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common variable immunodeficiency (CVID)

Etiology: 1) unknown 2) patients with isolated IgA deficiency may be at increased risk Epidemiology: 1) occurs in adults, generally 3rd or 4th decade of life 2) male to female ratio 1 to 1.3 3) predominantly in whites of European descent Pathology: 1) deficiency in one or more immunoglobulin (Ig) isotypes [1] 2) global isotype switching defect in some individuals 3) defects may occur in: a) B-cell survival b) number of circulating CD27+ memory B-cells (including IgM+CD27+ B-cells) c) B-cell activation after antigen receptor cross-linking d) T-cell signaling e) cytokine expression 4) prior to development of recurrent infection, serum immunoglobulins are normal 5) B-lymphocytes & plasma cells stop functioning & serum gamma-globulins decline 6) B-lymphocytes do not respond to antigenic stimulation by maturing into plasma cells or by secreting immunoglobulins 7) infection with encapsulated organisms a) Streptococcus pneumonia b) Haemophilus influenzae c) Streptococcus pyogenes (less common) d) Staphylococcus aureus (less common) 8) infection with atypical organisms a) Mycoplasma b) Ureaplasma 9) diarrhea with Giardia lamblia is common 10) infections generally associated with T-cell dysfunction may also occur a) fungal infections b) Pneumocystis carinii pneumonia (PCP) c) Herpes simplex d) Herpes zoster 11) reduced production of interleukin-2 (IL-2) 12) reduced expression of CD40 ligand by T-cells Genetics: 1) most cases are sporadic 2) some familial cases with inheritance pattern variable 3) isolated IgA deficiency is common in families of patients with common variable immunodeficiency 4) some pedigrees of IgA plus IgG deficiency map to the class III region of the major histocompatibility complex 5) associated with defects in TNFRSF13B Clinical manifestations: 1) heterogeneous disease 2) insidious presentation - symptoms developed before age 10 in 34% - age at symptom onset is highly variable - occurs in some patients in their 70s [5] 3) recurrent bacterial sinopulmonary infections - initially, infections may be mild or limited to sinusitis - with time, bronchitis & pneumonia, otitis media occur - lobar pneumonia (32%) - bronchiectasis (23%) - recurrent infection with encapsulated bacteria - due to Stretococcus pneumoniae, Haemophilus influenzae &/or Mycoplasma pneumoniae - infection-free intervals - increasing frequency of infections 4) episodes of acute bacterial infection with adequate response to appropriate antimicrobial agents - persistent cough, postnasal drip & nasal congestion 5) infection with respiratory viruses 6) enteropathy (9%) - diarrhea & malabsoption due to gastrointestinal infections with Norovirus, Campylobacter, Giardia 7) urethritis due to Mycoplasma, Ureaplasma 8) splenomegaly (26%) [5] 9) autoimmunity (29%) (see complications) 10) solid tumors & lymphomas (8%) 11) nodular lymphoid hyperplasia (20%) [9] Laboratory: 1) serum protein electrophoresis shows hypogammaglobulinemia 2) immunofixation electrophoresis (IFE) shows deficient IgA, IgM, IgG (all) & IgG subclasses (variable) [1] - IgM & IgE levels normal [10] 3) B-lymphocyte counts are normal, T-lymphocyte counts are normal 4) bone marrow or lymph node biopsy shows absence of plasma cells 5) absence of specific antibody response to vaccination - tetanus toxoid, pneumococcal polysaccharide vaccine 6) TNFRSF13B gene mutation 7) see ARUP consult [2] Special laboratory: - ability to mount a response to tetanus toxoid & pneumococcal vaccine is compromised Diagnostic criteria: - age > 2 years - serum IgG & either serum IgA or serum IgM level >= 2 standard deviations below the mean for patient age - absent isohemagglutinins or poor vaccine response Radiology: 1) chest X-ray 2) computed tomography (CT) of thorax to identify bronchiectasis Differential diagnosis: - isolated IgA deficiency - complement deficiency - cystic fibrosis - recurrent respiratory tract infections in childhood - autoimmune disorders not a complication Complications: 1) increased incidence of autoimmune disorders a) autoimmune hemolytic anemia b) immune-mediated thrombocytopenia c) rheumatoid arthritis d) pernicious anemia e) inflammatory bowel disease f) vitiligo [10] 2) increased risk of lymphoma & non-lymphoid malignancies - lymphomas occur commonly (450-fold increase in women) [10] - non-Hodgkin's lymphoma - weight loss, night sweats, lymphadenopathy - intravenous immune globulin does nor alter risk of lymphoma 3) gastric adenocarcinoma (50-fold increased incidence) 4) malabsorption - may contribute to vitamin B12 deficiency [1] 5) viral encephalitis due to enterovirus in patients with low immunoglobulins 6) bronchiectasis 7) granulomatous disease 8) response to vaccinations is poor [1] Management: 1) intravenous immune globulin 2) treat infection aggressively 3) interleukin-2 (IL-2) therapy (experimental) 4) look for occult malignancy in patients with longstanding common variable immunodeficiency 5) avoid live virus vaccines [1]

General

mixed cellular & humoral immune dysfunction syndrome

Database Correlations

OMIM 240500

References

  1. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  2. ARUP Consult: Common Variable Immune Deficiency - CVID The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/common-variable-immune-deficiency-syndromes - ARUP Consult: TACI-Associated Common Variable Immunodeficiency, TNFRSF13B Sequencing https://arupconsult.com/ati/taci-associated-common-variable-immunodeficiency-tnfrsf13b-sequencing
  3. Chapel H, Cunningham-Rundles C. Update in understanding common variable immunodeficiency disorders (CVIDs) and the management of patients with these conditions. Br J Haematol. 2009 Jun;145(6):709-27. PMID: 19344423
  4. Park MA, Li JT, Hagan JB, Maddox DE, Abraham RS. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008 Aug 9;372(9637):489-502 PMID: 18692715
  5. Amrol DJ What Are the Clinical Features of Common Variable Immunodeficiency? NEJM Journal Watch. Aug 6, 2014 Massachusetts Medical Society (subscription needed) http://www.jwatch.org - Gathmann B et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol 2014 Jul; 134:116. PMID: 24582312 http://www.jacionline.org/article/S0091-6749%2814%2900029-3/abstract
  6. Abolhassani H, Sagvand BT, Shokuhfar T et al A review on guidelines for management and treatment of common variable immunodeficiency. Expert Rev Clin Immunol. 2013 Jun;9(6):561-74; Review. PMID: 23730886
  7. Hampson FA, Chandra A, Screaton NJ et al Respiratory disease in common variable immunodeficiency and other primary immunodeficiency disorders. Clin Radiol. 2012 Jun;67(6):587-95. Review. PMID: 22226567
  8. Sharma V, Ahuja DM (images) Nodular Lymphoid Hyperplasia N Engl J Med 2016; 375:e3. July 21, 2016 PMID: 27468084 http://www.nejm.org/doi/full/10.1056/NEJMicm1514403
  9. Abbott JK, Gelfand EW. Common Variable Immunodeficiency: Diagnosis, Management, and Treatment. Immunol Allergy Clin North Am. 2015 Nov;35(4):637-58. Review. PMID: 26454311
  10. NEJM Knowledge+ Allergy/Immunology
  11. Lee TK, Gereige JD, Maglione PJ. State-of-the-art diagnostic evaluation of common variable immunodeficiency. Ann Allergy Asthma Immunol. 2021;127:19-27. PMID: 33716149
  12. Ameratunga R, Allan C, Woon ST. Defining Common Variable Immunodeficiency Disorders in 2020. Immunol Allergy Clin North Am. 2020 Aug;40(3):403-420. PMID: 32654689 Review.