Clinical Review

Common Variable Immunodeficiency: A Clinical Overview

Clinician Reviews. 2017 June;27(6):38-42

References

1. Bonilla FA, Barlan I, Chapel H, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(1):38-59.
2. Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545-556.
3. Barsotti NS, Almeida RR, Costa PR, et al. IL-10-Producing regulatory B cells are decreased in patients with common variable immunodeficiency. PLoS One. 2016;11(3): e0151761.
4. Rosenberg E, Dent PB, Denburg JA. Primary immune deficiencies in the adult: a previously underrecognized common condition. J Allergy Clin Immunol Pract. 2016;4(6):1101-1107.
5. Orange JS, Glessner JT, Resnick E, et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J Allergy Clin Immunol. 2011;127(6):1360-1367.e6.
6. Stray-Pedersen A, Sorte HS, Samarakoon P, et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J Allergy Clin Immunol. 2017;139(1):232-245.
7. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency—an update. Arthritis Res Ther. 2012;14(5):223.
8. Schwitzguébel AJ, Jandus P, Lacroix JS, et al. Immunoglobulin deficiency in patients with chronic rhinosinusitis: systematic review of the literature and meta-analysis. J Allergy Clin Immunol. 2015;136(6):1523-1531.
9. Chapel H. Common variable immunodeficiency disorders (CVID)—diagnoses of exclusion, especially combined immune defects. J Allergy Clin Immunol Pract. 2016;4(6):1158-1159.
10. Kakkas I. Clinical heterogeneity of common variable immunodeficiency. Hosp Chron. 2016;11(1):10-14.
11. Bonilla FA, Khan DA, Ballas ZK, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. J Allergy Clin Immunol. 2015;136(5):1186-1205.
12. Schussler E, Beasley MB, Maglione PJ. Lung disease in primary antibody deficiencies. J Allergy Clin Immunol Pract. 2016;4(6):1039-1052.
13. Harville TO. Could better categorization of pulmonary disease in common variable immunodeficiency ultimately allow for better treatment outcomes? Ann Allergy Asthma Immunol. 2014;113(4):336-337.
14. Oliveira JB, Fleisher TA. Laboratory evaluation of primary immunodeficiencies. J Allergy Clin Immunol. 2010;125(2):S297-S305.
15. Bogaert DJ, Dullaers M, Lambrecht BN, et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53(9):575-590.
16. De Vries E; European Society for Immunodeficiencies (ESID) members. Patient-centered screening for primary immunodeficiency, a multi-stage diagnostic protocol designed for non-immunologists: 2011 update. Clin Exp Immunol. 2012; 167(1):108-119.
17. Bertinchamp R, Gérard L, Boutboul D, et al. Exclusion of patients with a severe T-cell defect improves the definition of common variable immunodeficiency. J Allergy Clin Immunol Pract. 2016;4(6):1147-1157.
18. Fasano A, Catassi C. Celiac disease. N Engl J Med. 2012;367(25):2419-2426.
19. Park MA, Li JT, Hagan JB, et al. Common variable immunodeficiency: a new look at an old disease. Lancet. 2008;372(9637):489-502.
20. Cunningham-Rundles C, Maglione PJ. Common variable immunodeficiency. J Allergy Clin Immunol. 2012;129(5):1425-1426.
21. Bonilla FA, Barlan I, Chapel H, et al. International consensus document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4(1):38-59.
22. Chinen J, Notarangelo LD, Shearer WT. Advances in basic and clinical immunology in 2014. J Allergy Clin Immunol Pract. 2015;135(5):1132-1141.
23. Verma N, Thaventhiran A, Gathmann B, et al. Therapeutic management of primary immunodeficiency in older patients. Drugs Aging. 2013;30(7):503-512.
24. Jolles S. The variable in common variable immunodeficiency: a disease of complex phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545-556.
25. McCullagh BN, Comellas AP, Ballas ZK, et al. Antibody deficiency in patients with frequent exacerbations of chronic obstructive pulmonary disease (COPD). PLoS One. 2017;12(2):e0172437.
26. Wasserman RL. The nuts and bolts of immunoglobulin treatment for antibody deficiency. J Allergy Clin Immunol Pract. 2016;4(6):1076-1081.
27. Lingman-Framme J, Fasth A. Subcutaneous immunoglobulin for primary and secondary immunodeficiencies: an evidence-based review. Drugs. 2013;73(12):1307-1319.
28. Ducruet T, Levasseur M, Des Roches A, et al. Pharmacoeconomic advantages of subcutaneous versus intravenous immunoglobulin treatment in a Canadian pediatric center. J Allergy Clin Immunol Pract. 2013;131(2):585-587.
29. Driessen G, van der Burg M. Primary antibody deficiencies [educational paper]. Eur J Pediatr. 2011;170(6):693-702.
30. Kuruvilla M, de la Morena MT. Antibiotic prophylaxis in primary immune deficiency disorders. J Allergy Clin Immunol Pract. 2013;1(6):573-582.
31. Norlin AC, Hansen S, Wahren-Borgström E, et al. Vitamin D3 supplementation and antibiotic consumption—results from a prospective, observational study at an immune-deficiency unit in Sweden. PLoS One. 2016;11(9):e0163451.
32. Lougaris V, Ravelli A, Villanacci V, et al. Gastrointestinal pathologic abnormalities in pediatric- and adult-onset common variable immunodeficiency. Dig Dis Sci. 2015;60(8):2384-2389.
33. Wehr C, Gennery AR, Lindemans C, et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J Allergy Clin Immunol. 2015;135(4):988-997.
34. Shearer WT, Fleisher TA, Buckley RH, et al; Medical Advisory Committee of the Immune Deficiency Foundation. Recommendations for live viral and bacterial vaccines in immunodeficient patients and their close contacts. J Allergy Clin Immunol. 2014;133(4):961-966.

A number of conditions can cause immunosuppression. Transient reductions in serum Ig levels can occur in the presence of serious infections.²² Long-term, high-dose use of some medications, such as corticosteroids, or use of anticonvulsants may reduce antibody availability. Chronic illnesses, malignancy, and malnutrition can also play a role in immunosuppression.¹⁹ CVID shares features with a large number of primary immune diseases, and these as well as other causes of hypogammaglobulinemia must be excluded before the diagnosis of CVID can be made.¹

DIAGNOSIS

While infectious disease is a common reason patients seek medical care, few patients presenting with one will have CVID. Nevertheless, immunologic evaluations should be performed and appropriate referral to an immunology specialist is strongly recommended when more than one severe infection arises in a year’s time; when a pattern of severe or unusual infections presents over a period of time; when bronchiectasis is present; or when infections do not resolve with conventional treatment.¹⁶ In addition, the physical findings noted in the Table, when combined with a history of recurrent infections, autoimmune disorders, or lymphocytic malignancy, should prompt evaluation for CVID.^10,16,18,23

The diagnosis of CVID requires testing for low serum levels of total IgG, IgG subclasses, IgA, and IgM. In CVID, IgG and IgA levels will be reduced, and occasionally IgM levels will also be diminished.²⁴ Unless an active infection is present, there will be no change in the patient’s routine blood tests, such as the complete blood count and total complement levels.

The diagnosis is also based on demonstration of a deficient antibody response to protein (tetanus) and polysaccharide (pneumonia) vaccine antigens.²¹ A minimal reaction to these vaccines should prompt referral to an immunology specialist for additional testing and a plan of care.²⁵ However, whenever the index of suspicion for CVID is high, prompt referral to immunology should not be delayed to perform further testing.¹⁶

TREATMENT/MANAGEMENT

IgG replacement therapy, which treats the underlying pathophysiology of CVID by supplementing one of the deficient antibodies, is the standard treatment for CVID. IgG is considered a blood product since it is made from human plasma. Patients may experience untoward reactions to IgG replacement therapy, similar to transfusion reactions; such reactions commonly include back pain, low-grade fever, muscle and joint discomfort, and fatigue. These unpleasant effects can be minimized with the prophylactic use of antihistamines, antipyretics, or even glucocorticoids.²⁶

Although IgG replacement therapy has high upfront costs, it increases patients’ well-being considerably by preventing multiple or recurrent infections and the resultant hospitalizations for antibiotic therapy.²⁷ Home infusion of IgG can minimize costs as well as increase patient autonomy.²⁸ With home infusions, IgG is administered via a multisite subcutaneous route using a slow-infusion mechanical pump. Subcutaneous infusions generally take four to six hours, depending on the number of sites used. Some patients can infuse while they sleep, which increases patient satisfaction with the treatment.²⁷

A significant problem associated with CVID is the overuse of antibiotic therapy. Although it is a common practice to combine prophylactic antibiotics with IgG therapy in this population, this practice is not based on evidence.²⁹ Prophylactic antibiotic regimens are generally extrapolated from protocols to treat recurrent and prolonged infections in a non-CVID population.³⁰ Although infection must be actively treated, care should be taken to avoid excessive use of antibiotic therapy, lest this practice contribute to the development of more virulent, resistant organisms and create increased risk for this patient population.³⁰ Daily vitamin D supplementation (1,500-1,600 IU/d) is helpful to limit respiratory tract infections in immunodeficient patients without IgG supplementation who have 25(OH)D levels less than 75 nmol/L.³¹

Infections in persons with CVID can be severe and may lead to organ-system compromise, requiring aggressive therapy aimed at supporting the function of the affected organ systems. For example, patients with CVID can develop unrelenting vomiting and diarrhea, which may require inpatient admission for rehydration and stabilization until the infection can be treated adequately.³²

Treatment options remain limited for the subset of CVID patients who develop severe complications, such as interstitial lung disease or neoplasms. These complications are associated with a significant increase in patient mortality, and allogeneic hematopoietic stem cell transplantation may be indicated for patients who develop them. This potentially curative treatment is being explored in ongoing research trials.³³

Immunization of immunodeficient patients and their close contacts is a complicated but important process to ensure maximum protection from vaccine-preventable diseases; however, care must be taken to limit untoward reactions, such as transmission of disease via live agent vaccines.²¹ In general, when CVID is suspected or there is a family history of immune deficiency, inactivated vaccines should be given on schedule, but live-attenuated vaccines should be delayed until the evaluation is complete, because of the risk for disseminated infection. Specific guidance on this important aspect of patient care can be found in the Immune Deficiency Foundation’s vaccination recommendations.³⁴

Common Variable Immunodeficiency: A Clinical Overview

References

DIAGNOSIS

TREATMENT/MANAGEMENT

Pages

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