Late-onset and long-lasting autoimmune neutropenia: an analysis from the Italian Neutropenia Registry

Abstract

Primary autoimmune neutropenia (pAN) is typified by onset in early infancy and a mild/moderate phenotype that resolves within 3 years of diagnosis. In contrast, secondary AN is classically an adult disease associated with malignancy, autoimmunity, immunodeficiency, viral infection, or drugs. This study describes a cohort of 79 children from the Italian Registry who, although resembling pAN, did not fully match the criteria for pAN because neutropenia either appeared after age 5 years (LO-Np) or lasted longer than 3 years (LL-Np). These 2 categories compared with classical pAN showed a far inferior rate of resolution (P < .001), lower severity of neutropenia (P = .03), leukopenia (P < .001), lymphopenia (P < .001) with low B+ (P = .001), increased need of granulocyte colony-stimulating factor (P = .04), and increased frequency of autoimmunity over the disease course (P < .001). A paired comparison between LO-Np and LL-Np suggested that LO-Np had a lower rate of resolution (P < .001) and lower white blood cell (P < .001) and lymphocyte (P < .001) values, higher occurrence of apthae (P = .008), and a stronger association with autoimmune diseases/markers (P = .001) than LL-Np, thus suggesting a more pronounced autoimmune signature for LO-Np. A next-generation sequencing panel applied in a small subgroup of LO-Np and LL-Np patients identified variants related to immune dysregulations. Overall, these findings indicate that there are important differences among pAN LL-Np and LO-Np. Forms rising after 3 years of age, with low tendency to resolution, require tight monitoring and extensive immune investigations aimed to early identify underlying immunologic disease.

Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients

“…Patient ID226 carried multiple pathogenic or likely pathogenic variants that may have contributed to the disease outcome. In fact, though the ELANE mutation alone, unreported in the GnomAD database thus far, can explain the cyclic neutropenia of this patient, we cannot exclude that TNFRSF13B , present with a variant showing no homozygotes in the same database, may also be involved in the clinical phenotype [ 38 ].…”

Case Report: High Doses of Intravenous Immunoglobulins as a Successful Treatment for Late Onset Immune Agranulocytosis After Rituximab Plus Bendamustine

“…The pathophysiology of LON is unknown; meanwhile, several studies have investigated the potential mechanisms in relation to R. A possible mechanism that has been reported previously is immunological disturbance due to an aberrant B-cell reconstitution and formation of autoantibodies binding to the neutrophils or its precursors (6,7). Considering the immunemediated mechanism presented in this case, the literature shows a perplexing overlap between the different immune neutropenia syndromes, and it is sometimes difficult to make a clear distinction between autoimmune neutropenia (AIN), pure white blood cell aplasia (PWCA), or LON (10)(11)(12)(13). Also, a Tcell large granular lymphocyte population mediating granulocytic toxicity has been postulated due to studies that show proliferation of these cells in the bone marrow of patients with LON (14).…”

Diagnosis and management of neutropenia in children: The approach of the Study Group on Neutropenia and Marrow Failure Syndromes of the Pediatric Italian Hemato‐Oncology Association (Associazione Italiana Emato‐Oncologia Pediatrica ‐ AIEOP)

“…13,14 In cases of idiopathic neutropenia and autoimmune neutropenia, which last more than 24-36 months, immunological status must be investigated and a dedicated NGS panel may be applied, as per the center policy, to detect a possible dysregulation of the immune system or other related disorders, including SCN. 11 This is because neutropenia, as an epiphenomenon of primary immune dysregulation syndrome, may be misdiagnosed, and constitutional neutropenia may have an atypical clinical phenotype. 43…”

“…In contrast, in patients with idiopathic and autoimmune neutropenia, which rarely spontaneously remits, follow‐up may help identify evidence required to redefine the diagnosis (Table 4). 11 …”