

Treatment for XLA medications include:

Antibiotics: To prevent infections, some individuals with agammaglobulinemia are treated with antibiotics continuously. Others who do not have agammaglobulinemia take antibiotics for bacterial infections for a longer period.

Immunoglobulin (antibody) Replacement Therapy (IRT)

One of the most well-known and effective treatments for individuals with agammaglobulinemia or antibody scarcity is immunoglobulin (antibody) replacement therapy (IRT). The antibodies are replaced by Ig, which is administered subcutaneously (SCIG) or intravenously (IVIG).

Patients undergoing IRT should be aware of the possibility of blood-borne infections, IgA responses, and mild side effects such as headaches or low-grade fevers. IRT costs from $30,000 to $90,000 a year in the US.

Hematopoietic stem cell transplantation (HSCT)-

An alternative line of treatment for these patients is hematopoietic stem cell transplantation. Due to the time-consuming process and challenges in finding compatible donors, this treatment is less common. Allogeneic HSCT also carries increased hazards, such as graft-versus-host disease and rejection. Because HSCT is more common in underdeveloped nations due to financial constraints and high expenses, IVIG is less appropriate.

Treatment Market Players and Products -

Competitive Analysis -

In high-income nations, monthly intravenous immunoglobulin (IVIG) or weekly, or even biweekly, subcutaneous immunoglobulin (SCIG) infusions are the major treatments for agammaglobulinemia. IRT is administered for life. Systemic enteroviral infections and chronic lung disease are not entirely prevented by immunoglobulin replacement therapy, but it does minimize sinopulmonary infections.

As a result, life spans overall are less than those of the general population. Furthermore, a lifetime with IRT lowers quality of life. Increased emotional, social, and behavioural challenges were found in children with primary antibody deficits treated with IRT; these issues led to a decline in patient and parent quality-of-life ratings. The financial cost of immunoglobulin replacement therapy is another burden on society.

Recent Developments

• Leading worldwide manufacturer of plasma-derived medications, Grifols, announced in March 2022 that several European Union member state health authorities as well as the United Kingdom had approved XEMBIFY®, its novel 20% subcutaneous immunoglobulin (SCIG), for the treatment of primary and certain secondary immunodeficiencies.

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