The Spectrum of the Deficiency of Adenosine Deaminase 2: An Observational Analysis of a 60 Patient Cohort

Abstract

The deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessively inherited disease that has undergone extensive phenotypic expansion since being first described in patients with fevers, recurrent strokes, livedo racemosa, and polyarteritis nodosa in 2014. It is now recognized that patients may develop multisystem disease that spans multiple medical subspecialties. Here, we describe the findings from a large single center longitudinal cohort of 60 patients, the broad phenotypic presentation, as well as highlight the cohort’s experience with hematopoietic cell transplantation and COVID-19. Disease manifestations could be separated into three major phenotypes: inflammatory/vascular, immune dysregulatory, and hematologic, however, most patients presented with significant overlap between these three phenotype groups. The cardinal features of the inflammatory/vascular group included cutaneous manifestations and stroke. Evidence of immune dysregulation was commonly observed, including hypogammaglobulinemia, absent to low class-switched memory B cells, and inadequate response to vaccination. Despite these findings, infectious complications were exceedingly rare in this cohort. Hematologic findings including pure red cell aplasia (PRCA), immune-mediated neutropenia, and pancytopenia were observed in half of patients. We significantly extended our experience using anti-TNF agents, with no strokes observed in 2026 patient months on TNF inhibitors. Meanwhile, hematologic and immune features had a more varied response to anti-TNF therapy. Six patients received a total of 10 allogeneic hematopoietic cell transplant (HCT) procedures, with secondary graft failure necessitating repeat HCTs in three patients, as well as unplanned donor cell infusions to avoid graft rejection. All transplanted patients had been on anti-TNF agents prior to HCT and received varying degrees of reduced-intensity or non-myeloablative conditioning. All transplanted patients are still alive and have discontinued anti-TNF therapy. The long-term follow up afforded by this large single-center study underscores the clinical heterogeneity of DADA2 and the potential for phenotypes to evolve in any individual patient.

Adenosine Deaminase 2 Deficiency (DADA2): A Crosstalk Between Innate and Adaptive Immunity

“…The involvement of the B-cell compartment in DADA2 was evident since first reports. Zhou et al ( 1 ) described a B cells defect in terminal maturation and a tendency towards apoptosis, consistent with a clinical phenotype characterized by hypogammaglobulinemia and recurrent infections together with the typical inflammatory features ( 18 ) ( Figure 1 ).…”

“…These data, together with a remarkably lower proportion of Vγδ2+T cells ( 12 ), suggest that DADA2 CD8+ T cells may be involved in the development of refractory/recurrent viral infections observed in some patients ( 54 , 68 – 70 ). The defect in ADA2-deficient cytotoxic lymphocytes may be also linked to rare DADA2-associated manifestations, such as hemophagocytic lymphohistiocytosis (HLH) ( 1 , 5 , 56 ) or CD3+ CD8+ large granular lymphocytes ( 11 , 18 ).…”

The Growing Spectrum of DADA2 Manifestations—Diagnostic and Therapeutic Challenges Revisited

“…We strongly suggest a thorough diagnostic work-up in these individuals, including immunological laboratory investigations, as well as organ screening, including CNS, heart diagnostics and assessment of clinical signs of c-PAN ( Figure 2 ). As the use of anticoagulants may increase the chances of an ischemic stroke turning into a hemorrhagic stroke, these substances have to be applied rather cautiously ( 32 ).…”

Deficiency of Human Adenosine Deaminase Type 2 – A Diagnostic Conundrum for the Hematologist

“…Other than bone marrow failure syndrome manifestations recurrent fevers, oral ulcers, recurrent infections (including warts) have been reported in this subgroup of patients ( 32 , 41 – 43 ). Besides neutropenia, a recent report from NIH on 60 patients with DADA2 describes thrombocytopenia and pancytopenia in 10% of patients ( 44 ).…”

“…To date, more than a dozen such patients of DADA2 have been reported accompanied with predominant autoimmune cytopenia. In most of these patients the clues for etiological diagnosis have ranged from vasculopathic ulcers ( 30 ), stroke ( 1 ), low IgG/IgM or hypogammaglobulinemia ( 32 , 44 – 48 ), recurrent infections ( 18 , 49 ) including the vaccine pathogens ( 46 ). Lymphopenia, neutropenia, thrombocytopenia (Evans syndrome), lymphoproliferation with/without elevated double negative T-cells (raising a possibility of autoimmune lymphoproliferative syndrome) has also been reported in these patients ( 1 , 18 , 30 , 32 , 46 , 49 – 51 ).…”