National temporal trends and demographic disparities in primary immunodeficiency-related mortality in the United States, 1999–2024

Abstract Background: Primary immunodeficiency disorders (PIDs) comprise hundreds of rare, genetically defined conditions that confer susceptibility to infection, autoimmunity, and early death. Although therapeutic advances and neonatal screening have improved outcomes, contemporary population-level evidence on PID mortality and equity is limited. This study aimed to quantify national trends in PID-related mortality and to characterize disparities by race, sex, and urbanization. Methods: We extracted data from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) Multiple Cause-of-Death (MCD) database, identifying all U.S. deaths from January 1, 1999, through December 31, 2024, where the cause of death had ICD-10 codes D80–D84 listed as MCD. This spectrum encompasses predominantly antibody deficiencies (D80: hereditary or nonfamilial hypogammaglobulinemia, selective IgA/IgG/IgM deficiencies, hyper-IgM syndromes, and related entities), combined immunodeficiencies including classic severe combined immunodeficiency and its genetic variants (D81), syndromic or major-defect-associated immunodeficiencies such as Wiskott-Aldrich, DiGeorge, and hyper-IgE syndromes (D82), common variable immunodeficiency and its sub phenotypes (D83), and other specified or unspecified immunodeficiencies such as LFA-1 or complement defects (D84). Age-adjusted mortality rates (AAMRs) per 1,000,000 population were calculated by direct standardization to the 2000 U.S. population. Joinpoint regression generated annual percent change (APC) and average annual percent change (AAPC) for the overall population and strata defined by sex and race/ethnicity (non-Hispanic Black, non-Hispanic White, Hispanic). Urban–rural residence was examined with the 2013 NCHS Urban–Rural Classification, which CDC WONDER provides only through 2020; therefore, urbanization analyses cover 1999–2020. Mortality data for 2024 are provisional. Results: During the 26-year interval between 1999 and 2024, 27,616 PID-related deaths occurred. The overall AAMR declined from 4.85 in 1999 to 3.15 in 2024, corresponding to an AAPC of –1.33 %. Throughout the study, men retained higher AAMR than women (2024: 3.4 vs 2.9), yet both sexes showed significant declines (AAPC –1.9 % and –1.1 %, respectively). Initially, non-Hispanic Black individuals faced the highest burden, with an AAMR of (11.2) compared to (4.3) among non-Hispanic Whites and 3.8 among Hispanics. Remarkably, Blacks exhibited the steepest sustained improvement (AAPC –4.9%), such that by 2024 their mortality rate had fallen to 3.7, only marginally higher than Whites (3.4) and Hispanics (3.0). The Black-to-White gap narrowed from 2.6-fold to approximately 1.1-fold. From 1999 to 2020, rural residents consistently had higher mortality rates than urban residents; although both groups improved, the decline plateaued after 2015, with an AAPC of -2.45% and -3.36%, respectively. Conclusions: National PID-related mortality has decreased significantly since 1999, mainly due to rapid declines among non-Hispanic Black Americans, nearly eliminating long-standing racial disparities. Ongoing higher mortality rates among males and rural communities, along with a recent slowdown in progress, highlight the need for more access to newborn screening, curative treatments, and specialized care for all populations.