Background: Neutropenia is recognized as a defining or common element in a limited number of primary immunodeficiency diseases (PIDDs) (Dotta L et al. Immunol Let 2014; Cham B et al. Semin Hematol 2002); but, the overall prevalence of neutropenia within the more than 300 known PIDDs is not well described. Many of the PIDDs rely on a high index of clinical suspicion for diagnosis which may not be readily apparent to hematologists evaluating a neutropenic patient, underscoring the importance of understanding the rate of neutropenia in PIDDs and impact on clinical outcomes. The goal of this study was to evaluate the frequency and characteristics of neutropenia in a large registry of patients with primary immunodeficiency (PID).

Methods: The United States Immunodeficiency Network (USIDNET) is a research consortium that maintains a national registry for the collection of data on patients with PIDDs. The USIDNET was queried for data regarding patients aged 21 years or less. Data utilized included reported PID diagnosis, gene mutation, gender, race, status of patient (living or deceased), year of birth, age at death, age of disease diagnosis, and results of reported complete blood counts (CBCs). PID diagnoses were grouped according to the 2017 International Union of Immunological Societies (IUIS) Phenotypic Classification for Primary Immunodeficiencies (Bousfiha A et al. J Clin Immunol 2018). Mild, moderate, and severe neutropenia were defined as absolute neutrophil counts of 1000-1499 cells/μL, 500-999 cells/μL, and < 500 cells/μL, respectively. Data are presented with descriptive statistics. The frequency of neutropenia was compared between genders and by race using chi-square test analysis.

Results: An initial data request resulted in information on 1577 patients; 384 patients were eliminated from analysis given insufficient recorded registry data due to a lack of a documented absolute neutrophil count. An additional 48 patients were excluded given that complete blood cell counts were only reported following hematopoietic stem cell transplantation. Data was thus available for 1145 pediatric patients with PIDDs. A total of 2058 neutrophil values were analyzed with 62.7% (719) patients having only a single neutrophil value available for review. Overall, 15.8% of PIDD pediatric patients in the USIDNET registry had neutropenia, ranging from 12.01% (combined immunodeficiencies with associated or syndromic features) to 66.67% (defects in intrinsic and innate immunity) in IUIS categories (Table 1) and in USIDNET categories from 2.94% (autoimmune lymphoproliferative syndrome) to 75.00% (susceptibility to mycobacterial infections) (Table 2). Of PID patients with neutropenia, 20.4% had severe neutropenia, 33.1% had moderate neutropenia, and 46.4% had mild neutropenia. Neutropenia was most likely to be severe in patients with predisposition to severe viral infections as well as those with a defect in intrinsic and innate immunity (Tables 1-2). There was no statistically significant difference in neutropenia between genders (p = 0.64). However, females were more likely to have severe neutropenia than males (28% versus 16%; p=0.03). Additionally, 28% of African-American patients had recorded neutropenia while only 17% of Caucasians and 2% of Asian/Pacific Islanders were neutropenic (p=0.005). There was no statistically significant difference in severity of neutropenia and death nor in the rate of bacterial and fungal infections detected between neutropenic and non-neutropenic patients with 93% of patients in the dataset living at the time of data collection.

Conclusions: The frequency of neutropenia within pediatric patients diagnosed with PIDD is higher and more ubiquitous than previously suspected. Hematologists should consider a PIDD in the assessment of neutropenia, particularly if other concerning signs or symptoms are present. Although this evaluation did not detect a difference in morbidity or mortality, the data set was constrained by a limited number of CBCs per patient and the rarity of the PIDDs. The impact of neutropenia on PIDD outcomes requires further study, ideally through a prospective longitudinal study.

Acknowledgments: The U.S. Immunodeficiency Network (USIDNET), a program of the Immune Deficiency Foundation (IDF), is supported by a cooperative agreement, U24AI86837, from the National Institute of Allergy and Infectious Diseases (NIAID).


Dale:Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.

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