Systematic review on the diagnostic evaluation of pediatric evans syndrome

Abstract Background: Evans syndrome (ES) is a complex disorder of multi-lineage autoimmune cytopenias and is often a chronic, relapsing disease with significant morbidity and mortality. Children with ES have a high rate of inborn errors of immunity, autoimmune lymphoproliferative syndrome (ALPS), and/or rheumatologic disease. It is crucial to identify underlying etiologies to guide appropriate management, but no national guidelines on the recommended diagnostic evaluation for pediatric patients exist. Recognizing the breadth of underlying etiologies and the current landscape of the evaluation of ES would inform guidance on the recommended diagnostic workup and future research recommendations. Aims: To evaluate the current evidence to guide the diagnostic evaluation of children with Evans syndrome. Methods: In conjunction with the ITP Consortium of North America (ICON), a systematic literature review was conducted using MEDLINE®, EMBASE, Cochrane, CINAHL, PsycINFO, and Scopus libraries from 1980-2024. Studies were included if they involved patients with ES or multi-lineage cytopenias and reported on the diagnostic evaluation. Studies focused on single lineage cytopenias, post-transplant or pregnancy related cytopenias, treatment or outcomes, case reports, case series with <3 patients, and systematic reviews were excluded. Joanna Briggs Institute critical appraisal tools were used to assess risk of bias. Results: After removing duplicates, 2772 studies were screened by title and abstract, and 103 studies underwent full-text review. Twenty-six studies met inclusion criteria, including 5 prospective and 21 retrospective cohort studies (one case series). Ten were multi-center; the remaining were single center studies. The geographic distribution was diverse, including North America (n=10), Europe (n=10), Central and South America (n=2), Asia (n=3), Australia (n=1) and the Middle East (n=1). In total, there were 920 patients (52.9% male); mean age was 11.4 years (n=23 studies reporting). Most studies (73%) included pediatric patients only, with the remainder including less than one third of pediatric patients (or unknown). A definition for ES was provided in 24 (92.3%) studies. Of these, 13 (54%) included immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and/or autoimmune neutropenia (AIN), while 11 (45.8%) excluded AIN. Definitions for individual cytopenias were reported for ITP in 12 (46.2%), AIHA in 15 (57.7%), and AIN in 11 (42.3%) studies. Sixteen studies (61.5%) reported rates of primary ES, while 18 studies (69.2%) reported rates of secondary ES. The most common secondary ES etiologies evaluated included ALPS (n=11 studies), rheumatologic/systemic autoimmune disease (n=11), CVID (n=10), infection (n=9), monogenic disorders of immunity (n=7), and malignancy (n=6). Family history was reported in 5 studies. All studies reported some clinical features of ES, including lymphoproliferation (n=14 studies), recurrent or refractory cytopenias (n=10 each), enteropathy (n=10), frequent/recurrent infections (n=9), bleeding (n=9), prior autoimmune diseases (n=9), and chronic cytopenias (n=6). All studies reported diagnostic evaluations, including hemoglobin (n=12), platelet (n=11), and absolute neutrophil counts (ANC, n=8). Hemolytic anemia workup included direct antiglobulin test (n=19), lactate dehydrogenase (n=10), indirect bilirubin (n=8), and haptoglobin (n=7). Anti-neutrophil and anti-platelet antibodies were each reported in 7 studies. Testing for underlying etiologies included quantitative immunoglobulins (n=17), anti-nuclear antibodies (n=17), lymphocyte subsets (n=11), double negative T cells (n=10), anti-phospholipid antibodies (n=9), bone marrow studies (n=9), viral testing (n=9), vaccination response (n=2), and vitamin B12 (n=2). Three studies described imaging findings. Genetic testing was described in 10 studies, including single gene (n=3), panel (n=6), exome sequencing (n=2), and unknown methods (n=3). Discussion/Conclusion: Pediatric ES is rare, with limited data from mostly retrospective studies using variable definitions of ES. Rates of primary and secondary ES, underlying etiologies, and clinical characteristics of patients with ES are inconsistently reported. Although aspects of the diagnostic evaluation were reported in all studies, the data was heterogenous and limited. Standardized criteria and diagnostic protocols are needed to improve evaluation and management of pediatric ES.