Summary
Common variable immune deficiency (CVIDs) are the name for a group of conditions that affect how the body’s immune system makes antibodies and fights infections.
If you have a CVID you are unable to make protective antibodies and therefore become susceptible to infections. Both males and females can be affected by a CVID. The clinical features of a CVID can vary from mild in those who suffer only from infections, to severe in those with disease-related complications.
Antibodies belong to a particular type of protein called immunoglobulin, which is normally found in blood and body fluids. There are three major types of immunoglobulin, known as:
- Immunoglobulin G (IgG) – the most abundant and common immunoglobulin, found in blood and tissue fluids. IgG functions mainly against bacteria and some viruses.
- Immunoglobulin M (IgM) – found in the blood, IgM functions in much the same way as IgG but is formed earlier in the immune response.
- Immunoglobulin A (IgA) – found in blood, tears and saliva. IgA protects the tissues of the respiratory, reproductive, urinary and digestive systems.
All types are made up of antibodies against the germs that an individual has met during the course of his or her life.
People with a CVID have either low levels of immunoglobulin in their blood or none at all; all are unable to make functional antibodies of the IgG or IgA types, though some patients do make IgM antibodies. This means those affected can’t fight infection as well as people with a fully working immune system. Patients may have severe, persistent or repeated infections, often from the same germ. These infections are usually bacterial, but may also be viruses, parasites and fungi. The infections particularly affect the ears, sinuses, chest, lungs or gut – places that come into daily contact with infectious agents.
CVIDs are a range of different immune deficiencies, and the diagnosis is often used inappropriately to cover more severe ‘combined immunodeficiencies’ in which antibodies and immune T-cells do not work. The disorder is called ‘variable’ because of the extent and type of immune deficiencies. Furthermore, the clinical course varies from patient to patient. In some patients, there is a decrease in both IgG and IgA in the blood; in other patients, levels of all three major immunoglobulin types, IgG, IgA and IgM, may be decreased.
Since CVID patients are susceptible to bacterial infections due to missing antibodies, the aim of treatment is to replace those antibodies with purified immunoglobulins from the blood of healthy donors. Immunoglobulin therapy, combined with antibiotics for breakthrough infections, means that people with a CVID can live relatively normal lives with no restrictions on employment. Many patients with a CVID work in healthcare or on farms.
The immunoglobulin therapy aims to prevent both infections and thedevelopment of chronic lung disease. The outlook for patients with a CVID depends on how much damage has occurred to their lungs or other organs before diagnosis and how successfully infections can be prevented in the future by immunoglobulin therapy.
Common features leading to a diagnosis of CVID
Here are some of the common features that you may recognise and which, if repeated, persistent or severe, may have led your clinician to a diagnosis of CVID.
- Sinusitis – inflammation of the air-filled spaces (paranasal sinuses) that surround the nose
- Ear infections, such as otitis media
- Throat infections, such as tonsillitis or laryngitis
- Chest infections, such as bronchitis, pneumonia or pleurisy
- Enlarged lymph nodes in the neck, chest or abdomen
- Stomach and intestinal infections resulting in persistent diarrhoea or weight loss
- Enlarged spleen (found only on examination by a doctor)
- Bleeding or bruising (due to low platelet numbers in the blood)
- Severe anaemia due to the destruction of the red cells (haemolysis)
- Skin infection, such as abscesses and boils
- Oral ulcers in association with repeated infections
- Eye infections, such as conjunctivitis
- Autoimmune diseases, joint and bowel problems.
Diagnosis is challenging
The diagnosis of a CVID is challenging because a doctor needs to exclude other reasons for the failure of antibody production. A hallmark of a CVID is recurring infections, but infections at any age are common and, even when low immunoglobulins are found, it may take some time for the significance of this to be determined. Sometimes doctors find it hard to recognise when a person has ‘too many’ infections and that makes the diagnosis difficult to pin down.
Delay in diagnosis can be serious if infections are severe. In particular, pneumonia may cause structural scarring of the lungs (known as bronchiectasis).
Those affected can feel very frustrated and angry when a diagnosis is finally made, especially if they have suffered for a long time without recognition of the cause of their symptoms.
Making the diagnosis
A clinical immunologist usually makes the diagnosis of a CVID. Tests may be intensive at the beginning of the investigative process.
Diagnosis is confirmed by blood tests that check if there are low levels of serum IgG and IgA, and usually IgM. The doctor will also test for the presence of antibodies to previous immunisations or known infections. If antibodies are not
present in the blood, then the patient will have to be immunised again and blood taken 3–4 weeks later for retesting, to ensure that the previous negative test result was significant.
Lots of different genes may be altered in CVID, and sometimes genetic testing reveals that patients with more severe or unusual forms of a CVID have another related PID, often a combined immunodeficiency. Some centres offer genetic testing to families of affected children as part of clinical trials or studies.
Other tests may include:
- A computer tomography (CT) chest scan. Patients who have had multiple chest infections may have permanent damage to the tubes in the lungs, known as bronchiectasis. This is easily diagnosed on the CT scan. To take a CT scan, the scanner rotates around the patient, building a three-dimensional image that helps the doctor to see precise detail.
- Taking samples of any infected body fluids (e.g. pus or diarrhoea) and testing for what germs are present so that the doctor can decide which antibiotics might work best.
- An ultrasound scan of organs involved in the immune system, such as the spleen.
The few people (< 10%) with antibody failure presenting in childhood are called ‘CVID’ but may have a more severe primary immune deficiency (PID). Most people do not develop symptoms until they are very much older, with age at diagnosis ranging from 16 to 80 years old. The search for the causes of antibody failure is ongoing, though common viruses have largely been excluded.
The main treatment for a CVID is replacing the missing antibodies using immunoglobulin replacement therapy. This treatment can be given intravenously (dripped into a vein through a needle in the arm or hand) or subcutaneously (injected under the skin in the lower stomach or thigh). It is usually needed every day or week for subcutaneous therapy or every 2–4 weeks for intravenous therapy, depending on the individual. Patients can usually be taught to do the treatment for themselves at home. The dose is monitored by looking at how well the treatment protects the patient against infections, since adequate therapy reduces the rate and severity of bacterial infections and may prevent them entirely. A doctor will also do blood tests periodically (typically every 3–6 months, although this may be more frequent depending on your centre’s local policies) to check the safety of the immunoglobulin therapy, and levels of IgG.
Additional treatments may be needed for people affected by chronic sinusitis or chronic lung disease. Such treatments include long-term treatment with broadspectrum antibiotics or more specific antibiotics if the bugs causing the infection are known. If lung problems have developed, such as bronchiectasis, where the airways of the lungs become abnormally widened leading to a build-up of excess mucus, physical therapy, such as physiotherapy and specific exercises, may be needed to remove the mucus from the lung airways. Rare disease-related lung complications may sometimes require treatment with corticosteroids and/or related immune suppressant medicines.
As much more is being learned about the disease processes in CVIDs, finding better targeted treatments is an active research area for many immunology centres.
Immunisation
Not all vaccines are safe to be administered to patients with a CVID and therefore you should discuss any recommended or required vaccinations with your clinical immunology team before receiving a vaccine.
Lung problems
If chronic lung disease, such as bronchiectasis, has developed before diagnosis of a CVID, those affected may have a reduced ability to exercise. Your doctor may refer you for ‘lung function tests’. These are tests that measure how well your lungs are working. You may be referred to a physiotherapist, and specific exercises may be recommended to remove the mucus from the lung airways and improve your lung health.
Autoimmunity in CVID
People with a CVID may produce damaging antibodies that attack their own tissues (autoantibodies). These autoantibodies can attack and destroy blood cells (e.g. red blood cells or platelets) resulting in severe anaemia or very low platelet counts. Other autoimmune diseases include thyroid failure, skin changes with areas of depigmentation (vitiligo) or a form of intestinal malabsorption often mistaken for coeliac disease.
Painful joints and arthritis in CVID
Some people affected by a CVID may develop painful inflammation of one or more joints, known as arthritis. Arthritis associated with CVID can involve large joints, such as knees, ankles, elbows and wrists, with smaller joints, such as finger joints, rarely affected. Infection must be excluded; joint fluid may be removed using a fine needle and analysed for the presence of bacteria or mycoplasma, as this rare pathogen can sometimes be the cause of joint infections leading to pain and destruction of the joint. In the absence of infection, symptoms of joint inflammation usually disappear with immunoglobulin therapy.
Gut problems in CVID
People affected by CVID can often have gut problems, such as abdominal pain, bloating, nausea, vomiting and diarrhoea. Involvement of the gut – or as doctors refer to it, the gastrointestinal tract – may in some instances interfere with normal growth in children or lead to weight loss in adults, owing to malabsorption of nutrients from food. This may be due to infection with a range of common organisms, such as giardia, salmonella or campylobacter. These infections can be successfully treated.
Sometimes a small sample (biopsy) of bowel tissue is taken for examination to exclude infection and search for a cause. If unexplained inflammation is found, a non-absorbable corticosteroid may be given by your doctor.
Here we answer queries people have had about CVID. You may also find useful information in the following booklets:
Q. I have CVID and a multiresistant Streptococcus pneumoniae. Am I okay to breast feed my 5 month old daughter with that bug in my system?
A. We cannot give you patient specific advice but in general terms the possible transfer of a resistant bacteria in the airways is not a contraindication to breastfeeding, but some medicines used to treat it might be. We would encourage you to discuss with your health visitor and immunology team, but usually we would encourage breastfeeding where possible.
Q. Do you get ill being a carrier of CVID?
A. The majority of CVID are not directly heritable, that is CVID rarely runs in families so it is unusual to call individuals ‘carriers’, unless a known genetic mutation has been found in that family and the inheritance pattern is known. With knowledge of the genetic abnormality it should be possible to say whether carriers could be affected or not.
Q. Can people develop CVID later in life?
A. Yes. CVID diagnosis is most common in the 20 – 40 year age range, but much older adults and children can be diagnosed.
Q. I have had immunoglobulins checked and they were normal can I still develop CVID?
A. Some antibody deficiencies can evolve over time but if you were previously tested and your symptoms have not changed since that test then it is unlikely CVID will have developed.
Q. I have CVID and luckily have not been affected by many chest/airway infections. What can I do to help prevent an occurrence – exercise?
A. Yes – anything that gets the lungs moving and gets you breathing deeply is good physiotherapy. Exercise will keep the lungs healthy and help to fight off infections. Please have a look at our booklet ‘Looking after your lungs’.
Q. My daughter has been diagnosed with a primary immunodeficiency known as ICOS deficiency. This is a very rare condition and the available information is very limited. Please can you help?
A. ICOS is a monogenic cause of common variable immune deficiency (CVID). Monogenic means controlled by a single gene. Lots of different genes may be altered in CVID and sometimes genetic testing reveals patients with more unusual forms of CVID such as ICOS deficiency. In the case of ICOS the genetic fault results in the lack of the protein molecule called inducible costimulatory of activated T-cells (ICOS). This protein acts as an immune checkpoint and plays a role in cell-cell signalling, immune responses and regulation of cell proliferation.
Our booklet on CVID captures all the information relevant to ICOS including symptoms, diagnosis and treatment. ICOS is inherited in an autosomal recessive fashion with children inheriting a faulty gene from both their mother and father. To help explain this and genetic testing please download our booklet on the ‘Genetic aspects of primary immunodeficiency’.
Q. I have CVID and am thinking of having children. What are the chances of my children having a PID and what are the risks of children inheriting the disorder?
A. There are familial cases of CVID, but these are a small percentage of all patients. Unless you have had a genetic cause of your CVID identified then it is unlikely your child would be affected, at the moment the majority of CVID patients do not have a known genetic diagnosis. It is a good idea to discuss your concerns with your immunologist, who will be able to advise based on the unique features of your clinical case.
Q. Can having CVID cause bladder problems?
A. There are no proven links between CVID and bladder problems but recurrent urinary tract infections (UTIs) can be a problem for many individuals without immune problems.
Q. Are low platelet levels with CVID a common complication? And do I need to do anything about it?
A. Some people with CVID may produce damaging antibodies that attack their own tissues (autoantibodies). These autoantibodies can attack and destroy blood platelets, resulting in low platelet counts. This condition is known as immune thrombocytopenia (ITP). The occurrence of ITP in CVID is 5-10%, which is about 1000 times commoner than in the general population. Most adults with ITP do not require active treatment unless they have significant symptoms. Extremely low platelet levels can be treated with steroids, high dose IVIG sometimes other steroid sparing agents will be used to then maintain or improve the counts. Your immunology team will discuss treatment options with you.
Q. Why is Common Variable Immune Deficiency called ‘variable’?
A. This is because the clinical course of CVID can vary from patient to patient. It was originally called variable immunodeficiencies and noted to be common.
Q. How many people per year are diagnosed with CVID?
A. This not known accurately but in the UK probably about 100.
Q. How many people are currently affected by CVID in the UK?
A. About 1 in 50,000 people have CVID.
Q. What causes CVID?
A. CVID is a multi-gene disorder, so it has lots of causes, but with the 100,000 genome and Bridge project we are getting a better idea every day of the underlying genetic causes.
Q. Does everyone with CVID have the same condition and similar health problems?
A. No there is a whole spectrum of very mild to severe. Some people only get infections and others may get additional complications from a poorly regulated immune system.
Q. Do all people with CVID need immunoglobulin replacement therapy?
A. Yes, usually they do and this will be a decision made by your immunologist.
Q. What role do environmental factors play in causing CVID?
A. It is a combination of gene and environment that result in expression of most diseases, but no one particular environmental factor is known to be important at the moment in the development of CVID.
Q. At what age can you develop CVID?
A. Cases of CVID can occur at any age but most usually occur in the second or third decade of life.
Q. What more do we know about the causes of CVID?
A. This is a complex group of patients. We know of some genes that can cause CVID but for the vast majority of patients the cause is not known. About 90% of CVID are caused by sporadic genetic changes. Clinicians and researchers are starting to unravel the genetics of CVID using faster and cheaper ways of sequencing the DNA of patients.
Q. Why do people get CVID at different ages? If its genetic then why don’t we all get it when we are young?
A. Genetics are only part of the answer. For many complex diseases the genes we inherit can predispose us to a disorder, but the environment we live in and how genes are switched on and off affect when and how severely we are affected. As we understand more about the underlying causes, we may be able to answer this more fully.
Q. I developed CVID in my 50’s and now my much younger brother has developed CVID. Do we have the same gene mutation and why didn’t we get CVID at the same age?
A. It seems likely that you both have the same genetic predisposition. We know that having the mutation doesn’t necessarily mean you will get a disease (called variable penetrance) and that there may be ‘modifiers’ that may or not come into play that trigger CVID either early, as in your brother’s case, or later in life.
Q. Is there a link between CVID and lupus (SLE)?
A. Yes sometimes people with CVID can develop autoimmune conditions such as SLE. Autoimmunity happens when the body starts to attack its own tissues and organs. It is caused by changes in how the immune system works. The immune system simply stops recognising the difference between what is ‘self’ (auto – meaning belonging to the body) and shouldn’t be attacked, and foreign organisms that should be. The effects of this autoimmune attack are inflammation and damage to the tissues of the body. Other types of PID may also have associated autoimmune complications.
You read more about the health complications in PIDs here.
Q. What proportion of patients with CVID will develop autoimmunity and inflammatory problems?
A. Autoimmunity and inflammation are the most frequent complications in CVID. About 20-40% of children with CVID may have symptoms rising to over 40% when CVID develops in adults.
Q. Is a bone marrow transplant (BMT) an option for people with CVID?
A. This depends on the type of the CVID, its genetic basis and also the health problems, past and present that the person may have. We know, at present, that different genes can cause CVID and this is allowing doctors to subgroup CVID patients into those for whom BMT may or may not be a useful treatment option. There is not much historical information on BMT in CVID. In some cases the outcomes, where poor, have to be treated with caution because the BMT was sometimes done on patients who were already ill.
Q. Can medication for depression cause CVID?
A. Many medications can cause hypogammaglobulinaemia, a disorder where the body’s immune system does make enough or any antibodies. However, CVID is a distinct diagnosis made by your doctor where other causes such as medicines have been ruled out.
Q. My child has CVID and has epilepsy. I have been told that the medication she is on might have caused her CVID. Is there a link?
A. Many medications can cause hypogammaglobulinaemia, a disorder where the body’s immune system does make enough or any antibodies. However, CVID is a diagnosis where other causes of low circulating antibodies such as medicines have been ruled out. Anti-epileptics are a common cause of secondary hypogammaglobulinaemia, i.e. the medicine may cause the low antibodies and this is no longer primary immunodeficiency (PID) but secondary (SID). It is of course possible for a child to develop CVID and subsequently develop epilepsy and be put on medication for it, in which case the prior diagnosis of CVID would be unrelated to the meds.
Q. What suggestions do you have for fatigue associated with CVID?
A. The medical perspective
Fatigue is a frequent feature of many conditions that affect the immune system. For this reason Chronic Fatigue Syndrome (CFS) requires that underlying disorders are excluded in order to make the diagnosis. Fatigue in CVID should prompt your doctor to investigate for associated autoimmune conditions (e.g. low thryoid function, anaemia etc) and for complications such as granulomatous disease. If no other associated problems are found and it is CVID associated fatigue, then the management is the same as CFS. This includes graded exercise therapy and psychological support.
The patient perspective – here are their top tips
‘I’d say just rest and take it easy’.
‘I often get aches. I find that Epsom salt baths help. Epsom salts is the active ingredient in Radox Bath salts and it is a muscle relaxant. But you need a mug full in a bath. Don’t have more than 3 a week. It will be very expensive if you buy it from a chemist! About £2 to £3 a bath! I buy it in a 25 kilo bag over the Internet for under £50! And it last for ages!’
‘Get lots of sleep.’
‘Give yourself a timeout during the week.’
‘Accept that you do need to have ‘days off’ where you really do do NOTHING.’
‘Learn how far you can push yourself and know when to stop and rest.’
‘I have Matcha tea.’
‘Have a shower it can refresh you.’
Additions are made to these FAQs periodically. The questions were reviewed by Dr Matthew Buckland, Chairman of our Medical Advisory Panel, March 2018.
You can download our information booklet here.
