The Inflammatory Prequel of Pediatric Appendicitis

Abstract: AbstractBackground: Appendicitis is the most common disease requiring acute abdominal surgery in children, yet the pathogenesis of appendicitis is not fully understood. It can be challenging to diagnose appendicitis clinically, especially in young children, leading to high rates of initial misdiagnosis. It is not clear why some children are affected by a complicated disease course while others recover spontaneously. It has been proposed that different immune responses in different individuals propel the inflammation towards an uncomplicated or a complicated disease course. To date, there is no reliable measure to distinguish between patients with uncomplicated appendicitis and those with complicated appendicitis.Aims: To increase the knowledge of how the inflammatory processes anteceding pediatric appendicitis can be categorized, modulated, and detected.Methods: Papers I, IV and V were prospective clinical institution-based studies. Paper II was a retrospective institutionbased cohort study and Paper III a nationwide cohort study. In Paper I the diagnostic performances of four different clinical prediction scores for pediatric appendicitis were evaluated. In Papers II and III the associations of immunoglobulin E (IgE)-mediated allergy and complicated appendicitis in children were evaluated. In Paper IV we assessed the associations of biological stress, measured as hair cortisol concentrations (HCC) and pediatric appendicitis. In Paper V the associations of serum concentrations of IgE and T helper cell 2 (Th2)-associated cytokines with complicated appendicitis were evaluated.Results: The clinical prediction scores appendicitis inflammatory response (AIR) score and pediatric appendicitis risk calculator (pARC) displayed significantly higher specificity and positive predictive value and lower rates of negative appendectomies compared to the pediatric appendicitis score (PAS) and Alvarado score (I). Children with IgE-mediated allergy had a significantly reduced odds of complicated appendicitis (aOR 0.33 [95% CI 0.18-0.59], p<0.001 (II), and aOR 0.80 [95% CI 0.67-0.96], p=0.021 (III)). The risk of complicated appendicitis among allergic children was reduced by one-third compared to that in non-allergic children (IR 0.13 vs 0.20 per 1000 person-years, HR 0.68 [95% CI 0.58-0.81], p<0.001), while the risk of uncomplicated appendicitis did not vary with allergy status (IR 0.91 vs 0.91, HR 1.00 [95% CI 0.94-1.07], p=0.932). Seasonal antigen exposure was a protective factor for complicated appendicitis (aOR 0.82 [95% CI 0.71-0.94], p=0.004), and ongoing antihistamine medication was a risk factor (aOR 2.28 [95% CI 1.21-4.28], p=0.012) (III). An increase in HCC was associated with an increased risk of appendicitis (aOR 10.76 [95% CI 2.50-46.28], p=0.001) and complicated appendicitis (aOR 7.86 [95% CI 1.20-51.63], p=0.03) (IV). High concentrations of IL-13 were associated with an increased risk of complicated appendicitis (aOR 1.02 [95% CI 1.01-1.04], p=0.011). Serum concentrations of IgE, IL-4, and IL-9 were not significantly associated with the risk of complicated appendicitis (V).Conclusions: AIR score and pARC are superior to the PAS and Alvarado score for diagnosing appendicitis in children. Children with allergy have a lower risk of complicated appendicitis, but the same risk of uncomplicated appendicitis, compared to non-allergic children. Increased stress, measured as an increase in HCC, is associated with an increased risk of appendicitis and complicated appendicitis in children. High levels of IL-13 seem to be associated with an increased risk of complicated appendicitis in children.