LaBere, Brenna

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.

Introduction Very early-onset inflammatory bowel disease (VEO-IBD) involves children less than 6 years of age presenting with IBD. These patients are more likely to have inborn errors of immunity. We present a child with VEO-IBD, found to have compound heterozygous variants in the DUOX2 gene that expands on the rare association of VEO-IBD with DUOX2 insufficiency. Case Description A 5-year-old male presented with six months of watery diarrhea, with labs notable for thrombocytosis, elevated CRP, and fecal calprotectin to 1430 [ref ≤ 49 μg/g]. Endoscopy and colonoscopy with biopsy revealed intraepithelial lymphocytosis in the duodenum, eosinophilic infiltrate in the stomach, esophagitis without eosinophilia, and chronic active ileitis with eosinophils of 65/hpf in the terminal ileum, consistent with a diagnosis of Crohn’s disease. The patient underwent immune phenotyping given his young age, which revealed elevated sIL2R, IL-17, IL-5, IL-13, IL-10, and IL-6, T cell lymphocytosis, and a normal neutrophil oxidative burst. Targeted genetic sequencing revealed two heterozygous variants in the DUOX2 gene: one maternally inherited likely pathogenic splice site variant, c.2922-14_2925del; and one paternally inherited variant of uncertain significance (VUS), c.1528C>T (p.Arg510Trp). The VUS is within the peroxidase-like region of the gene, which plays a crucial role in enzyme function, has a high CADD score of 25, and has a GnomAD allelic frequency of only 0.001%, suggesting possible pathogenicity. The patient is currently doing well on infliximab, with interval normalization of his cytokines. Discussion The DUOX2 gene encodes for dual NADPH oxidase (DUOX), which is responsible for the release of hydrogen peroxide as part of the innate immune defense of gut epithelial cells. In mice, DUOX2 has been shown to play an integral role in maintaining immune homeostasis in the gut biome, with knockout models showing elevated IL-17C levels in the ileum. There are few reported cases describing the association of compound heterozygous variants in DUOX2 in patients with VEO-IBD, with this being the fourth patient, to the best of our knowledge. This case highlights the importance of further research to better understand the role of this gene in the development of inflammatory bowel disease. Table 1.DiagnosticsValueCytokine panelIL-2 <2.1 (ref range ≤ 2.1)IL-2R 2259.3 (ref range 175.3 - 858.2)IL-12 <1.9 (ref range ≤ 1.9)INF- γ <4.2 (ref range ≤ 4.2)IL-4 <2.2 (ref range ≤ 2.2)IL-5 19.1 (ref range ≤ 2.1)IL-10 11.1 (ref range ≤ 2.8)IL-13 2.5 (ref range ≤ 2.3)IL-17 5.5 (ref range ≤ 5.5)IL-1β <6.5 (ref range ≤ 6.7)IL-6 6.3 (ref range ≤ 2.0)TNF-α 2.5 (ref range ≤ 7.2)ImmunoglobulinsIgA – 69 (ref range 21 – 144)IgE – 4680 (ref range 2 – 524)IgG – 734 (498 – 1332)IgM – 82 (ref range 31 – 63)Lymphocyte subset panelAbsolute CD3 3080 (ref range 1400 – 3700)Absolute CD4 1969 (ref range 700 – 2200)Absolute CD8 876 (ref range 490 – 1300)Absolute CD45RA 1505 (ref range 430 – 1500)Absolute CD45RO 652 (ref range 220 – 660)Absolute HLADR 660 (ref range 50 – 180)Absolute CD19 594 (ref range 390 – 1400)Absolute CD20 552 (ref range)Absolute NK 170 (ref range 130 – 720)EGD/ColonoscopyDuodenum - Intraepithelial lymphocytosisEsophagus mid and distal – esophagitis up to 2 eos/hpfEsophagus upper – esophagitis up to 1 eos/hpfChronic active ileitis with eosinophils (up to 65/hpf)Neutrophil oxidative burstNormal granulocyte dihydrohodamine fluorescence suggesting normal NADPH oxidase activityPrimary immunodeficiency panel1. DUOX2a. c.2922-14_2925del (splice site). Het. Likely pathogenic. GnomAD AC 99. CADD 31.b. c.1528C>T (p.Arg510Trp). Het. VUS. GnomAD AC 3. CADD 25. Peroxidase-like region (mediates peroxidase activity).2. FOXI3a. c.713G>A (p.Arg238Gln). Het. VUS. GnomAD AC 3. CADD 28.8. Associated with T cell lymphopenia. Not clinically relevant.3. MS4A1a. c.352A>C (p.Ile118Leu). Het. VUS. CADD 17.01. Conflicting in silico prediction models. GnomAD AC 71. Associated with CVID. Not clinically relevant.4. POLD1a. c.520C>T (p.Arg174Trp). Het. VUS. Associated with AD mandibular hypoplasia, deafness, progeroid features and lipodystrophy and AR T cell immunodeficiency. GnomAD AC 12. Not clinically relevant.

Abstract Background We aimed to determine if pre-existing immunocompromising conditions (ICCs) were associated with the presentation or outcome of patients with acute coronavirus disease 2019 (COVID-19) admitted for pediatric intensive care. Methods Fifty-five hospitals in 30 US states reported cases through the Overcoming COVID-19 public health surveillance registry. Patients <21 years admitted 12 March 2020–30 December 2021 to the pediatric intensive care unit (PICU) or high-acuity unit for acute COVID-19 were included. Results Of 1274 patients, 105 (8.2%) had an ICC, including 33 (31.4%) hematologic malignancies, 24 (22.9%) primary immunodeficiencies and disorders of hematopoietic cells, 19 (18.1%) nonmalignant organ failure with solid-organ transplantation, 16 (15.2%) solid tumors, and 13 (12.4%) autoimmune disorders. Patients with ICCs were older, had more underlying renal conditions, and had lower white blood cell and platelet counts than those without ICCs, but had similar clinical disease severity upon admission. In-hospital mortality from COVID-19 was higher (11.4% vs 4.6%, P = .005) and hospitalization was longer (P = .01) in patients with ICCs. New major morbidities upon discharge were not different between those with and without ICC (10.5% vs 13.9%, P = .40). In patients with ICCs, bacterial coinfection was more common in those with life-threatening COVID-19. Conclusions In this national case series of patients <21 years of age with acute COVID-19 admitted for intensive care, existence of a prior ICCs were associated with worse clinical outcomes. Reassuringly, most patients with ICCs hospitalized in the PICU for severe acute COVID-19 survived and were discharged home without new severe morbidities.