What is Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)?
Common Variable Immunodeficiency Disorder (CVID) is not a single disease, but rather a collection of different conditions that affect the immune system in various ways. It’s a disorder where the body has lowered levels of certain proteins called immunoglobulins, specifically types G, A, or M. These proteins play a key role in our body’s defense against infections.
People with CVID often suffer from frequent infections, notably in the sinuses and lungs, plus autoimmune problems, certain types of diseases that cause abnormal tissue growth, and an increased risk of cancer. They also have difficulty producing antibodies, even though their body has an appropriate number of the cells typically responsible for this job.
CVID is the most common symptomatic disorder of the immune system reported worldwide. It can result from a range of genetic flaws, which are mostly specific molecular defects that we still can’t fully explain. It’s called “variable” because its symptoms and effects can vary widely from person to person.
What Causes Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)?
The exact cause of CVID, or Common Variable Immune Deficiency, is still unknown, even after over 40 years of study. What we do know is that both environmental and genetic factors may play a part. Roughly 20% of people with CVID have a family member with a particular type of immune deficiency involving some immune proteins known as IgA.
While the specific environmental factors are still unknown, some genetic issues can influence CVID. These issues can lead to problems with both B cells and T cells, types of white blood cells that play key roles in our immune system. These problems are caused by various genetic mutations which lead to deficiencies in proteins like CD19, ICOS, and TNF receptors. But interestingly, CVID can occur even when there’s no known genetic mutation. Other reported genetic issues affecting proteins such as MSH5, CD81, and CD20 are also associated with CVID.
It’s important to note that there’s no clear pattern in how CVID is inherited. It’s been reported in many different patterns, including autosomal dominant with variable penetrance, autosomal recessive, and X-linked forms.
Risk Factors and Frequency for Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)
Common Variable Immune Deficiency (CVID) is a condition that affects around 1 in 25,000 people. It’s particularly common in Northern Europe. This condition is usually diagnosed after puberty, most often between the ages of 20 and 45. It doesn’t affect certain racial groups or genders more than others.
Signs and Symptoms of Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)
Chapel and colleagues grouped CVID (Common Variable Immunodeficiency) into five types. They found that about 80% of patients fit only one type, while roughly 13% matched two. These types are:
- Uncomplicated: where patients mostly just suffer from infections
- Autoimmunity
- Polyclonal lymphocytic infiltration: this could come with a range of symptoms like abnormal lung tissues, unexplained swellings in the liver or spleen, and enlarged lymph nodes
- Enteropathy: identified when a biopsy finds lymphocyte infiltration into the mucus-secreting cells and inner linings of the intestine, which also have damaged hair-like structures called villi
- Lymphoid malignancy: a cancer that starts in the cells that become lymphocytes, a type of white blood cell
With newly diagnosed CVID patients, clinicians have to think about two things when assessing their conditions: those related to infection and those that are not caused by infection.
Throughout their lives or at the onset of the disease, CVID patients might experience the following symptoms:
- Infections caused by common organisms like the flu, strep, and staph, and rare kinds like Pneumocystis jirovecii and Mycoplasma pneumoniae, leading to:
- Recurrent infections in the sinuses and lungs that can cause bronchiectasis – a permanent widening of the airways which includes pneumonia, bronchitis, and sinusitis
- Ear inflammation
- Eye inflammation
- Infection in the joints
- Bacterial meningitis
- Systemic infection spread through the bloodstream
- Skin infections
- Persistent lung diseases that cause persistent coughing and difficulty breathing
- The formation of granulomas, which are clumps of immune cells
- Immune system-related disorders, including a low platelet count and abnormal red blood cell destruction by the immune system (immune thrombocytopenia and Coombs-positive autoimmune hemolytic anemia)
- Conditions like rheumatoid arthritis, systemic lupus erythematosus, dryness syndromes (like Sjogren’s syndrome), autoimmune thyroiditis, and white patches on the skin (vitiligo)
- Diseases of the stomach and intestines, including persistent diarrhea and absorption disorders due to various infections and autoimmune disorders
- Skin conditions, including hair loss (alopecia) and skin inflammation with damage to blood vessels (vasculitis)
It’s important to note that a physical examination of these patients might be normal. However, there could be signs and symptoms of chronic illness, such as;
- Nasal congestion from chronic sinusitis
- Scarring in the eardrums from recurrent ear inflammation
- Weight loss, night sweats, and fever (B symptoms) due to lymphoid malignancy
- Fingers and toes looking club-like, chronic productive cough, and difficulty breathing due to chronic lung disease
- Enlarged lymph nodes, enlarged spleen, joint inflammation, eye inflammation, oral thrush, etc.
Testing for Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)
If you have symptoms that suggest Common Variable Immunodeficiency Disorder (CVID), your doctor may need to carry out a series of laboratory tests and checks. These will help them determine whether it’s CVID or another condition causing your symptoms. Laboratory tests might include regular blood counts, tests called Coombs in cases of new anemia, and bone marrow biopsy among others. Your doctor will want to know if you reacted to vaccines such as tetanus, diphtheria, hepatitis, and pneumococcal, and they might carry out a type of test called ‘flow cytometry’ to look at certain types of cells in your body. They may even look at your sputum (mucus you’ve coughed up) to see what types of germs are present.
Checking your lungs is very important if you have suspected CVID. Although there isn’t a universal agreement on how to screen for lung diseases, some recommendations include regular checks for changes in your breathing and the consistency of your sputum. Tests to measure how well your lungs work (how well you can breathe and how well your lungs deliver oxygen to your blood) and x-rays of the chest may be performed. More advanced imaging such as high-resolution computed tomography (HRCT) can be used to look for damage to the lungs, and lung Magnetic Resonance Imaging (MRI) might be an option as a low-radiation alternative. Bronchoscopy and bronchoalveolar lavage, two techniques that involve looking directly into the lungs and collecting cells from the lungs, might be used if granulomas (a type of inflammation) are suspected in the lungs.
Apart from your lungs, your doctor may also check for disease in your lymph nodes and gastrointestinal tract, using imaging techniques like ultrasound, CT, or MRI. In certain cases, such as suspected lymphoma (a type of cancer), a lymph node biopsy (a test where a small piece of the lymph node is removed for examination) might be required. In case of certain neurological symptoms, analysis of your cerebrospinal fluid (the fluid that surrounds your brain and spinal cord) might be carried out.
If CVID is suspected, it’s common to find that IgG, a type of antibody, is below the normal limits in your blood. Other types of antibodies, like IgM and/or IgA, can also be below normal. The response of your body to certain vaccines and the levels of certain types of memory B cells in your blood can be examined using a technique called flow cytometry. Although not necessary for diagnosis, molecular analysis could be an option especially if there are other family members affected by CVID.
To rule out other diseases like cancer or autoimmunity in case of gastrointestinal disorders, pulmonary nodules, and certain skin findings, biopsies may often be required.
Treatment Options for Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)
Immunoglobulin replacement is the primary treatment for patients who can’t produce enough immunoglobulins on their own. This method can help reduce the risk of repeated infections and their complications. The treatment includes an initial slow infusion of intravenous immune globulin, or IVIG, followed by maintenance doses. Patients begin treatment after they have recovered from an active infection with appropriate hydration. The progress of the treatment is monitored by checking the levels of immunoglobulins in the patient’s body every six months. The dose is adjusted accordingly. The side effects of IVIG can vary from person to person and depend on various factors including dosage, infusion rate, organ dysfunction, and the brand of the product.
Active infections in patients are treated with longer courses of antibiotics. Before beginning treatment, results of sputum examination or bronchoalveolar lavage are taken. The use of prophylactic antimicrobials, which help prevent infections, is not routinely recommended. However, the patient is observed closely in case of any exacerbation of sinopulmonary infections. High-risk patients should take preventive measures during the flu season, and may consider antiviral therapy.
Autoimmune disorders in these patients can be treated with glucocorticoids as the first line of treatment. If glucocorticoids do not work, rituximab is the next option. In very severe cases, removal of the spleen could be considered. Treatment for rheumatologic diseases involves the same methods as for non-immunocompromised patients, along with immunoglobulin replacement.
Patients suffering from malignancies are treated based on general protocols. These patients should undergo testing for Helicobacter pylori infections and laboratory features of pernicious anemia due to their relation to stomach cancer.
Vaccination recommendation for these patients depends on the severity of their antibody deficiency. Those with mild deficiencies should follow the routine schedule for inactivated or subunit vaccines, and those with severe deficiencies should take particular vaccines as per their medical advice. Patients with mild deficiency might also benefit from a few live-attenuated vaccines, but these vaccines are usually not recommended for those with severe deficiencies.
There are a few other recommendations for the overall well-being of these patients. Prevention of pulmonary diseases, regular dental care, mental health support, hearing care are a few important aspects. These patients should not be given blood or blood components without testing for cytomegalovirus. Parents of patients should receive genetic counseling due to the possibility of their other children having the same disease.
What else can Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies) be?
When diagnosing CVID, which stands for Common Variable Immune Deficiency, doctors mainly check for hypogammaglobulinemia – a condition where the body doesn’t produce enough antibodies (or immunoglobulins).
This condition can either be primary or secondary. Primary hypogammaglobulinemia, often found in children, happens when the body naturally doesn’t produce enough of important antibodies like IgG1 and IgG2. Another form is hyper-immunoglobulin M syndromes – where one type of antibody is high, while others are low. Lastly, there can be other combined immune deficiencies.
Secondary hypogammaglobulinemia, on the other hand, can be caused by external factors like medication or conditions affecting bone marrow function. In other cases, the body might produce enough antibodies, but they’re being used up or lost too quickly. This can be due to diseases causing loss of protein such as those affecting the intestines and kidneys or due to severe burns.
What to expect with Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)
The data on medical complications and mortality rates come from a study that tracked 473 patients over 40 years in New York. The patient’s prognosis, or likely outcome, is influenced by the presence of lung complications, such as respiratory failure due to chronic lung disease, and cancers, particularly of the lymphoid type. Early and appropriate treatment can prevent or slow down the development of these conditions.
Non-infectious complications are quite common, affecting 60 to 70% of patients, and can increase the risk of death eleven-fold. However, deaths caused by bacterial infections have considerably decreased, thanks to the use of immune globulin therapy. Indeed, patients suffering only from infectious complications experience a 95% lower mortality risk.
Generally, patients with CVID – a form of immunodeficiency – have about a 20% mortality rate when compared to people of the same age and gender. Cancer cells in these patients do not necessarily resist standard treatments more than usual, but they are more likely to spread, necessitating more aggressive treatment, which might have severe side effects.
Certain factors can be used to predict the risk of death, including lower levels of a type of antibody called IgG, fewer circulating class-switched memory B cells, increased levels of another antibody called IgM, and a higher prevalence of autoimmune disease, granuloma formation, recurrent bacterial pneumonia, and lymphoid hyperplasia.
However, it is currently uncertain how effectively the replacing of IgG could prevent complications.
Possible Complications When Diagnosed with Common Variable Immunodeficiency (Immune Deficiency due to Low Levels of Antibodies)
Some people suffering from CVID, or Common Variable Immune Deficiency, might experience complications which at times could be the first indicators of the disease. People diagnosed and treated early on are not exempt from the possibility of future complications, which could impact their lifespan.
It’s vital to note that complications often come hand in hand with lung disease. Therefore, patients showing any symptoms linked to respiratory issues should be thoroughly checked using a High-Resolution Computed Tomography scan (HRCT).
Pulmonary complications do occur with varied frequency, with common ones being:
- Bronchiectasis: This affects around 20% of patients. It’s usually a response to repetitive bacterial infections or inflammation in the lower airways.
- Bronchospasm: Unusual constriction in the airways, causing difficulty in breathing.
- Obstructive and Restrictive Lung Disease: Conditions where insufficient air is reaching the lungs or the lungs can’t Fully expand.
- Granulomas: Tiny areas of inflammation in tissue.
CVID patients also have an elevated risk, approximately 4% to 25%, of developing cancer. The most common cancers reported are:
- Non-Hodgkin lymphoma: Mostly, it originates outside of the lymph nodes. Women above 30 are at greater risk. The B cell type, typically well differentiated, is the most common one found.
- Gastric Carcinoma: Tied to Helicobacter pylori infection and gastritis, it’s usually diagnosed in younger individuals compared to the general stomach cancer population. Typically, it’s a moderately to poorly differentiated adenocarcinoma with a high count of intra-tumor lymphocytes.