Understanding neutropenia secondary to intrinsic or iatrogenic immune dysregulation

Abstract

As a key member of the innate and adaptive immune response, neutrophils provide insights into the hematopoietic and inflammatory manifestations of inborn errors of immunity (IEI) and the consequences of immunotherapy. The facile recognition of IEI presenting with neutropenia provides an avenue for hematologists to facilitate early diagnosis and expedite biologically rationale care. Moreover, enhancing the understanding of the molecular mechanisms driving neutropenia in IEI—decreased bone marrow reserves, diminished egress from the bone marrow, and decreased survival—offers an opportunity to further dissect the pathophysiology driving neutropenia secondary to iatrogenic immune dysregulation, eg, immune checkpoint inhibitors and chimeric antigen receptor T-cell therapy.

Peripheral‐blood cytopenia, an early indicator of inborn errors of immunity

“…Age‐appropriate NHLS reference ranges were used for interpretation 26 . Severe cytopenia was defined as; anaemia (haemoglobin) less than −2SD below age‐appropriate reference range, thrombocytopenia less than 100 × 10 9 /l, neutropenia less than 1.5 × 10 9 /l and lymphopenia less than 3 × 10 9 /l, persistent cytopenia lasting more than one month despite optimal management, unusual cytopenia with an otherwise unexplainable cause and recurrent or refractory cytopenia as persistent despite optimal management 16,18,27,28 . Pancytopenia was defined as absolute white cell count less than 4 × 10 9 /l, haemoglobin less than 100 g/l and thrombocytopenia less than 150 × 10 9 /l 29–31 …”

“…The direct involvement of Bruton tyrosine kinase (BTK) in neutrophil development is unclear, but is thought to contribute to neutrophil differentiation resulting in neutropenia, likely explaining why neutropenia was predictive of hypogammaglobulinaemia in this cohort. 27,49 No clear association was seen with defects of phagocyte number or function to further divulge the association, likely attributable to the low numbe of cases in the cohort. One case however, with a confirmed ELANE mutation, did present with classical cyclic neutropenia.…”

“…2,18 Morphological findings of the peripheral-blood film may reveal salient features suggesting an IEI, such as giant azurophilic granules in Chediak-Higashi Syndrome (CHS), hypersegmented neutrophils with pyknotic nuclei and cytoplasmic vacuoles in Warts, Hypogammaglobulinemia, infections and Myelokathexis (WHIM) syndrome and abnormally small platelets in Wiscott-Aldrich syndrome (WAS)/X-linked thrombocytopenia (XLT). 27 The haematologist should be consulted early to guide decisions on flow cytometry and bone-marrow biopsy. Bone-marrow biopsy findings may help synchronise the differential such as myelodysplasia F I G U R E 5 Kaplan-Meier estimates of proportions of patients surviving according to full blood count parameters at presentation.…”

“…10,16 Neutropenia is common in IEI, an absolute neutrophil count less than 1.5 × 10 9 /l in patients over one year old or chronic neutropenia (lasting >3 months) a likely caveat. 27,49 The haematologists' early involvement is important as the peripheral-blood and bone-marrow findings along with careful clinical examination can guide the often lengthy differential (Table 1). 27 Non-immune causes such as severe infection common across all IEI groups, particularly in deficiencies of phagocyte number or function or bone-marrow infiltration, should also be considered (Figure 1C).…”

“…2,25 [Colour figure can be viewed at wileyonlinelibrary.com] cytopenia as persistent despite optimal management. 16,18,27,28 Pancytopenia was defined as absolute white cell count less than 4 × 10 9 /l, haemoglobin less than 100 g/l and thrombocytopenia less than 150 × 10 9 /l. [29][30][31]…”