Inborn Errors of Immunity Associated With Type 2 Inflammation in the USIDNET Registry

Abstract

Background: Monogenic conditions that disrupt proper development and/or function of the immune system are termed inborn errors of immunity (IEIs), also known as primary immunodeficiencies. Patients with IEIs often suffer from other manifestations in addition to infection, and allergic inflammation is an increasingly recognized feature of these conditions.

Methods: We performed a retrospective analysis of IEIs presenting with allergic inflammation as reported in the USIDNET registry. Our inclusion criteria comprised of patients with a reported monogenic cause for IEI where reported lab eosinophil and/or IgE values were available for the patient prior to them receiving potentially curative therapy. Patients were excluded if we were unable to determine the defective gene underlying their IEI. Patients were classified as having eosinophilia or elevated IgE when their record included at least 1 eosinophil count or IgE value that was greater than the age stratified upper limit of normal. We compared the proportion of patients with eosinophilia or elevated IgE with the proportion of samples in a reference population that fall above the upper limit of normal (2.5%).

Results: The query submitted to the USIDNET registry identified 1409 patients meeting inclusion criteria with a monogenic cause for their IEI diagnosis, of which 975 had eosinophil counts and 645 had IgE levels obtained prior to transplantation or gene therapy that were available for analysis. Overall, 18.8% (183/975) of the patients evaluated from the USIDNET registry had eosinophilia and 20.9% (135/645) had an elevated IgE. IEIs caused by defects in 32 genes were found to be significantly associated with eosinophilia and/or an elevated IgE level, spanning 7 of the 10 IEI categories according to the International Union of Immunological Societies classification.

Conclusion: Type 2 inflammation manifesting as eosinophilia or elevated IgE is found in a broad range of IEIs in the USIDNET registry. Our findings suggest that allergic immune dysregulation may be more widespread in IEIs than previously reported.

Keywords: IgE; atopy; eosinophilia; inborn error of immunity; primary immunodeficiency.

Figure 1

Selection of Eligible Patient Cohort. A consort diagram describing review of the USIDNET Registry data and selection of eligible patient data for analysis. USIDNET indicates United States Immunodeficiency Network; HSC, Hematopoietic stem cell; Ig, Immunoglobulin; CBC, complete blood count. *Elevated based on age-based reference interval.

Figure 2

Eosinophils and IgE stratified by age. Scatter plots show all patients included in the analysis with every reported Eosinophil (A) or IgE (B) value. Patient age was calculated as the time interval between their laboratory date and June 15^th of their birth year, as birth month and date were not provided for patient confidentiality and anonymity. Dashed line represents Eosinophil and IgE upper limits stratified by age based on reference populations (22, 23). Eosinophil upper limits correspond to 900 cells/μL in those <1 years, and 500 cells/μL for those 1 years of age and older (with values for individuals aged greater than 21 extrapolated to be 500 cells/μL). IgE level upper limits are: 6 to 12 months, 34 IU/ml; 1 to 2 years, 97 IU/ml; 3 years, 199 IU/ml; 4 to 6 years, 307 IU/ml; 7 to 8 years, 403 IU/ml; 9 to 12 years, 696 IU/ml; 13 to 15 years, 629 IU/ml; 16 to 17 years; 537 IU/ml; 18 years and older, 214 IU/ml (23). For individuals less than 6 months of age, the IgE level upper limit was extrapolated as 34 IU/ml.

Figure 3

Inborn errors of immunity associated with eosinophilia and elevated IgE. Volcano plots show the proportion of eosinophilia and elevated IgE on the x-axis. The y-axis shows the -log10 of the adjusted p-value based on the two-proportion z-test, performed by comparing the proportion of eosinophilia/elevated IgE for each gene to the proportion of values in the reference population falling above the upper limit of normal (2.5%). Dotted line indicates the significance threshold of the adjusted p-value at 0.05 and genes above the line are statistically significant. HGNC gene symbols used. (A) IEIs caused by monogenic defects in 29 genes (red) were found to be significantly associated with eosinophilia compared to the reference population age stratified upper limit. (B) IEIs caused by monogenic defects in 15 genes (red) were found to be significantly associated with elevated IgE compared to the age stratified upper limit.

Figure 4

Inborn errors of immunity genes associated with type 2 inflammation by disease category. IEI genes found to be associated with type 2 inflammation in our study are categorized according to IUIS Phenotypic Classification. HGNC gene symbols are used.

Figure 5

Distribution of laboratory values in inborn errors of immunity associated with type 2 inflammation compared to the reference population. The genes are ordered by adjusted p-value from lowest to highest for eosinophil count (A) and IgE level (B). For each gene, the box plot spans the interquartile range between the upper and lower quartile, with the median laboratory value marked by the black horizontal line across the colored box plot. The whiskers on either side of the box plot show the minimum and maximum laboratory values. The value above each whisker indicates the number of patients for each IEI that were evaluated for eosinophilia or IgE. HGNC gene symbols used.