Immune Regulation in Patients With Common Variable Immunodeficiency and Related Inborn Errors of Immunity (IEI)

Studies of Immune Regulation in Patients With Common Variable Immunodeficiency and Related Inborn Errors of Immunity (IEI)

This study aims to understand the causes and progression of Common Variable Immunodeficiency (CVID) and related inborn errors of immunity (IEI). These are conditions where the immune system does not function properly, leading to frequent infections and other complications such as gastrointestinal inflammation, lung and liver disease, autoimmune conditions, and an increased risk of certain cancers. By studying patients with CVI and related immune disorders, we hope to develop better ways to diagnose, treat, and prevent complications associated with these conditions.

Patients diagnosed with CVID or related immune disorders must be referred by their physician and medical records reviewed by the study team to confirm eligibility to participate in this study. Once enrolled, participants will undergo various tests, including blood draws, physical exams, and imaging studies like CT scans to track changes over time. We may collect samples such as blood, urine, stool, or saliva for research purposes. If a surgical procedure or biopsy is performed because it is medically necessary, we may collect an additional sample for research testing. Family members of patients may be asked to provide blood samples for comparison. Some tests may be done remotely if participants or family members cannot travel to the study site.

Who Can Participate

• Patients diagnosed with CVI or related IEI, such as X-linked agammaglobulinemia, Blau Syndrome or Yao Syndrome.
• Participants must be at least 2 years old.
• Family members of patients may include parents, siblings, grandparents, children, aunts, uncles, and cousins.
• Pregnant women already enrolled in the study will continue to participate, but new pregnant participants will not be enrolled.

Potential Risks and Benefits

• Risks: Blood draws may cause discomfort, bruising, or infection. Apheresis may cause dizziness, nausea, or muscle cramps; this procedure is to collect specific cells in the blood and is infrequently done on this protocol. Extra biopsies during clinically indicated procedures may increase the risk of complications; they will only be collected after the medically necessary biopsies are taken and if it is safe to collect any extra biopsies.
• Benefits: Participants may not receive direct medical benefits, but the study will contribute to a better understanding of CVID and related conditions, potentially leading to improved treatments.

Study Overview

• Status: Recruiting
• Conditions: CVID; XLA; Blau Syndrome; Yao Syndrome

Detailed Description

The purpose of this protocol is to carry out laboratory studies concerning the immunopathogenesis of Common Variable Immunodeficiency (CVI) and related inborn errors of immunity (IEI). Additionally, we aim to document and track the progression of known complications of these immune abnormalities. Complications associated with CVI include recurrent respiratory, granulomas, pulmonary insufficiency, gastrointestinal bacterial infections, enteropathy, nodular regenerative hyperplasia, lymphoid malignancy, and various autoimmune manifestations.

Patients with CVI and related IEI will be enrolled into this natural history study. Protocol procedures will include baseline measurements of and changes in lab studies. First- or second-degree genetically related family members (limited to mother, father, siblings, grandparents, children, aunts, uncles, and first cousins of an affected patient) may also be screened for clinical, in vitro, and genetic correlates of immune abnormalities. Changes in the patients' clinical state will be measured to determine the precursors of disease complications. This may lead to developments in improving preventive measures and novel treatment options for this population.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Kimberly L Montgomery-Recht, R.N.; Phone Number: (240) 422-7966; Email: kim.montgomery-recht@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: Ivan Fuss, M.D.; Phone Number: 301-761-7091; Email: ifuss@niaid.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

General population - Physician referral required

Description

• INCLUSION CRITERIA:
• Must have a verifiable diagnosis of common variable immune deficiency as defined by a decrease both in IgG and at least one other Ig isotype to below two standard deviations of normal control levels OR B-cell immunodeficiencies related to CVI (defined as selective IgA deficiency, selective IgG isotype deficiency, agammaglobulinemia, and hypogammaglobulinemia associated with Epstein-Barr virus infection), or hypogammaglobulinemia associated with other related inborn errors of immunity. This includes patients with a defined diagnosis of Blau or Yao Syndrome.
• Must be 2 years old or greater.
• Patients with repeated infections and suspected of having an inborn error of immunity.
• Patients must be referred by their primary medical care provider.
• On investigator s discretion, unaffected family members (mother, father, siblings, children, grandparents, aunts, uncles, and first cousins) may be asked for the provision of blood or buccal specimens for research purposes.
• Patients who are lactating, may be eligible and will only undergo tests and procedures, and/or receive medications for which data exists that proves that they are minimal risk to the child.
• Pregnant women will not be newly enrolled onto this protocol, however existing patients who become pregnant while on study will remain on study, as literature about pregnancy in CVI patients is sparse and outside providers have minimal knowledge about managing CVI during pregnancy. Pregnant women will only undergo tests and procedures, and/or receive medications for which data exists that proves that they are minimal risk to the fetus. Pregnant unaffected relatives will not be enrolled in this study).
• All patients must be willing to have research samples stored for future studies and/or other research purposes.
• NIH staff and family members of study team members may be enrolled in this study as this population may meet study criteria. Neither participation nor refusal to participate as a subject in the research will have an effect, either beneficial or adverse, on the participant s employment or position at the NIH. Every effort will be made to protect participant information, but such information may be available in medical records and may be available to authorized users outside of the study team in both an identifiable and unidentifiable manner. The NIH investigator will provide and request that the NIH staff member review the Frequently Asked Questions (FAQs) for Staff Who are Considering Participating in NIH Research and the Leavy Policy for NIH Employees Participating in NIH Medical Research Studies (NIH Policy Manual 2300-630-3).

EXCLUSION CRITERIA:

• Presence of other medical illnesses that would preclude individuals from undergoing routine diagnostic testing or testing for immunologic features of immunodeficiency.
• Presence of a condition or treatment, such as HIV, cytotoxic chemotherapy or malignancy, that in the investigator s opinion could interfere with evaluation of the condition under study.
• Pregnancy at the time of enrollment.
• Inability of an adult participant to provide informed consent for themselves (decisionally impaired adult).

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
General Population; Physician referral required

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Characterization of immune abnormalities	To characterize the physiologic, biochemical or genetic basis of theabnormality of immunity.	Ongoing
Establish pattern/pace of disease process	To establish the pattern and pace of change of disease (frequency, distribution, type and extent of infections, inflammatory lesions and abnormalities of immune function).	At 1 year and ongoing
Evaluation of organ dysfunction/damage resulting from immune abnormality	To establish the extent of organ involvement (infection and/or inflammation) and organ damage or dysfunction resulting from the abnormality of immune function.	Ongoing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess ability to participate in other studies	To assess the patient's ability to safely tolerate specific aspects of other diagnostic or therapeutic research protocols.	ongoing
Determine eligibility for other studies	To determine a patient's eligibility for other studies.	ongoing
Establish baseline of pattern/pace of disease process before participating in therapeutic trials	To establish a baseline assessment of the pace and extent of the disease before entering a therapeutic clinical trial.	ongoing

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Investigators: Principal Investigator: Warren Strober, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

General Publications

• Jaffe JS, Eisenstein E, Sneller MC, Strober W. T-cell abnormalities in common variable immunodeficiency. Pediatr Res. 1993 Jan;33(1 Suppl):S24-7; discussion S27-8. doi: 10.1203/00006450-199305001-00128.
• Mannon PJ, Fuss IJ, Dill S, Friend J, Groden C, Hornung R, Yang Z, Yi C, Quezado M, Brown M, Strober W. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology. 2006 Sep;131(3):748-56. doi: 10.1053/j.gastro.2006.06.022.
• Cunningham-Rundles C. Autoimmune manifestations in common variable immunodeficiency. J Clin Immunol. 2008 May;28 Suppl 1(Suppl 1):S42-5. doi: 10.1007/s10875-008-9182-7. Epub 2008 Mar 6.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 1990

Study Registration Dates

• First Submitted: November 3, 1999
• First Submitted That Met QC Criteria: November 3, 1999
• First Posted (Estimated): November 4, 1999

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 20, 2026
• Last Verified: April 14, 2026

More Information

Terms related to this study

• Keywords: Agammaglobulinemia; CVID; XLA; Humoral Immunodeficiency; Inborn Errors of Immunity; CVID enteropathy; Blau Syndrome; Yao Syndrome
• Additional Relevant MeSH Terms: Immune System Diseases; Hematologic Diseases; Immunologic Deficiency Syndromes; Lymphatic Diseases; Lymphoproliferative Disorders; Blood Protein Disorders; Hemic and Lymphatic Diseases; Agammaglobulinemia; Blau syndrome
• Other Study ID Numbers: 890158; 89-I-0158

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No