Common Variable Immunodeficiency (CVID)

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1:10,000 to 1:50,000
• The largest group of symptomatic primary immunodeficiencies in adults
• Age of onset in most patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship between 20 and 30 years
• Equal incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency between genders
• The median age of death from CVID is 44 years (for females) and 42 years (for males).

Etiology and Pathophysiology

Etiology

• Exact cause unknown
• Most cases are sporadic Sporadic Selective IgA Deficiency.
• Genetic mutations Genetic Mutations Carcinogenesis account for 10% of cases; however, a monogenic cause cannot be established in the majority of cases.
  • Linked to mutations in genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure that encode cell surface proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis, cytokine receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors, and major histocompatibility complex Major histocompatibility complex The genetic region which contains the loci of genes which determine the structure of the serologically defined (sd) and lymphocyte-defined (ld) transplantation antigens, genes which control the structure of the immune response-associated antigens, human; the immune response genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. Innate Immunity: Phagocytes and Antigen Presentation
  • Familial inheritance accounts for 10%–25%.
  • X-linked, autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance, and recessive patterns have been documented.

Pathophysiology

• B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions are phenotypically normal but unable to develop into immunoglobulin ( Ig Ig X-linked Agammaglobulinemia)-secreting plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cells, leading to insufficient amounts of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins: Types and Functions:
  • IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis: long-term immunity
  • IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions: secretory immunity
  • IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions: acute immune response against infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (in 50% of cases this immunoglobulin is deficient)
• Lack of Ig Ig X-linked Agammaglobulinemia increases the patient’s risk for recurrent infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease and developing impaired immune responses, such as autoimmune diseases Autoimmune diseases Disorders that are characterized by the production of antibodies that react with host tissues or immune effector cells that are autoreactive to endogenous peptides. Selective IgA Deficiency, granulomatous disease, and malignancy Malignancy Hemothorax.
• Most often, CVID patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship are infected by Haemophilus influenzae Haemophilus Influenzae A species of Haemophilus found on the mucous membranes of humans and a variety of animals. The species is further divided into biotypes I through viii. Haemophilus, Streptococcus Streptococcus Streptococcus is one of the two medically important genera of gram-positive cocci, the other being Staphylococcus. Streptococci are identified as different species on blood agar on the basis of their hemolytic pattern and sensitivity to optochin and bacitracin. There are many pathogenic species of streptococci, including S. pyogenes, S. agalactiae, S. pneumoniae, and the viridans streptococci. Streptococcus pneumoniae, and Staphylococcus aureus Staphylococcus aureus Potentially pathogenic bacteria found in nasal membranes, skin, hair follicles, and perineum of warm-blooded animals. They may cause a wide range of infections and intoxications. Brain Abscess.

Clinical Presentation

• Recurrent, mostly bacterial, infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease (pyogenic lung, sinus infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, persistent diarrhea Persistent Diarrhea Entamoeba spp./Amebiasis)
• Autoimmune disorders (rheumatoid arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis, autoimmune hemolytic anemia Autoimmune Hemolytic Anemia Autoimmune hemolytic anemia (AIHA) is a rare type of hemolytic anemia characterized by antibody production against self RBCs, leading to destruction of these cells in the spleen and other reticuloendothelial tissues. The disease is generally categorized as warm or cold, depending on the thermal reactivity of the autoantibodies. Autoimmune Hemolytic Anemia, type 1 Type 1 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus, lupus, vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo)
• Granulomatous disease ( granulomas Granulomas A relatively small nodular inflammatory lesion containing grouped mononuclear phagocytes, caused by infectious and noninfectious agents. Sarcoidosis in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy, lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions, and GI tract that resemble sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis on histologic examination)
• Lymphoid hyperplasia Hyperplasia An increase in the number of cells in a tissue or organ without tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. Cellular Adaptation ( lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, splenomegaly Splenomegaly Splenomegaly is pathologic enlargement of the spleen that is attributable to numerous causes, including infections, hemoglobinopathies, infiltrative processes, and outflow obstruction of the portal vein. Splenomegaly, and hepatomegaly)
• High risk of malignancy Malignancy Hemothorax (commonly associated with lymphoma Lymphoma A general term for various neoplastic diseases of the lymphoid tissue. Imaging of the Mediastinum, gastric, breast, colon Colon The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix: Anatomy, prostate Prostate The prostate is a gland in the male reproductive system. The gland surrounds the bladder neck and a portion of the urethra. The prostate is an exocrine gland that produces a weakly acidic secretion, which accounts for roughly 20% of the seminal fluid. , and ovarian cancer Ovarian cancer Ovarian cancer is a malignant tumor arising from the ovarian tissue and is classified according to the type of tissue from which it originates. The 3 major types of ovarian cancer are epithelial ovarian carcinomas (EOCs), ovarian germ cell tumors (OGCTs), and sex cord-stromal tumors (SCSTs). Ovarian Cancer)
• Miscellaneous symptoms (abdominal cramps Cramps Ion Channel Myopathy, constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation, malabsorption Malabsorption General term for a group of malnutrition syndromes caused by failure of normal intestinal absorption of nutrients. Malabsorption and Maldigestion, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery, anxiety Anxiety Feelings or emotions of dread, apprehension, and impending disaster but not disabling as with anxiety disorders. Generalized Anxiety Disorder, depression, and severe lethargy Lethargy A general state of sluggishness, listless, or uninterested, with being tired, and having difficulty concentrating and doing simple tasks. It may be related to depression or drug addiction. Hyponatremia)

Diagnosis

Diagnosis is difficult because of the diversity of phenotypes.

• Clinical history
  • Note type and frequency of infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease and family history Family History Adult Health Maintenance (especially looking for history of antibody deficiency)
  • Suspect CVID if patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship present with a history of recurrent infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, autoimmune disorder Autoimmune Disorder Septic Arthritis, granulomatous disease, or a lymphocytic malignancy Malignancy Hemothorax and the following physical signs suggestive of CVID:
    • Abdomen: abdominal pain Abdominal Pain Acute Abdomen, chronic/ bloody diarrhea Bloody diarrhea Diarrhea, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus
    • Head and neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess: alopecia Alopecia Alopecia is the loss of hair in areas anywhere on the body where hair normally grows. Alopecia may be defined as scarring or non-scarring, localized or diffuse, congenital or acquired, reversible or permanent, or confined to the scalp or universal; however, alopecia is usually classified using the 1st 3 factors. Alopecia, lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy
    • Respiratory: bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis, cough, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, pleuritic chest pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions: actinic keratosis Actinic keratosis Actinic keratosis (AK) is a precancerous skin lesion that affects sun-exposed areas. The condition presents as small, non-tender macules/papules with a characteristic sandpaper-like texture that can become erythematous scaly plaques. Actinic Keratosis, atopic dermatitis Dermatitis Any inflammation of the skin. Atopic Dermatitis (Eczema), eczema Eczema Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema), mollusca contagiosum, hyperpigmentation Hyperpigmentation Excessive pigmentation of the skin, usually as a result of increased epidermal or dermal melanin pigmentation, hypermelanosis. Hyperpigmentation can be localized or generalized. The condition may arise from exposure to light, chemicals or other substances, or from a primary metabolic imbalance. Malassezia Fungi, petechiae Petechiae Primary Skin Lesions, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions cancers, vitiligo Vitiligo Vitiligo is the most common depigmenting disorder and is caused by the destruction of melanocytes. Patients present with hypo- or depigmented macules or patches which often occur on the face, hands, knees, and/or genitalia. Vitiligo
    • Systemic: signs of malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries, weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
  • Need to exclude secondary causes of antibody deficiency, hypogammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency, T-cell deficiencies, and other primary immunodeficiencies (see table below)
• Laboratory findings
  • Marked decrease in IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis (and its subclasses), IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions, and IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions (some cases of CVID will not have diminished IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions but all will have decreased IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis and IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions)
  • Poor antibody response to vaccines ( tetanus Tetanus Tetanus is a bacterial infection caused by Clostridium tetani, a gram-positive obligate anaerobic bacterium commonly found in soil that enters the body through a contaminated wound. C. tetani produces a neurotoxin that blocks the release of inhibitory neurotransmitters and causes prolonged tonic muscle contractions. Tetanus and pneumococcal vaccines)
  • Low plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell levels
• Can test for specific gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations (but not necessary for diagnosis)
• In addition, assessment of comorbid conditions:
  • High-resolution computed tomography scanning to detect lung damage
  • Culture and sensitivity testing to identify causative organisms and guide antibiotic therapy of recurrent infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma and histologic examination of suspicious lesions to rule out lymphomas

Summary of findings needed for diagnosis

• At least one of the following:
  • Increased susceptibility to infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Autoimmune disease manifestations
  • Granulomatous disease
  • Unexplained polyclonal lymphoproliferation
  • Family history Family History Adult Health Maintenance of antibody deficiency
• AND marked decrease of IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis and IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions +/- decreases in IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions
• AND at least one of the following:
  • Poor immunological response to vaccines
  • Low plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products cell levels
• AND secondary causes of hypogammaglobulinemia Hypogammaglobulinemia Selective IgA Deficiency excluded
• AND diagnosis established after age four
• AND no evidence of T cell deficiency

Management

• Ig Ig X-linked Agammaglobulinemia replacement therapy to replenish Ig Ig X-linked Agammaglobulinemia isotypes:
  • May be given intravenously, subcutaneously, or rarely, intramuscularly
  • Side effects:
    • Swelling Swelling Inflammation at the insertion site
    • Chills Chills The sudden sensation of being cold. It may be accompanied by shivering. Fever
    • Headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess
    • Nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics
    • Fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia
    • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Hives Hives Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
• Immunosuppressants Immunosuppressants Immunosuppressants are a class of drugs widely used in the management of autoimmune conditions and organ transplant rejection. The general effect is dampening of the immune response. Immunosuppressants can also be used to control autoimmune symptoms.
• Antibiotic and/or antifungal Antifungal Azoles therapy for infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Short-term corticosteroid therapy may prevent non-anaphylactic reactions (common in this condition).

Differential Diagnosis

Congenital B-cell immunodeficiencies:

• X-linked agammaglobulinemia X-linked agammaglobulinemia X-linked agammaglobulinemia, also known as Bruton’s agammaglobulinemia or Bruton’s disease, is a rare, recessive genetic disorder characterized by the improper development of B cells, leading to a lack of mature B cells capable of responding to stimulation by cell-mediated immune responses or certain antigen-presenting cells. X-linked Agammaglobulinemia: also known as Bruton’s agammaglobulinemia, a recessive genetic disorder characterized by the improper development of B cells B cells Lymphoid cells concerned with humoral immunity. They are short-lived cells resembling bursa-derived lymphocytes of birds in their production of immunoglobulin upon appropriate stimulation. B cells: Types and Functions from immature to mature cells
• Selective IgA deficiency IgA deficiency A dysgammaglobulinemia characterized by a deficiency of immunoglobulin a. Selective IgA Deficiency: the most common primary immunodeficiency Immunodeficiency Chédiak-Higashi Syndrome, characterized by an undetectable serum IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions level in the presence of normal serum levels of IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis and IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship older than 4 years