Variation in Diagnostic Evaluation Patterns for Pediatric Evans Syndrome: Survey Results from the Pediatric ITP Consortium of North America (ICON)

Intro: Evans syndrome (ES) is defined as 2 or more concurrent or sequential autoimmune cytopenias, commonly immune thrombocytopenia (ITP) and autoimmune hemolytic anemia. ES is idiopathic or attributed to a broad array of underlying disorders. Pediatric ES (pES) carries significant morbidity related to the disease and side effects of therapy. There is no standard diagnostic approach for pES. The goal of this study was to describe current approaches to the diagnostic evaluation of pES. Results from this study will guide development of expert recommendations for the diagnostic evaluation of pES.

Methods: A cross-sectional survey was conducted among ITP Consortium of North America (ICON) members. The 18-question survey queried: typical work-up for pES, laboratory tests ordered, clinical symptoms impacting testing choices, testing practices for suspected autoimmune lymphoproliferative disorder (ALPS), inborn errors of immunity (IEI) and systemic autoimmune disorders, and routine genetic testing. The survey was distributed via email from 3/14-5/14, 2024. Two email reminders were sent.

Results: Forty-seven of 67 (70%) ICON members completed the survey. The majority (83%) of providers worked in the United States, 98% practiced at academic children’s hospitals, and 51% had >10 years experience in pediatric hematology-oncology.

Sixty percent (28/47) of providers reported when evaluating pES, they performed the same work-up each time. However, 40% (19/47) of providers reported the presence of clinical features such as refractory disease (95%, n=18), family history of autoimmunity (95%, n=18), lymphadenopathy (95%, n=18), hepatosplenomegaly (89%, n=17), duration of disease (84%, n=16), age (74%, n=14), growth failure (74%, n=14), infectious history (74%, n= 14), joint pains (74%, n=14), type 1 diabetes (68%, n=13), rash (68%, n=13), inflammatory bowel disease (58%, n=11), and presence of thyroid disease (56%, n=11) impacted their decisions related to the patient’s work-up.

There was consistency among providers in the routine laboratory tests ordered to evaluate pES: direct antiglobulin test (DAT) (100%, n=47), quantitative immunoglobulins (96%, n=45), anti-nuclear antibody test (ANA) (89%, n=42), flow cytometry for double negative T cells (DNTs) (89%, n=42), and lymphocyte subsets (83%, n=45). Although less than 50% of providers reported routine ordering of the following laboratory tests: C reactive protein, sedimentation rate, cytokine panels, bone marrow testing, anti-SSA, anti-SSB, ribonuclear antibodies, antiphospholipid antibodies (APLAs), complement levels and urinalysis testing.

The majority of providers (85%, n=40) performed genetic testing. Genetic testing typically were focused genetic panels via commercial labs (95%, n=38). The most commonly cited barriers to genetic testing were: 1) lack of insurance coverage, and 2) administrative burden (paperwork or consent forms).

In patients with suspected IEIs, providers often send vaccine titers (91%, n=42), immunoglobulin levels (96%, n=44), and T and B cell subsets (93%, n=43, 91%, n=42, respectively). For patients with suspected ALPS, DNTs were sent nearly universally (98%, n=46). However, testing for the primary accessory criteria that constitute definitive diagnosis ALPS, genetic testing and fas-mediated apoptosis testing, were sent by 87% and only 45%, respectively. In patients with suspected autoimmune conditions: DAT (100%, n=47), ANA (96%, n=45), double stranded DNA antibodies (83%, n=39), complement levels (78%, n=37), anti-smith antibodies (75%%, n=35), anti-SSa/ anti-SSb antibodies (72%, n=34), APLAs (72%, n=34), and thyroid testing (62%, n=29), were sent routinely.

Conclusions: This study reported variation in the general diagnostic evaluation for pES among pediatric hematology specialists with years of experience in managing autoimmune cytopenias. Although there was consistency in the context of suspected systemic autoimmunity, which may reflect greater familiarity with autoimmune disease entities. Increasingly, autoimmune cytopenias are attributed to underlying IEIs and autoinflammatory conditions. With the spectrum of causative diagnoses ever expanding, it is important for hematology providers to have a standardized and comprehensive framework for the diagnostic approach to pES. Future directions for ICON include development of standard pES diagnostic recommendations.