Chinga, Michell Lozano

Background T cell–mediated hepatitis is an uncommon cause of acute pediatric liver injury. Most patients respond to steroids, but management of refractory disease remains challenging. We describe four patients with non-monogenic CD8+ T cell–mediated hepatitis with close temporal presentation and variable response to therapies. All four patients had severe elevations in liver enzymes, synthetic dysfunction, hyperbilirubinemia, cytopenias, elevations in cytokines (supplemental table), and CD8+ T cell predominance on biopsy, without meeting criteria for autoimmune hepatitis. All underwent next-generation or whole-exome sequencing; no monogenic causes were elucidated. Broad infectious workup was unrevealing. Case 1 A 17-year-old male with epilepsy presented with abdominal pain and jaundice, with labs and biopsy consistent with portal and lobular hepatitis with CD8+ T cell predominance. Bone marrow aspirate (BMA) was reassuring. Hepatitis was refractory despite corticosteroids, tacrolimus, sirolimus, anakinra, intravenous immune globulin (IVIG), and anti-thymocyte globulin (ATG). Infliximab led to dramatic but incomplete improvement. He remains on steroids, tacrolimus, and infliximab, with planned hematopoietic stem cell transplantation (HSCT). Case 2 A 7-year-old female with type 1 diabetes presented with jaundice and abdominal pain, with labs and biopsy consistent with CD8+ T cell hepatitis. Steroids induced a partial response, while infliximab led to marked improvement. She transitioned to azathioprine and maintains normal liver enzymes. Case 3 A 5-year-old male with autism presented with fevers and abdominal distention, with labs and biopsy consistent with portal and lobular hepatitis with CD8+ T cell predominance. IVIG/steroids provided only a transient improvement. Tacrolimus normalized labs and enabled steroid discontinuation. Case 4 An 11-month-old healthy female presented with jaundice. Labs and biopsy were consistent with giant cell hepatitis with CD8+ T cell predominance, and no evidence of autoimmune hemolytic anemia. She was listed for liver transplantation. Partial steroid response prompted tacrolimus initiation, leading to normalization of labs and removal from transplant listing. Conclusion CD8+ T cell–mediated hepatitis may progress rapidly and be steroid refractory. Early initiation of infliximab or tacrolimus may prevent progression to liver failure. Case one represents a severe presentation with limited response; however, most avoided liver or hematopoietic stem cell transplantation. All cases presented within a three-month window, suggesting a possible infectious trigger. Tabular data are included as downloadable supplement files.

Introduction Hyperuricemia, pulmonary hypertension, renal failure, alkalosis (HUPRA) syndrome is a mitochondrial disease caused by mutations in SARS2 (seryl-tRNA synthetase 2), which plays a role in protein synthesis. Limited case reports describe an association of HUPRA with immunodeficiency; however, no in-depth immune phenotyping has been described. We present a case of HUPRA with recurrent infections and lymphopenia, with clinical improvement on immunoglobulin replacement therapy (IgRT). Case Description An 11-month-old male born at 29 weeks’ gestational age with pulmonary hypertension (PH) and tracheostomy dependence was admitted with recurrent fevers and worsening PH. History revealed prior Enterococcus faecalis bacteremia as well as Staphylococcus aureus and Pseudomonas aeruginosa tracheitis. Laboratory evaluation revealed mildly low IgG with normal IgM and IgA. Lymphocyte subsets revealed T cell, B cell, and natural killer cell lymphopenias, with CD4+ T cell compartment skewing to a memory phenotype, normal total switched memory B cells, and normal T follicular helper cells. Vaccine titers were not obtained, given receipt of only one set of vaccines. T cell proliferations were reassuring. Genetic testing revealed compound heterozygous mutations in SARS2, confirming a diagnosis of HUPRA. He is being treated with IgRT with significant clinical improvement. Discussion In case series, up to half of patients with HUPRA can present with increased infections, often with leukopenia. Multiple studies have shown that aminoacyl-tRNA synthetases can play a role in immune cell development, regulation, and autoimmunity through interactions with innate and adaptive immune responses. Additionally, hyperuricemia is known to induce innate and adaptive immune responses. It is difficult to know how these findings relate to the function of SARS2 or patients with HUPRA. Our patient was found to have multilineage lymphopenia with mildly low IgG, with significant clinical improvement on IgRT. More in-depth evaluations are needed to better understand the pathophysiology of immune dysfunction with SARS2 deficiency. This case provides in-depth immune phenotyping and a potential treatment option for others with HUPRA. Tabular data are included as downloadable supplement files.

AbstractBackgroundImmune thrombocytopenia (ITP) and Evans syndrome (ES) are manifestations of immune dysregulation. Genetic variants in immune‐related genes have been identified in patients with ITP and especially ES. We aimed to explore familial autoimmunity in patients with ITP and ES to understand possible contributions to chronicity.ProcedureWe assessed family history in two ways: via patient report for ITP and ES and by population‐based analysis using the Utah Population Database (UPDB) for ITP. A total of 266 patients with ITP and 21 patients with ES were identified via chart review, and 252 of the 266 patients with ITP were also identified in the UPDB.ResultsChart review showed familial autoimmunity in 29/182 (15.9%) and 25/84 (29.8%) of patients with newly diagnosed+persistent (nd+p) ITP and chronic ITP (cITP), respectively, (p = .009). The UPDB analysis revealed that autoimmunity in relatives of patients with nd+pITP was higher than in relatives of controls (odds ratio [OR]: 1.69 [1.19–2.41], p = .004), but was not significantly increased in relatives of patients with cITP (OR 1.10 [0.63–1.92], p = .734). Incomplete family history in medical records likely contributed to the observed discrepancy.ConclusionsThe findings suggest that familial autoimmunity may have a stronger association with the development of ITP rather than its duration. Twelve (57.1%) patients with ES reported autoimmunity in their relatives. UPDB analysis was omitted due to the small number of patients with ES. The use of population databases offers a unique opportunity to assess familial health and may provide clues about contributors to immune dysregulation features within families.