Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Kinase Transcriptional and Biochemical Function.

Autoinflammatory disease can result from monogenic errors of immunity. We describe a patient with early-onset multi-organ immune dysregulation resulting from a mosaic, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of >25 cytokines. By custom single-cell RNA sequencing, we examine mosaicism with single-cell resolution. We find that JAK1 transcription was predominantly restricted to a single allele across different cells, introducing the concept of a mutational "transcriptotype" that differs from the genotype. Functionally, the mutation increases JAK1 activity and transactivates partnering JAKs, independent of its catalytic domain. S703I JAK1 is not only hypermorphic for cytokine signaling but also neomorphic, as it enables signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, leading to the rapid resolution of clinical disease. These findings offer a platform for personalized medicine with the concurrent discovery of fundamental biological principles.

Outcomes of Primary Ileocolic Resection for Pediatric Crohn Disease in the Biologic Era.

OBJECTIVES: Current clinical algorithms position surgery as the last option in pediatric Crohn disease (CD). Studies suggest improved outcomes with earlier surgery, but pediatric postoperative outcomes data in the biologic era are limited. We aimed to describe the preoperative management and postoperative outcomes in a pediatric CD cohort who underwent ileocolic resection (ICR) at a tertiary care inflammatory bowel disease center over the last decade. METHODS: Single-center, retrospective study of pediatric (<18 years) CD patients who underwent ICR between 2008 and 2019 with primary outcome of rate of endoscopic recurrence (Rutgeerts' >i2) at 2 years post-ICR. Key secondary outcomes included endoscopic remission (Rutgeerts' i0), frequency of 30-day postoperative complications, anthropometric changes, and histologic recurrence. Uni- and multivariable analyses examined associations of clinical/laboratory characteristics with endoscopic recurrence. Factors predictive of 30-day complications were also analyzed. RESULTS: Seventy-eight children underwent ICR a median of 17.8 months (interquartile range [IQR] 2.6-53.9) from diagnosis. Median age at diagnosis and surgery was 13.8 (11.1-16.7) and 16.8 years (15.1-17.8), respectively. In the 41 patients with >1 post-operative endoscopy, the rate of endoscopic recurrence was 46% at 2 years (median time to recurrence: 10 [7-20] months). Histologic recurrence was present in 44% in endoscopic remission (κ = 0.11, P = 0.53). Endoscopic recurrence was associated with younger age at diagnosis and longer disease duration. 30-day complications occurred at a rate of 18%; only 1% experienced severe complications. All anthropometric measures significantly improved after surgery. CONCLUSIONS: Given the inherent risk of postoperative recurrence associated with age and disease duration, children would benefit from postoperative surveillance and effective prophylaxis.

Pediatric Crohn Disease and Multisystem Inflammatory Syndrome in Children (MIS-C) and COVID-19 Treated With Infliximab.

Coronavirus disease 2019 (COVID-19) may lead to a severe inflammatory response referred to as a cytokine storm. We describe a case of severe COVID-19 infection in a recently diagnosed pediatric Crohn disease patient successfully treated with tumor necrosis factor-alpha (TNF-α) blockade. The patient presented with 5 days of fever, an erythematous maculopapular facial rash, and abdominal pain without respiratory symptoms. SARS-CoV-2 polymerase chain reaction was positive. Despite inpatient treatment for COVID-19 and a perianal abscess, the patient acutely decompensated, with worsening fever, tachycardia, fluid-refractory hypotension, elevation of liver enzymes, and transformation of the rash into purpura extending from the face to the trunk, upper and lower extremities, including the palmar and plantar surfaces of the hands and feet. Cytokine profile revealed rising levels of interleukin (IL)-6, IL-8, and TNF-α, higher than those described in either inflammatory bowel disease or severe COVID-19 alone. The patient was treated with infliximab for TNF-α blockade to address both moderately to severely active Crohn disease and multisystem inflammatory syndrome in children temporally related to COVID-19. Within hours of infliximab treatment, fever, tachycardia, and hypotension resolved. Cytokine profile improved with normalization of TNF-α, a decrease in IL-6, and IL-8 concentrations. This case supports a role for blockade of TNF-α in the treatment of COVID-19 inflammatory cascade. The role of anti-TNF agents in patients with multisystem inflammatory syndrome in children temporally related to COVID-19 requires further investigation.

De Novo Crohn's Disease of the Pouch in Children Undergoing Ileal Pouch-Anal Anastomosis for Ulcerative Colitis.

BACKGROUND: Approximately 10% of children with ulcerative colitis (UC) undergo colectomy with ileal pouch-anal anastomosis (IPAA). We aimed to describe the postoperative outcomes, with an emphasis on chronic pouch inflammation including de novo Crohn disease (CD) at a tertiary care inflammatory bowel disease center. METHODS: Electronic medical records of all children who underwent colectomy ≤18 years between 2008 and 2017 were reviewed. Clinical and laboratory data were recorded. Primary outcome was frequency of chronic pouch inflammation including de novo CD. Secondary outcomes included early (≤30 days from index surgery) and late postoperative complications. Descriptive statistics (median and interquartile range) summarized the data and univariate analysis tested associations with outcomes. RESULTS: Fifty-eight children underwent colectomy and 56 completed IPAA. Median age at diagnosis was 14 years (12-16.2) and at colectomy 16.2 years (14.2-17.7) with median follow-up of 13 months (5-43). Sixty-six percent underwent 3-stage IPAA and 78% were biologic exposed. Eleven had chronic pouchitis, 73% antibiotic refractory and 25% met criteria for de novo CD by median of 19 months (9-41). A total of 21% and 50% experienced early and late surgical complications, most commonly ileus and recurrent IPAA stricture. The pouch failure rate was 3.6%. Chronic pouch inflammation was associated with a later diagnosis of de novo CD (P = 0.0025). CONCLUSIONS: In pediatric UC, CD is not uncommon after IPAA. Chronic pouch inflammation often precedes a diagnosis of de novo CD. Families should be informed of the short- and long-term outcomes in children before UC surgery.

Autoimmune hemolytic anemia: An unusual presentation of hemophagocytic lymphohistiocytosis in a pediatric post-liver transplant patient.

Hemophagocytic lymphohistiocytosis (HLH), a rare condition characterized by immune dysfunction with uncontrolled activation of macrophages and hypersecretion of cytokines, has only been reported in a small number of pediatric patients following solid organ transplant (SOT). The diagnosis of HLH after SOT is especially difficult, as several of the diagnostic criteria, including fever, splenomegaly, and cytopenias, are nonspecific and can be seen with other post-transplant complications. Autoimmune hemolytic anemia (AIHA) has also been reported after pediatric SOT and is thought to be related to immunosuppression, specifically tacrolimus. Although HLH and AIHA have been separately described following SOT, there have been no reports of them occurring together in post-liver transplant (LT) patients. We report the first case of autoimmune hemolysis as the presenting symptom of HLH in a pediatric post-LT patient.

Combined Brain Mapping and Compact Intraoperative MRI for Brain Tumor Resection.

BACKGROUND: Surgery on patients with lesions in the dominant hemisphere for language is best done with awake language mapping. Intraoperative MRI (iMRI) has also been proposed as an ideal method for tumor resection control in patients with primary brain tumors. OBJECTIVES: This study examines the feasibility of low-field iMRI during awake craniotomy and tumor resection. METHODS: 36 patients underwent awake resection with a compact iMRI for guidance. Outcomes were grouped using an A-D classification. Outcome A was defined as gross total resection (GTR) without iMRI, B as GTR achieved secondary to iMRI findings, C as resection stopped due to mapping but prior to iMRI, and, finally, D as resection stopped after iMRI had showed residual tumor but subsequent mapping limited further resection. RESULTS: Diagnoses included primary brain tumors in all but 2 patients: 1 had mesial temporal sclerosis and 1 cysticercosis. Overall, outcomes A and D were the most common with 12 patients each, outcome C was the least common occurring in only 3 patients, and outcome B occurred in 9 patients. Hence, in 12 patients, iMRI led to increased tumor resection while in another 12 brain mapping limited the extent of resection. CONCLUSIONS: Combined awake language and motor mapping and iMRI guidance is feasible for resection of brain lesions. A compact iMRI has unique advantages for this approach.