Clinical and immunological prophyle of long lasting and late onset neutropenia: beyond primary autoimmune and idiopathic neutropenia

Primary idiopathic (pIN) and autoimmune neutropenia (pAN) of childhood are a benign, self- limiting disorders. pAN patients with atypical features i) early onset but persistence >36 months (named Long Lasting-LL) or ii) Late Onset-LO, rising >3 years and persisting >12 months, were recently shown to display a different immune-hematological profile versus typical pAN. In the present study we analyze a cohort of LL/LO pAN and pIN aiming to identify the immunological pattern and the genetic background. Clinical, immunological and genetic data (NGS panel of 162 immunodeficiency/disimmunity/bone marrow failure genes) of patients with pIN and pAN in the Italian Neutropenia Registry from 2005 to 2022 were retrived.Table 1. (abstract: 130) (A) Dynamic of Hematological prophyle; (B) Appearance of autoimmunity overtime (C) Lymphocytes subsets according to age (William T. Shearer, J Allergy Clin Immunol 2003and Leslie R. Bisset, Eur J Haematol 2004)(A)Median Value (IQR)DiagnosisMid- follow-upLast visitWhite Blood cells (×109/L)3.15 (2.8–4.03)3.3 (2.65–3.83)3.23 (2.43 – 4.13) (p= 0.099)Absolute neutrophil Count (×109/L)0.73 (0.3–1.07)0.91 (0.51–1.25)1.03 (0.45–1.46) (p<0.001)Abolute Lymphocyte Count (×109/L)1.71 (1.4–2.54)1.64(1.31–1.93)1.54 (1.14–1.85) (p<0.001)CLow N(%)Normal N(%)High N(%)T-profileCD3+§12 (19)50 (79)1 (2)CD3+CD4+§13 (21)50 (79)0CD3+CD8+§16 (25)47 (75)0CD3CD45RA+ (Naïve)^10 (17)23 (38)27 (45)CD3CD45RO+ (Memory)^20 (33)22 (37)18 (30)CD3CD4CD25brCD45RA+ (T regulatory)^40 (67)15 (25)5 (8)Gamma/delta T cells^3 (5)20 (33)37 (62)HLADR+^10 (17)23 (38)27 (45)B-profileCD19+§16 (25)45 (71)2 (4)CD19+CD27+ (memory)^23 (38)37 (62)0CD27-CD10++CD38++ (Transitional)*11 (32)18 (51)6 (17)CD27-CD10+-CD38+-IgD+ (Naïve)*12 (34)12 (34)11 (32)CD27+IgD+IgM+ (Marginal zone)*7 (20)14 (40)14 (40)CD27+IgD-IgM- (Switched memory)*21 (60)9 (25)5 (15)CD27+IgD-IgM+ (Pre-switched)*030 (85)5 (15)CD27+IgD+IgM- (IgD memory)*033 (94)2 (6)CD27-IgD- (Double negative)*015 (43)20 (57)*B profile (CD19+ excluded) has been performed in 35/63 patients.^60/63 data available. Table 1. (abstract: 130) (A) Dynamic of Hematological prophyle; (B) Appearance of autoimmunity overtime (C) Lymphocytes subsets according to age (William T. Shearer, J Allergy Clin Immunol 2003and Leslie R. Bisset, Eur J Haematol 2004) *B profile (CD19+ excluded) has been performed in 35/63 patients. ^60/63 data available. Sixty-three patients (31 females, 32 pAN, 18 LL) with a median age at onset of 9.2 years (IQR 2.0–15.6) and median follow-up of 5.2 years (IQR 4.0–8.2) were eligible. Neither autoimmunity nor other cytopenias were associated to neutropenia at onset. Autoimmune manifestations appeared in 19 (30%) patients, cumulative risk at 6 years was 22.9% (CI 95% 12.9–38.5) (Table 1B). Forty-five patients (71%) suffered of at least one infection, of which severe in 16% of cases. The majority of patients (75%) showed leukopenia and lymphocytes’ decrease overtime (p <0.001) (Table 1A) without immunoglobulin impairment. Twenty-five% of patients had low B and NK cells. T/B profile is reported in Table 1C. Increased CD27+IgD+IgM+ (14/35, 40%) with reduced CD27+IgD-IgM- B cells (21/35, 60%) emerges with a significant increase in CD27-IgD- B cells (20/35, 57%) and T-regulatory and B-memory cells depletion. Genetic analysis performed in 58/63 (92%) of the cohort revealed 6 (10%) pathogenic variants in TNFRSF13B (4), CARD11 (1), FASL (1). LL and LO neutropenias show different clinical and immunological pattern compared to pAN and pIN since their onset. Leukopenia and progressive lymphocytopenia seem to be anticipatory signals that worsen overtime. A peculiar immunological pattern in a subgroup of patients seems to suggest that an underlying immune-dysregulationlead to an exhaustion of B-maturation and a consequent propensity to autoimmunity. These neutropenias would deserve more precise characterization by enlarging the cohort and applying more comprehensive genetic analysis.