Diagnostic clues in patients with clinical malabsorption and pathological small intestinal villous atrophy: Immune-mediated type and beyond

Table 3 Summary of evolving definitions proposed for common variable immunodeficiency disease

Update	ESID and the PAGID in 1999[61]	IUIS in 2017[58]	ESID in 2019[62]	IUIS in 2019[59] and in 2022[60]	IUIS in 2024 (https://iuis.org/committees/iei/)
Description	Probable CVID (a marked decrease1 in serum IgG and IgA levels) and possible CVID (a marked decrease in one of the major isotypes, IgM, IgG, or IgA). Both need to fulfill all of the following criteria; (1) Onset of immunodeficiency at greater than 2 years of age; (2) Absent isohemagglutinins and/or poor response to vaccines; and (3) Excluded defined causes of hypogammaglobulinemia	Rename PIDs, including CVID, as IEIs. A total of 354 IEIs were categorized into 9 tables	At least one of the following: (1) Increased susceptibility to infection; (2) Autoimmune manifestations; (3) Granulomatous disease; (4) Unexplained polyclonal lymphoproliferation; and (5) Affected family member with antibody deficiency. And marked decrease of IgG and marked decrease of IgA with or without low IgM levels (measured at least twice; < 2 SD of the normal levels for their age). And at least one of the following: (1) Poor antibody response to vaccines (and/or absent isohemagglutinins); i.e., absence of protective levels despite vaccination where defined; and (2) Low switched memory B cells (< 70% of age-related normal value). And secondary causes of hypogammaglobulinemia have been excluded (e.g., infection, protein loss, medication, malignancy). And diagnosis is established after the fourth year of life (but symptoms may be present before). And no evidence of profound T-cell deficiency, defined as 2 of the following (y < years of life): (1) CD4 numbers/microliter: 2-6 years < 300, 6-12 years < 250, > 12 years < 200; (2) %naïve of CD4: 2-6 years < 25%, 6-16 years < 20%, > 16 years < 10%; and (3) T-cell proliferation absent	Increase to 416 and 485 IEI, respectively, and categorized into 10 tables	Increase to 555 IEI and categorized into 10 tables (similar to IUIS 2022). Unknown Genetic defect; Low IgG and IgA and/or IgM; Clinical phenotypes vary: Most have recurrent infections, some have polyclonal lymphoproliferation, autoimmune cytopenias and/or granulomatous disease

¹Marked decrease means at least 2 SD below the age-adjusted mean.

ESID: European Society for Immunodeficiencies; PAGID: Pan-American Group for Immunodeficiency; IUIS: International Union of Immunological Societies; CVID: Common variable immune deficiency; PIDs: Primary immunodeficiency diseases; IEIs: Inborn errors of immunity.