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COMMON VARIABLE IMMUNODEFICIENCYP,PID,HYPOGAMMAGLOBULINEMIA

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primary immunodeficiency-hypogammaglobulinemia- common variable immunodeficiency -an essay for master degree 2009 e mail mahmood_yasin37@yahoo.com

primary immunodeficiency-hypogammaglobulinemia- common variable immunodeficiency -an essay for master degree 2009 e mail mahmood_yasin37@yahoo.com

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  • 1. بسم الله الرحمن الرحيم
  • 2.
    • Review of genetic aspect and recent advances in common variable immunodeficiency as a main cause of hypogammaglobulinemia.
    • An essay by
    • DR/Rehab Mohammed Lepshteen
    • DR/MAHMOOD YASEEN
  • 3.
    • Contents
    • Chapter I: Primary immunodeficiency.
    • Chapter II: Primary hypogammaglobulinemia.
    • Chapter III: Common variable immunodeficiency.
  • 4. Primary immunodeficiency diseases
    • Primary immunodeficiency diseases (PIDs) are a class of disorders in which there is an intrinsic defect in the human immune system.
    • PIDs predispose affected individuals to increased rate and severity of infection, immune dysregulation with autoimmune disease, and malignancy .
    • The incidence for all PIDs together ranges from 1 / 2,000 to 1 / 10,000 live births
  • 5.
    • Primary immunodeficiency diseases are classified according to the affected limb of immune system into:
    • a) Defects in innate immunity:
    • i) Phagocytic dysfunction .
    • ii) Complement deficiencies.
    • b) Defects in adaptive immunity:
    • i) Humoral immune deficiency.
    • ii ) Cellular immune deficiency.
    • iii) Combined immunodeficiency .
    • Geha et al.,2007 summarized the classification of adaptive PIDs according to the last Committee of the International Union of Immunological Societies (IUIS) as follows :
    • A –T and B cell immunodeficiencies that include:
    • B- Predominantly antibody deficiencies
    • C- Other well-defined immunodeficiency syndromes
  • 6.
    • Etiology of PIDs:
    • Primary immunodeficiency diseases are heritable disorders of immune system function.
    • Many are associated with single gene defects, whereas others may be polygenic .
    • Complications of PIDs:
    • PIDs cause increased susceptibility to infection, autoimmune disease, and malignancy
  • 7.  
  • 8.
    • Diagnosis of PIDs :
    • Laboratory testing for the diagnosis of PIDs can be a time intensive and expensive .
    • There are four levels of laboratory testing for diagnosis of PIDs (Schroeder, 2007).
    • Jayabal , 2007 summarized the tests to detect immunodeficiency according to the suspected causes of immunodeficiency as follows:
    • 1- Complete blood count and differential.
    • 2- Quantitative serum Ig analysis by rate nephlometry .
    • 3- Antibody response tests by testing the Antibody response to pneumococcal ,tetanus, and diphtheria intramuscular vaccination. Also, cell mediated immunity testing by Candida and tetanus skin response tests .
    • 4- Immunoglobulin G subclass analysis.
    • 5- B and T cell number .
    • 6- Lymphocyte surface markers e.g. CD3, CD4 ,CD8 ,CD19 .
    • 7- Phagocyte function studies of monocytes and neutrophils.
    • 8- Natural killer cytotoxicity studies.
    • 9- Complement screening of C3,C4,CH50.
    • 10-Enzymes assay of adenosine deaminase , and purine nucleotide phosphorylase.
    • 11-Biopsies from bone marrow, lymph nodes ,skin ,thymus ,and rectum according to suspected causes.
    • 12- Familial and genetic studies.
  • 9.  
  • 10. Lines of treatment of PIDs The four principal general categories of therapy include: 1-Bone marrow and hematopoietic stem cell transplantation : hematopoietic stem cell transplantation (HSCT) is a very effective treatment for many of PIDs . The initial successful application of stem cell transplantation in 1968 in two patients with Sever combined immuno-deficiency (SCID )gave evidence that a new donor derived immune system can reverse the poor prognosis in many PIDs . 2-Gene therapy: The first true success of human gene therapy was reported with the correction of several patients with X-linked SCID by ex vivo transduction and reinfusion of stem cells with a functional copy of the gamma chain gene by using a retroviral vector (Bonilla and Geha .,2003). Now, all gene therapy using retroviral vectors for immunodeficiency are freezed after the occurrence of T cell leukemia in two of the 10 children administered gene therapy for SCID with IL2RG gene mutation. It was found that the retroviral gene construct of the IL2RG gene inserted itself on the oncogene LMO2 that is aberrantly expressed in acute lymphocytic leukemia of childhood. Thus, insertional oncogenesis was the probable cause of the T-cell leukemia in these two cases .
  • 11.
    • Lines of treatment of PIDs
    • 3-Intravenous Igs (IVIG) and subcutaneous Igs (SCIG):
    • Immunoglobulin replacement therapy is now the standard therapy for most antibody deficiencies. The half-life of IgG is approximately 21 days, and standard replacement doses of 400–600 mg/kg given every 3-4 weeks are usually a sufficient replacement . The regular injections of Igs reduces the annual incidence of infections from 12.4% to 3.2%. Immunoglobulin replacement can be given by subcutaneous injection , but Intramuscular immunoglobulins does not have a role in the management of immunoglobulin deficiency .
    • 4- Anti-microbial prophylaxis and treatment (Bonilla et al., 2005).
  • 12.
    • Prognosis
    • Certain severe PIDs e.g., SCID become apparent early in life, with only a short asymptomatic period after birth. Without an effective early intervention, the majority result in death during the first two years of life .
    • Patients with antibody or complement deficiencies can have near normal life spans if their deficiencies are diagnosed early, managed properly, and are not affected by concurrent chronic diseases.
    • The mortality causes in PIDs patients was due to respiratory infections in 43.8% , hematological disorders in 31.3% , GI complications in 9.3%,ENT complications in 9.3% , and CNS complications in 6.3%.
  • 13. Primary hypogammaglobulinemia
    • Hypogammaglobulinemia means a low level of any or all of the immunoglobulins because all of the immunoglobulins fall in the category of the serum gamma globulins .
    • Immunoglobulin deficiencies are a heterogeneous group of disorders that include :
    • I-primary hypogammaglobulinemia where B cells has intrinsic defects.
    • II- secondary hypogammaglobulinemia where B cells has normal function but other diseases affect serum antibodies level .
  • 14.
    • I -The primary hypogammaglobulinemia:
    • Primary hypogammaglobulinemia is the most common type of primary immuno -deficiency, and it accounts together for approximately half of all PIDs.
    • primary immunoglobulin deficiencies may be due to :
    • A – B cell or humoral immunodeficiency: The most common primary humoral deficiencies are:
    • 1 - IgA deficiency.
    • 2 - Common variable immunodeficiency (CVID).
    • 3 - X-linked and autosomal recessive agammaglobulinemias.
    • 4 - Transient hypogammaglobulinemia of infancy.
    • 5 - IgG subclass deficiency.
    • 6 - Specific antibody deficiency.
    • 7 - Hyper-IgM syndrome.
    • B- Combined immunodeficiency: Both humoral and cellular immunity are impaired.
    • C- Specific syndromes accompanied by antibody deficiency : It include Wiskott -Aldrich syndrome, and ataxia- telangiectasia .
  • 15.
    • II-Secondary hypogammaglobulinemia:
    • Secondary hypogammaglobulinemia occurs due to a variety of conditions that include :
    • 1-Immunoglobulin loss due to renal or gastrointestinal diseases.
    • 2-Decreased immunoglobulin production due to bone marrow diseases and malignancies .
    • 3-Medications e.g. antirheumatic drugs such as sulfasalazine and gold, systemic steroids, phenytoin, carbamazepine , and androgen replacement therapy.
    • 4-High-stress states e.g. during reduced calorie intake, sleep deprivation , and extreme physical activity (Rose and Lange, 2006).
  • 16. Common primary hypogammaglobulinemias A – B cell or humoral immunodeficiency:
    • 1- Selective IgA deficiency (sIgAD):
    • Selective IgA deficiency (sIgAD) is the most common PID in humans. According to estimates based on blood donation analyses, sIgAD incidence is 1 / 300 – 1 / 700 which is the highest incidence of all PIDs.
    • The diagnostic criteria of sIgAD includes any Male or female patient greater than 4 years of age who has a serum IgA of less than 7 mg/dl , and normal serum IgG and IgM after exclusion of other causes of hypogammaglobulinemia .
  • 17. Common primary hypogammaglobulinemias A – B cell or humoral immunodeficiency:
    • 2) X-linked and autosomal recessive agammaglobulinemias:
    • In agammaglobulinemia, there is sever decrease in B cells count and serum immunoglobulin levels. The causes of agammaglobulinemias are :
    • a- X-linked Burton's agammaglobulinemia: Due to Burton's tyrosine kinase (BTK) gene defects.
    • b- Autosomal recessive agammaglobulinemia with genetic defects in:
    • X-linked agammaglobulinemia (XLA) is the most common disorder of primary agammaglobulinemia as it accounts for 80% to 90% of all cases . In XLA due to mutations of Bruton's tyrosine kinase (Btk), there is lack of the enzyme or the generation of a non-functional enzyme leading to disturbance of the signaling pathway responsible for the maturation of pro-B cells to mature memory B cells.
  • 18.
    • 3) Transient hypogammaglobulinemia of infancy (THI):
    • Transient hypogammaglobulinemia of infancy is a heterogeneous disorder characterized by reduced serum IgG levels in early infancy .
    • Maternal IgG in the infant disappears after birth with a half-life of 25-30 days, and intrinsic IgG production usually begins immediately after birth.
    • In transient hypogammaglobulinaemia of infancy, intrinsic immunoglobulin production is delayed for up to 36 months, resulting in low IgG and IgA concentrations , but IgM concentration may be normal or low .
    • In the majority of patients immunoglobulin concentrations normalise between 2 and 4 years of age (Esser,2008).
  • 19.
    • 4) IgG subclass deficiency (IgGSD):
    • IgG exists as four subclasses i.e. IgG1 normally has the highest serum concentration, followed by IgG2, IgG3, and IgG4.
    • Patients may have a normal level of total IgG despite a markedly reduced IgG subclass .
    • IgGSD is defined as an abnormally low level of one or more IgG subclasses in patients with normal levels of total IgG and IgM.
    • The major clinical association with IgGSD is recurrent Sino pulmonary bacterial infection .
    • 5) Specific Antibody Deficiency (SAD):
    • SAD is characterized by normal concentrations of IgG, IgA, IgM, and IgG subclasses and abnormal IgG antibody responses to polysaccharide vaccines.
    • 6) The hyper IgM Syndrome (HIgM):
    • The hyper-IgM syndrome (HIgM) comprises Inherited defects in class switch recombination resulting in immunodeficiency . Patients have normal B cell count but low memory B , normal or increased IgM, and low or absent levels of IgA, IgG and IgE(Eley,2008).
  • 20. The pattern of B lymphocytes and immunoglobulin level in various types of primary hypogammaglobulinemia (Eley , 2008). Raised IgM ,Low IgG and IgA. Normal 6-HIGM Normal Normal 5-Specific antibody Deficiency. Normal Normal 4-Isolated IgG Deficiency. Low IgG, IgA , and IgM. Absent/low 3-X-linked and autosomal recessive agammaglobulinemias Low IgG and IgA, Normal/low IgM. low 2-CVID Low IgA ,Normal IgG, IgM. Normal 1-Selective IgA. Immunoglobulins B cells Disease
  • 21. Common primary hypogammaglobulinemias B- The combined immunodeficiencies:
    • Severe combined immunodeficiencies (SCIDs):
    • It is a group of genetic disorders characterized by profoundly defective T cell differentiation and B cell defects . Most patients die before the end of the second year due to infectious complications unless they receive BMT.
    • SCID is a pediatric emergency. If the diagnosis is made at birth or shortly thereafter, definitive therapy in the form of bone marrow stem cell transplantation can result in a survival rate as high as 97%, regardless of the molecular type of SCID .
  • 22. Common primary hypogammaglobulinemias C- Specific syndromes accompanied by antibody deficiency:
    • 1- Wiskott-Aldrich syndrome (WAS):
    • The classic WAS triad : thrombocytopenia/small platelets, recurrent infections as a result of immunodeficiency, and eczema.
    • Immunologic abnormalities characteristic for patients with WAS involve both B and T cell function and include defective monocyte chemotaxis as well as abnormal morphology of stimulated dendritic cells .
    • 2-Ataxia-telangiectasia (AT):
    • Ataxia- telangiectasia (AT) is an autosomal recessive inherited disease caused by inactivation mutation of the ATM gene.
    • It is a multisystemic disease with progressive neurologic dysfunction , especially in the cerebellum, oculocutaneous telangiectasia , immunodeficiency , recurrent sinopulmonary infections and high incidence of neoplasms .
  • 23. Laboratory testing of hypogammaglobulinemia
    • A- Specific tests for humoral immune function:
    • 1- Quantitative IgG, IgM, IgA, and IgE.
    • 2- IgG subclasses.
    • 3- B cell numbers in peripheral blood (CD19, CD20).
    • 4- Measurement of Antibody responses to test immunizations.
    • 5- In vitro IgG synthesis by mitogen-stimulated purified B cells.
    • 5- cultured in the presence of anti-CD40 and lymphokines.
    • 6- In vitro B cell proliferation with anti-CD40 and IL-4 effect.
    • 7- Biopsies: rectal mucosa; lymph nodes (if appropriate).
    • 8- Molecular and mutation analysis (e.g., Btk, μ heavy chain) (Chapel et al.,2007).
  • 24.
    • Measurement of Antibody responses to test immunizations includes :
    • 1-T cell dependent humoral immune response :
    • Tetanus toxoid , diphtheria toxoid, and conjugated pneumococcal polysaccharide vaccine are common T cell dependent antigens which is suitable for diagnostic tests of T cell dependant humoral immunity.
    • Protective levels of diphtheria and tetanus toxoids are titers greater than 0.01IU/ ml. The usual post- immunization response exceeds 1.0 IU/ml or a four fold rise above pre-immunization level.
    • 2-T cell independent humoral immune response:
    • The T cell independent immune response is measured by using the polyvalent unconjugated pneumococcal polysaccharide vaccine.
    • Titers exceeding 2 microgram/ml ,or a four fold rise of post-immunization titers are considered normal response.
  • 25.
    • B- Tests for T cell mediated immune function in cases of combined immunodeficiency:
    • 1- Absolute lymphocyte count.
    • 2- T cell, T subset, and NK cell enumeration (CD3, CD4, CD8; also CD16, CD56).
    • 3- Delayed-type hypersensitivity skin tests (only in older children and adults for candida, tetanus toxoid, mumps).
    • 4- In vitro proliferation of lymphocytes to mitogens (PHA, ConA), allogeneic cells, and specific antigens e.g. candida , tetanus toxoid.
    • 5- Production of cytokines by activated lymphocytes.
    • 6- Expression of activation markers e.g. CD40L, CD69, and lymphokine receptors e.g. IL-2 receptor γ chain, IFN-γ receptor after mitogenic stimulation.
    • 7- Enumeration of MHCI and MHCII expressing lymphocytes.
    • 8- Chromosome analysis e.g. probe for 22q11.
    • 9- Enzyme assays e.g. ADA, PNP.
    • 10- Biopsies: skin, lymph node, and thymus (if appropriate)
    • 11- Molecular and mutation analysis e.g., CD40L, γc chain, Jak3, ZAP-70 (Chapel et al.,2007).
  • 26.
    • Common variable immunodeficiency
    • Definition and incidence:
    • CVID represents a heterogeneous group of immunologic disorders characterized by low immunoglobulins concentration , defective specific antibody production , and increased susceptibility to bacterial infection .
    • B cells may be normal or low , and patients often have decreased numbers of switched memory B cells .
    • The prevalence has been estimated from 1/10,000 to 1/50,000.
    • HISTORICAL :
    • Janeway et al., 1953 described the first case associated with CVID.
    • Cooper et al., 1971 suggested the name of variable hypogamma -globulinemia due to the variable nature of the patients .
    • Douglas et al., 1974 and Geha et al., 1974 independently was the first to use the name of common variable immunodeficiency in a widely published medical journals.
  • 27.
    • Classification of CVID
    • The heterogeneity of common variable immunodeficiency calls for a classification addressing pathogenic mechanisms as well as clinical relevance.
    • There are 4 classification trials:
    • I-Bryant's classification of CVID 1990:
    • II- Warnatz's classification of CVID (Freiburg classification,2002
    • III- Piqueras's classification (Paris classification,2003):
    • IV-The EUROclass classification,2008:
  • 28. Classification of CVID
    • I-Bryant's classification of CVID 1990:
    • 1-Lack of B lymphocytes (difficult to differentiate from Briton's agammaglobulin-emia).
    • 2-Decreased B lymphocytic count that produce neither IgG nor IgM.
    • 3-B lymphocytes present , IgM synthesis active, but IgG synthesis disturbed.
    • 4-Proper B lymphocytic count , normal IgG and IgM synthesis, but specific antibody synthesis is disrupted .
    • II-Warnatz et al. classification of CVID (Freiburg classification,2002 ) :
    • 1- CVID group I that comprises patients with CD27+IgM-IgD- switched memory B cells below 0.4% of total peripheral blood B lymphocytes. Group I can be subdivided according to increased or normal numbers of CD19+CD21 immature B cells into:
    • a) Group Ia which includes patients with an increased proportion of CD19+CD21- immature B cells. There was significant clustering of patients with splenomegaly and autoimmune cytopenias in Group Ia.
    • b) Group Ib which includes patients with normal levels of CD19+CD21 immature B cells.
    • 2- CVID group II that includes all patients with normal numbers of CD27+IgM-2IgD- switched memory B cells (> 0.4%).
  • 29. Classification of CVID
    • III-Piqueras et al. classification (Paris classification,2003):
    • Patients were categorized into three groups:
    • Group MB0 with almost no memory B cells whether switched or non switched. There is a higher prevalence of splenomegaly , granulomatous disease, and lymphoid proliferation in group MB0.
    • Group MB1 with defective switched memory (IgD-CD27+) but normal non switched (IgD+CD27-) memory B cells. A downexpression of activation markers on B cells characterized the group MB1 patients e.g. CD25, CD21, CD80, and CD86. MB1 group was associated with an upexpression of activation markers on T cells e.g. HLA-DR, CD95,and CD57 . Splenomegaly was also frequent in group MB1 .
    • Group MB2 with normal switched (IgD-CD27+) memory B cells.
    • IV-The EUROclass classification:
    • The EUROclass trial was initiated to develop a consensus of two existing classification schemes ((Paris and Freiburg ) based on flow cytometric B cell phenotyping and the clinical course
  • 30.
    • The EUROclass classification:
    • The incidence of splenomegaly and granulomatous disease is increased in patients of (smB-) group .
    • The incidence of splenomegaly was significantly increased in (smB-CD21 low ) group of patients compared to the subgroups without expanded CD21low B cells (smB- CD21normal, and smB+ CD21normal).
    • Granulomatous disease was also more common in (smB-CD21 low) subgroup, while it was nearly absent in (smB+CD21normal ) group (Wehr et al.,2008).
    EURO Class classification >1% B cells (group B+) ≤ 1% B cells (group B-) (smB+) group with >2% switched memory B cells ( smB-) group with less than or equal to 2% switched memory B cells
  • 31.
    • 1-Monocytes dysfunction:
    • Although reduced Igs secretion from B cells is the hallmark of CVID, other immunological abnormalities such as monocyte / macrophage abnormalities are seen in a considerable proportion of patients.
    • 2-Natural killer cells dysfunction:
    • A decreased absolute numbers of peripheral blood natural killer cells have been observed in a subgroup of CVID patients .
    • 3-Dendritic cells (DCs) dysfunction:
    • Dendritic cells are professional antigen-presenting cells that are specialized in the uptake of antigens and their transport from peripheral tissues to the lymphoid organs. DCs from patients with CVID display severely disturbed differentiation and maturation with decreased expression of the co-stimulatory molecules CD80, CD86 and HLA-DR and impaired IL-12 production (Bayry et al.,2004).
    The role of Innate immunity defects in CVID
  • 32. The role of acquired immunity defects in CVID
    • B cells defects in CVID :
    • The production of antibodies by B lymphocyte derived plasma cells is regulated by a complex array of cellular and molecular interactions that take place between antigens and cells of the innate and adaptive immune system .
    • Late B cell differentiation appears to be defective in many CVID patients, resulting in normal numbers of mature B cells but decreased numbers of functional plasma and/or memory B cells (Ko et al.,2005).
  • 33. The stages of B cells development and the defect in CVID and IgAD which occurs in late stages during activation and differentiation of B cells into plasma cells ( Kokron et a.,2004).
  • 34. The role of acquired immunity defects in CVID
    • T cell interaction defects in CVID :
    • About one-half of patients with CVID show T cell dysfunction (Fernández-Ruiz et al., 2007).
    • The abnormalities of T cells in CVID include :
    • The defective thymopoiesis of naive T cells.
    • The decreased activation and proliferation of T cells.
    • The impairment of T cell dependant humoral immune response.
    • The role of cytokine defects in CVID :
    • IL-12 synthesis was increased in CVID patients.
    • Many Patients with CVID have insufficient production of IL-2 and IL-10 Excess.
  • 35. Known Genetic abnormalities in CVID :
    • Four gene mutations are found in about 10% of CVID patients .These four mutated genes are :
    • ICOS gene on chromosome 2q.
    • CD19 gene on chromosome 16p.
    • TNFRSF13C gene on chromosome 22q.
    • TNFRSF13B on chromosome 17p (Kopecky and Lukesova ,2007).
  • 36. Clinical Presentation of CVID patients
    • Patients of CVID are at risk for:
    • Chronic lung diseases e.g. bronchiectasis, and a sarcoid-like lung disease.
    • Gastrointestinal diseases e.g. inflammatory, malignant, and infectious complications.
    • Liver diseases : 10% of patients will have some type of liver disease (HBV, HCV, primary biliary cirrhosis) or evidence of granulomatous disease.
    • Autoimmune diseases : the prevalence in CVID is 22% .It includes autoimmune hemolytic anemia, idiopathic thrombocytopenia purpura, rheumatoid arthritis, and pernicious Anemia.
    • Granulomatous infiltration .
    • Lymphomas
  • 37.
    • Diagnostic criteria of CVID:
    • According to the guidelines of the international union of immunodeficiency and the European union of immunodeficiency , common variable immunodeficiency criteria are classified into :
    • probable criteria :
    • Male or female patient who has a marked decrease of IgG (at least 2 standard deviations below the mean value for age) ,and a marked decrease of at least one of the isotypes of IgA ,or IgM, and fulfills all of the following criteria:
    • Onset of immunodeficiency at above 2 years of age.
    • Absent isohemagglutinins and/or poor response to vaccines.
    • Defiened causes of hypogammaglobulinemia have been excluded .
    • B - possible criteria :
    • Male or female patient who has a marked decrease (at least 2 standard deviations below the mean value for age) in at least one of the major isotypes ( IgG,IgA ,or IgM) and fulfills all of the following criteria:
    • 1- Onset of immunodeficiency at above 2 years of age.
    • 2- Absent isohemagglutinins and/or poor response to vaccines.
    • 3- Defiened causes of hypogammaglobulinemia have been excluded (Bernatoweska et al.,2007).
  • 38.
    • Therapeutic guidelines for CVID:
    • Prophylaxis by Igs injection :
    • 1- Intravenous immunoglobulins (IVIG) : initial dose of 0.5 -0.8 g/kg b. w., next dose approximately 0.4-0.6 g/kg b. w ., every 2-4 weeks. The dose depends on the clinical course of the disease ,and should control infections. IgG levels should achieve at least 5-6 g/ l., and increased in bronchiactasis to 7-9g/l.
    • 2- Subcutaneous IgG : The same as above dosage but divided into weakly doses of 0.1-0.15g/kg/week.
    • B-Prophylaxis by antimicrobials :
    • C- Management of infections: By increasing IVIG and antibiotics according to the pathogen.
  • 39.
    • Summary and conclusion
    • CVID and PIDs patients had increased rate of infection, especially respiratory and gastrointestinal infection, autoimmune diseases, lymphoid cancer, and hematological diseases as thrombocytopenia and hemolytic anemia.
    • The delay in diagnosis and treatment of CVID and PIDs leads to increase in morbidity, mortality, and suffering of the patients due to complications . The early discovery improves the patient's prognosis and reserved medical efforts.
  • 40.
    • The absence of official registration in the developing countries leads to underestimation of PIDs incidence, delayed diagnosis, and increased morbidity due to complications. Primary hypogammaglobulinemia accounts for more than 50% of all PIDs, and one of its main causes is common variable immunodeficiency (CVID).
    • A good health education of the medical staff about PIDs and CVID for early diagnosis, official registration , early prophylaxis of infection, and treatment of complications to decrease the morbidity and mortality of PID patients and improve their quality of life.
  • 41. الحمد لله رب العالمين و شكرا لأساتذتي و السادة الحضور
  • 42. الحمد لله رب العالمين و شكرا لأساتذتي و السادة الحضور