Common Variable Immune Deficiency

Compared to other human immune defects, CVID is a relatively frequent form of primary immunodeficiency, found in about 1 in 25,000 persons; this is the reason it is called “common.” The degree and type of deficiency of serum immunoglobulins, and the clinical course, varies from patient to patient, hence, the word “variable.” In some patients, there is a decrease in both IgG and IgA; in others, all three major types of immunoglobulins (IgG, IgA and IgM) are decreased. In still others there are defects of the T-cells, and this may also contribute to increased susceptibility to infections as well as autoimmunity, granulomata and tumors.

To be sure that CVID is the correct diagnosis, there must be evidence of a lack of functional antibodies and other possible causes of these immunologic abnormalities must be excluded. Frequent and/or unusual infections may first occur during early childhood, adolescence or adult life. Patients with CVID also have an increased incidence of autoimmune or inflammatory manifestations, granulomata and an increased susceptibility to cancer when compared to the general population. Sometimes it is the presence of one of these other conditions that prompts an evaluation for CVID.

The medical terms for absent or low blood immunoglobulins are agammaglobulinemia and hypogammaglobulinemia, respectively. Due to the late onset of symptoms and diagnosis, other names that have been used in the past include “acquired” agammaglobulinemia, “adult onset” agammaglobulinemia, or “late onset” hypogammaglobulinemia. The term “acquired immunodeficiency” refers to a syndrome caused by the AIDS virus (HIV) and should not be used for individuals with CVID, as these disorders are very different.

Clinical Features of Common Variable Immune Deficiency

Both males and females may have CVID. In the majority, the diagnosis is not made until the third or fourth decade of life. However, about 20% of patients have symptoms of the disease or are found to be immunodeficient in childhood. Because the immune system is slow to mature, the diagnosis of CVID is generally not made until after the age of 4.

The usual presenting features of CVID are recurrent infections involving the ears, nasal sinuses, bronchi (breathing tubes) and lungs (respiratory tract). When the lung infections are severe and occur repeatedly, permanent damage with widening and scarring of the bronchial tree, a condition termed bronchiectasis, may develop.

The organisms commonly found in these sinopulmonary infections are bacteria that are widespread in the population and that often cause pneumonia (Hemophilus influenzae, pneumococci, and staphylococci) even in people who do not have CVID. The purpose of treatment of lung infections is to prevent their recurrence and the accompanying chronic and progressive damage to lung tissue. A regular cough in the morning and the production of yellow or green sputum may suggest the presence of chronic bronchitis or bronchiectasis.

Patients with CVID may also develop enlarged lymph nodes in the neck, the chest or abdomen. The specific cause is unknown, but enlarged lymph nodes may be caused by infection, an abnormal immune response or both. Similarly, enlargement of the spleen is relatively common, as is enlargement of Peyer’s patches which are collections of lymphocytes in the walls of the intestine.

In some cases, other collections of inflammatory cells, called granulomas, can be found in lungs, lymph nodes, liver, skin or other organs. These are largely composed of cells called monocytes and macrophages. They may be a response to an infection, but the cause is not really known.

Although patients with CVID have depressed antibody responses and low levels of immunoglobulins in their blood, some of the antibodies that are produced by these patients may attack their own tissues (autoantibodies). These autoantibodies may attack and destroy blood cells, like red cells, white cells or platelets. Although, most individuals with CVID present first with recurrent bacterial infections, in about 20% of cases the first manifestation of the immune defect is a finding of very low platelets in the blood or severe anemia due to destruction of red cells. Autoantibodies may also cause other diseases such as arthritis or endocrine disorders, like thyroid disease.

Gastrointestinal complaints such as abdominal pain, bloating, nausea, vomiting, diarrhea and weight loss are not uncommon in CVID. Careful evaluation of the digestive organs may reveal malabsorption of fat and certain sugars or inflammatory bowel disease. If a small sample (biopsy) of the bowel mucosa is obtained, characteristic changes may be seen. These changes are helpful in diagnosing the problem and treating it. In some patients with digestive problems, a small parasite called Giardia lamblia has been identified in the biopsies and in the stool samples. Eradication of these parasites by medication may eliminate the gastrointestinal symptoms.

Some patients with CVID who may not be receiving optimal immunoglobulin replacement therapy may also develop a painful inflammation of one or more joints. This condition is called polyarthritis. In the majority of these cases, the joint fluid does not contain bacteria. To be certain that the arthritis is not caused by a treatable infection; the joint fluid may be removed by needle aspiration and studied for the presence of bacteria. In some instances, a bacterium called Mycoplasma may be the cause and can be difficult to diagnose. The typical arthritis associated with CVID may involve the larger joints such as knees, ankles, elbows and wrists. The smaller joints, like the finger joints, are rarely affected. Symptoms of joint inflammation usually disappear with adequate immunoglobulin therapy and appropriate antibiotics. In some patients, however, arthritis may occur even when the patient is receiving adequate immunoglobulin replacement.

Finally, patients with CVID may have an increased risk of cancer, especially cancer of the lymphoid system or gastrointestinal tract.

Diagnosis of Common Variable Immune Deficiency

CVID should be suspected in children or adults who have a history of recurrent bacterial infections involving ears, sinuses, bronchi and lungs. The characteristic laboratory features include low levels of serum immunoglobulins, including IgG, often IgA and sometimes IgM. Another part of the diagnosis of CVID is to determine if there is a lack of functional antibody. This is done by measuring serum levels of antibody, against vaccine antigens such as tetanus or diphtheria, measles, mumps, or rubella, hemophilus or pneumococcal polysaccharide. Patients with CVID have very low or absent antibody levels to most of these vaccines.

Immunization with killed vaccines is used to measure antibody function, and this functional testing is crucial prior to beginning treatment. These tests also help the physician decide if the patient will benefit from immunoglobulin replacement therapy and can be key in obtaining insurance authorization for this therapy. The number of B- and T-lymphocytes may also be determined and their function tested in tissue cultures.

Genetics and Inheritance of Common Variable Immune Deficiency

Patients with CVID usually have normal numbers of the cells that produce antibody (B-lymphocytes), but these cells fail to undergo normal maturation into plasma cells, the cells capable of making the different types of immunoglobulins and antibodies for the blood stream and secretions.

The genetic causes of CVID are largely unknown, although recent studies have shown the involvement of a small group of genes in a few patients. These include inducible co-stimulatory (ICOS) and a few other proteins on B-cells. These appear to be causes of autosomal recessive CVID. Mutations in a cell receptor (TACI) needed for normal growth and regulation of B-cells have also been found in about 8% of patients with CVID. However, a causative role of TACI mutations in this immune defect is not yet clear, since some of these mutations can be found in people with normal immunoglobulins. As these are very rare gene defects for the most part, genetic testing is not yet required or indicated for the diagnosis of CVID.

Treatment of Common Variable Immune Deficiency

The treatment of CVID is similar to that of other disorders with low levels of serum immunoglobulins. In the absence of a significant T-lymphocyte defect or organ damage, immunoglobulin replacement therapy almost always brings improvement of symptoms. Immunoglobulin is extracted from a large pool of human plasma; it consists mostly of IgG and contains all the important antibodies present in the normal population. (See chapter titled “Immunoglobulin Therapy and Other Medical Therapies for Antibody Deficiencies.”)

Patients with chronic sinusitis or chronic lung disease may also require long-term treatment with broad-spectrum antibiotics. If mycoplasma or other chronic infections are suspected, antibiotics specific for those organisms may be indicated. If bronchiectasis has developed, a daily pulmonary toilet regimen (chest physiotherapy and postural drainage) may be needed to mobilize the secretions from the lungs and bronchi and make them easier to cough up.

Patients with gastrointestinal symptoms and malabsorption should be evaluated for the presence of Giardia lamblia, rotavirus and a variety of other gastrointestinal infections. In some cases inflammatory bowel disease is found, and this is treated by the medications normally prescribed for patients who are non-immunodeficient. Maintaining a balance between the immunosuppression used to control the autoimmune process while avoiding compounding the defects of the underlying primary immunodeficiency requires close cooperation between the patient and the various specialists involved in their care. (See chapter titled “Autoimmunity in Primary Immunodeficiency.”)

If autoimmune or inflammatory disease, granulomas, or tumors develop, the treatment is usually the same as would be given to a person with a normal immune system. However when patients with CVID have these complications, there is a tendency for them to be less responsive to therapy. Regular checkups including lung function are recommended.

Expectations for Patients with Common Variable Immune Deficiency

Immunoglobulin replacement therapy combined with antibiotic therapy has greatly improved the outlook of patients with CVID. The aim of the treatment is to keep the patient free of infections and to prevent the development of chronic inflammatory changes in tissues. The outlook for patients with CVID depends on how much damage has occurred to their lungs or other organs before the diagnosis is made and treatment with immunoglobulin replacement therapy started, as well as how successfully infections can be prevented in the future by using these therapies. The development of autoimmune disease, inflammatory problems, granulomata or malignancy can have a significant impact on the quality of life and response to treatment.

Excerpted from the IDF Patient & Family Handbook for Primary Immunodeficiency Diseases FIFTH EDITION. Copyright 2013 by Immune Deficiency Foundation, USA. This page contains general medical information which cannot be applied safely to any individual case. Medical knowledge and practice can change rapidly. Therefore, this page should not be used as a substitute for professional medical advice.

Reference: primaryimmune.org/about-pri...

Common Variable Immunodeficiency. CVID information.

Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency in adults. It is often diagnosed late when there is less scope to prevent complications. An account published by a patient and the accompanying medical view highlights important issues for better diagnosis and management.[1]

CVID is an umbrella diagnosis in that it encompasses a group of genetic disorders which result primarily in hypogammaglobulinaemia or failure of antibody production.[2] Often, specific genetic defects cannot be identified, unlike with some of the other immunodeficiency disorders. Patients typically present with recurrent infections, particularly of the respiratory tract. Gastrointestinal disease, autoimmune and inflammatory features and lymphoma are also more common in CVID.

Attempts to produce a universally accepted definition of CVID have proved difficult. The current definition, produced in 1999, relies on three criteria, all of which need to be met:[3]

Hypogammaglobulinaemia with IgG levels two standard deviations below the mean.

Impaired vaccine responses or absent isohaemagglutinins.

Exclusion of other causes of hypogammaglobulinaemia.

Whilst this definition is useful to assist in management decisions it has been criticised on the grounds that it does not take account of clinical symptoms and leads to over-reliance on the response to vaccines in the diagnosis of the condition.

Pathophysiology

In CVID there are, as implied in the name, many and varied immune-system abnormalities. To understand these, some understanding of immunology is helpful. The most common defect is in antibody formation but there are related defects in both humoral and cell-mediated lymphocytic responses.

Defective humoral responses:

Failure in differentiation of B lymphocytes.

A variety of defects at a cellular level has been described, including defects in surface molecules, absence of IgA and IgG production, increased rates of apoptosis, impaired DNA repair and others.

There is a deficiency of isotype switched memory B cells in peripheral blood. This is associated with problematic clinical complications and outcomes such as inflammatory and autoimmune conditions.

Defective cell-mediated responses. These are complex but can be summarised as:

Defective T-cell signalling.

Defective interactions between T and B lymphocytes.

CVID is characterised by:

Low levels of most or all of the immunoglobulin classes.

Lack of B lymphocytes or plasma cells capable of producing antibodies.

Frequent bacterial infections.

CVID is diverse in clinical presentation, the types of deficiency and the presence of associated diseases.The sequelae of this antibody deficiency syndrome include:

Impaired terminal B-cell differentiation which leads to varying degrees of hypogammaglobulinaemia:

Reduced levels of IgG and IgA, which are characteristic.

50% of patients also having reduced IgM levels.

50% of patients have T-lymphocyte dysfunction as well.

Susceptibility to recurrent infection by encapsulated bacteria (mainly Streptococcus pneumoniae and Haemophilus influenzae type b).

However, CVID, like other immunodeficiency disorders, is further complicated by a plethora of systemic immunopathology, such as autoimmune disease, lymphoproliferative disease, malignancy and sarcoid-like granulomas.

Aetiology[2]

There are defects in both the innate and adaptive immune systems but the cause is unknown.[4]

Genetic factors:

A disease-causing gene for an autosomal dominant CVID/IgA deficiency has been found on chromosome 4q.[5]

10% of patients with CVID have a first-degree family member with IgA deficiency.[6]

No clear pattern of inheritance has been identified.

There is a possible association with use of antirheumatic or anti-epileptic drugs.[7][8]

Epidemiology[2]

It is found in one per 25,000-50,000 subjects, depending on the ethnicity of the population. The frequency may be lower in some populations such as those in Northeast Asia.[3]

It affects male and females equally.[9]

Females have more switched memory B cells and tend to be diagnosed later and live longer.[4]

Presentation

CVID can present in infants, young children, adolescents and adults.

The diagnosis is usually made between the ages of 20 and 40 years but in 20% of cases it is diagnosed before the age of 20.[2]

CVID presents often with recurrent bacterial infection:

The most common are sinusitis, pneumonia, bronchitis, otitis, conjunctivitis and gastrointestinal infection.[10]

Septicaemia and central nervous system infections can also occur.

Persistent diarrhoea and malabsorption (causing failure to thrive in children) from gastrointestinal infections. These include Giardia lamblia (the most common), salmonella, shigella and campylobacter.[11]

Some patients present with mycobacterial or fungal infection.

Some present with Pneumocystis jirovecii.

Viral infection is uncommon although some may suffer from recurrent herpes zoster infection.

There may be associated diseases particularly:

Autoimmune diseases

Malignancies

Granulomatous disease

Dermatological manifestations

Differential diagnosis

Other diseases which may need to be excluded are:

Cystic fibrosis.

Immotile cilia syndromes.

Allergy.

Other primary immune deficiencies including:

Selective IgG subclass deficiency.

IgA deficiency.

Selective deficiency in the response to polysaccharide antigens.

Bruton's agammaglobulinaemia.

Severe combined immunodeficiency.

Protein-losing enteropathy.

Thymoma.

Transient hypogammaglobulinaemia secondary to infection.

Investigations

Greater awareness of the primary immunodeficiency disorders among generalists is still needed to avert late diagnosis and subsequent chronic ill health in patients.[1] Detailed investigation is complex and beyond the scope of general practice. Basic investigations may give some general clues with the history but referral for diagnosis is needed.

Generally, serum immunoglobulins are reduced. Serum hypogammaglobulinaemia is the key finding present in all patients with CVID but tests of immune function should also be used.[3] Further investigation is required to exclude other causes of antibody deficiency, especially in the over 50 age group. Investigation to exclude: B-cell lymphoproliferative disease, protein-losing diseases and iatrogenic or drug-related causes. The possible investigations can be summarised as:

Laboratory studies:

Autoantibody testing.

Serum electrophoresis.

Immunoelectrophoresis.

Radial immunodiffusion methods.

Immunoturbidimetric methods.

Assessment of antibody response.

Assessment of T and B lymphocytes by flow cytometry.

In vivo measures of T-cell function by assessing localised immunological skin responses.

Other measures of T-cell activity.

Imaging. This is likely to be required and may have to be extensive, including different modalities (CT scanning, MRI) according to the clinical manifestations of disease.

Further investigations, such as pulmonary function tests, bronchoscopy, microbiological and histological testing, may be required to diagnose associated diseases.

Associated diseases

Patients with CVID may have:

Bronchiectasis (particularly if presenting later), which is common.

Autoimmune diseases occurring more often than in the general population, including:

Granulomatous disease affecting:

Lungs

Spleen

Liver

Granulomatous diseases affect 15% of patients at presentation.

Malignancy:

B-cell lymphomas occur more commonly.

The risk of gastric cancer is 50 times greater in CVID.

Malignant melanomas occur in CVID.

Dermatological diseases:

Alopecia areata.

Skin granulomas - both sarcoid-like (non-necrotising) and tuberculoid (necrotising).

More widespread granulomatous disease.

Increased risk of squamous cell carcinomas and actinic keratosis.

Increased risk of polymorphic light eruption and atopic dermatitis.

Such dermatological diseases are not markers for the disease and CVID should only be considered if there are other manifestations which might implicate CVID as the cause (for example, recurrent infections).

Management[2][3]

It is likely that referral will be required to establish the diagnosis and plan treatment of the disease, the varied associated diseases and complications. It is an uncommon and complicated disease requiring both a multidisciplinary approach to care and the employment of good shared care arrangements. This involves sharing information with patients and their GPs. Information for patients and GPs about the disease and the management of the disease is essential for good care of patients.

Antibiotics for bacterial infection, usually chest or sinus infection.

Postural drainage where bronchiectasis has developed.

Immunoglobulin replacement therapy:

This can be given intravenously (most commonly) or subcutaneously.

Patients may require lifelong three-weekly infusions to maintain IgG levels above 7-8 g/L (immunoglobulins have a three-week half-life).

Infusions may delay progression to bronchiectasis by reducing the number of infections.

They may improve life expectancy and quality of life.

Unfortunately, infusions have no effect on the autoimmune or granulomatous disease which accompanies CVID.

Infusions carry a risk of acquiring transmissible infections, particularly hepatitis C.

Corticosteroids

TNF-alpha antagonists have also been used with some degree of success.[7]

Immunisations

The measles, mumps and rubella (MMR) and varicella vaccines are not recommended in patients receiving replacement immunoglobulin therapy, because the vaccines may be inactivated.

Inactivated vaccines can be given to patients with CVID but these may not be effective because of the underlying antibody deficiency.

The influenza vaccine is commonly recommended annually.

Complications

There are many potential complications due to the wide-ranging nature of the disease.

Prognosis[2]

This depends on the extent of lung damage as a consequence of infection, severity of autoimmune disease and the development of a malignancy. Numbers of switched memory B cells may also play an important role. Women tend to be diagnosed later and live longer.

Further reading & references

Taraldsrud E, Fevang B, Aukrust P, et al; Common variable immunodeficiency revisited: normal generation of naturally occurring dendritic cells that respond to Toll-like receptors 7 and 9. Clin Exp Immunol. 2014 Mar;175(3):439-48. doi: 10.1111/cei.12239.

Wood PM; Primary antibody deficiency syndromes. Curr Opin Hematol. 2010 Jul;17(4):356-61.

1. Reynolds-Wooding A; Common variable immunodeficiency. BMJ. 2008 Oct 17;337:a1855. doi: 10.1136/bmj.a1855.

2. Tam JS, Routes JM; Common variable immunodeficiency. Am J Rhinol Allergy. 2013 Jul-Aug;27(4):260-5. doi: 10.2500/ajra.2013.27.3899.

3. Ameratunga R, Woon ST, Gillis D, et al; New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clin Exp Immunol. 2013 Nov;174(2):203-11. doi: 10.1111/cei.12178.

4. Sanchez-Ramon S, Radigan L, Yu JE, et al; Memory B cells in common variable immunodeficiency: clinical associations and sex differences. Clin Immunol. 2008 Sep;128(3):314-21. Epub 2008 Jul 11.

5. Finck A, Van der Meer JW, Schaffer AA, et al; Linkage of autosomal-dominant common variable immunodeficiency to chromosome 4q. Eur J Hum Genet. 2006 Jul;14(7):867-75. Epub 2006 Apr 26.

6. Park JH, Resnick ES, Cunningham-Rundles C; Perspectives on common variable immune deficiency. Ann N Y Acad Sci. 2011 Dec;1246:41-9. doi: 10.1111/j.1749-6632.2011.06338.x.

7. Agarwal S, Cunningham-Rundles C; Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep. 2009 Sep;9(5):347-52.

8. Cojocaru IM, Cojocaru M; Reactions of the immune system in epilepsy. Maedica (Buchar). 2010 Jul;5(3):201-6.

9. Park MA, Li JT, Hagan JB, et al; Common variable immunodeficiency: a new look at an old disease. Lancet. 2008 Aug 9;372(9637):489-502.

10. Aydin Z, Gursu M, Ozturk S, et al; A case of primary immune deficiency presenting with nephrotic syndrome. NDT Plus. 2010 Oct;3(5):456-8. doi: 10.1093/ndtplus/sfq083. Epub 2010 May 11.

11. Moise A, Nedelcu FD, Toader MA, et al; Primary immunodeficiencies of the B lymphocyte. J Med Life. 2010 Jan-Mar;3(1):60-3.

Disclaimer: This article is for information only and should not be used for the diagnosis or treatment of medical conditions. LUpus Patients Understanding & Support (LUPUS) has used all reasonable care in compiling the information but make no warranty as to its accuracy. Consult a doctor or other health care professional for diagnosis and treatment of medical conditions.

Reference: patient.info/doctor/common-...

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  • Another great post, thanks Ros!

    Now I'll cut & paste an excerpt from my reply to your post earlier this week re ANA:

    "as I understand it, respectable research has found that 50% of patients develop CVID (common variable immune deficiency, a form of PID) within 5 years of diagnosis with SLE. And 67% of those patients' SLE activity decreases after the onset of CVID, suggesting that loss of B cells or functional antibody may have contributed to clinical remission"

    I think it's fantastic you're posting this info on the Primary Immunodeficiency (PID) CVID. I do see CVID mentioned on some forums, but there are other totally respectable lupus forums where there is virtually no familiarity with this type of immunodeficiency. And certainly very little understanding that primary immunodeficiency can occur along side SLE due to causes other than treatment with immunosuppression meds. My feeling is that it's very important we understand this can & does happen.

    I'm an example of a SLE patient whose symptomatology & bloods monitoring are resulting in a diagnosis of a PID:

    In my case, immunology's investigations are indicating CVID. My Vasculitis type lupus is infant onset, but systemic treatment with immunosuppressives didn't begin until my 50s. Lab blood test results show my hypogammaglobulinaemia (G, A, M) existed before lupus clinic immunosuppression treatment began a few years ago. I also characteristically have had lymphopenia & low complements, but my ANA went untested until my 50s and since then has been neg. in my 30s-40s medic's misdiagnosed a rare tumour of the connective tissue as arthritis...by the time it was recognised & amputated, the tumour was 14 years old and had become malignant (chnodrosarcoma). Research rheumatologists tell me that these sort of malignancies do characterise patients like me, and do influence both the character & course of their version of immune dysfunction & connective tissue disorder.

    During immunology investigations over the past year +, I've made no antibody response to pneumonia vaccines & haemophilus B. So immunology has me on daily prophylactic antibiotics with a view to starting IV Ig this year. I'm also vascular type EDS with dysautonomia. I'm on a very effective daily combined therapy SLE treatment plan (low dose myco + low dose pred + hydroxy + low dose amitrip).

    These 2 excerpts from your post underline the points I've tried to make earlier in my reply:

    "Patients with CVID also have an increased incidence of autoimmune or inflammatory manifestations, granulomata and an increased susceptibility to cancer when compared to the general population. Sometimes it is the presence of one of these other conditions that prompts an evaluation for CVID...

    ...The development of autoimmune disease, inflammatory problems, granulomata or malignancy can have a significant impact on the quality of life and response to treatment."

    Again, many thanks Ros, for helping us to better understand the significance of these important subjects: knowledge is power

    🍀🍀🍀🍀 Coco

  • Anything I can do, I will. Like you, I believe that patients need and deserve accurate and up to date information. There are too many unreliable sources on the internet.

    Thank you VERY much for posting. If you have the time, perhaps you can visit the LuPUS Message Board.

    My way of thanking you is to award you LUPUS-SUPPORT and Volunteer Badge. I hope that is OK. I want to encourage more people to become active in helping themselves and other people within a supportive environment. Any suggestions welcome!

    With good wishes,

    Ros

  • Gosh: this is a BIG honour, Ros....am speechless 🤗

    Many thanks!

    Sorry: i forget how to find the Message Board...

    WBW

    Coco

  • The honour is mine to have you.

    Any problems in registration let me know. I alogging off for today!

    We also have another website called the LuPUS Message Board where you can also post questions and talk to other people. Registration is FREE and we offer free information and free online psychological support. We specialise in psychological support with our own counsellor/psychotherapist available.

    By becoming a Member, you will have access to the private forums and because they are private, only Members have access and even bots and search engines are forbidden.

    When you register, please use the following format for entering your date of birth: nn-nn-nnnn where n=number. Please use the "-" separator and not "/".

    Finally, please go to: lupus-support.org/LuPUSMB and Sign Up.

    I look forward to talking with you more!

    Sometimes we need to talk to people who understand and who are not family or friends.

    With good wishes!

    Ros

    Disclaimer: No attempt is made to diagnose or to make any medical judgement. You are advised to seek the advice from your own physician. LUpus Patients Understanding & Support (LUPUS) is not a substitute for your own doctor.

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