Hypogammaglobulinemia

What is Hypogammaglobulinemia?

Hypogammaglobulinemia is a condition that results from low levels of serum immunoglobulin or antibodies in the body. Think of immunoglobulins as the front-line soldiers of the body’s immune system. They detect foreign substances, like bacteria or viruses, causing the body to eliminate these invaders. Hypogammaglobulinemia is the most common type of primary immunodeficiency, which means it’s a type of disorder that makes people more likely to get infections.

People can be diagnosed with this condition at any age, but it’s usually detected around the range of 20 to 40 years. Interestingly, diagnosis can often occur either between ages 6 to 10 or 20 to 40, as there can be two peaks of diagnosis age. Also, while rare, people over 50 can also exhibit symptoms of this condition.

Hypogammaglobulinemia can make both children and adults more susceptible to recurrent infections, allergies, the development of tumors (neoplasms), and conditions where the body attacks its own cells (autoimmunity). Even though we previously thought such disorders mostly developed in childhood, it’s increasingly being recognized in adults too.

Common variable immunodeficiency (CVID), a condition where the body cannot produce enough antibodies, is frequently behind hypogammaglobulinemia in adults. In children, the most common cause is X-linked agammaglobulinemia (XLA), a genetic disorder that prevents the formation of normal amounts of specific antibodies.

What Causes Hypogammaglobulinemia?

Hypogammaglobulinemia is a condition where the body doesn’t produce enough antibodies. It can be caused by either genetic factors (primary) or acquired factors (secondary). Genetic factors can involve genetic disorders or abnormalities that arise while the immune system is growing. On the other hand, secondary causes might include things like certain medications, nutritional problems, infections, cancer therapy, kidney syndromes, other metabolic diseases, and harmful environmental conditions. Doctors must figure out if the cause is primary or secondary to choose the right treatment.

There are different types of primary hypogammaglobulinemia, these include X-linked Agammaglobulinemia, Common Variable Immunodeficiency (CVID), Hyper IgM syndrome, Selective Ig deficiency, and Transient hypogammaglobulinemia of Infancy.

X-linked Agammaglobulinemia is the first-known genetic cause of hypogammaglobulinemia. It is due to a mutation in a gene responsible for the production of antibodies. The result is a lack of mature cells that produce antibodies.

Common Variable Immunodeficiency is a disorder which affects cells of the immune system, causing an inability to produce enough antibodies. This could be because of faults in the cells’ genetic material or because of other issues, such as increased cell death. It can involve defects in many parts of the cells, and is often carried through genes.

Transient Hypogammaglobulinemia of Infancy is a temporary condition in babies where antibody levels are lower than usual. These levels usually return to normal by the time a child is 2-6 years old. It’s not entirely clear why this happens, but it might be due to factors like failing T-cells and low levels of certain proteins, among other reasons.

Selective IgA Deficiency sees lowered or completely absent levels of a specific type of antibody, IgA. This could be due to genetic factors, certain medications or infections. It’s also found in certain conditions like ataxia-telangiectasia.

Lastly, Hyper-IgM Syndrome is a rare genetic disorder where you have normal to high levels of IgM antibodies, but low levels of others (IgG, IgA and IgE). This is caused by mutations that change how B-cells (a type of white blood cell) work. These mutations can be found on the X-chromosome and other chromosomes.

Risk Factors and Frequency for Hypogammaglobulinemia

X-Linked Agammaglobulinemia is a condition that isn’t very common, with about 1 in 379,000 live births (or 1 in 190,000 male births) in the United States containing this condition.

When we look at primary immune deficiencies, Common Variable Immunodeficiency is usually the most frequent after selective IgA deficiency. This condition has a high occurrence rate, affecting about 1 in every 10,000 to 50,000 live births. It’s particularly common in northern Europe, where approximately 1 in 25,000 individuals have CVID. This condition usually begins to show signs mostly after puberty in children, but about 25% of all people with CVID will start showing symptoms in childhood or adolescence, with the most typical age of diagnosis being 8 years old. More males have this condition than females, with a ratio of about 5 to 3.

THI is another condition that is more common in males, with double the number of male cases as female ones (a ratio of 2 to 1). However, the cause of this condition is unknown and it is usually diagnosed retrospectively.

Signs and Symptoms of Hypogammaglobulinemia

Patients with chronic illnesses might show certain signs and symptoms, or physical examination may appear normal. Some common problems might include:

Recurrent infections, particularly in the areas of the sinus and lungs. These infections can be caused by a variety of bacteria. It’s common for these patients to need multiple courses of antibiotics to clear the infections. Scarring on the eardrum from repeated ear infections can sometimes be seen during physical exams.
By the time they’re 2 years old, over 50% of patients with X-linked agammaglobulinemia (XLA) have had severe infections from specific bacteria and viruses. Chronic Variable Immune Deficiency (CVID) patients tend to get sinus and lung infections and complications like lung damage, irrespective of their age. Almost 75% of these patients have had at least one episode of bacterial pneumonia before they are diagnosed. Other types of infections that can affect the urinary and digestive systems have also been reported in CVID and XLA patients. Sometimes, patients present symptoms related to nervous system involvement, like seizures, unsteadiness, muscle weakness, headaches, loss of vision, or even coma. Sometimes, they may also get infections which usually affect people with weak immune systems. In some cases, high levels of IgM immune proteins can be due to congenital rubella syndrome.
Autoimmune problems where the body’s immune system attacks its own cells causing blood cell disorders, inflammation of multiple joints, and other immune problems.
Enlargement of the liver and spleen, and enlarged lymph nodes in the arms and legs.
Allergic diseases, like asthma, skin inflammation and hives, and hay fever. Children with deficiency in IgA immune protein are at a higher risk of developing allergies to food and medicine.
Delayed growth or development, failure to thrive, poor food intake, digestive problems like diarrhea and abdominal pain. With XLA, the tonsils and adenoids might be absent in adulthood due to prophylactic (preventative) treatment with antibiotics during childhood. In CVID, digestive problems presenting with diarrhea, loss of weight, and inability to absorb nutrients from food are common in children and adults.
Abnormalities detected in the ear, nose and throat, and heart abnormality like the ones seen in DiGeorge or CHARGE syndromes in children. Findings might include eardrum perforation, scarring, possible hearing loss, or abnormal pattern of the throat lining with lack of tonsillar tissue, and nasal discharge.
The risk of developing cancer increases in older populations. Around 25% of Chronic Lymphocytic Leukemia (CLL) patients develop long-term hypogammaglobulinemia (a state of decreased level of antibodies in the body). Adults with IgA deficiency may develop complications like stomach cancer and lymphoma.

Testing for Hypogammaglobulinemia

When a person’s body has low levels of a type of protein called immunoglobulin G (IgG), it can suggest a condition known as hypogammaglobulinemia. Think of IgG as a type of soldier in your body that fights off infections. The European Society of Immunodeficiency (a group of experts) says that for a person to be diagnosed with hypogammaglobulinemia, they need to have IgG levels that are far lower than what is average for their age group. In adults, anything less than 5g/L could indicate this condition.

Apart from low levels of IgG, patients might also have decreased amounts of IgA and IgM, other types of soldiers that help protect the body from infection. While IgM is typically present in large amounts during an initial immune response and mostly stays within the vessels, it’s IgG that’s most abundant in both vessels and tissues and plays a key role in activating the immune response.

To diagnose hypogammaglobulinemia and evaluate the body’s immune response, doctors often:

1. Measure serum Immunoglobulin levels (IgM, IgG, IgA) with lab tests like a complete blood count (CBC) along with checking antibody levels in response to vaccines or infections. If these tests lean towards a particular type of hypogammaglobulinemia known as X-Linked Agammaglobulinemia (XLA), doctors might do more tests to specifically look at the different types of white blood cells.

– In adults and kids with another type of hypogammaglobulinemia called Common Variable Immunodeficiency (CVID), certain types of antibodies might be missing or not detectable. To diagnose CVID, doctors need to see decreased IgG along with low levels of IgM and/or IgA, with specific reference values for kids.

2. Check how well the body produces antibodies, which are important soldiers in the immune defense system. They do this by looking at, among other things, how many antibodies are produced in response to routine vaccines – this is often normal in Transient Hypogammaglobulinemia of Infancy (THI) but not in XLA.

– If a child’s body responds well to vaccines and produces a good amount of antibodies, it’s unlikely that they have CVID.

3. Use a test called flow cytometry to look at different subtypes of white blood cells, to distinguish between different types of hypogammaglobulinemia. This test is important because it can show, for example, no circulating B cells which is characteristic of XLA, versus the presence of B-cells in CVID, IgA deficiency, and hyper-IgM syndromes.

4. Conduct a genetic test if the decreased Ig and B-cells have been found, to confirm the diagnosis. This happens especially when there’s no family history of hypogammaglobulinemia – it helps to identify other potential B-cell defects and helps with genetic counseling. Genetic testing isn’t usually required for diagnosing CVID, but can provide insights on how the disease may be inherited.

5. Do some additional blood tests, like CRP and ESR which check for inflammation and antinuclear antibody testing which checks for autoimmune conditions. These tests are done mainly if the patient has active infections or symptoms of an autoimmune condition. In some cases, doctors might also consider a lymph node biopsy or a bone marrow biopsy if there’s a suspicion of other conditions like lymphoma or myelodysplasia.

In summary, diagnosing hypogammaglobulinemia involves a series of lab tests, checks on immunoglobulin levels, functional antibody production, flow cytometry, genetic testing, and a suite of other tests based on individual cases. This ensures that a detailed and accurate diagnosis is made so that the right treatment plan can be put in place.

Treatment Options for Hypogammaglobulinemia

There are several steps to take for anyone with a weakened immune system or those prone to frequent infections. These steps include practicing good hand hygiene, drinking treated water, and ensuring proper protection from respiratory diseases.

One common treatment is IV Immunoglobulin replacement therapy, which helps to supplement the immune system. However, it’s important to note that this therapy only replaces a specific part of the immune system (IgG) and not others (IgM or IgA). People receiving this treatment need to have their Immunoglobulin levels checked every six months. The dosage of this treatment may need adjustments based on the person’s production of IgG and their weight. Side effects can vary from inflammatory reactions, rarely an allergic reaction, headaches, or issues with red and white blood cells. It is not suggested for all conditions. Those with normal B cells or certain antibody impairments may not benefit from it. People usually tolerate this treatment well, but in rare cases, a severe allergic reaction can occur, especially for those with low levels of IgA. Hence it is necessary to screen for anti-IgA antibodies before administering the treatment.

Antibiotics are often used to treat active infections or even given on a regular basis to prevent future ones. Such antibiotics are crucial for those who have continuous respiratory issues due to frequent lung infections.

Patients may also be given steroid medications to treat issues related to blood cell counts. High dose IVIG and another medicine called rituximab have proven helpful as additional treatments along with steroids.

In severe cases, a procedure known as a hematopoietic stem cell transplant might be suggested. If there is no response to other treatments, the removal of the spleen (a procedure called a splenectomy) may be considered.

Based on the severity of the patient’s condition, certain vaccines would be recommended. High-risk patients are suggested to take the seasonal flu shot. In cases of severe antibody deficiency, live vaccines aren’t recommended but vaccines for influenza, HPV, anthrax, and rabies can be given. However, decisions around vaccines need to be carefully made to ensure the benefits outweigh potential risks.

If children continue to have respiratory symptoms after treatment, they might need allergy testing. This check helps to rule out asthma or allergies contributing to frequent sinus or lung issues. Those with frequent ear infections need to be aware of potential hearing loss, which might affect their school performance.

Some other conditions that might resemble hypogammaglobulinemia (low levels of immunoglobulins in the blood) include the following:

Reactions to certain drugs – these can include antimalarial medications, phenytoin, penicillamine, and glucocorticoids. If the patient is showing signs of a weakened immune system, the doctor might stop the drug and then recheck the immunoglobulin levels.
Genetic disorders – examples include Hyper IGM immunodeficiency, X-linked agammaglobulinemia, X-linked SCID, Trisomy 18 and 21, and ataxia-telangiectasia. If these are suspected, a genetic evaluation is typically recommended to check for any chromosomal involvement or defects.

In addition, infections such as CMV, EBV, HIV, Rubella, and congenital Toxoplasma gondii may also lower immunoglobulin levels. If there is strong suspicion of these infections, a PCR test might be carried out. It’s also worth noting that certain types of cancer like Chronic lymphocytic leukemia, Non-Hodgkin’s lymphoma, and B cell malignancies could also manifest similarly to hypogammaglobulinemia. An oncological assessment with appropriate tissue biopsies may be beneficial in such cases.

Systemic disorders like severe burns, nephrotic syndromes, severe diarrhea, and malnutrition can also lower immunoglobulins. Therefore, a detailed medical history and examination are crucial to rule out these possible causes.

What to expect with Hypogammaglobulinemia

The main factors affecting the outlook for a patient are complications involving the lungs and the presence of cancer. The use of antibiotics and a treatment called IVIG therapy have helped to reduce death rates from bacterial infections. Acting quickly can help delay or even prevent these complications. However, it’s not quite clear exactly how much IgG replacement is needed to prevent complications.

Patients with a condition known as THI who show low levels of IgM and IgA tend to recover slowly. On the other hand, those who were breastfed for longer periods of time seem to recover faster. For patients with a condition known as Hyper-IgM syndrome, death can occur due to secondary infections which are not typically dangerous, malignancies (cancer), and diseases affecting the liver and the biliary tract, which is part of the liver structure.

Possible Complications When Diagnosed with Hypogammaglobulinemia

People with hypogammaglobulinemia, a condition with lower than normal levels of antibodies, have several health risks, even if this condition is identified early. Lung issues can result in a shortened life span. The main complication is bronchiectasis, or abnormal widening of the airways in the lungs. This disorder occurs in roughly 20% of people who experienced repeated infections, and it might cause worsening respiratory symptoms, similar to obstructive or restrictive lung disease.

To regularly check lung health, doctors recommend getting a high-resolution CT scan. Another long-term risk is cancer. Usually, this danger becomes more significant during the fourth to fifth decade of life, encouraging regular medical check-ups. High-dose treatments of IVIG (intravenous immunoglobulin), which are antibodies delivered directly into the bloodstream, can promote a better life quality by reducing lung complications, if started early in the disease course.

Common Health Risks:

Lung complications leading to shorter lifespan
Bronchiectasis or the abnormal widening of airways
Worsening respiratory symptoms
Possible development of cancer

Preventing Hypogammaglobulinemia

It’s important for parents and adult patients to be aware of certain warning signs. These could indicate a condition called hypogammaglobulinemia, which affects the immune system. Some of these signs include repeated infections in the lungs and sinuses, allergies, and long-lasting fevers. If someone is experiencing a severe allergic reaction, it might be time to get checked out by a doctor who specializes in the immune system. If patients have a condition called Common Variable Immune Deficiency (or CVID) and their family members get sick often, they should also get checked out, as they might be more prone to certain deficiencies and conditions like CVID.

Practicing good hand washing, having clean surroundings, catching infections in the early stages, and following prescribed treatments can improve symptoms and long term health. Sometimes, medications and certain diseases can cause hypogammaglobulinemia. If you’re taking long term medications like glucocorticoids, or if you’ve had unexpected weight loss, malnutrition, or a family history of early deaths due to infections or cancer, it’s important to talk to your doctor. They can help manage these factors properly, ensuring the best possible care for your condition.

Frequently asked questions

Hypogammaglobulinemia is a condition that results from low levels of serum immunoglobulin or antibodies in the body.

Hypogammaglobulinemia is not very common, with about 1 in 379,000 live births (or 1 in 190,000 male births) in the United States containing this condition.

Signs and symptoms of Hypogammaglobulinemia include: - Recurrent infections, particularly in the areas of the sinus and lungs. These infections can be caused by a variety of bacteria. It's common for these patients to need multiple courses of antibiotics to clear the infections. Scarring on the eardrum from repeated ear infections can sometimes be seen during physical exams. - By the time they're 2 years old, over 50% of patients with X-linked agammaglobulinemia (XLA) have had severe infections from specific bacteria and viruses. Chronic Variable Immune Deficiency (CVID) patients tend to get sinus and lung infections and complications like lung damage, irrespective of their age. Almost 75% of these patients have had at least one episode of bacterial pneumonia before they are diagnosed. Other types of infections that can affect the urinary and digestive systems have also been reported in CVID and XLA patients. Sometimes, patients present symptoms related to nervous system involvement, like seizures, unsteadiness, muscle weakness, headaches, loss of vision, or even coma. Sometimes, they may also get infections which usually affect people with weak immune systems. In some cases, high levels of IgM immune proteins can be due to congenital rubella syndrome. - Autoimmune problems where the body's immune system attacks its own cells causing blood cell disorders, inflammation of multiple joints, and other immune problems. - Enlargement of the liver and spleen, and enlarged lymph nodes in the arms and legs. - Allergic diseases, like asthma, skin inflammation and hives, and hay fever. Children with deficiency in IgA immune protein are at a higher risk of developing allergies to food and medicine. - Delayed growth or development, failure to thrive, poor food intake, digestive problems like diarrhea and abdominal pain. With XLA, the tonsils and adenoids might be absent in adulthood due to prophylactic (preventative) treatment with antibiotics during childhood. In CVID, digestive problems presenting with diarrhea, loss of weight, and inability to absorb nutrients from food are common in children and adults. - Abnormalities detected in the ear, nose and throat, and heart abnormality like the ones seen in DiGeorge or CHARGE syndromes in children. Findings might include eardrum perforation, scarring, possible hearing loss, or abnormal pattern of the throat lining with lack of tonsillar tissue, and nasal discharge. - The risk of developing cancer increases in older populations. Around 25% of Chronic Lymphocytic Leukemia (CLL) patients develop long-term hypogammaglobulinemia (a state of decreased level of antibodies in the body). Adults with IgA deficiency may develop complications like stomach cancer and lymphoma.

Hypogammaglobulinemia can be caused by either genetic factors (primary) or acquired factors (secondary). Genetic factors can involve genetic disorders or abnormalities that arise while the immune system is growing. On the other hand, secondary causes might include things like certain medications, nutritional problems, infections, cancer therapy, kidney syndromes, other metabolic diseases, and harmful environmental conditions.

Reactions to certain drugs, genetic disorders, infections such as CMV, EBV, HIV, Rubella, and congenital Toxoplasma gondii, certain types of cancer like Chronic lymphocytic leukemia, Non-Hodgkin's lymphoma, and B cell malignancies, and systemic disorders like severe burns, nephrotic syndromes, severe diarrhea, and malnutrition.

The tests needed for diagnosing hypogammaglobulinemia include: 1. Measurement of serum Immunoglobulin levels (IgM, IgG, IgA) through lab tests like a complete blood count (CBC) and checking antibody levels in response to vaccines or infections. 2. Evaluation of antibody production by looking at the number of antibodies produced in response to routine vaccines. 3. Flow cytometry to examine different subtypes of white blood cells. 4. Genetic testing, especially if there is no family history of hypogammaglobulinemia, to confirm the diagnosis and identify potential B-cell defects. 5. Additional blood tests, such as CRP and ESR to check for inflammation, and antinuclear antibody testing to check for autoimmune conditions. 6. Lymph node biopsy or bone marrow biopsy in certain cases to investigate other conditions like lymphoma or myelodysplasia.

One common treatment for Hypogammaglobulinemia is IV Immunoglobulin replacement therapy, which helps to supplement the immune system by replacing a specific part of the immune system (IgG). However, it's important to note that this therapy does not replace other parts of the immune system (IgM or IgA). Patients receiving this treatment need to have their Immunoglobulin levels checked every six months, and the dosage may need adjustments based on their production of IgG and weight. Antibiotics are also often used to treat active infections or prevent future ones, and steroid medications may be given to treat issues related to blood cell counts. In severe cases, a hematopoietic stem cell transplant or splenectomy may be suggested. Vaccines may also be recommended based on the severity of the patient's condition.

The side effects when treating Hypogammaglobulinemia can include inflammatory reactions, allergic reactions (rarely), headaches, and issues with red and white blood cells. However, it is important to note that not all conditions benefit from IV Immunoglobulin replacement therapy, and severe allergic reactions can occur, especially for those with low levels of IgA. Screening for anti-IgA antibodies before administering the treatment is necessary.

The prognosis for Hypogammaglobulinemia depends on several factors, including the presence of complications involving the lungs and the presence of cancer. The use of antibiotics and IVIG therapy have helped to reduce death rates from bacterial infections. Acting quickly can help delay or prevent these complications, but the exact amount of IgG replacement needed to prevent complications is not clear.

You should see an immunologist or an immunology specialist for Hypogammaglobulinemia.