Clinical Review

Common Variable Immunodeficiency: A Clinical Overview

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

Author(s):

Often appearing as recurrent or recalcitrant infections, the diagnosis of common variable immunodeficiency (CVID) is often missed. Patients remain untreated for long periods of time, resulting in complications. Arm yourself with expert information about this rare genetic disorder.

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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.
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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.

IN THIS ARTICLE

Diagnosis
Treatment/management
Physcial signs suggestive of CVID in patients with appropriate history
Case outcome

A 60-year-old woman with a recent history of air and cruise ship travel presented with symptoms consistent with acute sinusitis. She had a 34–pack-year history of cigarette smoking but had quit at age 50. Her medical history was significant for hypothyroidism, hypertension, coronary artery disease, mild asthma, and COPD. Past surgical history included coronary artery bypass, abdominal hysterectomy, and cholecystectomy. Her medications included inhaled bronchodilators, thyroxin, hydrochlorothiazide, nitrates, ß-blockers, and calcium channel blockers.

Over the next five years, she presented with frequent episodes of respiratory illness for which she received multiple courses of antibiotics, inhaled bronchodilators, and oral as well as inhaled corticosteroids. She consequently became increasingly sensitized to multiple antibiotic classes and was frequently hospitalized for the treatment of her respiratory illnesses.

Common variable immunodeficiency disorders (collectively known as CVID) are the most common clinically significant immunodeficiency diseases among adults.¹Manifesting clinically as frequent, unusually severe or recalcitrant bacterial infections of the ear, sinus, respiratory tree, and/or gastrointestinal tract, CVID is genetically induced.² Additionally, these disorders can predispose individuals to autoimmune conditions and to cancers involving B lymphocytes.³ Often thought to be a disease of younger people, CVID can occur across the age span.⁴

The immune dysfunction that characterizes CVID is believed to result from underlying genetic defects that affect the differentiation of B cells, leading to faulty immunoglobulin (Ig) synthesis. Recent advances that allow the detection of multiple novel susceptibility loci for CVID have dramatically increased our understanding of the pathophysiology and pathogenesis of this disorder.⁵ These advances are being used to refine the diagnostic parameters of CVID and in the future may help clinicians tailor treatment protocols to specific genetic defects.^5,6

Although considered rare, CVID is often unrecognized; the incidence is likely much higher than the current estimates of 1:10,000 to 1:50,000.⁷About 13% to 23% of individuals with chronic sinusitis are thought to be affected by CVID.⁸ While it is most commonly diagnosed during the second and third decades of life, it can be diagnosed at any time during the lifespan.⁴ A high burden of disease is associated with this disorder, as hospitalizations and costly, aggressive treatment regimens are needed to manage the resultant bacterial infections and sequelae.²

Increased awareness of CVID among primary care providers is needed to assure prompt diagnosis and to avoid unnecessary complications associated with delayed treatment. The diagnostic workup is complex, and referral to immunology for specific diagnosis and treatment is strongly advised. Recognition is the first step, and primary care providers must include primary immunodeficiency disorders, including CVID, in their differential to avert a missed diagnosis and to ensure optimal treatment.⁹

CLINICAL MANIFESTATIONS/PATIENT HISTORY

Frequent and severe infections are a hallmark of CVID. The most common types of infections seen in CVID are sinusitis, conjunctivitis, otitis media, bronchitis, pneumonia, and gastroenteritis.¹⁰ These primary bacterial infections can disseminate, causing septicemia and/or central nervous system infection.¹¹ The usual infectious pathogens are encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae, but atypical infections due to organisms such as Pneumocystis carinii and Mycoplasma pneumoniae also occur in some patients.^12,13

Ten percent to 40% of cases of chronic diarrhea are the result of CVID.^4,10 Common causative organisms include Giardia, salmonella, Shigella, and Campylobacter.¹⁰Patients with CVID are also susceptible to fungal and mycobacterial infections, but with the exception of herpes simplex and herpes zoster, viral infection is uncommon.¹⁴ CVID also predisposes patients to a myriad of autoimmune, granulomatous, and malignant diseases.¹⁵

Although the majority of CVID cases occur sporadically, family history is helpful in securing the correct diagnosis.¹⁵ Known immunodeficiency, unusual susceptibility to infections, autoimmune diseases, hematologic malignancy, or death caused by infection in other family members should increase the provider’s index of suspicion for CVID.¹⁶

Many genetic defects have been implicated in CVID, yet the wide phenotypic expression found even in persons with similar genetic profiles implies that CVID has a complex genetic transmission pattern.¹⁵ Known or suspected consanguinity in parents or grandparents increases the risk for CVID.⁶

Although these family history elements occur infrequently, they increase the likelihood of severe opportunistic infection, which can cause organ damage or even death.^1,17 Being alert for these elements of family history can help to avoid delays in diagnosis and treatment and eventual organ damage.²

DIFFERENTIAL DIAGNOSIS

When considering the differential diagnosis for the primary features of CVID, other etiologies that should be considered include allergies, environmental exposures, uncontrolled gastroesophageal reflux disease, structural abnormalities of the upper respiratory tract, and celiac disease.^5,10,18,19 Far less common but still worthy of consideration are other genetic conditions, such as primary ciliary dyskinesia, cystic fibrosis, thymic dysfunction or carcinoma, and protein-losing enteropathies.^20,21

Common Variable Immunodeficiency: A Clinical Overview

References

CLINICAL MANIFESTATIONS/PATIENT HISTORY

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DIFFERENTIAL DIAGNOSIS

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