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Non-Infectious Complications of Common Variable Immunodeficiency

Non-Infectious Complications of Common Variable Immunodeficiency

Common variable immunodeficiency (CVID) is the most common type of symptomatic primary immune deficiency disorder, affecting approximately 1 out of every 25,000 persons. The most recent guidelines suggest CVID in the presence of the following: low immunoglobulin (Ig) G levels, based on age; either low IgM or IgA; poor antibody response after vaccination; older than 4 years of age; and no secondary causes of hypogammaglobulinemia. Secondary causes of hypogammaglobulinemia can include liver disease, nephrotic syndrome, protein-losing enteropathy, or medication-induced hypogammaglobulinemia.

The most common presentation of CVID is recurrent sinopulmonary infections, including sinusitis and pneumonias. GI infections can also be common, with many presenting with infectious diarrhea. While the majority of patients with CVID typically present with these recurrent infections, some patients can present with non-infectious autoimmune and inflammatory complications. It is important for the provider to be aware of the non-infectious complications of CVID to ensure prompt diagnosis.

Non-infectious presentation can include autoimmune complications, which are common in CVID—specifically autoimmune cytopenias, which occur in up to 20% of patients with CVID. Autoimmune manifestations can also include enteropathy, atrophic gastritis, pernicious anemia, alopecia, vitiligo, psoriasis, hypothyroidism, and type 1 diabetes mellitus, among many others. Systemic lupus erythematosus, vasculitis, autoimmune pancreatitis, and recurrent aphthous ulcers may also be seen.

Other non-infectious presentations may include chronic lung diseases. These are frequent complications seen with CVID, and include asthma, bronchiectasis, and interstitial lung disease. Non-infectious GI complications may include inflammatory bowel disease, autoimmune conditions, or GI-related malignancies. GI-related complications are associated with increased morbidity and reduced quality of life in patients with CVID. Hepatic complications include chronic liver diseases such as primary biliary cholangitis, cirrhosis, portal hypertension, and esophageal varices, among others. Specifically, granulomatous hepatitis and nodular regenerative hyperplasia of the liver are extremely rare outside of CVID, so work-up should be done in patients presenting with these conditions. Additionally, patients with CVID have an elevated risk of lymphoma compared to the general population, with non-Hodgkin lymphoma being most common.

When encountering patients with various autoimmune conditions in clinical practice, one should consider screening patients for hypogammaglobulinemia, especially those with cytopenia. Laboratory tests including quantitative immunoglobulins, complete blood count, comprehensive metabolic panel, lymphocyte subsets, as well as measurement of antibodies to vaccines (most commonly, Streptococcus pneumonia titers; but diphtheria toxoid, tetanus toxoid, and Haemophilus influenzae can also be ordered). Vaccine response would be assessed with repeated antibody measurements approximately 4-6 weeks after vaccination, with most patients with CVID having inadequate or no response to vaccination. If there is appropriate response to vaccination, then other etiologies besides CVID will need to be considered.

Patients with suspected immunodeficiency should be referred to a clinical immunologist for further evaluation. Depending on the patient's presentation, further studies—including chest and abdominal imaging, spirometry, endoscopy or colonoscopy, or lymph node biopsies—could be ordered. It is important for providers to be aware of the non-infectious complications of CVID to allow for prompt work-up of these patients and to prevent delayed diagnosis and further complications.

References
  • Bonilla FA, et al. International consensus document (ICON): Common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38.
  • Ho HE, Cunningham-Rundles C. Non-infectious complications of common variable immunodeficiency: Updated clinical spectrum, sequelae, and insights to pathogenesis. Front Immunol. 2020;11:149.
  • Lee TK, et al. State-of-the-art diagnostic evaluation of common variable immunodeficiency. Ann Allergy Asthma Immunol. 2021;127:19.
  • Oksenhendler E, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008;46:1547.

Filed under: Allergy/Immunology

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