What is Agammaglobulinemia (Hypogammaglobulinemia)?
Agammaglobulinemia, or hypogammaglobulinemia, is a rare immune disorder that a person can be born with. Its main characteristic is having very few or even no mature B cells. B cells are important parts of your immune system because they produce antibodies, the proteins that fight off infections. Therefore, having few or no B cells can make a person more likely to get recurrent infections. Children with this disorder usually start showing signs around six months of age, which is when the temporary protection from their mother’s immunity reduces.
There are several types of agammaglobulinemia, including:
- X-linked agammaglobulinemia (XLA), which was first discovered by a doctor named Ogden Bruton in 1952.
- X-linked agammaglobulinemia with growth hormone deficiency.
- Autosomal recessive agammaglobulinemia (ARAG).
What Causes Agammaglobulinemia (Hypogammaglobulinemia)?
X-linked agammaglobulinemia is a condition that is caused by a change, or mutation, in a gene called the Bruton tyrosine kinase (BTK) gene. This gene is found on the X chromosome’s long arm. BTK is crucial in the development of B cells, a type of white blood cell, which develop in our bone marrow. Over 500 different mutations have been linked to this disease, including changes in the sequence of the gene, insertions, deletions, and errors in the splicing of the gene.
Another form of agammaglobulinemia, called autosomal recessive agammaglobulinemia, is caused by changes in other genes that are involved in B cell development. About 15% of these cases are thought to be autosomal recessive. The cause of this form of the disease is complicated, as it involves a variety of different genes located on chromosomes 22, 14, and 9.
In addition to these primary forms of the condition, other factors can cause secondary immunodeficiency, or a weakened immune system. Some medications or viral infections can affect the function of T and B cells, our main immune system warriors. Some of these medications include steroids, methotrexate, and others. An example of a viral infection that causes this is HIV, which particularly affects a type of T cell, leading to an increased risk of infections and cancers.
This condition can also occur in people with chronic lymphocytic leukemia, a type of cancer affecting white blood cells. Around 85% of these patients develop this condition over the course of their disease. The risk increases with the disease’s progression, so it’s crucial to keep an eye on patients’ antibody levels to spot any deficiencies early.
Lastly, congenital rubella infections, or rubella infections present at birth, can also impact the immune system’s development, leading to weakened immunity or other abnormalities in immune responses.
Risk Factors and Frequency for Agammaglobulinemia (Hypogammaglobulinemia)
X-linked agammaglobulinemia is a condition that is passed down through families, and it mainly affects the BTK gene. Often, the mothers of those affected are healthy carriers. Roughly half of the people with this condition have family members who’ve had it before, while between 15% to 20% of the cases happen out of the blue.
This is a very rare condition, occurring in roughly 1 out of every 200,000 live births. In terms of male newborns, the frequency is about 1 in 100,000.
Rarely, this condition has been seen in conjunction with growth hormone deficiency—only about 10 cases have been reported. The boys in these cases had low or undetectable levels of B-lymphocytes, a type of white blood cell. Medical professionals speculate that this might be due to a second mutation in the BTK gene, causing both agammaglobulinemia and a very short stature.
Signs and Symptoms of Agammaglobulinemia (Hypogammaglobulinemia)
In early life, babies get protection against different illnesses from their mother’s antibodies. However, from 6 to 12 months old, these antibodies start to decrease. This can lead to a condition known as X-linked Agammaglobulinemia (XLA) where children often suffer from recurring infections like ear infections, sinusitis, bronchitis, and pneumonia. In fact, more than half of the children with XLA experience severe infections within their first two years.
XLA patients often get sick with bacteria like Streptococcus pneumoniae and Haemophilus influenzae. Other infections can be caused by Staphylococcus aureus, Pseudomonas, and Mycoplasma species. Less often, they might get opportunistic infections from fungi like Pneumocystis jirovecii.
People with XLA are also more likely to develop bacterial infections in their blood. Around 3% to 4% of patients with XLA can develop bacterial meningitis, primarily caused by Streptococcus pneumoniae and Haemophilus influenzae type B. Other bacteria that can cause this include Pseudomonas, Neisseria meningitidis, Staphylococcus aureus, Escherichia coli, and Listeria monocytogenes. Conditions like septic arthritis and osteomyelitis are also commonly seen in patients with XLA.
Digestive system infections are frequent in XLA patients. Particularly, Giardia lamblia, a microscopic parasite, is often found in patient’s stool samples; this can lead to chronic diarrhea and reduced nutrient absorption. Another unusual pathogen, Campylobacter jejuni, can cause digestive problems, blood infections, and skin lesions.
During a physical examination, doctors may notice signs of recurring and long-lasting infections in the lungs and sinuses, such as postnasal discharge, ear drum perforation, finger clubbing, and bronchiectasis (damage to the lung airways). The absence or shrinking of lymph nodes and tonsils can be key clues for a XLA diagnosis. Some patients may also show signs of not growing as they should.
Testing for Agammaglobulinemia (Hypogammaglobulinemia)
X-linked agammaglobulinemia (XLA) is a condition related to the immune system that one is born with. It can cause severe infections and chronic lung disease like bronchiectasis. It’s very important to diagnose this condition early to improve a patient’s life expectancy and quality of life.
To diagnose XLA, doctors rely on clues from the patient’s symptoms, medical history and physical examination. They may also consider if anyone else in the patient’s family has XLA. After that, a series of laboratory and genetic tests are conducted.
The first lab tests comprise a complete blood count, measurement of the different types of immune proteins (IgG, IgA, and IgM) in the blood, and checking the body’s immune response against common vaccines like tetanus or diphtheria.
Typically, patients with XLA have low or almost undetectable levels of all types of immune proteins in the blood and show no immune response to vaccines. If these preliminary test results are positive, doctors can confirm the diagnosis of XLA by examining the types and number of immune cells in the blood and identifying a certain gene mutation.
Newborn screening tests can also detect XLA and other defects related to the immune system. One such test involves detecting specific genetic markers in the blood which are indicative of early stages of immune cell development. Their absence suggests defects in the development of immune cells, which is seen in XLA.
Patients with this condition often suffer from repeated infections, particularly of the sinus and lungs. Doctors use different diagnostic methods such as breathing tests, exercise tests, and imaging like MRI and CT scans. Collecting and analyzing sputum and blood samples is also common. However, the process of diagnosis and treatment isn’t standardized and can vary quite a bit.
In children, these tests are usually done less frequently and are more complex compared to adults. For example, infants might need to be sedated for some imaging tests, and lung function tests may not be as reliable in children under 6 years old.
As these patients are at a high risk for lung infections and complications, they are usually treated with a wide range of antibiotics even before the diagnosis is confirmed. Other tests that help confirm the diagnosis include examining the lungs and collecting lung fluid samples. Regular hearing assessments should also be part of the medical care for these patients.
It’s worth noting that some forms of XLA are linked with growth hormone deficiency, but currently there are no guidelines for routinely monitoring growth hormone levels in patients with XLA.
Treatment Options for Agammaglobulinemia (Hypogammaglobulinemia)
To protect themselves from infections, patients should focus on hygiene measures like washing their hands regularly and avoiding inhaling respiratory droplets. It’s also recommended to stay away from untreated drinking water if possible.
For patients with X-linked agammaglobulinemia, a beneficial treatment has been the use of intravenous immunoglobulins (IVIG), which has significantly improved their lives. This treatment involves replacing a patient’s immunoglobulins either through the veins every 3-4 weeks or under the skin every 1-2 weeks. Depending on the patient’s specific situation, dosage and frequency might be adjusted over time. For example, some patients with chronic sinusitis or lung disease may need higher treatment levels.
However, IVIG treatment has some drawbacks. It can protect against most common infections, but not so much against rare ones if the donors haven’t been exposed to those pathogens before. Also, only one type of immunoglobulin, IgG, gets replaced during treatment, leaving out others like IgA and IgM which also play essential roles in protecting the body, particularly on our body’s surface areas. Another downside is that IVIG treatment tends to be costly, making it unsustainable especially in less fortunate regions.
An alternative to IVIG treatments is subcutaneous administration of IgG, meaning the medication is injected under the skin. It’s a safe option with fewer side effects than IVIG, and patients can even do it at home. Some minor side effects like swelling, redness, and tenderness might occur but usually go away within a day.
Another treatment approach is hematopoietic stem cell transplantation (HSCT), but it’s not a very popular option. It’s a complex process and it’s not always easy finding a suitable donor. There’s also a risk of the body rejecting the transplant and suffering from a condition where the transplant attacks the patient’s body. However, some people find HSCT a more feasible option due to a lack of resources and the high costs of IVIG treatments.
Stem cell gene therapy, which alters a patient’s genes to cure X-linked agammaglobulinemia, is also being explored as a potential treatment. However, it’s not yet fully developed and can come with severe complications due to how the therapy integrates into our chromosomes. This may increase the risk of cancer and in some cases, lead to death. Research is ongoing to improve this treatment, but its long-term success remains to be seen.
Aside from IVIG, patients may also need strong antibiotics to manage current or potential infections. Depending on the patient, prolonged use of antibiotics may be necessary to treat continuous lung infections or chronic sinusitis. However, it’s unclear which specific antibiotic regimen is most effective for patients with X-linked agammaglobulinemia. Usually, patients start with amoxicillin, trimethoprim-sulfamethoxazole, or azithromycin and may switch to other options if these are not effective. These antibiotics aim to fight off a variety of bacterial infections.
Patients who develop a lung disease called bronchiectasis may benefit from lung hygiene, regular use of macrolide antibiotics, and inhaled corticosteroids. The need for inhaled medication to open up the airways longer remains debated.
What else can Agammaglobulinemia (Hypogammaglobulinemia) be?
Diagnosing X-linked agammaglobulinemia, a genetic condition that affects the body’s ability to fight infections, can be tricky. It can resemble other conditions, so doctors need to carry out a detailed investigation to rule them out. These conditions include:
- Common Variable Immunodeficiency (CVID)
- Transient Hypogammaglobulinemia of Infancy (THI)
- Autosomal-Recessive Agammaglobulinemia (ARA)
- Severe Combined Immunodeficiency (SCID)
All these conditions can cause low or no B cells (a type of white blood cell), and affect the body’s antibody response, which is vital for fighting infections.
However, additional lab tests can help point towards a diagnosis of X-linked agammaglobulinemia. For example:
- Patients with SCID also have a low T cell (another type of white blood cell) count, while those with X-linked agammaglobulinemia have normal T cell counts.
- People with X-linked agammaglobulinemia generally have fewer B cells than those with CVID, although this isn’t always the case.
In THI, there’s a low level of a specific antibody called IgG, and potentially decreased IgA and IgM levels. However, children usually grow out of this condition, and their immunoglobulin levels (protein used by the immune system to identify and neutralize foreign objects) normalize by the age of four. The condition might be caused by the suppressing effect of maternal antibodies on a child’s immunoglobulin production.
Finally, genetic testing for a mutation in the BTK gene can help doctors to differentiate X-linked agammaglobulinemia from these other conditions.
What to expect with Agammaglobulinemia (Hypogammaglobulinemia)
In the past 20 years, children in developed countries with a rare genetic disorder called X-linked agammaglobulinemia have seen a significant improvement in their survival rate and overall health outlook. This development is largely due to early detection, quick and judicious use of antibiotics, and regular administering of immunoglobulins, a type of protein the immune system uses to fight off bacteria and viruses. Thanks to these treatments, children with this disorder are now often living past their teenage years into adulthood and lead productive, fulfilling lives, despite having to miss school or work more frequently and being hospitalized more often than the average male.
However, even with regular immunoglobulin treatment, around 10% of patients with X-linked agammaglobulinemia continue to suffer from severe infections or chronic lung disease. Bronchiectasis, a condition that damages the airways, is both a leading cause of death and long-term health issues among these patients.
In developing countries, the prognosis for patients with X-linked agammaglobulinemia remains poor. Many children die before the condition is even diagnosed, and many of the surviving patients suffer permanent lung damage by the time they are diagnosed.
Possible Complications When Diagnosed with Agammaglobulinemia (Hypogammaglobulinemia)
The main long-term issue for patients with X-linked agammaglobulinemia (XLA) is chronic lung disease, with bronchiectasis being most common. In one study, it was found that nearly half the patients with XLA had chronic lung disease, and the condition was more frequent in patients over the age of 20.
Although XLA patients can manage childhood viral infections due to maintained T cell function, they are more susceptible to specific enteroviruses like Polio, Coxsackie, and Echo viruses. These viruses can result in chronic inflammation of the brain and spinal cord, leading to gradually worsening neurological conditions such as unsteady movements, abnormal skin sensations, cognitive skill loss, developmental backtracking, and hearing loss. In some cases, these viruses trigger symptoms like fever, headaches, seizures, and even paralysis. Enteroviral infections can also affect the muscles and skin, causing a condition similar to dermatomyositis, which typically involves a red skin rash and swelling around the skin.
Compared to other primary immune deficiency disorders, individuals with XLA have a reduced risk of inflammatory and autoimmune diseases. However, these patients may exhibit symptoms related to inflammatory bowel disease, arthritis, and similar conditions. Long-term survivors also show a considerable increase in cancer rates, with the incidence of colorectal cancer being 30 times higher. Additionally, XLA patients face a risk of malignancies including lymphoproliferative disorders, stomach cancer, and colorectal cancer.
Common Health Risks in Patients with X-linked Agammaglobulinemia:
- Chronic lung disease
- Susceptibility to Polio, Coxsackie, and Echo viruses
- Persistent brain and spinal cord inflammation
- Gradually worsening neurological conditions
- Symptoms similar to inflammatory bowel disease and arthritis
- An increase in colorectal cancer rates
- Risk of lymphoproliferative disorders, stomach cancer, and colorectal cancer
Preventing Agammaglobulinemia (Hypogammaglobulinemia)
Patients who have inherited immune system disorders should be made aware that their children might also have these medical conditions. It’s essential that they understand the different treatment options available for these disorders. Additionally, they should be informed about the significance of closely monitoring pregnancies, and the potential for therapeutic abortions if necessary. Finally, it’s crucial that these patients are educated on the importance of avoiding marriage between close relatives.
