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Gene Expression Profiling in Pediatric Appendicitis
Bhavjinder K Dhillon1, Simone Kortbeek2,3, Arjun Baghela1
1Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
Perforated appendicitis (PA) in children involves a dysregulated immune response, unlike simple appendicitis (SA). A four-gene signature accurately predicts PA, aiding in early diagnosis and treatment for pediatric appendicitis.
Area of Science:
- Pediatric Surgery
- Immunology
- Genomics
Background:
- Appendicitis is a common pediatric surgical emergency with variable severity.
- Differentiating simple appendicitis (SA) from perforated appendicitis (PA) is crucial for timely and appropriate treatment.
- Understanding the mechanistic differences between SA and PA can improve diagnostic and therapeutic strategies.
Purpose of the Study:
- To elucidate the mechanistic underpinnings of appendicitis severity in children.
- To develop improved diagnostics and treatments for pediatric appendicitis.
- To identify potential blood-based biomarkers for differentiating SA and PA.
Main Methods:
- Prospective exploratory diagnostic study (Gene Expression Profiling of Pediatric Appendicitis - GEPPA).
- Whole-blood transcriptomic profiling of 71 children (5-17 years) with suspected appendicitis.
- Analysis of gene expression patterns to identify differences between SA and PA.
Main Results:
- Perforated appendicitis (PA) is characterized by a dysregulated immune response, including dampened interferon pathways.
- Gene expression in PA patients showed similarities to sepsis signatures, indicating immune suppression.
- A four-gene signature demonstrated 85.7% accuracy in predicting PA versus SA.
Conclusions:
- Perforated appendicitis (PA) in children is associated with a dysregulated immune response.
- Findings support the development of improved diagnostics for appendicitis severity.
- Early identification of PA can inform management and prevent complications.
Importance:
Appendicitis is the most common indication for urgent surgery in the pediatric population, presenting across a range of severity and with variable complications. Differentiating simple appendicitis (SA) and perforated appendicitis (PA) on presentation may help direct further diagnostic workup and appropriate therapy selection, including antibiotic choice and timing of surgery.
Objective:
To provide a mechanistic understanding of the differences in disease severity of appendicitis with the objective of developing improved diagnostics and treatments, specifically for the pediatric population.
Design, Setting, And Participants:
The Gene Expression Profiling of Pediatric Appendicitis (GEPPA) study was a single-center prospective exploratory diagnostic study with transcriptomic profiling of peripheral blood collected from a cohort of children aged 5 to 17 years with abdominal pain and suspected appendicitis between November 2016 and April 2017 at the Alberta Children's Hospital in Calgary, Alberta, Canada, with data analysis reported in August 2023. There was no patient follow-up in this study.
Exposure:
SA, PA, or nonappendicitis abdominal pain.
Main Outcomes And Measures:
Blood transcriptomics was used to develop a hypothesis of underlying mechanistic differences between SA and PA to build mechanistic hypotheses and blood-based diagnostics.
Results:
Seventy-one children (mean [SD] age, 11.8 [3.0] years; 48 [67.6%] male) presenting to the emergency department with abdominal pain and suspected appendicitis were investigated using whole-blood transcriptomics. A central role for immune system pathways was revealed in PA, including a dampening of major innate interferon responses. Gene expression changes in patients with PA were consistent with downregulation of immune response and inflammation pathways and shared similarities with gene expression signatures derived from patients with sepsis, including the most severe sepsis endotypes. Despite the challenges in identifying early biomarkers of severe appendicitis, a 4-gene signature that was predictive of PA compared to SA, with an accuracy of 85.7% (95% CI, 72.8-94.1) was identified.
Conclusions:
This study found that PA was complicated by a dysregulated immune response. This finding should inform improved diagnostics of severity, early management strategies, and prevention of further postsurgical complications.
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