Common variable immunodeficiency (CVID); a case study.Introduction
Immunoglobulins or humoral antibodies are a group of structurally related proteins that recognize the antigens and initiate mechanism that destroys them. The basic immunoglobulin (Ig) molecule is made up of four polypeptide chains consisting of a pair of heavy (H) chains (Mr 50-75 kDa each) and a pair of light (L) chains (Mr 22 kDa each) (1). There are five types of H chain ([gamma], [alpha], [mu], [delta], and [epsilon]) and two types of L chain ([kappa] and [landa]. The amino acid sequences of the variable regions at the N-terminal ends of the four chains determine the antigenic specificity of the particular antibody molecules (2). Immunoglobulins are synthesized by plasma cells, the progeny of B-stem cells in bone marrow. More mature B-cells which are found mainly in blood and lymph nodes develop receptor immunoglobulins on their surface membranes (2). In the presence of an antigen, plasma cells are proliferated and developed from these B-cells and then secrete specific antibodies capable of binding additional antigen.
There are three major groups of immunoglobulins in the serum which are IgM, IgG (four subclasses), and IgA (two subclasses) and two minor groups which are IgD and IgE. IgM is the most primitive and least specialized immunoglobulin with a pentameric structure. It is the first antibody that appears in response to antigenic stimulation. IgG is the major immunoglobulin produced by plasma cells, making up 70-75% of the total immunoglobulins, which is produced in response to most bacterial and viral infections (2). IgG is the only immunoglobulin that can cross the placental barrier providing passive immune protection for the fetus and newborn. IgA is a monomer and the idiopathic immunoglobulin present in the respiratory and gastrointestinal mucosa. It can exist in a dimeric form called secretory IgA due to additional secretory peptide called "J piece" (3). This form can be found in tears, sweat, saliva, milk, colostrum, and bronchial and gastrointestinal secretions. While IgE is known as the idiopathic immunoglobulin associated with allergic and anaphylactic reactions, IgD is the only group of immunoglobulins with unknown function.
Immunodeficiency can be classified to primary or inherited causes (rare) and secondary causes (common). There are more than 200 clinical phenotypes of primary immunodeficiency (PID) identified and about 100 of them now have well-defined molecular genetic basis. One of the most frequently encountered PID is common variable immunodeficiency (CVID) or acquired hypogammaglobulinaemia. Kalha and Sellin, however, argue that CVID is the second most common PID, second to selective IgA deficiency (4). Nevertheless, CVID is the most clinically significant form of PID. The clinical course and the degree or type of serum immunoglobulins deficiency varies from patient to patient, hence, the word "variable".
A nine year old Caucasian female presented to the Paediatric Assessment Unit (PAU) at Southland Hospital in Invercargill with chronic cough, lethargy, anorexia, and weight loss. She had been discharged from Christchurch Hospital recently with related conditions.
Immunoglobulins (IgG, IgA, and IgM) were measured on a Roche Cobas 6000 (C501 unit) using an immunoturbidimetric assay according to manufactures' methods. The immunoglobulins concentrations (Table 1) showed a low IgA concentration but a normal IgG concentration which is an atypical finding for CVID. A normal IgG concentrations in this case however, can be explained by the immunoglobulin replacement (Intragam) therapy given while she was treated in Christchurch Hospital in the previous month. Presumably, early CVID diagnosis had been made by the immunologists team at Christchurch Hospital. Unfortunately, the immunoglobulins concentrations result prior to Intragam infusion were not available. A blood specimen was taken for lymphocyte surface markers studies. The results (Table 2) showed normal amounts of CD4 and CD8. However, a low number of LGL/NK cells were identified in the blood, which indicates that the ability of immune system to recognize virus infected cells and certain tumor cells may have been compromised.
A blood specimen was also sent to LabPlus Auckland for B-cell memory cell studies. The results in Table 3 shows reduced switched memory B-cell, consistent with a B-cell maturation defect. A confirmation of CVID diagnosis was therefore made due to lack of LGL/NK cells and a B-cell maturation defect. The patient was sent to Starship Hospital, Auckland for further assessment due to her chest involvement with cryptogenic organizing pneumonia after no growth was found in the blood cultures. She was later discharged from Starship Hospital with three weekly Intragam infusion of 12 gram (maintenance dose) and 50 mg of Prednisone.
A month later, the same patient again presented to the PAU at Southland Hospital, Invercargill with three days history of becoming increasingly unwell following her most recent Intragam infusion. She had symptoms of worsening lethargy, anorexia, nausea, and low grade fever. She also appeared pale and jaundiced. Upon examination, she had a mild splenomegaly and a palpable lymph node in her right neck.
The blood count results (Table 4) indicate autoimmune haemolytic anaemia (AIHA) due to a very low haemoglobin level and an elevated reticulocytes count. This finding is supported by an elevated total bilirubin (Table 5), a very low haptoglobin level (<0.05 g/L; reference range 0.30-2.70 g/L) and a positive antiglobulin test (Coombs test). It is not possible however, to decide whether AIHA was due to CVID complication, Intragam infusion, or underlying infection. She was admitted to the Children Ward at Southland Hospital the same day. Blood transfusion was delayed due to the presence of an autoantibody in her serum. A blood specimen was sent to New Zealand Blood Service in Auckland for crossmatch before she was transfused with three units of red blood cells over the subsequent two days. Blood cultures were taken peripherally and via PICC line but no growth reported. Initially, Gentamicin and Vancomycin were given intravenously to treat possible infective cause for AIHA. Later, Vancomycin was replaced by Teicoplanin. After commencing intravenous (IV) antibiotics and transfusion, her clinical condition improved. She was discharged three days later with complete five days IV antibiotics, suspended Intragam infusion, 10 mg daily Prednisone, 20 mg daily Omeprazole, and 5 mg daily Folic Acid.
CVID is a disorder characterized by a low level of serum immunoglobulins and an increased susceptibility to infections. In most patients, there is a decrease level in both IgG and IgA. However, it has been found in some patients that all three major types of immunoglobulins (IgG, IgA, and IgM) are decreased (5). Past studies on the cells of the immune system in patients with CVID have shown a degree of lymphocyte abnormalities. Only less than 1% of patients with CVID have a low number of B-cells with the majority patients are found to have a normal number of B-cells, but they fail to undergo normal maturation which is shown by reduced switched memory B-cells in the B-cell memory cell studies (6). Consequently, they lack the mechanism of plasma cell differentiation. Some patients, however, lack enough function from helper T-cells necessary for a normal antibody response which is shown by a low CD4 count or reversed CD4/CD8 ratio (7).
The lymphocyte surface markers studies of the patient in this case study showed a low number of LGL/NK cells. Beside helper T-cells abnormality, a low number of LGL/NK cells may provide alternative explanation for a finding by Kalha and Sellin that some CVID patients have a lack of proliferative responses to T-cell receptor stimulation and decreased expression IL-2, IL-4, IL-5, and interferon (IFN)-y (4). LGL/NK cells account for up to 15% of blood lymphocytes and express neither T-cell nor B-cell antigen receptor. They release IFN-y and other cytokines such as IL-2 when activated, therefore they are essential in the regulation of haemopoiesis and immune response (8). The finding of gene defects in CVID has been difficult because of its heterogeneity. However, it has been proposed to be an autosomal dominant condition, affecting both males and females equally (9). Family studies have suggested that CVID gene defects are found in chromosome 2, 11, 16, 17 and 22. The following table shows the different types of CVID according to its gene defect found in Online Mendelian Inheritance in Man (10).
The prevalence of CVID is found to be higher in northern European descent with an estimated incidence of between 1:50,000 and 1:200,000. CVID can develop at any age but in general, it has a bimodal age of onset which peaks between ages 1-5 and 18-25 (11). The mortality rate from CVID remains high despite therapy due to delayed diagnosis and by the fact that the immune defects involve the humoral and cell-mediated system (4).
The signs and symptoms of CVID include hypogammaglobulinaemia (IgG, IgA, and/or IgM), poor titre response to vaccination with polysaccharide and protein antigens (e.g. tetanus and diphtheria), and recurring infections (due to pneumococcus, hemophilus and mycoplasma) which cause bronchitis, pneumonia, sinusitis, conjunctivitis, and otitis (11,12). These infections normally respond well to antibiotics but recur upon the discontinuation of medication. Additional symptoms such as viral infection, enlarged spleen or lymph nodes, fatigue, gastrointestinal problems (often due to Giardia lamblia), and polyarthritis/joint pain may also present (4,5,11). Even though antibody responses are depressed, patients with CVID may develop autoimmune diseases (5). These antibodies commonly attack either red cells (autoimmune haemolytic anaemia (AIHA)), white cells, or platelets. CVID may also cause additional complications such as chronic lung disease, liver disease, gastrointestinal disease, lymphoma, and granulomatous infiltration.
Generally, the diagnosis of CVID can be made by demonstrating hypogammaglobulinaemia together with poor or absent response to immunization and characteristic clinical manifestation. This is, however, a diagnosis of exclusion. The signs and symptoms of CVID can be confused with X-linked hypogammaglobulinaemia. A more specific diagnosis of CVID can also be made by performing lymphocyte surface markers and B-cell memory cell studies. Patient with CVID may show a low number of CD4 (therefore reversed CD4/ CD8 ratio) and/or a low number of LGL/NK cells in the lymphocyte surface markers studies. On the other hand, the B-cell memory studies may show reduced switched memory B-cells.
The main treatment of CVID is immunoglobulin replacement therapy. It can be given intravenously (IVIG), intramuscularly (IMIG), and subcutaneously (SCIG). The goal of the therapy is to maintain serum IgG above 5 g/L at all time. IVIG Intragam is the most common immunoglobulin replacement therapy in New Zealand. It is a sterile, preservative free solution containing 6 g of human protein and 10 g of maltose in each 100 mL. At least 90% of the protein is IgG monomer and dimer. For CVID patients, the dose of Intragam is individualized in the range of 0.2 to 0.6 g per kg body weight per month (13). It can be given as a single dose or as two equal doses at fortnightly intervals. It can also be given undiluted or diluted with up to 2 parts of 0.9% saline or 5% glucose. Intragam contains trace amount of IgA (< 0.025 mg/mL) which may provoke anaphylaxis in patient with IgA antibodies, such as those with IgA deficiency. Intragam can be given to patients with a complete IgA deficiency if the IgA is completely removed (4). Intragam therapy may induce side effects, such as headache, anaemia, nausea, vertigo, neutropenia, thrombocytopenia, and fatigue (13). Together with antibiotics therapy, immunoglobulin therapy has greatly improved the prognosis of patients with CVID. Steroids may also be given to reduce the inflammatory response. However, the prognosis of CVID also depends how much damage has been occurred to the organs due to autoimmune diseases, infections, and malignancies (5). While SCIG is relatively new treatment, it is widely believed that IMIG is painful and less effective. Intravenous IL-2 replacement has also been considered since the discovery of IL-2 deficiency in CVID (4).
In conclusion, common variable immunodeficiency is a primary immunodeficiency characterized by hypogammaglobulinaemia and increased susceptibility to infections. This autosomal dominant disorder is mainly caused by lymphocyte abnormalities. Besides measuring immunoglobulins concentrations, further testing such as lymphocyte surface markers and B-cell memory cell studies are necessary for correct diagnosis. It is not possible to heal CVID, but it can be controlled by immunoglobulin therapy replacement.
(1.) Smith AF, Beckett GJ, Walker SW, Rae PW. Lecture Notes on Clinical Biochemistry. 6th Ed. Blackwell Science, London; 1998: 91-93.
(2.) Johnson AM. Amino acids, peptides, and proteins. In: Burtis CA, Ashwood ER, Bruns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 4th Ed. Philadelphia: WB Saunders, Philadelphia; 2006: 533-595.
(3.) Lindsey BJ. Amino acids and proteins. In: Bishop ML, Fody EP, Schoeff L. Clinical Chemistry: Techniques, Principles, Correlations. 5th Ed. Lippincott Williams & Wilkins, Philadelphia; 2005: 198-199.
(4.) Kalha I, Sellin JH. Common variable immunodeficiency and the gastrointestinal tract. Curr Gastroenterol Rep 2004; 6: 377-383.
(5.) Blaese RM, Winkelstein J. Patient and Family Handbook for Primary Immunodeficiency Diseases. 4th Ed. Immune Deficiency Foundation, Illinois; 2007.
(6.) Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 2008; 111: 77-85.
(7.) Webster AD. Clinical and immunological spectrum of common variable immunodeficiency (CVID). Iran J Allergy Asthma Immunol 2004; 3: 103-113.
(8.) Roitt I, Brostaff J, Male D. Immunology. 6th Ed. Mosby, London; 2001: 21-22; 304.
(9.) Nijenhuis T, Klasen I, Weemaes CM, Preijers F, de Vries E, van der Meer JW. CVID in a family: an autosomal dominant mode of inheritance. Neth J Med 2001; 59: 134-139.
(10.) Online Mendelian Inheritance in Man (OMIM). 607594, 240500, 613943, 613494, 613495, 613496. http://www. omim.org [Accessed July 10th 2011].
(11.) Sneller MC. Common variable immunodeficiency. Am J Med Sci 2001; 321: 42-48.
(12.) Rezaei N, Aghamohammadi A, Nourizadeh M, Kardar GA, Pourpak Z, Zare A, et al. Cytokine production by activated T cells in common variable immunodeficiency. J Investig Allergol Clin Immunol 2010; 20: 244-251.
(13.) NZBLOOD. NZBS Clinical Compendium; Intragam[R]P. CSL Limited; April 28th,2008.
Christian Christian, BMLSc MNZIMLS, Medical Laboratory Scientist
Automation Department, Southern Community Laboratories, Southland Hospital, Invercargill
CC conceived and researched the study and substantively drafted the article. The author declares no conflicts of interest.
Author for correspondence
Christian Christian, Automation Department, Southern Community Laboratories, Southland Hospital, PO Box 828, Invercargill. Email: email@example.com
Table 1. Immunoglobulins concentrations. Immunoglobulins Result Reference range IgG (g/L) 9.2 6.1-15.7 IgA (g/L) 0.2 [down arrow] 0.3-2.4 IgM (g/L) 1.0 0.5-2.4 Table 2. Lymphocyte surface markers. T Cells Result Reference range CD3 (x[10.sup.9]/L 1.02 0.60-2.60 CD4 (CD3+) (x [10.sup.9]/L) 0.56 0.40-1.70 CD8 (CD3+) (x [10.sup.9]/L) 0.46 0.20-1.10 LGL/NK Cells CD56 (CD3-) (x [10.sup.9]/L) < 0.02 0.07-0.70 [down arrow] B Cells CD19 (x [10.sup.9]/L) 0.51 0.07-0.60 Total lymphocytes (x [10.sup.9]/L) 1.6 1.5-5.7 Table 3. B-cell memory cell studies. Memory naive B-cell Result Reference range CD19 32.2% CD20 32.3% Naive B-cells 88.5% 57.7-79.7% Naive B-cell phenotype: CD27-IgD+ Memory B-cells 6.7% [down arrow] 8.7-18.7% Memory B-cell phenotype: CD27-IgD+ Switched B-cells 1.2% [down arrow] 5.0-21.0% Switched B-cell phenotype: CD27-IgD+ Immunologist comment: Reduced switched memory B-cells. Consistent with a B-cell maturation defect. Table 4. Blood count Result Reference range Haemoglobin (g/L) 49[down arrow] 115-150 PCV 0.15[down arrow] 0.33-0.42 MCV (fL) 78 75-92 MCH (pg) 25.3[down arrow] 26.0-32.0 Platelets (x[10.sup.9]/L) 272 150-430 WBC (x[10.sup.9]/L) 9.7 4.0-12.0 Neutrophils (x[10.sup.9]/L) 6.7 1.80-7.50 Lymphocytes (x[10.sup.9]/L) 2.2 1.40-5.00 Monocytes (x[10.sup.9]/L) 0.7 0.20-1.00 Eosinophils (x[10.sup.9]/L) 0.0 < 1.0 Basophils (x[10.sup.9]/L) 0.1 < 0.3 Retic. Count (x[10.sup.9]/L) 160[up arrow] 20-90 Table 5. Liver function tests Result Reference range Total bilirubin ([micro]mol/L) 37[up arrow] 2-21 Alk. Phosphatase (U/L) 161 90-420 GGT (U/L) 32 < 51 ALT (U/L) 116[up arrow] 8-31 AST (U/L) 106[up arrow] < 40 Total Protein (g/L) 68 60-80 Albumin (g/L) 39 35-50 Globulin (g/L) 29 23-34 Table 6. Types of CVID according to its gene defect (Adapted from reference 10). Type Gene/locus MIM number Chromosome Gene/locus CVID1 607594 2q33 ICOS CVID2 240500 17p11.2 TNFRSF13B CVID3 613943 16p11.2 CD19 CVID4 613494 22q13.1-q13.31 TNFRSF13C CVID5 613495 11q12 MS4A1 CVID6 613496 11p15.5 CD81