Primary Immunodeficiency in Children With Autoimmune Cytopenias: Retrospective 154-Patient Cohort

Abstract

Background: Primary immunodeficiency is common among patients with autoimmune cytopenia.

Objective: The purpose of this study is to retrospectively identify key clinical features and biomarkers of primary immunodeficiency (PID) in pediatric patients with autoimmune cytopenias (AIC) so as to facilitate early diagnosis and targeted therapy.

Methods: Electronic medical records at a pediatric tertiary care center were reviewed. We selected 154 patients with both AIC and PID (n=17), or AIC alone (n=137) for inclusion in two cohorts. Immunoglobulin levels, vaccine titers, lymphocyte subsets (T, B and NK cells), autoantibodies, clinical characteristics, and response to treatment were recorded.

Results: Clinical features associated with AIC-PID included splenomegaly, short stature, and recurrent or chronic infections. PID patients were more likely to have autoimmune hemolytic anemia (AIHA) or Evans syndrome than AIC-only patients. The AIC-PID group was also distinguished by low T cells (CD3 and CD8), low immunoglobulins (IgG and IgA), and higher prevalence of autoantibodies to red blood cells, platelets or neutrophils. AIC diagnosis preceded PID diagnosis by 3 years on average, except among those with partial DiGeorge syndrome. AIC-PID patients were more likely to fail first-line treatment.

Conclusions: AIC patients, especially those with Evans syndrome or AIHA, should be evaluated for PID. Lymphocyte subsets and immune globulins serve as a rapid screen for underlying PID. Early detection of patients with comorbid PID and AIC may improve treatment outcomes. Prospective studies are needed to confirm the diagnostic clues identified and to guide targeted therapy.

Keywords: Evans syndrome; anemia; autoimmune cytopenia; immune dysregulation; neutropenia; primary immunodeficiency; thrombocytopenia.

Figure 1

Electronic medical record search strategy and patient inclusion/exclusion criteria for patients with autoimmune cytopenia. ICD-9 and ICD-10 diagnosis codes queried refractory cytopenia with multi-lineage dysplasia (D46.A), autoimmune hemolytic anemia (D59.1, 283.0), acquired hemolytic anemia unspecified (D59.9, 283.9), immune thrombocytopenic purpura (D69.3, 287.31), autoimmune neutropenia (D70.8, 288.09), Evans syndrome (D69.41, 287, 32), and disease of blood and blood-forming organs unspecified (D75.9). *Secondary cytopenias defined as cytopenia caused by bone marrow or solid organ transplantation, malignancy or medication-induced.

Figure 2

Autoimmune cytopenias in the AIC-PID group are often refractory to first line therapy. The diagram depicts the distribution of patients with varying degrees of response to treatment (percentage of patients with no, partial or full response to first, second, third and fourth line treatment shown by color gradient as indicated); therapeutic grouping by first line (IVIG, corticosteroids, Rho(D) immune globulin), second-line (rituximab), third line (mycophenolate mofetil [MMF], cyclosporine), adjunct thrombopoietin receptor agonists [TPO-RA]) and fourth-line treatment (splenectomy) for the AIC-PID and AIC-only groups. (A) Patients treated in the AIC-PID group, (n = 15) 88.2% of AIC-PID patients. (B) Patients treated in the AIC-only group, (n = 76) 55% of AIC-only patients.